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From PB
@pbookman: I’ve registered for #VMworld 2014 U.S. See you there? Watch for disruptive news with GPU ;) http://t.co/URdsTohUht
Have no idea if this relates to us. But just saw it and thought I share
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VMware buys CloudVolumes. Here's our full analysis.
If rewriting your Windows desktop app was so easy, you would have done it by now. Long live Windows remoting!
Teradici releases standalone software-only PCoIP host agent which you can install into any* Windows environment!
If DaaS is your first move to the cloud, you're doing it wrong
Why VDI use will never hit 100%. (And why that's ok.)
VMware buys CloudVolumes. Here's our full analysis.
Written on Aug 21 2014
by Brian Madden
Yesterday VMware announced that they acquired CloudVolumes for an undisclosed amount. Originally called SnapVolumes, CloudVolumes was founded in 2011 by Matt Conover and Shaun Coleman, (and friend of the site Harry Labana joined them this past April after writing several blog posts on BrianMadden.com about them over the past two years).
CloudVolumes is a software company with a product in the Windows application delivery / containerization / "layering" space. Essentially they let you take a before and after snapshot of an application when you install it, and all the changes are written into a VMDK or VHD disk image that can be mounted (even when a user is logged in) to a machine. Once mounted, the CloudVolumes agent hooks the disk image into the disk chain and all the files, registry settings, services, etc. just sort of instantly "show up" in the target computer. (CloudVolumes puts their containers in VMDKs when used with VMs, and VHDs when used with physically-installed copies of Windows.
To be clear, CloudVolumes doesn't do any kind of isolation for "problem" apps like ThinApp or App-V, rather, their focus is on making different apps available within different VMs or while making them appear as if they've been locally-installed. They talk about wanted to make Windows application delivery, installation, and removal as simple as the way mobile apps work in iOS or Android.
Over the past few months, Harry's been referring to this as "disposable IT"—the concept that today's IT staff doesn't want to spend a lot of time troubleshooting static (i.e. "persistent") user environments, rather, they just want to hit a "refresh" button to put that environment back to a steady state and move on to better things.
This concept of course is not new. In fact it's the dream of "non-persistent" VDI that VMware's been pushing since 2006. That concept always sounded good in theory, but in practice it's been difficult to implement since all we really had was "shared base images" plus "app virtualization"—a combination which was unwieldily to manage and left a lot to be desired in the "compatibility" department. (Kevin Goodman explains it as "going through all the pain to virtualize all your apps with App-V or ThinApp just to get them to a point where you can install them on demand is like killing an ant with a sledgehammer.)
Several vendors offer solutions that are conceptually similar to CloudVolumes, including Unidesk, FSLogix, and Liquidware Labs.
Why VMware?
Ok, so now VMware owns CloudVolumes. Cool.
I want to dig into why this makes sense and what VMware plans to do with them, but first we should take a step back and look at where VMware is on their renewed path to EUC.
First, if you've heard VMware's Desktop GM Sumit Dhawan talk in the past few months, you would have heard him talk about customers' three-phase approach to the virtualizing the Windows desktop and Windows applications:
The first phase is taking Windows desktop applications from the physical to datacenter.
The second phases is about disaggregation and then re-aggregation, which is much more complex since there are some real roadblocks that exist in terms of costs and tradeoffs. (Just look at all the arguments about persistent versus non-persistent images, layering, etc.)
The third phase is about refining the user experience across devices, including things like transforming apps so they make sense on whatever form factor the user has at that moment, breaking apps into micro apps that only expose what the user needs, developing new mobile apps from existing desktop apps, etc.
Now let's map those three phases to what VMware is doing:
VMware Horizon 6 added RDSH support, app publishing, and seamless Windows to VMware's Horizon portfolio.
Yesterday's purchase of CloudVolumes is how VMware believes they'll be able to deliver usable images and apps that don't have the tradeoffs of Linked Clones + ThinApp.
Stay tuned. (PowWow maybe? Others?)
Why didn't VMware just use Mirage?
I talked to Sumit Dhawan on the phone yesterday, and one of the questions I asked him was why VMware had to buy CloudVolumes. Couldn't they just use the layering that's part of Mirage?
Sumit told me that they initially looked at this, and that while the concept of the layers is similar in some ways between Mirage and CloudVolumes, the two products are actually quite different. Mirage was built for physical machines that are loosely connected which receive their layers via the network and the WAN, wheres CloudVolumes is built for always-connected clients which want to mount their layers from a fast reliable location.
I also asked Sumit about ThinApp and how it fits into this. He didn't have specifics to talk about, but its easy to infer that the ThinApp product (or at least bits of its technology) could fit nicely into what CloudVolumes could grow to be at VMware. (To be clear, ThinApp was about both isolating bad apps and providing a simple package that was easy to deploy to users. Obviously CloudVolumes handles the deployment part of what ThinApp did, but for the few apps that actually cause problems when installed next to other apps, it would be great if parts of the core ThinApp IP could be integrated into what CloudVolumes can deliver.)
What's the impact of this acquisition for the layering space?
Citing the way VMware dropped support for Citrix when they bought Desktone, Paul Stansel wrote on CitrixTips.com that he's worried VMware will make CloudVolumes a VMware-only solution. When I talked to Harry Labana on the phone yesterday, he mentioned that CloudVolumes can be very strategic to VMware and can be more than just a line-item feature in View, so it's certainly possible that Citrix XenApp and XenDesktop customers could buy it, (especially if they're running on vSphere), but overall I tend to agree that most likely this will end up being a VMware-only solution.
Paul also wrote "this may ultimately force Citrix to do is make something useful out of PVDs (Personal vDisks—technology they got from their RingCube acquisition). They promised for years that PVDs would be more flexible and roam with the users, but that promise has never been realized. PVDs are often complicated to support and one of the least mature technologies Citrix offers."
While I don't necessarily agree that PVDs are the same thing as CloudVolumes, I definitely agree that Citrix is (or certainly will now) try to position PVDs as their version of CloudVolumes. We should also keep in mind that there are other vendors who have similar solutions to CloudVolumes, (like the companies I mentioned before: FSLogix, Unidesk, and Liquidware Labs).
Actually, speaking of Liquidware Labs, I know I'm not the only one who believes this company was created for the sole purpose of being acquired by VMware, and they have to be kicking themselves again now, saying, "Seriously?? They bought those F-ing guys??" Fifty bucks says the next Liquidware product will be something to refine the Windows application user experience from mobile devices. :)
Seriously it will be interesting to see how Unidesk and Liquidware position themselves next week at VMworld as they'll both be there as sponsors. (Looks like Kevin Goodman made a fortuitous decision when he decided that FSLogix would not exhibit!)
Overall though this is a good move by VMware. Yeah, we're going to see Unidesk, FSLogix, and Liquidware talk about how their solution is better. Yeah, we're going to see Citrix try to position PVDs and/or buy one of these companies. But in the grand scheme of things, I like the concept of what these companies are doing. It fits well with my long term vision about Windows apps being around forever and many of them ultimately ending up in some datacenter with just the UIs being remoted. I might even go so far as to say that with these types of technologies, maybe something approaching a "non-persistent" disk image could work. (Not the true "non-persistent" of 2008, but something more like it.)
Congrats to VMware and CloudVolumes. Good move for both. And, frankly, congrats to Unidesk, FSLogix, and Liquidware who can now sell to 100,000 Citrix customers who will soon want this CloudVolumes-like thing too.
DB on ACHN
We have been watching this story from the sidelines, but we are now
upgrading again to Buy. Our concerns had been around clinical & mgmt
execution. We see many points of evidence that suggest execution has
improved. We lowered our discount rate by .5% due to better execution.
ACHN is developing a nuke (key value) but has other HCV assets in the clinic.
Long-term risk/reward is attractive. Key nuke data expected this fall (Oct/Nov).
Execution has certainly improved in the past 12 mos from our previous DG
driven by concerns around long-term execution & lack of real catalysts.
Mgmt execution has improved over the past 12 months. We think new CMO &
team (previously at Pharmasset) are a key factor. Co has gotten their PI off
clinical hold, started nuke studies in timelines guided, and conducted a
successful sofosbuvir+NS5A.
Key risk is little is known about nuke. Nuke data in fall is a MAJOR catalyst
ACHN started dosing in Ph1 for 3422 in June in New Zealand. We note Gilead
ran their studies in NZ and studies are very well run there. The Ph1 study (in
GT1 only) is 14 days in healthies followed by 7 day placebo study in HCV
patients. The dosing starts at 50mg and they expect to enroll around 100
healthy & HCV pts. We know it was tested vs. Gilead’s nuke in preclinical
models & showed higher potency in GT3 (~7 fold greater).
On positive nuke data, we see ACHN FVs of $14-$21/sh (50-130% upside)
On bad data, we see ACHN FVs of $1.25 (cash)-$4/sh (60-87% downside)
Our base case assumes 40% prob of success (POS) since ACHN program has
made progress in ‘14. Every 10% POS is worth $5-6/sh. We currently assume
Achillion peak sales of $3B (10% peak share) launching in ‘18 and a 5% lower
price point vs. GILD. We think good data is data similar to Idenix’s data which
showed 4.1-4.3 logs reduction in GT1-3 pts. Cash value at $1.25/sh, but we
don’t think stock trades to cash since they have other assets though key value
driver is the nuke.
If Ph1 data looks compelling, we could see ACHN FVs would be ~$30-40/sh
(~200-300% upside) if co were acquired based on our M&A scenario model
We have always believed that having a nuke will be essential to a competitive
long-term regimen in HCV. Currently only GILD, Merck, and ACHN have nukes
that are in development or on market. According to the press, ACHN has been
cited for many years as a takeover target but has recently comeback into focus
in a reported article in CNBC recently on 6/14/14. This occurred after Idenix
was acquired by Merck for ~$4B at similar stage as ACHN’s fall data readout.
Ne TP Buy & TP $17/sh; Execution improvement matters ahead of big data
Our TP is based on a prob-adjusted DCF analysis (12% discount rate). Risks
include: nuke failure, lack of execution, and safety issues
maytepper thanks very nice target of 25
Roth Capital Reiterates Buy On TG Therapeutics Following Clinical Study Initiation
August 15, 2014 3:55 Healthcare
TG Therapeutics (TGTX) announced the initiation of a novel three drug combination study assessing the chemo-free combination of TG-1101 + TGR-1202 + Imbruvica. This study will be added as a component of the ongoing Phase I study of the combination of TG-1101 and TGR-1202. This triple chemo-free combination study has the potential to represent the beginning of the shift from chemobased oncology therapies to target-based, chemo-free approaches to cancer treatment.
In reaction to the study initiation, Roth Capital analyst Joseph Pantginis today issued a note in which he reiterated a Buy rating on TGTX stock with a $25 price target.
Pantginis wrote, “This study will be the first time combination of a BTK inhibitor (Imbruvica) with a PI3K-delta inhibitor (TGR-1202). We believe this triple chemo-free combination study is signaling the future direction of cancer therapy, one in which targeted therapies will represent the main therapeutic paradigm for cancer treatment. We believe this combination study will appeal to many oncologists who wish to have options for chemo-free and therefore less toxic options for treating their patients. With target-based options, the toxicity profile diminishes significantly, although adverse events will still be part of the treatment, but we believe that in the case of drugs such as those used in this new combination trial, the safety profile will make them more favorable.”
whats that mean?? sorry i am not techie
Nice tweets
dougheuring
@dougheuringaria
@pbookman very nice mention of $any and $goog and chromebook http://t.co/L7fNlGSJW5 - 15 Aug
More Tweets
dougheuring
@dougheuringaria
@pbookman can you comment on this at all? Sphere3D's Glassware that is integrated into Chromebook.
are we are already INTEGRATED? - 15 Aug
Peter Bookman
@pbookman
RT @dougheuringaria @Sphere3D Glassware that is integrated into Chromebook.
are we are already INTEGRATED? >html5 client on any device ;)
interesting comment in the seeking alpha piece
Tech Alpha , contributor
Comments (29) | + Follow Following - Unfollow | Send Message
Tech Alpha 38
Followers3
» Jack, as the best of my knowledge Sphere3d has just completed the developments of its flagship product Glassware this year and started pushing it through major distribution channels including its primary partner Overland's mass enterprise customers list over the past few months. Therefore, a lot is happening fast, and the company hasn't disclosed most contracts it signed or is negotiating for the purpose of technological secrecy and/or business confidentiality I think. The Chestfield school district is the rare one that slipped out media's mouth.
Several other ones that the company announced recently are:
Uniprint: http://bit.ly/1qbCDgQ
Novarad (a big medical institution): http://bit.ly/1qbCAll
Ericsson: http://bit.ly/1qbCABA 3D_MSP_FinalV3 - 052714.pdf
In addition, the company has signed cooperative agreement with Dell recently: http://bit.ly/1qbCDgW
As we know, Dell is making a huge effort in marketing its Chromebooks. That's maybe one of the reasons Chestfield School district chose Chromebook + Glassware. So, I expect that we'll see a flurry of new contracts/business wins for Sphere3d in this section in coming months.
CELG: Otezla TRx 725, -2% wk/wk and NRx 427, -10% wk/wk in 19th week of launch
Q2 sales were $5M, which undercaptured because of free titration starter packs that lead to commercial drug after reimbursement approval.
We see greater appreciation for Otezla over the next couple quarters, because scripts are tracking much higher than Xeljanz's launch, implying Q3 cons estimates of $29M are achievable. PFE's Xeljanz reported TRx/NRx of 573/376 in its 19th week of launch (ending 03/22/13), and $22M during its second full quarter of launch.
PCYC/JNJ: Imbruvica TRx 978, +4%% wk/wk, and NRx 380, +3%% wk/wk
PCYC reported strong Q2 Imbruvica sales of $110M vs. cons $89M. Management declined future guidance but based on run-rate and growing sales moderately, our Imbruvica APP predicts $450M+ this year.
GILD: Zydelig week 2 TRx is 15, + 150% wk/wk, and NRx 15, +150 % wk/wk; compared to week 2 TRx/NRx of 64/64 (week ending 11/22/13) for Imbruvica
GILD's Zydel
Sovaldi TRx is 6898, -2% wk/wk and NRx is 2582, -8% wk/wk (week ending 8/08/14).
First impression
US Sovaldi TRx tracking -11% QTD (vs. +76% Q/Q in Q2). GILD reported Q2 Sovaldi sales of $3.5B ($3.0B US and $449M OUS). Thus, Q3E should be $3B x 0.89 = ~2.7B. We expect scripts to be weaker in Q3 vs. Q2, primarily due to warehousing effects ahead of pending "all-oral" approval in the fall (PDUFA Oct 10th).
Thanks to ROB CO. For providing.
Dew
What the over and under odds date til
Pcyc buys them ??
CS on bmy
Pause in UNITY-4 Concerning; Commercial Impact Unclear with Other Studies Continuing
¦ Unspecified protocol adjustment leads to UNITY-4 delay. Enrollment in BMY's UNITY-4 hepatitis C (HCV) study for their three-drug fixed-dose combination (FDC) has been temporarily suspended to allow for the implementation of a protocol amendment. While the delay is likely temporary and may turn out to be inconsequential, we believe it may lead investors to question the potential of the regimen until we see the full data from UNITY 1- 3 next year. Investors are currently giving BMY only modest share in HCV but delays or safety concerns could pose downside risk to estimates in 2H 2015 and beyond, while providing some potential upside to the other players in the market (GILD, ABBV/ENTA and MRK). HCV is important to BMY (we assume $730M in BMY HCV sales in 2015, peaking at $1.33Bn in 2019), but our bullish view on the stock is driven much more by their leadership position in immuno-oncology (I-O) and that is obviously not changed by today's news.
Acad. Nice post from investorvillage
I think most analysts don't see how similar the P2 ADP trial is to the P3 PDP trial.
-Both trials are treating 200 patients for 6 weeks that have psychosis with delusion/hallucinations.
- The hallucinations in both PDP and ADP are primarily visual not auditory.
-Dr Ballard was the co-PI for the P3 PDP and is again the PI for the ADP trial.
-29 patients in the PDP P3 were baseline measured on the MMSE as cognitively impaired.
-That equalled 30% of all PDP patients who received Pima and those 29 outperformed all the other patients.
-The MMSE will also be used to measure baseline cognition in the ADP trial.
-The other PI for the PDP trial was Dr Cummings and he is the inventor of the NPI-NH which is ADP primary endpoint.
-So I believe in 3Q 2015 we get ADP results that will match Pima's p=.001 we saw in the P3 PDP.
-Then Piper's current $46 target price will again be raised.
Merck insomnia drug approved
RBC update on arwr.
We think "trifecta" of safety, efficacy and durability of data shows the drug is fundamentally "working" and supports blockbuster HBV opportunity on track. Detailed update at AASLD, including higher 3mg cohort, will likely be another de-risking event in November.
Key points:
Big picture: We think ARWR reported "fundamentally" solid Phase IIa ARC-520 data in Hepatitis B, showing knockdown of the Hep B "target" and good safety. There was some expectation data could show a "1-log" knockdown, but we repeatedly said in prior notes this is more of a sentiment/expectations phenomenon and 0.8 log was more likely; in fact, we reiterate experts say 0.5 to 1.0 log knockdown is all very promising on single-dose and it doesn't matter if it's 0.8 or 0.9 log, etc. It doesn't change the promising odds of success in Phase II/III and it all indicates the stock is cheap vs. the huge multi-billion dollar opportunity. We know: 1) more doses could obviously improve on this early-stage study, 2) higher doses (being tested now at 3mg), and 3) longer duration/follow-up in Phase IIb data in 2015 will have a very good chance of increasing the functional "cure" in Hep B pts from current 2% annually.
Thus, we are buyers on any weakness and think the stock will trade back up, as fundamental investors should know the data clearly shows the drug is working and the hypothesis of improving the cure rates in Hep B is absolutely alive and well.
What happened? Phase IIa data was reported on blinded cohorts of one dose of 1mg and 2mg of ARC-520 in HBV pts. Data showed 1) dose response of "modest" knockdown of S-antigen at 1mg and "substantial" knockdown at 2mg, consistent with preclinical models, including previously known chimp data (consensus and we agree this implies ~0.7-0.8 log knockdown), 2) data could get better as some 2mg pts are still showing more knockdown, 3) new higher 3mg cohort is likely to show even better data due to the fact they're in a sweet spot of dose response (2mg much better than 1mg, so going to 3mg is probably a little better than 2mg), 4) durability is great as knockdown is even longer than expected going out to 2 months vs expectations of only 1 month, and 5) good safety data across many pts including no rash (using oral antihistamine), no serious adverse events, and no discontinuations.
What's next? 1) ARWR is enrolling the third cohort at 3mg now with data around AASLD, 2) Phase IIb with multiple doses will start by YE with data around H2:15. We predict we will see some functional cures in that data that are better than the current low bar of weak drugs today.
Q2 expenses were in-line and with $188.5M in cash, we estimate ample runway into 2H:16.
Valuation:
Our $35 price target is a SOTP analysis of probability-a
Cowen. MRK comments.
Merck (MRK $56, Market Perform)
Anacetrapib (CETP inhibitor for raising HDL and lowering LDL) – MRK will present the results of the 306 HF patient, Phase III REALIZE trial later this year, although it will not be the basis for filing. There are three interims in the large, Phase III registrational trial, REVEAL, at 2.5, 3 and 3.5 years, with the first interim in 2015. Study conclusion is reached when 1900 events are accrued. REVEAL has a MACE endpoint; MRK believes the addition of angina would add noise to the final data (LLY’s evacetrapib Phase III trial includes angina as an endpoint). We peg anacetrapib sales at $1.2B in 2020.
MK-8931 (BACE Inhibitor for Alzheimer’s disease) – MRK has two studies underway. The first is in mild/moderate patients with an 18 month endpoint. MRK states that
enrollment of this trial is on track, with study completion in 2017. A second study is looking at the prodromal population with a 24 month endpoint. These patients are harder to identify. Enrollment in this trial started slow, but has been picking up. We peg MK-8931 sales at $300MM in 2020.
Immune Oncology – Depending on the data from various studies, it appears that MRK will try to file pembrolizumab in lung earlier than Q4:15, and perhaps early in 2015. MRK believes there could be differences between the various PD-1 agents although would not elaborate on any data it may have generated along these lines and whether it believes such differences are clinically important. It does believe the most important differentiating feature is how the products are developed. MRK is testing pembrolizumab in an array of hematologic diseases. MRK has a LAG3 in preclinical development. MRK has not decided whether to advance a preclinical OX-40 candidate. MRK’s anti-GITR shows striking responses in combination with pembrolizumab. We believe new data at ESMO (September 24-26) may include data of pembrolizumab in lung/melanoma, head & neck, and potentially bladder. We peg pembrolizumab sales at $2B in 2020.
Hepatitis C – MRK will have data from a drug interaction study of the Idenix nuc shortly. It is comfortable with the safety profile of the Idenix nuc given preclinical data and given that the chemical structure is a uridine-based backbone as opposed to a purine-based backbone; uridine-based products have not encountered safety issues whereas purine-based products have encountered safety issues. Further data on HCV/ RNA declines will be available at AASLD.
RBC arwr.
August 12, 2014
Arrowhead Research Corp.
Hep B data already looks good so far and likely could get even better - Outperform
Impact:
ARWR data looks good and durability longer than expected. Doc feedback said anything from 0.5 to 1.0 log is strong.
First impression
ARWR reported initial top-line Phase IIa data that shows good knockdown of s-antigen, good durability, and good safety. We think they could get even better knockdown with higher doses and more duration and like how ARWR keeps going to higher doses. We expect the stock to trade up on this news as this shows the drug is working, hitting its target, and safety is good. Docs say that knocking down s-antigen with more doses, and more time, could lead to higher cures in Hep B and much higher than current therapy so this is fundamentally positive.
1. Overall s-antigen drop is "similar to non-human primate" studies which implies for investors around -0.8 log reduction
2. The duration of drop appears to be MUCH longer than expected including 2mg arm still demonstrating knockdown after 8 weeks (2 months)
3. The 2mg dose appears to have pts continuing to decline even at 8 weeks.
4. Safety appears fine no notable issues. No serious adverse events and no dropouts.
5. Third cohort (3mg/kg) opened and dosed w/ no difference in safety (ie that's good) and no increased frequency of Aes. Will also begin another cohort of 3mg.
4:30pm ET Conf call 855-215-6159 ...82825377
I was buyer of arwr. After hours. LONGTERM hold for me
Data to me looks very good and is safe.
From DB
Arrowhead Research {Ticker: ARWR.OQ, Closing Price: 12.85 USD, Target Price: 45.00 USD, Recommendation: Buy}
Here are our quick takes on the ph2a data:
We view this data as very positive at a single dose.
We find safety very encouraging at 1, 2, and 3mg/kg dosing
We expect the 2 or 3mg/kg dose will likely achieve the one long KD in surface antigen. Co notes pts still on 2mg dose and 3mg has been cleared to start. The co notes that the 2mg dose looks substantially better than the chimp data at 1mg.
We view the longer than expected duration of returning to baseline as very positive and a better dosing frequency than monthly is positive
Overall we view the data as positive and supportive of safety, the first proof of concept in humans, and further validating the co’s RNA platform technology
We see ARWR FVs of $35-$45/sh on Ph 2a data. Possible upside of ~100-150%
We think risk/reward is favorable into data in the 3Q14 for Ph2A. Our base case assumes 40% success to $5.2B peak HBV sales of ARC-520. We also assume 20% success to $2B peak platform sales. On the downside, we see ARWR FVs of $12-$16/sh (neg 6-30%). Cash value $4/sh (down 80%).
Cowen. Achn. We Think The Risk/Reward Of Owning Achillion Shares Is Favorable, Says Cowen
In a research note released August 7th, Cowen and Company analyst Phil Nadeaureaffirmed an Outperform rating on Achillion Pharmaceuticals (ACHN), following the release of ACHN’s second-quarter results where they suffered a net loss of $15.7MM and ended the quarter with $132MM in cash. Proof-of-concept data from nuc ACH-3422 are on track for the Fall, and ACHN expects to soon release results from an 8 week combination of its NS5A ACH-3102 with GILD’s sofosbuvir. No price target was assigned.
Nadeau wrote, “Achillion is developing drugs for the treatment of infectious diseases, and is particularly focused on HCV. Achillion’s Phase II candidates include sovaprevir (PI) and ACH-3102 (NS5A). Based on promising pre-clinical data, ACHN nominated ACH-3422, a uridine analog nuc, for clinical development. ACHN initiated a Phase I trial for ACH-3422 in Q2:14, and initial proof-of-concept data are expected during H2:14. The recent acquisition of Idenix by Merck for $4B highlights the value of a safe and effective HCV nucleotide, and we think development of ACH-3422 alone could create significant shareholder value. With a number of promising wholly owned candidates, we think it also quite possible that ACHN could have its own internal DAA regimen. We believe that ACHN will appreciate significantly should its internal IFN-free HCV regimens be successful, or should it be acquired for its HCV assets. We therefore think the risk/reward of owning ACHN shares is favorable.”
Will see if PB. Responds???
@dougheuringaria: @pbookman What's this.Google (GOOG) to Acquire Sphere 3D Corp (ANY) In Stock Predicts Sierra World Equity Review http://t.co/Nu4XV74AnR
HUNTINGTON'S
Re: new Publication..."We have identified four well-tolerated lead ASOs that potently and selectively silence muHTT at a broad range of doses [in a humanized mouse model of HD] throughout the central nervous system for 16 weeks or more"
Mol Ther. 2014 Aug 7. doi: 10.1038/mt.2014.153. [Epub ahead of print]
In vivo evaluation of candidate allele-specific mutant huntingtin gene silencing antisense oligonucleotides.
Southwell AL1, Skotte NH1, Kordasiewicz HB2, Ostergaard ME2, Watt AT2, Carroll JB3, Doty CN1, Villanueva EB1, Petoukhov E1, Vaid K1, Xie Y1, Freier SM2, Swayze EE2, Seth PP2, Bennett CF2, Hayden MR1.
Author information
1Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
2ISIS Pharmaceuticals, Carlsbad, California, USA.
3Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham, WA, USA.
Abstract
Huntington disease (HD) is a dominant, genetic neurodegenerative disease characterized by progressive loss of voluntary motor control, psychiatric disturbance, and cognitive decline, for which there is currently no disease-modifying therapy. HD is caused by the expansion of a CAG tract in the huntingtin (HTT) gene.
The mutant HTT protein (muHTT) acquires toxic functions, and there is significant evidence that muHTT lowering would be therapeutically efficacious. However, the wild-type HTT protein (wtHTT) serves vital functions, making allele-specific muHTT lowering strategies potentially safer than non-selective strategies. CAG tract expansion is associated with single nucleotide polymorphisms (SNPs) that can be targeted by gene silencing reagents such as antisense oligonucleotides (ASOs) to accomplish allele-specific muHTT lowering.
Here we evaluate ASOs targeted to HD-associated SNPs in acute in vivo studies including screening, distribution, duration of action and dosing, using a humanized mouse model of HD, Hu97/18, that is heterozygous for the targeted SNPs.
We have identified four well-tolerated lead ASOs that potently and selectively silence muHTT at a broad range of doses [in a humanized mouse model of HD] throughout the central nervous system for 16 weeks or more after a single intracerebroventricular injection.
With further validation, these ASOs could provide a therapeutic option for individuals afflicted with HD.
Molecular Therapy (2014); doi:10.1038/mt.2014.153.
PMID: 25101598 [PubMed - as supplied by publisher]
PB tweet.
@pbookman: RT @Darkkasser: Tomorrow meeting @Belgium with CEO @Sphere3D and big investors.
Belgium beer for Peter? >Which Peter? ;)
Citi on clvs.
Investment strategy
We rate Clovis Neutral/High Risk (2H) as we are less optimistic on the outlook for CO-1686 in lung cancer and rucaparib in ovarian cancer given the increased competition we expect both drugs to face. In our view, CO-1686 is a highly potent and effective drug for T790M EGFR mutations (that occurs in ~50% of all lung cancer patients that fail Tarceva). While CO-1686 should be successful in getting approval in both 1st and 2nd line lung cancer, we believe that Astra Zeneca’s AZD9291 offers a better profile (QD, no QTc prolongation, no hyperglycemia) and could be first to market. As Astra Zeneca is likely to become one of the dominant long-term oncology players, they are now moving to combine AZD9291 with their PD-L1 antibody and with other TKis. This will likely help them dominate this segment long term. Clovis’ rucaparib (PARP inhibitor) is now in pivotal studies in ovarian cancer, a validated target for PARP inhibitors. But its profile is less compelling than other PARPs and it is behind in the race to the market. As the PARP field is also heating up in the race to combine with other drugs, rucaparib is facing an uphill battle.
Valuation
Our target price of $53 is based on 20x our 2020 non-GAAP EPS estimate and discounted by 10% annually. We believe this low multiple is justified due to the strong competition facing Clovis’ pipeline. We apply a discount rate of 10% on top of our probability of success adjustment on sales. We use 2020 as our valuation year as we believe it will be the second year of profitability for Clovis which will accurately reflect the future prospects for earnings growth.
Risks
We rate Clovis Oncology High Risk. We believe that Clovis’ pipeline is facing the usual development, regulatory, commercial and competitive risks. In particular, we believe that both CO-1686 and rucaparib are facing stiff competition from companies that are ahead in development. In addition, Clovis’ competition is moving to combine their drugs into combination regimens that can further differentiate those drugs over Clovis’. This will make it tough for Clovis to compete.
If the negative impact of these risk factors is greater than we anticipate, the shares may have difficulty achieving our target price. If the impact of these factors is less than we anticipate or if the competitive landscape changes to favor Clovis, there is upside risk to our target price.
Cowen. GWPH target 110
We Expect GW’s Shares To Outperform As Its Pipeline Progresses, Says Cowen
In a research report published yesterday, Cowen and Company analyst Phil Nadeau reaffirmed an Outperform rating on GW Pharmaceuticals (GWPH) with a $110 price target, following the financial results for the third quarter. GW reported £1.3MM Sativex sales vs. Nadeau’s estimate of £1.0MME. Net loss for the quarter was £6.9MM corresponding to GAAP EPS of (£0.03), in line with Nadeau’s estimate. GW ended FQ3 with £168.3MM in cash inclusive of £69.5MM from the June follow-on offering.
Nadeau wrote, “GW’s most advanced program is Sativex, an oromucosal spray containing THC and CBD. We estimate Sativex WW sales in MS spasticity of just over $100MM by 2020. Sativex in the treatment of opioid-refractory cancer pain represents a more significant commercial opportunity. We project a 2016 U.S. launch, and that Sativex will achieve $350MM in U.S. sales by 2020, driving GW to profitability. Epidiolex is an oral liquid formulation of a highly purified extract of CBD for use in children with intractable forms of pediatric epilepsy. Given high demand and unmet need, we think development could be rapid and project $175MM in revenue by 2020. GW is undervalued based on Sativex and Epidiolex, with no contribution from the rest of the pipeline. We expect GW stock to outperform the market over the next 12 months as Sativex and Epidiolex progress”.
Thanks. Here is piper on ACAD. Target 46
PiperJ - E.U. Regulatory Strategy is a Positive Time and Risk Reducer. Reiterate OW & $46 price target...$354 million in cash...Alzheimer's psychosis study, & others making progress..
ACADIA Pharmaceuticals (ACAD) Overweight
E.U. Regulatory Strategy is a Positive Time and Risk Reducer
PRICE: US$20.77
TARGET: US$46.00
C O N C L U S I O N
Acadia reported 2Q financials yesterday. No major updates on the U.S. pimavanserin (pima') program, but for Europe the company now plans to file the MAA for pima' in Parkinson's disease psychosis (PDP) on the single 020 study. Although we had previously published this as a possibility, and we expect ACADIA will be successful in obtaining E.U. as well as U.S. approval with this plan, we believe that the new strategy will represent time line contraction and risk reduction for some investors.
• We continue to maintain a modest level of sales in the U.S. in 2015, but move our EU sales to 2016 anticipating a mid-to-2H15 MAA filing. With an eye to eventual label expansion, we view pima' as a pipeline in a product candidate and reiterate our Overweight rating. We are rolling our discount period to YE15 resulting in a new $46 price target (from $42).
• The company ended 2Q with $354M in cash and we model no further financing for ACAD. Pre-commercial activities from the pima' commercial team are progressing and Acadia maintained guidance to an NDA filing "near" YE. Acadia reiterated its plans to field a specialist sales force in the U.S. targeting primarily neurologists. The company characterized its interactions with the FDA as positive and data from the stability testing batches are consistent with data from the clinical trials. Supportive clinical studies like drug-drug interaction are also on track according to management commentary.
• Fully informed E.U. filing strategy. The European filing plans were made following discussions with member states and consultants that Acadia said were previously working at the highest levels in the EMA. Acadia considers the clinical package for submission very good and believes filing is the "optimal" path to approval vs. seeking additional scientific advice.
• Alzheimer's psychosis study, and others (soon), making progress. In support of our pipeline-in-a-product thesis for pima', Acadia is studying pima' in a Phase II study in Alzheimer's disease psychosis (ADP). Recall this study is being run at a single (large) site in the U.K. Final data collection is late 2015 according to clinicaltrials.gov, although we suspect that these timelines may not account for actual progress in the study and that data may come closer to mid '15. In addition, protocol plans are being formed for studies in improving sleep, likely to be conducted in Parkinson's patients, which may start later this year or in early 2015. Acadia is also working on the design (duration, patient population, etc.) of a study in schizophrenia that is likely to start in 2015.
R I S K S T O A C H I E V E M E N T O F P R I C E TA R G E T
Emergence of a safety signal in the ongoing continuation trial for pima'.
C O M P A N Y D E S C R I P T I O N
ACADIA is focused on neurological and psychiatric diseases.
hey guys have not had time to post notes but i did on twitter from jmp, bmo, and rbc.
goodluck guys
dough
ACAD update from Jason napodano
@JNapodano: $ACAD - Acadia On Track With Pimavanserin Development Program >> http://t.co/NmbLZOVKiU
RBC. On tkmr
August 4, 2014
Tekmira Pharmaceuticals Corporation
Thoughts on Ebola program "call option"; our thesis is on Hep B...
Impact:
Ebola attention continues to grow; visibility is low on this program although it is an upside call option.
First impression
We've said TKMR is an inexpensive small cap biotech with significant upside potential vs. downside potential because of not just one but multiple programs (cancer, Hep B, and Ebola, and more) moving along. While we acknowledge there is the potential for TKMR to land significant revenues due to its Ebola program, this should only be considered a long-term upside opportunity as it is very interesting and could be considered as a treatment option for governments, but visibility is very low and predicting what happens with pandemic outbreaks and government contracts can be risky. Long term, we estimate it could be a periodic $100M/yr product mainly via safety stocking contracts with DoD. Importantly, our core investment thesis is primarily built around the Hep B program due to clearer visibility on what constitutes proof-of-concept, clinical development path, and commercialization market opportunity evidenced by other recent anti-viral blockbusters.
TKMR's Ebola program is in a multi-dose, dose-escalation healthy- volunteer Phase I study but was put on clinical hold recently by FDA to address cytokine release (immune response, feeling sick/flu, fever, etc.) which may be due to fact it is doing without pre-medication of steroids which could help logistical profile of the drug and could be an advantage long-term. The company has said this should be fairly temporary and expects to address the straight-forward issue and plans to resume the program soon (perhaps just dose with pre-medication...).
It is possible the recent Ebola outbreaks in West Africa could motivate FDA to move the TKMR program off hold sooner if the issue is indeed fairly simple, and if it is removed off clinical hold soon that (and more outbreaks) could be a catalyst for the stock. Under normal timelines, TKM- Ebola falls under the Animal Rule by the FDA and would have to go through further animal testing and then a large (100s) safety trial in healthy human volunteers, until reaching the market potentially by 2018.
We will monitor the ongoing developments with the Ebola outbreak and acknowledge media attention to this program may cause TKMR stock to be volatile. So far 1300 pts have been afflicted with Ebola this year including 700 deaths mostly in West Africa. Recently 2 American missionaries were stricken with Ebola and are coming back to the US and will be quarantined. According to media reports, the two US patients were given another pre-clinical experimental therapy.
Outperform Speculative Risk
RBC. On aria.
August 4, 2014
Ariad Pharmaceuticals, Inc.
Could it be a win-win situation in both scenarios? Maybe
Our view: ARIA will report Q2 results Wed AM. Iclusig expectations of $13.8M for the quarter are reasonable and in-line with our estimates. Notably, sentiment is at lows as catalysts in the near-term are lacking and earlier/front-line strategy still undetermined and far away. We maintain Sector Perform as LT visibility remains uncertain; however, we appreciate there might be 2 ways to win in the long-term....
Key points:
Big picture: Sentiment in ARIA remains lackluster as expectations on Iclusig's re-launch remain modest and long-term front-line expansion opportunity unclear. In the short-term, investors are watching quarterly Iclusig sales and if Q2 beats (we think in-line to beat), this could provide at least an incremental boost in confidence that Iclusig can at least become a $300-350M+ WW orphan drug for T315i with "orphan pricing power" and if it's "only" a T315i drug over the long run then they could significantly increase the price in parallel with its "unmet need" in this rare targeted population of 15% of CML patients (the first way it could be a win over the long-run). Patient long-term bull investors say thus that at 5x sales, ARIA is a $2-3B candidate (or takeout at some point) vs. current $1B valuation. The second way to win long-term is if it actually did move "earlier" in treatment then the bigger $1B opportunity could get re-visited again and that would be lots of potential upside since few investors think that will happen. So either it's a niche premium priced drug if they can never move earlier, or it's back into the earlier lines which opens up lots more opportunity.
Q2 will be the first full quarter since Iclusig's relaunch and cons $13.8M seems achievable. As of April, there were ~400 patients on Iclusig. So if we estimate by end of Q2 (Jun), there were 500 pts on drug (50 net new adds/ month), that translates to ~$10M in US (taking into account 1/3 on lower dose, which is half the price). This could be conservative if we consider how last year in Q2, patients on the drug increased from 325 to >610 to report $13.9M in sales. Whereas this year at end of Q1, there were similarly 340 patients on the commercial drug. We estimate modest 15% Q/Q growth in EU of $3.8M.
For the year, we are at $88M vs. cons $69M but the difference is likely due to our assumption of approx. $18M in accrued sales to France under ATU will be booked in Q4.
Several questions: 1) Has ARIA determined a solution to keep the lower 15mg dose at price parity with the higher 30/45mg doses? 2) Has FDA agreed to the new protocol to explore first induction then lower dose maintenance? 3) What are the potential changes to the EU label when final CHMP recommendations are released in Oct? 4) Is a potential partnership for Japan still in the works by end of 2014?
186.3 Market Cap (MM):
1,053 0.0%
2015E
126.0
(0.97) NM
Q4
8.4A 42.5E
(0.40)A (0.19)E
RBC on aria.
August 4, 2014
Ariad Pharmaceuticals, Inc.
Could it be a win-win situation in both scenarios? Maybe
Our view: ARIA will report Q2 results Wed AM. Iclusig expectations of $13.8M for the quarter are reasonable and in-line with our estimates. Notably, sentiment is at lows as catalysts in the near-term are lacking and earlier/front-line strategy still undetermined and far away. We maintain Sector Perform as LT visibility remains uncertain; however, we appreciate there might be 2 ways to win in the long-term....
Key points:
Big picture: Sentiment in ARIA remains lackluster as expectations on Iclusig's re-launch remain modest and long-term front-line expansion opportunity unclear. In the short-term, investors are watching quarterly Iclusig sales and if Q2 beats (we think in-line to beat), this could provide at least an incremental boost in confidence that Iclusig can at least become a $300-350M+ WW orphan drug for T315i with "orphan pricing power" and if it's "only" a T315i drug over the long run then they could significantly increase the price in parallel with its "unmet need" in this rare targeted population of 15% of CML patients (the first way it could be a win over the long-run). Patient long-term bull investors say thus that at 5x sales, ARIA is a $2-3B candidate (or takeout at some point) vs. current $1B valuation. The second way to win long-term is if it actually did move "earlier" in treatment then the bigger $1B opportunity could get re-visited again and that would be lots of potential upside since few investors think that will happen. So either it's a niche premium priced drug if they can never move earlier, or it's back into the earlier lines which opens up lots more opportunity.
Q2 will be the first full quarter since Iclusig's relaunch and cons $13.8M seems achievable. As of April, there were ~400 patients on Iclusig. So if we estimate by end of Q2 (Jun), there were 500 pts on drug (50 net new adds/ month), that translates to ~$10M in US (taking into account 1/3 on lower dose, which is half the price). This could be conservative if we consider how last year in Q2, patients on the drug increased from 325 to >610 to report $13.9M in sales. Whereas this year at end of Q1, there were similarly 340 patients on the commercial drug. We estimate modest 15% Q/Q growth in EU of $3.8M.
For the year, we are at $88M vs. cons $69M but the difference is likely due to our assumption of approx. $18M in accrued sales to France under ATU will be booked in Q4.
Several questions: 1) Has ARIA determined a solution to keep the lower 15mg dose at price parity with the higher 30/45mg doses? 2) Has FDA agreed to the new protocol to explore first induction then lower dose maintenance? 3) What are the potential changes to the EU label when final CHMP recommendations are released in Oct? 4) Is a potential partnership for Japan still in the works by end of 2014?
186.3 Market Cap (MM):
1,053
RBC on arwr icpt.
ARWR ARC-520 Phase IIa - guidance is Q3 and perhaps on the Q2 earnings call on Aug 12th; the release is based on timing of enrollment of second cohort (2mg) estimated in May. Our base case is a 0.5-1.0 log HBsAg knockdown as docs tell us anything above 0.5 log is good. Co said they'd like to see 1.0 log and if it doesn't hit 1.0 log they'd probably just dose up to 3mg quickly and get data in a few months. Fundamentally, 0.5-1.0l og is good but Street will likely want to see higher the better and anything higher than 1.0 log will be seen as solid, in our view. We reiterate we do not expect to see an ALT flare after only one dose here and Street is indifferent on that as well.
ICPT Phase IIb ("FLINT") data in NASH patients might come end of month but co has already said feedback from NIDDK is it may take longer now. Discussions suggest a meeting with NIDDK was not yet set up for July and the agency needs more time for data input and analysis before getting a meeting on the calendar. Our view is that the data will surely be noisy and possibly confusing for many investors unless it's a clear win defined by: 1) LDL <20-25% delta "placebo-subtracted" and hence better than prior Phase IIa, and 2) hit stat sig on reversal of fibrosis. We don’t expect it to hit stat sig on fibrosis so the stock might trade off, but if it does hit, the stock could potentially trade up $100 or more towards our bull case in this home run scenario. See our recent initiation from June 30th for further details (link).
Pete. Here is PB reply
@pbookman: @PeteHermann1 Sandboxes simply are a hosted demo where press and sales can interact with GW to work and experience the product directly
Aspire Trial Positive- previous UBS comments...
In addition, the late-stage ASPIRE data should establish Kyprolis-Rd (KRd) as the standard of care in 2/3rd line myeloma and significantly increase Revlimid duration beyond current utilization. With the phase-3 ASPIRE data looming, there should be a new outlet for upward revenue revisions as long-duration KRd should become the standard of care in myeloma if data are sufficiently positive.
Roden estimates US Revlimid revenues would increase by as much as $676 million by 2020 assuming duration grows to 18 months in the 2nd/3rd line setting.
Awesome tweet. Maybe someone else can post
All of the tweets on this subject. Good stuff
@pbookman: @rspiratla @SimonBramfitt Sandboxes for press and sales beginning deployments next week. ;) Woot!
?? Merck & Co. UBS
Getting Its Mojo Back
Key things we learned on the conference call
(1) On M&A, mgt pointed to value-added bolt-on deals (eg, Idenix) and not large deals. (2) Regarding Pembro, mgt appeared confident about the upcoming Oct 28 PDUFA and indicated it was ready to launch. Merck also indicated that there will be more Pembro data at ESMO and ASH. (3) Mgt was also excited about the Suvorexant (low expectations from the Street) PDUFA in mid-August and expects to launch late this year or early 2015, depending on the timing of the DEA decision on product scheduling. (4) On IMPROVE-IT, the last patient visit will occur in September, and mgt expects to share top-line data in 4Q. (5) On anacetrapib, we could see the first interim analysis in 1H15. (6) Regarding HCV, mgt expects to share some C-SWIFT data at AASLD.
Additional items
(7) EMs grew +2%, with growth in China (+6% Y/Y), Brazil, and Turkey partially offset by tender timing and weakness in Ukraine, Egypt, and Mexico. For the full year, mgt continues to expect good EM growth. (8) In Japan, the 6% decline in sales was due primarily to price decreases and the negative impact from suspended HCV vaccines promotion. (9) Gardisil benefited from ~$30M of public sector orders. Mgt indicated that it is initiating its promotional efforts ahead of the fall flu vaccine season. (10) Isentress benefited from US buying patterns.
Thoughts on the stock: We still like it
It was good to see the stock respond to a solid quarter, and we think there is more to go. Merck has a play in both of the two key therapeutic areas of innovation (I\O and HCV) as well as a few low expectation late-stage, primary care products (Suvo, Bridion, Odanacatib). We think this pipeline combined with tight cost controls can drive high single-digit 5 year EPS growth and push the stock higher.
Valuation: We maintain our Buy rating and PT of $64
Our DCF analysis assumes $47 for the base business and $17 for the pipeline.
PB on the shorts. @pbookman: RT @rspiratla: please protect our stock from shorts. Anyone listening? >We will focus on building our value and defend through execution ;)
Rbc notes regn
Regeneron Pharmaceuticals, Inc
Eylea approvals comes ahead of Aug. PDUFA; Label shows differentiation
Positive – Eylea DME approval and label differentiation were anticipated but approval in early 3Q gives confidence in sales acceleration.
The FDA approved REGN’s Eylea ahead of the 8/18 PDUFA date. The label will show less frequent dosing with Eylea and no mention of fatal events as on the Lucentis label plus both now have similar indications. Next is Eylea 2Q sales and 2014 guidance on the Aug. 5 earnings call, BRVO PDUFA of 10/23, and Eylea/ophthalmology franchise updates with Phase I mono- and combo-studies and new technologies. We like REGN shares for 2014/2015 based on top-line execution and pipeline growth and diversification, and remain buyers, especially on any pullbacks.
Label is differentiated 1: Less frequent dosing vs. Lucentis. Lucentis 0.3mg has once monthly intravitreal injection as the recommended dose. Eylea 2mg can be dosed once monthly for the first 5 doses followed by an injection every 2 months. The annual injection burden per label would be 12 injections for Lucentis vs. 8 or so for Eylea for year 1 and 12 injections for Lucentis vs. 6 for Eylea starting year 2.
Label is differentiated 2: No mention of deaths unlike for Lucentis. The Lucentis label specifically mentions fatal events occurring more frequently in patients treated monthly vs. control. Currently, the Eylea label does not include any such as warning.
Approval is sooner than expected; PDUFA was 8/18. The PDUFA date for DME was 8/18 and the approval on 7/29 is roughly 3 weeks ahead of expectations. Next up is the BRVO PDUFA where the date is 10/23. Eylea is approved for wet AMD, CRVO and DME now. Lucentis is approved for wet AMD, RVO and DME.
Doesn’t impact 2Q but could impact 3Q and 4Q:14. We currently forecast 2Q:14 Eylea sales of $411.9M for Eylea vs. consensus at $418.4M. Based on 1Q:14 commentary (underlying demand growth of 25% over 1Q:13 and 3% sequential growth over 4Q:13 if no inventory impact) plus 2Q:14 Lucentis results, which did not show erosion, we believe Eylea sales numbers are achievable and possibly beatable. For ex-US sales, which partner Bayer reports, we forecast $242.1M, which is up from $218M reported in 1Q:14 and could be a source for a beat.
2014 Eylea consensus is at the high end; guidance may not be changed.
RBC forecasts 2014 Eylea sales of $1.73B vs. consensus at $1.77B and REGN guidance of $1.7-1.8B. Given the uncertainty around the current quarter, we believe even a modest raise or even reiteration could be a meaningful positive signal for the Street and shares could respond favorably.
There currently is 2700 ovrl available at 3.20 after hours. Cheap IMHO
I bought 3000 there already.
Clive Ballald slide show. Acad
http://www.rcpsych.ac.uk/pdf/IC14%20TC1%20P3%20Ballard%20Clive.pdf
ACAD post if anyone interested full of links and quotes etc etc
ACAD all that you need to know ACAD is must own stock for 1-2 years imho
Double Shot
ACAD has been guiding for a Pima NDA near the end of 2014. A priority review could get NDA approval in 4-6 months. ACAD could also announce at the end of 2014 the 12 week ADP trial has become fully enrolled. ADP results should arrive about 4 months later. I've noticed that most alz drugs take a stock's price up considerably just before results despite the fact that for the last 10 yrs all of these alz drugs have consistently failed in their trials. The Pima ADP trial is only a P2 but if Pima gets good results the neuros would probably substitute Pima for the black box atypicals that are endangering their ADP patients. So in a way Pima's P2 ADP trial is the equivalence of a P3. A year from now ACAD should have already filed Pima's NDA and may have reached full enrollment in ADP. Imo those 2 events happening close together should cause ACAD's price to rise sharply in late 2014.
ADP
I liked this brief response to a Napodano article on Pima. I'd add that the atypicals drugs were all originally designed and tested in schizo patients well under age 60. Only later were they tried in the elderly and all have consistently shown more severe side effect problems in this very different and more drug sensitive population.
http://seekingalpha.com/article/1830812-acadias-pimavanserin-is-the-next-blockbuster-for-psychosis?
source=tracking_email_activity_alerts&ifp=1&v=1389530700
I am a psychiatrist & dementia (formerly schizophrenia) researcher who came upon this article, looking for reports on PIM in other dementias (AD, DLB, FTLD). I'm not an investor (I know enough to know I don't know enough). PIM may be hugely important. It is the first non D2-antagonist antipsychotic. There is a huge need for a non neuroleptic treatment for agitation in patients w/ dementia. PIM may fail if it turns out to be like buspirone (an anxiolytic useless acutely), but if results in AD match PDP, PIM could have a transformative effect on geriatric neuropsychiatry analogous to the atypical antipsychotics replacing 1st generation agents.
from napadano in jan 2014
but you never know! What seems true about pimavanserin is the more we learn, the more it reinforces our belief that this will be a very big drug for Acadia. Results from the -020 study recently published in The Lancet held up well to peer-review. Acadia's market research shows that 30-50% of Parkinson's patients will develop psychosis over the course of the disease, and there are limited treatment options that don't impact motor function. The -020 study enrolled only patients with severe disease, but Acadia believes that pimavanserin use in the real world may start earlier in less severe patients, potentially halting the progression of psychosis in the Parkinson's patient from the start. The clean safety and toxicology profile of pimavanserin should allow more aggressive and earlier-stage use in our view. Management is currently conducting drug-drug interaction studies with pimavanserin as one of the final necessary steps prior to filing the NDA later this year. Manufacturing and CMC work is also progressing on plan.
Acadia also recently began a Phase 2 study with pimavanserin in Alzheimer's disease psychosis (ADP). Management is particularly excited about this ADP opportunity. The 200-patient Phase 2 ADP study mirrors the successful design Phase 3 -020 study, and includes a brief psycho-social therapy prior to randomization to help reduce placebo response. The study is being conducted through a large network of research care homes established as part of the National Institute for Health Research (NIHR) Maudsley Biomedical Research Unit in the United Kingdom. The primary efficacy endpoint is the Neuropsychiatric Inventory - Nursing Home (NPI-NH) scale to measure psychosis (hallucinations and delusions), agitation/aggression, and sleep/nighttime behavior.
Acadia is also starting to talk about the commercialization of pimavanserin. This is a market the company knows well, having conducted three large Phase 3 studies at over 100 centers around the country. We think 75 full-time representatives should be an efficient number to promote the drug in the U.S. Ultimately, we think Acadia expands its pipeline to include another Parkinson's product, but it's a bit early to start writing on as to what makes the most sense, although we've got our best guesses no doubt. Our financial model assumes Acadia launches the drug in early 2016. In the end, we think pimavanserin is a blockbuster product, and that makes the stock an attractive core-holding for biotech investors
Euro study showing the deadly side effects of current antipsychotics
Nice timing to have these results arrive just before Europe considers accepting Pima based on the single P3.
http://www.clinicalpsychiatrynews.com/specialty-focus/schizophrenia-and-psychosis/single-article-pa
ge/antipsychotics-boosted-cvd-events-in-elderly.html
Antipsychotics boosted CVD events in elderly
Ballard's Presentation
The jump in ACAD's price might be related to Dr Ballard's presentation that occurred over the weekend. The Doc is also the PI for the ongoing Pima ADP trial. Note the end of the abstract of his talk below says:
"The results regarding the sub-group with cognitive impairment will be reviewed in detail. Conclusions will be drawn regarding current best practice and likely future directions."
MMSE was used to measure cognitive impairment and no one allowed to start with a score below 21. It could be a predictor for the ongoing ADP trial which is also using the MMSE test. If the doc told the audience that Pima worked better in the cog impaired subgroup then that might be related to Monday's pop.
http://www.siumed.edu/cme/alzheimer/pdf/AbstractBook_WEB2014.pdf#page=101
?13th International Geneva /Springfield Symposium on Advances in Alzheimer Therapy Clive Ballard
TREATMENT OF PSYCHOSIS IN PARKINSON’S DISEASE AND PARKINSON’S DISEASE DEMENTIA
Clive Ballard1, R. Mills2, H. Williams2, A. Corbett1, J. Cummings3
1King’s College London, UK; 2ACADIA Pharmaceuticals, California, USA; 3Cleveland Clinic, Ne- vada, USA
Email: clive.ballard@kcl.ac.uk
Psychosis is common and impactful in people with Parkinson’s disease with and without dementia, but there are no licensed first line pharmacological therapies. Best practice guidelines regarding adjustment of Parkinson’s medications and the identification and treatment of delirium will be reviewed and the potential role of non-pharmacological treatments will be discussed, including new data from a non-pharmacological treatment lead in phase of a recent large RCT. Previous evi- dence regarding clozapine, quetiapine and other atypical antipsychotics and cholinesterase inhibi- tors for the treatment of psychosis in PD and related dementias will be discussed. The results of a recent placebo controlled RCT of pimavanserin in people with Parkinson’s disease psychosis (with or without cognitive impairment) demonstrated significant improvement of psychosis, improved global outcomes and reduced caregiver burden with pimavanserin treatment compared to placebo over 6 weeks with good tolerability. The results regarding the sub-group with cognitive impairment will be reviewed in detail. Conclusions will be drawn regarding current best practice and likely future directions.
Pima may work better in men
The abstract below shows alz psychosis in females appears to be more related to Tau while the alz psychosis in males is more alpha-synuclein related. It could mean that Pima works better in males. That's because Parkinsons shows more alpha-synuclein related disease than alz and in the P3 PDP trial Pima treated males improved by 7.3 points while Pima females improved only 4.7 on the SAPS-PD. Pima's odds of success might rise if the ongoing ADP trial recruits more males than females. I am very confident Pima will work for ADP because in the most cognitive impaired PDP group Pima worked best on those patients. Curious to know if there were more males in that group.
---------------------------
http://www.neurobiologyofaging.org/article/S0197-4580(14)00237-1/abstract
Psychotic Alzheimer's disease is associated with gender-specific tau phosphorylation abnormalities
Jeremy Koppelemail address, Chris Acker, Peter Davies, Oscar L. Lopez, Heidy Jimenez, Miriam Azose, Blaine S. Greenwald, Patrick S. Murray, Caitlin M. Kirkwood, Julia Kofler, Robert A. Sweet
published online 07 March 2014.
Abstract
Converging evidence suggests that psychotic Alzheimer's disease (AD + P) is associated with an acceleration of frontal degeneration, with tau pathology playing a primary role. Previous histopathologic and biomarker studies have specifically implicated tau pathology in this condition. To precisely quantify tau abnormalities in the frontal cortex in AD + P, we used a sensitive biochemical assay of total tau and 4 epitopes of phospho-tau relevant in AD pathology in a postmortem sample of AD + P and AD - P. Samples of superior frontal gyrus from 26 AD subjects without psychosis and 45 AD + P subjects with psychosis were analyzed. Results of enzyme-linked immunosorbent assay demonstrate that AD + P females, but not males, had significantly higher levels of phosphorylated tau in the frontal cortex. In males, but not females, AD + P was associated with the presence of a-synuclein pathology. These results support a gender dissociation of pathology in AD + P. The design of future studies aimed at the elucidation of cognitive and/or functional outcomes; regional brain metabolic deficits; or genetic correlates of AD + P should take gender into consideration.
Kings College Blog on Pima
(This might be an interesting blogger to follow because Kings College in London is the site of the P2 ADP trial.)
http://www.thementalelf.net/treatment-and-prevention/medicines/antipsychotics/new-study-demonstrate
s-effectiveness-of-antipsychotic-pimavanserin-for-parkinsons-disease-psychosis/
New study demonstrates effectiveness of antipsychotic Pimavanserin for Parkinson’s disease psychosis
Apr 16 2014
Raphael Underwood
When we think of Parkinson’s disease (PD), hallucinations and delusions are probably not the first symptoms that come to mind. And yet, it is estimated that nearly half of all patients with PD experience psychotic symptoms at one time or another.
Although deficits in motor function are seen as the hallmark of PD, it is the non-motor symptoms such as depression that are highly predictive of drop in quality of life. In fact, psychotic symptoms specifically predict the need to be placed in a nursing home (Chaudhuri et al., 2006).
Unlike schizophrenia, hallucinations in PD are primarily visual rather than auditory or somatic (Chen, 2004), and can initially be benign. As disease severity increases however, paranoid delusions and delirium can become frequent and distressing (Chaudhuri et al., 2006).
The cause of PD psychosis is not fully understood. Due to the link between excess dopamine and psychosis, one might think that dopamine agonists typically prescribed to treat motor symptoms in PD would be responsible. In reality, PD psychosis has been associated with a range of factors, including old age, dementia, comorbid depression, general illness severity and, indeed, dopaminergic medication (Weintraub & Hurtig, 2007).
It's estimated that nearly half of all Parkinson's disease patients experience psychotic symptoms at some point
It’s estimated that nearly half of all Parkinson’s disease patients experience psychotic symptoms at some point
Antipsychotics primarily exert their therapeutic effect by blocking D2 dopamine receptors, which in PD can worsen symptoms. As a consequence, NICE guidelines advise against using typical and atypical antipsychotics, except clozapine for severe psychosis (National Collaborating Centre for Chronic Conditions, 2006), so it is important that a more viable and efficacious treatment for PD psychosis be found.
A recent paper in the Lancet examines a new antipsychotic called Pimavanserin, which has been specifically designed to treat PD psychosis. In a comment published alongside the article, Dr. Susan Fox of the University of Toronto summarised that:
In The Lancet, Jeffrey Cummings and colleagues present a randomised, double-blind, placebo-controlled trial showing benefit and safety of the non-dopaminergic drug Pimavanserin for the treatment of psychosis in patients with Parkinson’s disease.
Rather than blocking dopamine receptors, Pimavanserin works as a selective serotonin 5-HT2A inverse agonist. An inverse agonist works by binding to the receptor as an agonist would, but decreases the activity at this receptor, effectively working as an antagonist.
Genetic polymorphisms in the 5-HT2A receptor have been linked with psychosis. Furthermore, the binding of such receptors has been found to increase in PD, particularly in visual regions of the brain, thus thought to underlie the visual hallucinations common in PD psychosis. By decreasing the activity of this receptor, Pimavanserin may therefore help reduce psychotic symptoms.
Methods
The study team screened participants at 52 centres in the USA and two in Canada. The original sample consisted of 199 patients over the age of 40, having had Parkinson’s disease for at least one year, and whose psychotic symptoms began after the onset of PD. Their psychotic symptoms also had to occur on a weekly basis, and be severe enough to warrant treatment with antipsychotics. Participants were randomised into one of two arms:
Placebo
40 mg of Pimavanserin once-daily
The duration of the trial was 6 weeks, with assessments completed at baseline, and days 15, 29, and 43. The primary outcome measure was symptom reduction, using a version of the Schedule for Assessment of Positive Symptoms adapted for Parkinson’s disease (SAPS-PD). Additional outcomes included participants’ caregivers being asked to measure caregiver burden, night-time sleep quality and daytime wakefulness. Finally, masked site investigators evaluated change in clinical global severity (CGI-S) and improvement (CGI-I) at the end point.
A 2-week lead-in of brief psychosocial therapy was also used to elicit a placebo response prior to the study commencing, thus in theory limiting the impact of the placebo effect during the trial.
The analysis was conducted using the mixed model repeated measures method, useful for dealing with participant dropout in longitudinal studies, a potential source of Type I error (false positives).
Results
185 participants were included in the final sample, 95 receiving pimavanserin, 90 receiving placebo
shutterstock_3415435
Patients on Pimavanserin had fewer symptoms, reduced caregiver burden and improvements in sleep and clinical global impression ratings
Mean SAPS-PD scores were lower in the treatment arm, showing a decrease in symptoms of -5·79 compared with -2·73 for those in the placebo group. This equates to a difference of -3·06 (95% CI -4·91 to -1·20; p=0·001), with a standardised effect size (Cohen’s d) of 0.5
Patients in the treatment arm also had significantly greater improvements in both clinical global impression ratings, showed reduced caregiver burden, and improvement in night-time sleep without increasing daytime sedation
Crucially, there was no evidence of motor function impairment relating to the treatment in either group
Conclusions
The authors conclude that:
As a selective 5-HT2A inverse agonist, pimavanserin is to our knowledge the first in a new class of therapeutic agents able to confer antipsychotic benefit in Parkinson’s disease psychosis without unnecessary receptor activity that compromises safety and tolerability.
In the accompanying comment, Dr Fox indicates that Pimavanserin may:
…offer an alternative therapy for patients with Parkinson’s disease psychosis without worsening motor symptoms.
Discussion
The study was well-designed all around. The sample was reasonably large, and the team sampled from a large number of sites across the USA and two in Canada. The groups were well matched for age and gender, and these variables did not have any significant effect on outcome measures. They also employed a novel method of limiting the placebo effect by giving all participants daily psychosocial interaction two weeks before commencing the trial.
The effect size for the primary outcome, 0.5, is considered a “medium” effect size (although this is somewhat arbitrary). The magnitude of such an effect size is typically considered clinically meaningful.
Virtually all participants were on dopaminergic drugs for PD, which the trial did not require a reduction of at study entry. This would indicate that Pimavanserin can be safely taken alongside standard PD medication.
Limitations
The study was funded by ACADIA Pharmaceuticals, the company that manufactures Pimavanserin. Additionally, the author publishing the accompanying commentary had previously consulted for ACADIA. While this naturally raises alarm bells regarding bias, it is commendable that the study was registered with ClinicalTrials.gov before being conducted. Many big Pharma companies have been encouraged to pre-register trials in recent years so as to ensure that all clinical trials are published, even those with null findings (an issue of great importance according to Bad Science writer Ben Goldacre).
Although this is the longest trial of pimavanserin to date (and longer than most PD psychosis RCTs), it is still relatively short (6 weeks). Since psychosis is predictive of nursing home admission in PD, a longer trial would be more useful in capturing this outcome. Longer trials may also help shed light on potential adverse effects of the medication that would not crop-up in a shorter trial (e.g. weight gain).
It was not explained why 40 mg was chosen as the dose of Pimavanserin to be given to all participants in the treatment arm of the trial. It’s worth noting that the small number of previous trials of Pimavanserin in humans scaled dosage up from 20 to 60 mg without adverse effects.
The primary outcome was an overall drop of -3.06 in SAPS-PD scores. The SAPS-PD is a new measure adapted for this population, so it is difficult to know how clinically meaningful the result is. To their credit, the authors did isolate scores for hallucination and delusion items of the SAPS, showing a similar drop of -3.37 (95% CI -5·40 to -1·35, d= 0.50). With each item on a 6-point scale representing the frequency and intensity of a symptom, a 3-point drop seems meaningful, but there is no indication in the article of whether this drop is on one item or spread across several.
No Therapeutic Drug Monitoring (TDM) was reported. TDM measures concentrations of medication in the blood or plasma. Since each individual metabolises medication differently, the desired or adverse effects of a drug will correlate more closely with TDM measures than dosage.
In the accompanying published comment, Dr. Fox points out that overall PD duration was not explicitly stated, although the average disease rating for all participants indicated a mild-to-moderate severity. She also points out that while the adverse infections some participants suffered in the study were unrelated to the treatment, these infections may have been treated with antibiotics, potentially affecting psychosis scores.
What Docs Say
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Christopher Goetz, MD, professor of neurology and pharmacology at Rush University Medical Center in Chicago, “The results are very exciting because this is a major unmet need in Parkinson's disease. ”The combination of effectiveness and safety seen for pimavanserin makes a lot of sense given the selectivity of the drug for the serotonin system, the same system that clozapine works on. The complexity of the system contributed to the long delay in the development of novel serotonergic agents unlike typical antipsychotics, which exert their effects through the relatively simpler dopamine system.
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Daniel Weintraub, MD, associate professor of psychiatry and neurology at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. “Up until now we have had only one medication, clozapine, that we know works, but it is not commonly used, and another that is frequently used, quetiapine, but we don't have scientific evidence that it works.”
“I see pimavanserin becoming the predominant antipsychotic being used in Parkinson's disease, replacing existing agents as a first-line treatment. I see it as having a very significant impact on psychosis in Parkinson's disease.”
http://journals.lww.com/neurotodayonline/Fulltext/2013/12050/Success_for_Pimavanserin_in_Parkinson_s_Disease.1.aspx
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Clive Ballard, MD, Professor of Age Related Diseases at King's College in London
"The -020 Study results presented in The Lancet suggest that pimavanserin has the potential to provide a safe, well-tolerated, and effective alternative to existing antipsychotic drugs. Current atypical antipsychotics are often used off-label to treat PDP despite increasing evidence that they are associated with serious safety issues and are poorly tolerated in this fragile and elderly patient population."
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Jeffrey Cummings, M.D., Sc.D., Director of Cleveland Clinic Lou Ruvo Center for Brain Health
"Among Parkinson's patients, psychosis causes great distress for patients and caregivers and is the leading cause of institutionalization. These data indicate that pimavanserin, a selective 5-HT2A inverse agonist, confers a meaningful clinical benefit in patients with PDP and has the potential to be an important new treatment option for this condition for which there is no approved therapy in the U.S."
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Bryan Roth M.D., Ph.D., Michael Hooker Distinguished Professor of Pharmacology at the University of North Carolina School of Medicine.
"This is a landmark study and will potentially bring a new treatment option to large numbers of individuals with psychotic-spectrum disorders.
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Herbert Meltzer, M.D. Brain & Behavior Research Foundation Scientific Council Member and NARSAD Distinguished Investigator Grantee, recipient of the Lieber prize for Outstanding Achievement in Schizophrenia Research
“This is the first major novel advancement in the treatment of psychosis in the last 25 years and can be expected to have a big impact shortly in the treatment of all types of psychosis, especially schizophrenia and psychotic mood disorders,” says Dr. Meltzer.
http://bbrfoundation.org/brain-matters-discoveries/fda-expedites-new-psychosis-treatment-developed-by-scientific-council
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Dr. Michael Okun is the co-founder of the University of Florida Center for Movement Disorders and Neurorestoration, the National Medical Director for the National Parkinson Foundation
There has been a critical unmet need for better drugs in order to address hallucinations and psychosis in Parkinson's disease. Typically we choose quetiapine (seroquel) or clozapine (clozaril) instead of the classical dopamine blocking drugs for treatment of psychosis associated with Parkinson's disease. The classical drugs tend to worsen the motor symptoms of Parkinson's disease. Pimavanserin is a new drug that works without blocking the dopamine receptor."
"It is possible that Pimavanserin will be another great alternative for some patients with Parkinson's disease, especially since it does not worsen motor symptoms. One also wonders if in severe cases it could be added on to seroquel or clozaril to improve treatment of difficult to control hallucinations and psychosis."
http://parkinsonsecrets.com/blog/2013/10/26/will-pimavanserin-be-the-next-big-hallucinationpsychosis-drug-in-parkinsons-disease
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Joseph H Friedman MD Movement Disorders Program, Butler Hospital, Alpert Medical School of Brown University, Department of Neurology, Providence, RI
Pimavanserin, a 5HT2A inverse agonist, has no motor side effects, and a remarkable safety profile that is comparable to placebo. Its antipsychotic effects coupled with its lack of motor side effects could make it an ideal drug for treating psychotic symptoms in PD, a major unmet need. One Phase III trial in PDP has demonstrated excellent tolerability and significant benefit. The FDA agreed to the filing of a planned new drug approval (NDA) for an indication in the treatment of PDP. http://informahealthcare.com/doi/abs/10.1517/14656566.2013.819345
3 Case studies
When Should Antipsychotics for the Management of Behavioral and Psychological Symptoms of Dementia be Discontinued?
http://www.annalsoflongtermcare.com/article/antipsychotics-discontinued-management-behavioral-psychological-symptoms-dementia
Posted: 4/15/2014 Volume 22 - Issue 4
Annals of Long-Term Care: Clinical Care and Aging. 2014;22(4):24-29.
Michael Gordon, MD, FRCPC
Affiliations: Palliative Care, Baycrest Geriatric Healthcare System, Toronto, Ontario, Canada; University of Toronto,
Abstract: Dementia in the older population is increasingly common, with many of these individuals requiring care in assisted living facilities or long-term care facilities. Others can be cared for at home with substantial support mechanisms. Regardless of setting, the behavioral and psychological symptoms of dementia often cause significant disruption and discordance between those experiencing the symptoms and their caregivers, other patients and residents, and family members. The use of antipsychotics in such situations and settings is common; however, these medications have many untoward side effects. In this article, the author discusses the possibility of lowering the dose of these medications with an ultimate goal of discontinuation, even in those deemed “stable” recipients of this class of medications.
With the number of elderly persons increasing, including those living with dementia, the challenges of providing optimal care is a great challenge to policymakers and frontline practitioners, as a variety of medical, psychosocial, community-based, and institutional factors need to be carefully considered. This is particularly true when the behavioral and psychological symptoms of dementia (BPSD) manifest, which often leads to the use of antipsychotic medications (also known as neuroleptics) as a means of calming the patient and relieving their agitation and apparent suffering, while ensuring the safety and security of those around them and enabling healthcare professionals to provide proper care. Although these medications are sometimes necessary, clinical evidence and research generally advocates weaning individuals with BPSD off these medications. This article outlines two prototypical case studies that exemplify how discontinuation of these treatments can be beneficial in some cases, as well as a third case that shows the need to continue the medication in others. Following these cases, the use of antipsychotic medications for BPSD is reviewed, including the benefits and drawbacks of using these agents and factors that healthcare providers need to carefully consider.
Case 1: Successful Weaning Off an Atypical Antipsychotic
JS is an 87-year-old man with a 3-year history of gradual but progressive cognitive decline. He initially responded well to donepezil and a supportive home environment, where a devoted wife cared for him; however, she refused to accept external help to share the challenge of his care and gradually became overwhelmed by the “36-hour–like” day. This prompted her to explore the possibility of enrolling him in social programs run by a nearby seniors agency for those with dementia, but he expressed reluctance and she decided that she did not want to “move him” around from day to day. As JS’s word-finding became an issue and his speech became hesitant, he proceeded to become periodically agitated. Subsequently, his primary care physician prescribed small doses of risperidone, which led to less frequent outbursts.
With the support of her children and a social worker from a geriatric center, JS’s wife hesitantly agreed to employing a personal support worker (PSW) for 4 hours a day to help with his personal care and to enable her to “get out of the house” for a few hours and to run errands. She also agreed to enroll him once a week at the seniors’ program she had previously investigated to see if it would be appealing to him and give him “something to do” other than being home alone with her and the PSW. He seemed to enjoy the program, and the staff noted that he began to participate in some of the activities and to engage others in conversation, which was something he had not done for quite a while as his cognitive impairment progressed. In addition, many in the program recognized him, as he had been in business for many years in the neighborhood, and this recognition became a source of enjoyment for him.
On a follow-up clinic visit, it was apparent that he was somewhat stooped over when he walked. There was also less spontaneous facial expression and evidence of bilateral cogwheel rigidity, but his gait was still reasonable despite his turning being slow. A review of previous physical examinations did not show evidence of parkinsonism. His wife was somewhat concerned about his “slowing up,” but she was relieved by the improvement in his behavior, which she attributed to both the risperidone and the full-time PSW.
After a discussion that involved weighing the potential risks and benefits of decreasing the risperidone and perhaps discontinuing it altogether, she decided to proceed with gradually decreasing the dose and monitoring his gait, mobility, and the fluidity of his movements against his behavior. Over a 2-month period, JS was gradually weaned off the medication with no recurrence of his behavioral outbursts and an improvement in his flow of speech, gait, posture, and facial mobility.
Case 2: Successful Weaning Off a Conventional Antipsychotic
ND is a 91-year-old man who was admitted to a nursing home from his home, where his wife had cared for him with the assistance of a full-time PSW. When she died, ND’s children decided to keep him at home, but he became increasingly withdrawn and noncommunicative. A month after his wife’s death, ND was admitted to a general hospital because of an infection, which turned out to be from his urinary tract. While hospitalized, he became highly confused and agitated. He was treated with haloperidol parentally and then put on oral doses of the same medication, which seemed to calm him down. His infection responded to antibiotic treatment and he was discharged to home with medications to address his prostatic hypertrophy and incomplete bladder emptying.
He appeared comfortable at home, but his children noted that he was far less communicative than before his hospitalization. Despite having received a dementia diagnosis several years earlier, his level of function and communication had been such that he could perform his basic activities of daily living with minimal help. Although his speech was often repetitive, he was able to recount important stories of his life, especially to his youngest daughter; thus, she became particularly upset by his loss of communicative skills and lack of social engagement following his acute hospitalization for the infection.
After he was settled in the nursing home, she brought up her concerns about the changes that occurred, especially his loss of interactive and communication skills and interests, which were the symptoms that precipitated the decision to admit him to the nursing home. This decision was made partially for care and partially to ensure he was in a safe environment that provided a range of social and stimulating activities. She was disappointed that her father did not seem to be particularly engaged or interested in the recreational activities available. When she spoke to the physician about her concerns, the possibility of depression was discussed, with the potential to add antidepressants to his medication regimen, which still included the haloperidol prescribed more than a year earlier during his acute care hospitalization.
Instead, a geriatric consultation was sought. After the evaluation, rather than introducing another psychoactive drug, the decision was made to gradually decrease the dose of haloperidol, with a goal of discontinuing it altogether if feasible. Over a 2-month period, the medication dosage was decreased in small increments weekly until the dose was so low that it was discontinued. This process resulted in improvement in the patient’s affect and engagement levels. Antidepressants were not added to his regimen. After 3 months, the patient was more animated and the daughter told the geriatrician during a follow-up meeting, “You gave me my father back.”
Case 3: Unsuccessful Weaning Off an Atypical Antipsychotic
EL is an 87-year-old woman who was being followed in a geriatric medicine clinic for 1 year. She had a diagnosis of schizophrenia, although the details of her earlier mental status were not clear from her family. For the previous 9 years, she had evidence of moderate dementia with increasing BPSD. She was receiving donepezil for her cognition issues, which the family felt had benefitted her and initially helped with her BPSD; however, she had been titrated to quetiapine to better control the BPSD, with the most recent maintenance dose being 50 mg at bedtime and 37.5 mg in the morning. She seemed to tolerate this regimen well and was reasonably stable, but was occasionally drowsy during the day.
After a geriatrician consulted with the family, the decision was made to lower the dose of quetiapine, with a goal of weaning the patient off it completely. This recommendation was made to the primary care physician, who began to gradually decrease the medication. For the first 3 weeks during the process, there were no discernible problems. Thereafter, EL became somewhat agitated, but the physician continued to decrease the dose based on the assumption that she would eventually manage without the medication. By the time she had a follow-up appointment at the geriatric clinic, which occurred 3 months after the dose was discontinued altogether, the family reported that she was severely agitated and began to experience hallucinations, which had not occurred while she was on the neuroleptic medication.
Attempts were made to calm EL down by reintroducing the quetiapine, gradually increasing the doses, and adding trazodone to help with her sleep. Because the family became unable to carry on with home care due to her BPSD, she was admitted to the geriatric psychiatry unit. After 2 months of readjusting her psychoactive medications, her BPSD gradually became adequately controlled, enabling her to be discharged to home on a slightly higher dose of the neuroleptic than she had received prior to the attempt at discontinuation.
Discussion
Any practitioner who cares for geriatric patients, particularly those living with dementia, has to grapple with the use of antipsychotics for managing behavioral issues, regardless of whether the patient is in the community, an acute care setting, or in long-term care (LTC). There are two classes of antipsychotics that can be used: conventional antipsychotics (also known as typical antipsychotics), which are first-generation agents that were first developed in the 1950s to treat psychosis; and atypical antipsychotics, which are second-generation agents that emerged in the 1980s.1 Both types have similar mechanisms of action and block receptors in the brain’s dopamine pathways. For many years, atypical antipsychotics were thought to be safer and cause fewer extrapyramidal neurological effects; however, as their use has increased, more side effects have been observed, leading some to question whether there should be a distinction between these first- and second-generation agents.1 Regardless, none of these agents has been approved by the US Food and Drug Administration (FDA) to manage BPSD, and they are prescribed off-label for this purpose.
When antipsychotics are prescribed, it is typically to prevent the patient from inflicting self-harm and/or harm to others, while enabling healthcare professionals and caretakers to provide necessary care. In addition to the scenarios described by the aforementioned cases, a variety of other factors can trigger behavioral problems in older people with a known underlying cognitive impairment and necessitate the use of antipsychotics. These factors include infections, surgery, changes in medication, and any other acute medical insult, as these can also lead to delirium, which may not always be readily identified.2 In such cases, if the patient’s condition responds to these agents, they may be continued whether the patient moves into an LTC facility or returns to the community with personal care support. Yet as case 1 and case 2 demonstrate, slowly weaning patients off these medications may be beneficial, and there has been a push by various regulatory and authoritative bodies to limit antipsychotic prescribing for BPSD.
Major Measures to Decrease Antipsychotic Prescribing in Long-Term Care
There has been a shift away from the use of antipsychotics in the treatment of BPSD, especially in the LTC setting. In the United States, the Omnibus Budget Reconciliation Act of 1987 (OBRA), which limited the use of psychotropic medications in LTC residents, appears to have achieved much of its desired effects. Although updates of OBRA guidelines have liberalized some dosing restrictions, the 2007 iteration required gradual dose reductions of all antipsychotics in nursing home residents, with staff having to document at least two attempts to reduce these medications during the first year of treatment for newly admitted residents and for established residents initiated on these medications.3 In addition, if the drug is continued beyond the first year, gradual dose reductions must be attempted at least once annually unless contraindicated (eg, target symptoms worsened during most recent attempt at dose reduction).3
Other jurisdictions have used different methods to regulate antipsychotic medication use. For example, in the province of Ontario, Canada, the Coroners’ Committee on Geriatrics and Long-Term Care provides recommendations aimed at reducing harm and unnecessary deaths among elderly patients receiving healthcare services.4-6 A recent report of that committee recommended the following when addressing the issue of dementia and behavior: (1) Allied healthcare staff and physicians in LTC facilities should be provided with education on pharmacologic and nonpharmacologic management of BPSD; (2) Ministry of Health and LTC funding should be made available to LTC facilities to assist with the nonpharmacologic management of challenging behaviors, particularly after a resident’s admission to a new environment; and (3) All LTC facilities should have immediate access to outreach teams to assist with the management of BPSD or specialized behavior units to accept residents in transfer for more in-depth assessment and treatment.6
In 2008, the FDA required manufacturers to add a Boxed Warning to conventional antipsychotic drugs to warn about an increased risk of death associated with the off-label use of these agents to treat behavioral problems in older people with dementia.7 Previously, in 2005, the FDA required a similar Boxed Warning to be added to atypical antipsychotic drugs. Both warnings indicate that clinical studies have shown antipsychotic drugs to be associated with an increased risk of death when used in elderly patients treated for dementia-related psychosis.7 In fact, when the FDA decided to include the warning on atypical antipsychotic drugs, it reported that studies demonstrated a 1.6- to 1.7-fold increase in mortality with use of antipsychotics compared with placebo.8 The Table outlines the conventional and atypical agents included in the FDA’s action.
Antipsychotics, behavioral and psychological symptoms of dementia, BPSD, neuroleptics
In 2012, the American Geriatrics Society (AGS) published its Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults.9 These guidelines, which were developed by an interdisciplinary expert panel that reviewed the literature to identify adverse drug reactions (ADRs) in older patients, advise against the use of antipsychotic medications to treat BPSD, noting that they can cause adverse central nervous system effects and increase the risk of stroke and mortality in these patients. Therefore, per the guidelines, they should be avoided unless nonpharmacological options have failed and the patient is a threat to himself/herself or others. This recommendation was based on high-quality evidence and is categorized as strong.9
The Centers for Medicare & Medicaid Services (CMS) also launched an initiative in 2012 to curtail the use of antipsychotics to manage BPSD in US nursing home residents.10 This initiative set a national goal to reduce off-label antipsychotic use by 15% by December 31, 2012. As part of the initiative, CMS developed a multidimensional action plan that focused on public reporting, public awareness, regulatory oversight, technical assistance/training, and research. One training tool it developed specifically for nursing homes is its “Hand in Hand” program, which teaches staff how to employ nonpharmacological alternatives in caring for patients with BPSD.
Perceptions of Antipsychotic Use in Long-Term Care
With the preponderance of data recommending against the use of antipsychotics for BPSD and numerous warnings of their ADRs, there is a tendency for these agents to be viewed negatively. Yet they can be beneficial in some patients, as shown by the case 3 patient, who experienced negative effects when these agents were discontinued, which led to the inability of her family to continue to care for her in the community. After the antipsychotic was reinstated, she was able to return home to her family, improving her quality of life. Even the AGS’s Beers criteria, which recommend against using these agents, acknowledge they may be necessary if the BPSD has become so severe that the patient poses a safety risk to himself/herself or to others.9 This stance is in agreement with numerous published reports that note that these agents may be deemed clinically necessary during states of acute delirium or when behavioral manifestations of dementia become severe.11-15 Therefore, the motivation to use such drugs or continue them is not always sinister.
Nevertheless, a message that often resurfaces in the popular press, which is reflective of contemporary medical reporting, is the notion that even when the initial indications for the use of antipsychotics have been reasonable and correct, a bad outcome necessitates extreme measures, from establishing special medication units for those with risky behaviors to eliminating psychoactive medications from the LTC landscape altogether. During such events, unhappy family members, the media, and certain healthcare professionals who oppose the use of these medications may imply that the antipsychotic was used simply as a “medical restraint” to reduce the staff’s workload. In some situations, healthcare professionals who have never worked in LTC facilities are asked to comment on these cases, and these individuals rely on the literature to support their antineuroleptic positions. In contrast, most physicians experienced in geriatric care understand that although these medications may be characterized as “medication restraints,” this characterization does not paint a fair and complete picture of the role of these agents.
Another factor that often leads to medications being denigrated is off-label status, as is the case when using antipsychotics for BPSD; however, it is important to consider what “off-label” really means. For many medications, the trials that enabled them to be approved focused on one particular condition; however, over time, clinical assessments and scholarly papers outlining successful clinical experiences with these agents for other conditions have led their use to be expanded by the medical community, despite these indications not being included in the drugs’ official prescribing information.16 It is essential for healthcare providers to remember that many medications are used successfully for indications that have not been specifically approved by the FDA. For example, angiotensin-converting enzyme inhibitors are now often used in patients with diabetes to decrease their risk of renal disease, which is in keeping with the medical research literature, despite the absence of a specific formal FDA indication for that use.16-18
On the other hand, when some healthcare providers who prescribe antipsychotics for BPSD witness an amelioration of frightening and disruptive neuropsychological behaviors upon administering these agents, they may be reluctant to wean these patients off these medications. Yet as case 1 and case 2 show, these agents may only be needed temporarily in some patients, and slowly discontinuing these treatments may improve these individuals’ quality of life.
Principles of Instituting and Tapering Antipsychotics
Putting aside the off-label designation and the literature that shows antipsychotics to have negative effects, there is also literature to support the use of these agents in the care of some older patients when their agitation or aggression is due primarily to their dementia, rather than to another confounding factor, such as uncontrolled pain.12-15 In such situations, a trial of a neuroleptic within a process of titration to match the clinically positive benefits versus the negative aspects of their use is not unreasonable; if fact, in some situations this is absolutely necessary to avoid serious self-harm or harm to others. The key to this process is the acknowledgement of a parallel plan that undertakes the gradual decrease in dosage after some degree of stability is achieved for a reasonable period of time.12-15 Until the literature better defines this period, 3 to 6 months may be reasonable to start with. During this time, the patient should be carefully evaluated for clinical stability and evidence of any untoward side effects, such as gait issues, somnolence, and parkinsonian symptoms.
With this process, it is hoped that any factors that induced or perpetuated the agitation or aggressive behavior will also have been addressed and resolved, such that the environment is as suitable and conducive as possible for a trial of decreasing the dosage. If the gradual decrease in dosage proves successful, a further trial of discontinuation is warranted, during which careful monitoring of the clinical and behavioral situation is undertaken using reports from medicine, nursing, social work, recreational therapy, and the family, particularly if the person is in an LTC or assisted living environment.
There are no hard and fast rules regarding the tapering process; however, because antipsychotics are often substantially fat-soluble, they are stored in the body, and any changes in dose will take time before the actual blood and tissue levels reach a new equilibrium. Subsequently, it takes time to observe a therapeutic impact. Although geriatric medicine generally recommends a prescribing approach that starts low and goes slow, this should be implemented in reverse with regard to antipsychotics: go slow as you start to go low. For example, the dose could be decreased by one-quarter per week, with the goal of weaning the patient off the drug in 4 to 6 weeks. Such a slow titration enables the healthcare provider and caregivers to observe how the change in dose is affecting the patient. If untoward effects are observed, there is a chance to push the dose back up from a reasonable level, rather than having to titrate upwards all over again, as occurred with the patient in case 3.
Optimizing Outcomes With Nonmedication Interventions
To ensure the safety and optimal function of patients with BPSD, as well as to protect those around them, it is often clinically crucial to use behavioral and environmental interventions in addition to medication interventions. Over the years, many nonmedication interventions have been found to be beneficial in defusing behavioral manifestations of dementia, including a variety of sensory interventions (eg, aromatherapy, thermal bath, calming music, massage) and pet therapy.19-25 In addition to curtailing disruptive behaviors, these interventions may also improve the quality of life of those affected. For example, a study that examined animal-assisted therapy for nursing home residents with BPSD found that this intervention also increased the residents’ level of social interaction.26
Some researchers have suggested that pain management may be effective in many individuals with dementia who are agitated by pain that is not readily identified because of an inability of this population to identify their symptoms accurately.27 It is important for healthcare providers to remember that pain management starts with nonpharmacological approaches, including ensuring comfortable positioning and a peaceful environment while addressing lifestyle factors, such as sleep, diet, exercise, and social activities. In addition, many of the nonmedication interventions for BPSD may prove beneficial in pain reduction. When nonpharmacological approaches fail, analgesics can be considered.
Regardless of the methods used, the interprofessional healthcare team needs to be involved, and the entire team should be included in any education initiatives. These steps are important so that it is not only the physician who determines what methodologies may best suit the needs of the patient, the patient’s family, and those responsible for frontline care, as everyone in the team may have important insights to contribute.19-25
Conclusion
The use of antipsychotics for the treatment and amelioration of BPSD is common practice across a wide range of care environments. The medications may be beneficial in achieving the goals of calming the person living with dementia’s disruptive and often disturbing symptoms. With the acknowledgment of the potentially negative short- and long-term adverse effects of this class of medications, it is often worthwhile to undertake a trial of decreasing the dosage, with a goal of discontinuing it altogether if the results are positive. During this process, carefully monitoring patient outcomes is essential. If the patient’s agitation or aggression increases during or after the weaning process, the antipsychotic may need to be reinstituted.
We have a problem; we need to deal with it."
Use of antipsychotics soaring at Ontario nursing homes
http://www.thestar.com/news/canada/2014/04/15/use_of_antipsychotics_soaring_at_ontario_nursing_homes.html
Powerful, potentially lethal drugs are used off-label to control behaviour among dementia patients at alarming rates in some homes
Napodano
Acadia Remains On Track With Pimavanserin Program
http://seekingalpha.com/article/2198223-acadia-remains-on-track-with-pimavanserin-program
May. 7, 2014
Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. (More...)
Summary
NDA for pimavanserin in PDP expected to be filed late 2014. This would put a PDUFA late 2015.
Phase 2 program in ADP, a significant value-driver in our opinion, continues on plan, with data expected late 2015.
Our DCF model pegs fair-value between $25-30 per share, making the stock attractive for long-term investors at today's price of $17.
On May 6, 2014, Acadia Pharmaceuticals (ACAD) reported financial results for the first quarter 2014. Revenues in the first quarter totaled $30,000 compared to $417,000 for the first quarter of 2013, with the decrease primarily due to the conclusion of Acadia's 2003 research collaboration with Allergan, Inc. (AGN) in March 2013.
Net loss for the quarter totaled $17.8 million, or $0.19 per share, compared to a net loss of $6.1 million, or $0.08 per share, in the first quarter of 2013. The net loss included $3.2 million in non-cash, stock-based compensation expense. R&D expenses increased to $11.7 million compared to $4.4 million in the first quarter of 2013, with the increase being driving by the pimavanserin Phase 3 program expenses as well as by increased personnel and stock-based compensation expenses. SG&A expenses increased to $6.3 million in the first quarter of 2014, compared to $2.2 million in the first quarter of 2013. The increase was mainly driven by increased stock-based compensation costs, personnel costs, and professional fees, including costs related to pre-commercial activities.
Acadia exited the first quarter with approximately $369.3 million in cash, cash equivalents, and short-term investments. The cash position was strengthened by a $198 million equity raise in March 2014. For 2014, management now anticipates having greater than $300 million in cash, cash equivalents and short-term investments at the end of the year. We forecast that this will be enough cash to fund the company into 2017.
Clinical and Regulatory Update
There were a number of updates provided during the first quarter conference call, which we summarize below:
Acadia continues to make steady progress in the Parkinson's Disease Psychosis (PDP) development program, including stability testing of pimavanserin registration batches and supportive studies, which include standard drug-drug interaction studies. During the first quarter, the company completed an assessment of the initial three months of stability data from the pimavanserin registration lots and confirmed that the data are consistent with historical data observed with the clinical trial formulations. The company continues to accumulate data in the registration stability program and expects to have six month stability data available during the second quarter of 2014. We believe twelve month data will be required during the FDA's review of the NDA.
There was substantial progress made with supportive studies that include customary short duration drug-drug interaction (DDR) studies. This is important because patients with PDP are frequently on a number of concomitant medications. The company is now in the process of finalizing the planned DDR program, and thus far the safety profile of pimavanserin appears consistent with what has been observed in the long-term PDP safety extension studies.
The Phase 3 PDP open label safety extension trial (015 Study) is designed to continue until pimavanserin is commercially available. This study has provided the company with a large amount of valuable, long-term safety data regarding the use of pimavanserin in PDP patients. The company has already far exceeded the ICH guidelines for required one year exposures with well over 250 patients having been treated for one year or longer, over 100 patients having been treated for at least two years, and the longest patient exposure exceeds eight years.
Management continues to indicate that they remain on track for a planned NDA submission near the end of 2014. In support of this, pre-NDA meetings with the FDA will commence in the second quarter of 2014, which will allow Acadia to outline the NDA submission and its organization.
In regards to registration in the EU, there has been an initial series of interactions with the regulatory agencies from several EU member states. The company characterized these initial interactions as very informative, with the 020 Study being seen as a strong study with the medial needs of patients with PDP being appreciated in the EU. These meetings will continue so as to clarify the pathway for registration in the EU. Ultimately, we believe Acadia will seek to partner pimavanserin for commercial launch in Europe, but at this time a partnership seems unlikely prior to finalizing plans for the MAA.
The Phase 2 clinical trial of pimavanserin in ADP, Study-019, is currently underway and will follow a similar design of the successful Phase 3 trial in PDP in incorporating a screening period with brief psychosocial therapy and a limited number of trained raters. Study-019 is a randomized double-blind, placebo-controlled study seeking to enroll about 200 patients. The study will be conducted through a network of research care facilities established as part of the Biomedical Research Centre for Mental Health at King's College, London. This institution incorporates a geographically focused network of nursing care homes that will facilitate the use of a limited number of raters. As in the PDP trial, this is expected to limit statistical "noise" in the efficacy analysis. Patients will be randomized 1:1 between pimavanserin and placebo, treated for 12 weeks, with the primary efficacy endpoint being the change from baseline to Week 6. Endpoints will include the neuropsychiatric inventory and the nursing home (NPINH) scale with measurements of psychosis, aggression, agitation, sleep, nighttime behavior, and other exploratory endpoints. We believe this study will report out in late 2015.
In addition to ADP, the company is planning a number of new studies to examine additional indications for pimavanserin. One particular area of interest to the company is sleep disturbance, which is a frequent problem to patients with neurological disorders including both PDP and ADP. The company has observed long sedating sleep related benefits of pimavanserin including in the 020 Study, where pimavanserin demonstrated significant improvement in nighttime sleep, with the improvement not accompanied by any sedation effects. In addition, pimavanserin produced a significant improvement in daytime wakefulness in PDP patients, with patients having severe nighttime disturbances benefiting the most from pimavanserin therapy. Interestingly, the positive effects of pimavanserin nighttime sleep and daytime wakefulness did not tolerate the psychosis measures, indicating that sleep and wakefulness may represent independent treatment benefits of pimavanserin use. The company indicated that additional studies in sleep disturbances may allow for further characterization and highlight the potentially important clinical benefits associated with pimavanserin use.
Another area of focus for broadening the pimavanserin clinical program is schizophrenia. The company believes that pimavanserin's selective mechanism of action and attractive clinical profile may enable it to be used in multiple ways to improve the therapy for patients with schizophrenia. First, pimavanserin may be used as a co-therapy together with low doses of existing atypical antipsychotic drugs to enhance the clinical profile. Secondly, pimavanserin may be used as a monotherapy in the maintenance phase of schizophrenia treatment, as the selective action of the drug may allow for effective symptom control while avoiding interactions with dopamine and other receptors that are linked to many of the side effects caused by existing antipsychotics. The company's commercial assessment has reinforced the idea that schizophrenia treatment represents a sizable commercial opportunity and study designs in the schizophrenia program are currently on-going with the company set to share further details on this program later in the year. Our enthusiasm for the use of pimavanserin in schizophrenia is low due to the significant number of generic typical and atypical molecules on the market. We do not believe combination therapy will be attractive to treating physicians and we do not believe the efficacy of pimavanserin monotherapy is strong enough to drive meaningful use.
The company briefly discussed some of the other programs in the R&D portfolio. Acadia has two clinical stage programs in partnership with Allergan, Inc. in the areas of chronic pain and glaucoma, along with preclinical development of an additional compound as a potential new treatment for glaucoma. The company also has two additional preclinical programs, the ER-beta and Nurr-1 programs, which are being pursued as potential treatments for Parkinson's and other neurological diseases. The ER-beta program is being supported by a grant from the National Institute on Neurological Disorders and Stroke, with preclinical studies in the Nurr-1 program being supported by a grant from the Michael J. Fox Foundation. We assign no value to these programs. Clinical work with Allergan has been stalled for years and we do not include pre-IND candidates in our valuation models.
Conclusion
Pimavanserin is looking like a blockbuster drug for PDP and ADP. We encourage investors to read our article from November 2013 outlining our beliefs as to why we believe this will be the case. However, despite our enthusiasm for the drug, we continue to see limited meaningful new "news" over the next six to nine months to drive the stock price. Our DCF valuation pegs fair-value between $25 and $30 per share, which might be attractive to investors at today's price of only $17. We anticipate the NDA filing late 2014. The expected PDUFA will be 12 months later, or late 2015. We are not anticipating results from the Phase 2 ADP -019 trail until late 2015 as well.
Co-Authored by David Bautz, PhD.
Cocaine
>Pima's 5HT2A antagonistic effect may be useful in treating cocaine addicts.<
Pretreatment with either a 5-HT2C agonist or 5-HT2A antagonist decreases cocaine self-administration
Stephen Kohut1, Jack Bergman1 and Nancy Mello1
1Alcohol and Drug Abuse Research Center McLean Hospital/Harvard Medical School Belmont MA United States
April 2014
The FASEB Journal
vol. 28 no. 1 Supplement 848.9
Abstract
Cocaine’s abuse related effects have been attributed to its interaction with dopamine systems. However, ligands that target the serotonin 5-HT2C and 5-HT2A receptor subtypes have been reported to modulate dopaminergic activity and several of the abuse related effects of cocaine. This suggests that ligands selective for specific serotonin receptor subtypes may be effective anti-cocaine medications. The present study investigated whether pretreatment with a 5-HT2C agonist (Lorcaserin) or a 5-HT2A antagonist (M-100907) could alter cocaine's reinforcing effects in rhesus monkeys. Two groups of male rhesus monkeys (n=4/group) were trained under a fixed ratio 30 (FR30) schedule to respond for food (1 g banana flavored pellets) and cocaine (0.01 mg/kg/inj). Baseline cocaine (0.003-0.1 mg/kg/inj) self-administration followed an inverted-U shaped function with maximal rate of responding at 0.01 mg/kg/inj. Pretreatment with Lorcaserin (0.56 or 1.0 mg/kg, IM) or M-100907 (0.32 or 1.0 mg/kg, IM) reduced rate of responding for doses of cocaine at the peak and on the descending limb of the function. Food-maintained responding was only modestly decreased after pretreatment with either serotonergic compound. These findings suggest that 5-HT2C agonism and/or 5-HT2A antagonism may be novel approaches to the treatment of cocaine addiction
Deutsche Bank
http://www.media-server.com/m/s/zb6fhsuk/lan/en
1) Two FDA meetings scheduled this qtr 1 for CMC stability and the other to discuss aspects of NDA.
2) Uli said they had strong CMC data for 3months, using same manuf used in trials which showed 3 yrs of stability.
3) Sleep trial will be for parkinson's patients with sleep problems- not psychosis
4) PDP seen in 40% of patients frequently 5 yrs after dx and partially due to dopamine agonist drugs.
5) Majority of PDP patients are at home not nursing homes. Keeping them there could be a cost benefit for Pima.
6) Pima will get significant pricing-comparable to current atypicals. Caregiver burden will help pricing in Europe.
7) Will be a advisory panel and it will be before PDUFA date.
8) 1st time I remember hearing infarct dementia as a possible target.
9) Uli thinks the ADP design is "great" and expects a "good outcome" but said it should take 2 yrs for data.
10) NPI-NH used in the ADP trial will also measure irritability, anxiety and sleep besides the psychosis.
JPM says PDP=$1 Billion for ACAD in US Alone
UPDATE: JPMorgan Starts Acadia Pharmaceuticals (ACAD) at Overweight
http://www.streetinsider.com/Hot+New+Coverage/JPMorgan+Starts+Acadia+Pharmaceuticals+(ACAD)+at+Overweight/9488615.html
May 15, 2014
JPMorgan initiated coverage on Acadia Pharmaceuticals (NASDAQ: ACAD) with a Overweight rating and a price target of $33.00.
Analyst Cory Kasimov said, "We are initiating coverage of ACADIA Pharmaceuticals with an Overweight rating based on the potential of pimavanserin in Parkinson’s Disease Psychosis (PDP) and, to a lesser extent, in Alzheimer’s Disease Psychosis (ADP)."
"Psychotic symptoms develop in 20-50% of PD and AD pts, though there are currently no approved therapies to treat them. While antipsychotics are used off-label, they are associated with significant side effects. In contrast, pimavanserin has been shown to be effective in the treatment of PDP with a remarkably clean safety/tolerability profile. In PDP alone, we (conservatively) estimate pimavanserin has peak sales potential of ~$1B in just the US, and ADP represents ~3-4x that opportunity. Thus, with a high probability of success (highly positive Phase 3 data in hand), we believe ACAD’s paucity of 2014 catalysts plus the recent biotech sell-off have combined to create a highly compelling long-term investment opportunity. Our December 2014 price target of $33 reflects 80% probability of success in PDP and 30% in ADP," he added.
Pima's Sleep Maintenance dose could be 5mg
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137254/
Morning administration of pimavanserin resulted in a statistically significant increase of slow wave sleep during the subsequent night in healthy volunteers. This effect was observed after a single administration and was sustained over 13 days with repeated administration. The two highest doses of pimavanserin (5 and 20 mg) had a greater effect on slow wave sleep than the two lowest doses. Doses of 5 mg and 20 mg and associated mean plasma levels ranging from 8.5 to 35.0 ng/mL showed robust and significant increases in parameters directly related to slow wave sleep. Increased plasma levels generally were associated with higher magnitude of effects. These dose dependent observations are consistent with a shift to deeper sleep.
That pimavanserin did not significantly increase total sleep time indicates that the increase in slow wave sleep occurs at the expense of some other sleep stages. Results indicate that the two highest doses of pimavanserin significantly decreased stage 2 sleep and spindle frequency activity, the spectral hallmark of stage 2. All REM sleep parameters were left unchanged by pimavanserin indicating that the drug did not interfere with the REM sleep regulation mechanism. Pimavanserin also did not affect sleep onset latency.
Pimavanserin was administered in the morning due to its relatively long time to peak effect (Tmax) of about 6 hours and a long half-life of about 55 hours30. Furthermore, pimavanserin is safe and well tolerated when administered in the morning as indicated by the safety parameters, including CPT, measured in the present study when plasma levels of pimavanserin were at or near their peak. Moreover, pimavanserin was shown to be safe and well tolerated at single doses up to and including 300 mg and multiple doses up to 100 mg once daily in the morning for 14 days30, much higher doses than those utilized in the present study. A dose of pimavanserin just before bedtime would need to be sufficiently high to produce effective plasma levels within the first hour. For example, a single dose of 20 mg pimavanserin produces a similar plasma level (9.2 ng/mL)30 as 5 mg pimavanserin produces at plasma steady-state (8.5 ng/mL). It is likely that a higher dose would cross the efficacy plasma level threshold earlier, but lower doses may be sufficient to maintain efficacy across days or weeks.
In the normal population, percent of slow wave sleep decreases with age resulting in a greater percent of stage 1 and stage 2 sleep34. Benzodiazepines can cause an increase in stage 2 sleep and a decrease in slow wave sleep35. Non-benzodiazepine receptor agonists and melatonin receptor agonists have no affect on SWS or other aspects of sleep architecture. In contrast, the present results showed that pimavanserin increased slow wave sleep. It has been suggested that an increase in slow wave sleep might be associated with improved sleep quality36. However, the present study with pimavanserin did not measure quality of sleep nor was it statistically powered to be able to measure such a subjective effect.
One limitation of this study was that the effects of pimavanserin were measured in healthy adults. Additional studies evaluating the efficacy of pimavanserin in patients with insomnia are warranted. Such studies should include both objective (PSG) and subjective assessments in order to gain a clear understanding of efficacy for the treatment of sleep maintenance insomnia.
The increases in slow wave sleep induced by pimavanserin were consistent with the increases in slow wave sleep induced by ritanserin15,16,17,18 and eplivanserin25. The results also were consistent with a 5-HT2A receptor mechanism underlying slow wave sleep. Slow wave sleep may act as a useful biomarker for 5-HT2A receptor antagonism or inverse agonism in translational drug development. Additionally, recent review articles support pursuing the role of increased slow wave sleep in the treatment of insomnia37,38.
Another non-benzodiazepine receptor mechanism recently has been identified that also increases slow wave sleep and thus has potential for the treatment of insomnia. Gaboxadol, for example, is an extrasynaptic gamma-aminobutyric acid (GABA) receptor agonist rather than a traditional post-synaptic receptor agonist like the benzodiazepine receptor ligands39. Gaboxadol has been shown to increase total sleep time and decrease the number of awakenings and time spent awake after sleep onset in healthy adults40,41 without affecting next day cognitive performance or mood41. However, the development of gaboxadol has been discontinued. Unlike the selective effect on slow wave sleep that pimavanserin and the 5-HT2A receptor antagonists or inverse agonists have, gaboxadol also decreases the time it takes to fall asleep and/or the perception of shorter sleep latency40,41. Such GABA receptor modulators may therefore need to be administered shortly before bedtime whereas pimavanserin can be administered at any time of day as it is not sedating and does not induce sleep. In the present study, pimavanserin was administered once daily in the morning; significant effects were measured on sleep with no effect on performance either the evening before or the morning after the PSG nights. Chronic morning treatment of a long-lasting, non-sedating drug would be a new approach to the selective treatment of sleep maintenance insomnia. Only one other drug, low-dose doxepin, an antidepressant drug acting primarily as a histamine H1 antagonist at these low doses, has shown efficacy in the treatment of sleep maintenance insomnia.13
Pimavanserin was safe and well-tolerated in healthy adults and showed robust effects on sleep architecture, including increasing slow wave sleep and decreasing awakenings after sleep onset. These data suggest that pimavanserin should be evaluated for the treatment of sleep maintenance insomnia, with the potential to avoid interfering with other aspects of sleep architecture. Despite the limitations of benzodiazepines and agonists at benzodiazepine receptors, these agents remain the most effective and widespread treatments for insomnia. Much more research, including large placebo-controlled randomized clinical trials in patients with insomnia are needed to determine whether pimavanserin demonstrates both objective and subjective improvements in sleep in a patient population. That pimavanserin does not affect sleep latency onset suggests that future trials should target patients with difficulty maintaining sleep rather than patients with difficulty initiating sleep. Further, the dose-response relationships in a patient population need to be determined. Lastly, future research on the implications of a slow onset and long duration of action on the ideal timing of dosing (morning versus evening) need to be conducted.
Neuro Talk
JP Morgan initiates coverage on ACAD with $33 TP after speaking to 5 neurologists about Pima.
Docs we spoke with highlight the need for safer antipsychotics for use in these elderly patient populations. Antipsychotics have black-box warnings against use in elderly dementia patients due to an increased risk of death, though they are widely used off-label. We spoke with 5 neurologists (community and academic), all of whom were impressed with pimavanserin’s clean Phase 3 safety profile. They all indicated they would use pimavanserin in their PDP patients, and likely off-label in other elderly patients with psychosis given the lack of other safe/approved options. http://www.investorvillage.com/smbd.asp?mb=523&mn=833&pt=msg&mid=13849817
------------------------------------------------
Jefferies keeps TP at $38 after talking to 14 neurologists.
Specialists Suggest Pimavanserin Profile Could Expand PDP Treatment. We spoke with 14 specialists on how they treat PD-related psychosis (PDP). All use either Seroquel or clozapine to treat psychosis to varying degrees. However, there were two camps on how early to begin antipsychotic therapy. One camp advocated a more conservative approach to wait until psychosis becomes bothersome. The other camp advocated prescribing antipsychotics early under the assumption that psychosis inevitably worsens. From four different specialists: “often transient psychosis is a prelude to chronic psychosis and those patients get drug,” “not going to wait until it becomes a chronic issue,” “I don’t see psychosis as transient. If it happens as part of the disease state, then it’s chronic,” “the thing about non-troublesome psychosis is that it affects the way you’re treated Parkinson’s disease so I would rather give antipsychotics early.” Physician feedback leads us to believe that the benign safety and proven efficacy profile of pimavanserin may help with conversion to earlier use in the former camp and perhaps more aggressive use overall. For instance, one of the self-described conservative treaters stated that “pimavanserin’s safety does make it more appealing,” and a self-described aggressive treater stated that he would “give pimavanserin even faster because it’s well tolerated.”
http://www.investorvillage.com/smbd.asp?mb=523&mn=853&pt=msg&mid=13913846
-----------------------
Daniel Weintraub, MD, associate professor of psychiatry and neurology at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.
“Up until now we have had only one medication, clozapine, that we know works, but it is not commonly used, and another that is frequently used, quetiapine, but we don't have scientific evidence that it works.”
“I see pimavanserin becoming the predominant antipsychotic being used in Parkinson's disease, replacing existing agents as a first-line treatment. I see it as having a very significant impact on psychosis in Parkinson's disease.”
http://journals.lww.com/neurotodayonline/Fulltext/2013/12050/Success_for_Pimavanserin_in_Parkinson_s_Disease.1.aspx
---------------------------------------------
Herbert Meltzer, M.D. Brain & Behavior Research Foundation Scientific Council Member and NARSAD Distinguished Investigator Grantee, recipient of the Lieber prize for Outstanding Achievement in Schizophrenia Research
“This is the first major novel advancement in the treatment of psychosis in the last 25 years and can be expected to have a big impact shortly in the treatment of all types of psychosis, especially schizophrenia and psychotic mood disorders,” says Dr. Meltzer.
http://bbrfoundation.org/brain-matters-discoveries/fda-expedites-new-psychosis-treatment-developed-by-scientific-council
-------------------------------------------------
Dr. Michael Okun is the co-founder of the University of Florida Center for Movement Disorders and Neurorestoration, the National Medical Director for the National Parkinson Foundation
There has been a critical unmet need for better drugs in order to address hallucinations and psychosis in Parkinson's disease. Typically we choose quetiapine (seroquel) or clozapine (clozaril) instead of the classical dopamine blocking drugs for treatment of psychosis associated with Parkinson's disease. The classical drugs tend to worsen the motor symptoms of Parkinson's disease. Pimavanserin is a new drug that works without blocking the dopamine receptor."
"It is possible that Pimavanserin will be another great alternative for some patients with Parkinson's disease, especially since it does not worsen motor symptoms. One also wonders if in severe cases it could be added on to seroquel or clozaril to improve treatment of difficult to control hallucinations and psychosis."
http://parkinsonsecrets.com/blog/2013/10/26/will-pimavanserin-be-the-next-big-hallucinationpsychosis-drug-in-parkinsons-disease
------------------------
Joseph H Friedman MD Movement Disorders Program, Butler Hospital, Alpert Medical School of Brown University, Department of Neurology, Providence, RI
Pimavanserin, a 5HT2A inverse agonist, has no motor side effects, and a remarkable safety profile that is comparable to placebo. Its antipsychotic effects coupled with its lack of motor side effects could make it an ideal drug for treating psychotic symptoms in PD, a major unmet need. One Phase III trial in PDP has demonstrated excellent tolerability and significant benefit. The FDA agreed to the filing of a planned new drug approval (NDA) for an indication in the treatment of PDP. http://informahealthcare.com/doi/abs/10.1517/14656566.2013.819345
Better with Time
If you go to the link below you'll see the Lancet paper with 6 graphs showing pima's sig stat effect in the P3 PDP trial. Those graphs over 6 weeks show not only that Pima had a good effect but that effect in each test but one appeared to get better over the last 2 weeks. The ongoing ADP trial will have 6 week and 12 week scores so if the improving trend continues then the ADP could show better numbers than the PDP patients. 12 weeks is also the minimum needed to show a difference in cognition scales. I think ACAD hopes to show patients on Pima don't deteriorate as fast as placebos. The current antipsychotics appear to worsen dementia for some of these patients. The only drug class that can slow dementia's progress are the acetylcholinesterase inhibitors like Aricept. They tend to help for about 6 months. But several papers have been published showing that less sleep and more psychosis leads to more dementia. Since Pima improves both I think there is a decent chance Pima could also slow the cognitive loss seen in ADP.
http://digitalreprints.elsevier.com/i/209565/2
(hit graphs to enlarge)
AARP's lawyer "hopefully we can replicate this nationwide"
AARP aligning with geriatric litigants is not something a corporation running a nursing home wants to see. This could force a reduction in blackboxed antipsychotics use in elderly patients.
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http://www.aarp.org/health/drugs-supplements/info-2014/antipsychotics-overprescribed.1.html
Drug Abuse: Antipsychotics in Nursing Homes
These dangerous medications are prescribed at an alarming rate without the patient's consent
by Jan Goodwin, AARP Bulletin, July/ August 2014
Pimavanserin: The Most Underestimated Blockbuster In Biotechnology
http://seekingalpha.com/article/1743612-pimavanserin-the-most-underestimated-blockbuster-in-biotechnology?source=yahoo
Dr Okun on Pima
Dr. Okun is the co-founder of the University of Florida Center for Movement Disorders and Neurorestoration, the National Medical Director for the National Parkinson Foundation, as well as the author of several books including Ask the Expert about Parkinson's Disease, Lessons from the Bedside, and his latest book Parkinson's Treatment: 10 Secrets to a Happier life due out in 2013. His new book will be translated into 20 languages so that it can be made available to Parkinson's disease sufferers around the world. Dr. Okun has been published in journals such as the New England Journal of Medicine and people travel from around the world to seek his opinion on best treatment approaches for this disease.http://parkinsonsecrets.com/blog/2013/10/26/will-pimavanserin-be-the-next-big-hallucinationpsychosis-drug-in-parkinsons-disease
Will Pimavanserin be the next big hallucination/psychosis drug in Parkinson's disease
October 26, 2013
There has been a critical unmet need for better drugs in order to address hallucinations and psychosis in Parkinson's disease. Typically we choose quetiapine (seroquel) or clozapine (clozaril) instead of the classical dopamine blocking drugs for treatment of psychosis associated with Parkinson's disease. The classical drugs tend to worsen the motor symptoms of Parkinson's disease. Pimavanserin is a new drug that works without blocking the dopamine receptor.
Here are the tips about what you need to know about Pimavanserin for treatment of Parkinson's disease related psychosis.
- Though classically we think about the dopamine receptor in Parkinson's disease as underpinning psychosis symptoms, serotonin has also been implicated
- Lysergic acid diethylamide and phencyclidine (PCP) seem to stimulate 5HT2A serotonin type of receptors. Stimulation of these receptors may lead to hallucinations.
- Most available antipsychotic drugs block the 5HT2A receptor and the D2 dopamine receptor
- It is possible that the 5HT2A blocking mechanisms of newer antipsychotics may underpin their benefit with low side effect portfolio
- Pimavanserin is a 5HT2A inverse agonist (binds to the same receptor as an agonist; an agonist would stimulate the receptor, but an inverse agonist would do the opposite and reduce stimulation below basal levels at that particular brain receptor)
- Pimavanserin is not thought to have motor side effects (i.e. tardive dyskinesia, parkinsonism)
- The emerging safety profile has shown it is superior to other available antipsychotics
- There is one Phase III trial that has shown benefit
- The company is planning to pursue FDA approval for Parkinson's disease (it has been previously more used in Schizophrenia)
It is possible that Pimavanserin will be another great alternative for some patients with Parkinson's disease, especially since it does not worsen motor symptoms. One also wonders if in severe cases it could be added on to seroquel or clozaril to improve treatment of difficult to control hallucinations and psychosis
Alzforum on Pima
Parkinson’s Antipsychotic Looks Good in Phase 3 Trial
http://www.alzforum.org/new/detail.asp?id=3635
8 November 2013. More than half of all people with Parkinson’s disease experience some form of psychosis, typically hallucinations or delusions. However, the FDA has approved no drug to treat such symptoms in these patients. Now, results of a Phase 3 clinical trial suggest that might change soon. In the November 1 Lancet, scientists led by Clive Ballard, Kings College London, and Jeffrey Cummings, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, report that pimavanserin, under development by Acadia Pharmaceuticals, San Diego, reduced psychosis in patients with Parkinson’s disease (PD). The drug had few side effects in this six-week trial. Alzforum briefly reported on these results when they were presented at a recent conference (see April 2013 conference story). “If this medication is eventually FDA-approved, it almost certainly will be the first-line drug for treatment of psychosis in PD,” said William Ondo, University of Texas, Houston.
Researchers have tested antipsychotic drugs approved for psychiatric disorders for their ability to control PD psychosis, with mixed success. Quetiapine, approved to treat symptoms of schizophrenia, seemed effective against PD psychosis in a small trial (see Fernandez et al., 2009), but failed in four larger ones (see for example, Shotbolt et al., 2009). Clozapine seems effective (see Pollak et al., 2004), but causes a host of side effects, including low white blood cell count; physicians rarely prescribe it. Neither drug has the right mix of safety and efficacy necessary to gain FDA approval for PD psychosis. Other antipsychotics can worsen the motor symptoms of PD because they block dopamine receptors. Clozapine and quetiapine have a weaker affinity for those receptors, antagonizing serotonergic receptors mostly, while quetiapine also hits adrenergic receptors.
Enter pimavanserin, a serotonin inverse agonist. It elicits the opposite response of serotonin by blocking the intrinsic basal activity of 5-HT2A receptors, which are associated with PD psychosis (see Ballanger et al., 2010). Pimavanserin leaves dopaminergic, adrenergic, muscarinic, and histaminergic receptors untouched. A previous Phase 3 trial had hinted at the drug’s efficacy, but unusually big improvements in the placebo group may have masked a more significant benefit. This second trial aimed to minimize placebo effects and reevaluate the safety and efficacy of pimavanserin.
From centers in the United States and Canada, the scientists recruited 199 people, 40 and older, who had a diagnosis of PD psychosis. To limit placebo effects, the scientists first gave patients two weeks of non-pharmacological psychosocial therapy. Anyone who improved to a predetermined score on the Parkinson’s disease-adapted scale for assessment of positive symptoms (SAPS-PD)—a test of hallucinations, delusions, and agitation—was excluded from the rest of the trial. Ninety-five of the remaining patients received pimavanserin, while 90 took placebo pills for six weeks.
Overall, pimavanserin alleviated psychotic symptoms in patients without worsening motor symptoms. Treated patients improved 37 percent on the SAPS-PD, compared with a 14 percent bump for those on placebo. The former also reported sleeping better at night and remaining more alert during the day, while caregivers reported being burdened less. Scores of motor performance showed no decline, even trending toward a slight improvement. That three different types of blinded observers—central raters who scored videos of the SAPS-PD tests, local site investigators who administered global assessments, and caregivers who completed a standard caregiver assessment form—all saw significant improvements, suggesting pimavanserin’s effect is robust, remarked Cummings.
One red flag was that 10 patients in the treatment group left the study, versus two in the placebo group. A high dropout rate is typical in this type of patient population, yet Cummings acknowledged that the higher rate in the treated group likely reflects side effects for which clinicians should be alert. They include peripheral edema (typically excess fluid in the legs) and confusion. Two deaths occurred in the drug group and one in the placebo cohort, though the authors claim that none appeared to be caused by pimavanserin.
Of the choices for the treatment of PD psychosis, how does pimavanserin measure up? It is hard to say, because no study has compared them head-to-head, said commentators. Joseph Friedman, Butler Hospital, Brown University, Providence, Rhode Island, guessed that pimavanserin falls somewhere between quetiapine and clozapine in terms of effectiveness, and would be better tolerated than any other antipsychotic. Ondo pointed out that pimavanserin led to improvements on secondary endpoints as well. “That’s fairly impressive because it points to global improvement in patients taking this drug,” he said. In an accompanying editorial, Susan Fox of Toronto Western Hospital, in Ontario, Canada, cautioned that the trial was brief. Psychosis itself fluctuates over short periods, which could explain these short-term benefits, she wrote.
The authors acknowledged that they cannot make inferences about long-term treatment based on this trial. Many of its participants continue to take pimavanserin on an “open-label” basis. Based on unpublished data, these patients have thus far tolerated pimavanserin over several years with lasting benefits, wrote the authors.
Cummings noted that the FDA has indicated that no further trials need to be completed, so he thinks approval seems likely. “This would be a huge step for the field, because so few drugs have been shown in rigorous clinical trials to treat behavioral changes in neurological disorders,” Cummings said. He anticipates that researchers will next explore pimavanserin’s ability to treat psychotic symptoms in other neurodegenerative diseases, such as Alzheimer’s and dementia with Lewy bodies. In these diseases, antipsychotic drugs are widely used, particularly in nursing homes, but they have come under fire for their safety record (see Oct 2005 news story and Jan 2009 news story).—Gwyneth Dickey Zakaib
Excellent tolerability and significant benefit"
Pimavanserin for the treatment of Parkinson's disease psychosis
October 2013, Vol. 14, No. 14 , Pages 1969-1975 (doi:10.1517/14656566.2013.819345)
http://informahealthcare.com/doi/abs/10.1517/14656566.2013.819345
Joseph H Friedman 1,2 MD
1 Movement Disorders Program, Butler Hospital, 345 Blackstone Blvd, Providence, RI 02906, USA
2 Alpert Medical School of Brown University, Department of Neurology, Providence, RI 02906, USA +1 401 455 6669;
Introduction: Parkinson's disease (PD) is a neurobehavioral disorder defined by its motor features. Its treatment is frequently complicated by the presence of psychotic symptoms, most prominently hallucinations and delusions. These cause major distress and are the primary cause for nursing home placement. Current treatment requires either a reduction in medications for mobility or the addition of atypical antipsychotics, none of which are approved in the United States, and which are associated with major potential drawbacks.
Areas covered: Information from extensive personal experience, a Pubmed literature search plus a direct request to Acadia Pharmaceuticals was used for this review. A brief review of the clinical problem and its current state of treatment will be followed by a discussion of pimavanserin and its potential role in treating PD psychosis (PDP). Several observations have implicated serotonin in the physiology of psychotic symptoms. Lysergic acid diethylamide, phencyclidine, and similar drugs that activate 5HT2A serotonin receptors produce psychotic syndromes, and almost all antipsychotic neuroleptics share the property of blocking the 5HT2A receptor as well as the dopamine D2 receptor. The reduced motor side effects of the second-generation antipsychotics have been ascribed to these drugs having greater 5HT2A antagonism than the first generation. Studies in animal models of psychosis have suggested benefits from drugs blocking the 5HT2A receptor alone without the motor side effects seen with D2 receptor antagonism.
Expert opinion: Pimavanserin, a 5HT2A inverse agonist, has no motor side effects, and a remarkable safety profile that is comparable to placebo. Its antipsychotic effects coupled with its lack of motor side effects could make it an ideal drug for treating psychotic symptoms in PD, a major unmet need. One Phase III trial in PDP has demonstrated excellent tolerability and significant benefit. The FDA agreed to the filing of a planned new drug approval (NDA) for an indication in the treatment of PDP.
Dr. Meltzer was on to something good"
http://www.wardrounds.northwestern.edu/summer-fall-2013/features/fast-forward-drug-approval/
Written by
Cheryl SooHoo
Northwestern University Feinberg School of Medicine
Summer/Fall 2013
Fast Forward to Drug Approval
Rare FDA Decision Expedites New Drug Developed By Northwestern Neuropharmacologist
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Psychiatrist Herb Meltzer sadly watched the agitated woman accuse her son of trying to poison her. Although not her physician, Dr. Meltzer certainly recognized the devastating effects of his mother-in-law’s Parkinson’s disease psychosis (PDP). Occurring in up to half of all patients with Parkinson’s, symptoms of the psychotic disorder may include hallucinations and delusions. The development of PDP often leads to institutionalization and increased mortality.
“I was on the sidelines,” explains Dr. Meltzer, professor of psychiatry and physiology and director of the Translational Neuropharmacology Program at Northwestern University Feinberg School of Medicine. “I told my brother-in-law it was the disease talking, not his mother.”
Ironically, Dr. Meltzer has been far from the sidelines and right on the PDP playing field for quite a while. In fact, he may soon see a drug he helped develop become the first approved treatment for the disorder. In early April, Dr. Meltzer celebrated, along with colleagues at ACADIA Pharmaceuticals in San Diego for which he has been a clinical advisor, the stunning announcement: the Food and Drug Administration (FDA) had expedited the company’s path to filing a new drug application (NDA) for pimavanserin, a selective serotonin (5-HT)2A receptor blocker. Typically, the FDA requires data from two successful pivotal Phase III clinical studies affirming a drug candidate’s safety and efficacy before the agency will even consider an NDA. Just as ACADIA was planning to launch another Phase III study this spring to fulfill this requirement, the FDA decided the company had amassed enough data to support an NDA filing.
“This action on the part of the FDA is extremely unusual,” says Dr. Meltzer, who designed ACADIA’s initial “proof-of-concept” trial of pimavanserin, a drug he had initially suggested ACADIA develop to treat schizophrenia, with PDP as a secondary indication. “The FDA staff decided that results from my small clinical study and the first successful Phase III study were sufficient to establish efficacy and safety.”
Bringing a safe and effective drug to market is a monumental achievement. Pimavanserin is not yet there but has significantly moved within striking distance with this recent nod from the regulatory agency.
24 YEARS IN THE MAKING
Dr. Meltzer’s collaboration with ACADIA began in 2000. The company wanted to develop a drug targeting the serotonin 5-HT 2A receptor, a neurotransmitter ACADIA believed played a key role in schizophrenia based upon basic research from Dr. Meltzer and their own studies. A distinguished schizophrenia investigator, then at Case Western Reserve University, Dr. Meltzer welcomed ACADIA’s offer to translate his ideas about developing safer and more effective drug treatments for psychosis. Through his provocative and groundbreaking research, Dr. Meltzer originally championed the idea that blocking the 5-HT2A receptor would lead to better antipsychotic drugs with fewer side effects. Existing drugs often impaired motor function because they targeted the dopamine D2 receptor. Of the 14 different types of serotonin receptors in this complex area of study, Dr. Meltzer zeroed in on the 5-HT2A type—the same receptor that leads to hallucinogenic properties of LSD and mescaline. It was an ideal target to complement weak D2 receptor blockade in schizophrenia and as a standalone treatment for PD psychosis.
“In the 1980s, I identified the drug clozapine as the first antipsychotic for treatment-resistant schizophrenia,” says Dr. Meltzer, explaining what led him to propose the development of a drug like pimavanserin. Never approved in the United States, clozapine had been withdrawn as an antipsychotic in Europe due to toxicity issues. “I was interested in understanding the drug’s motor system effects. Clozapine was different from first-generation antipsychotics. Unlike the so called ‘typical’ drugs then in wide use, clozapine didn’t produce parkinsonian symptoms, such as muscle stiffness, slowed movement and tremor, or tardive dyskinesia, abnormal involuntary muscle movements of the face, trunk and limbs.”
Prior to Dr. Meltzer’s research, the commonly accepted view was that the psychotic behavior of schizophrenia resulted mainly, if not exclusively, from excessive activity of the neurotransmitter dopamine stimulating one of its key receptors, the D2 type in the limbic brain. Similarly, PDP develops after initiating replacement therapy for the loss of dopamine neurons by administering the precursor of dopamine, L-DOPA. First-generation antipsychotic drugs work by blocking dopamine D2 receptors in the area of the brain involved in functions such as reality testing, reward, emotion, and memory. This action, however, results in the unwanted motor disturbance of antipsychotic drugs.
As co-PI for the single clinical study that led to the FDA-approval of clozapine for treatment- resistant schizophrenia, Dr. Meltzer dedicated his basic research effort to understanding why clozapine and other “atypicals” (called such because they don’t cause motor movement problems) worked. In 1988, in a widely cited landmark paper that generated 2,700 citations, the results of the clozapine trial in schizophrenia were published. In 1989, just a few months later, Dr. Meltzer and his colleagues published the results of their efforts to understand the pharmacologic basis for atypical antipsychotic drugs. The core concept? Strong 5-HT2A and weaker D2 receptor blockade, a ratio which is also known as the “Meltzer Index.” In the same papers, Dr. Meltzer proposed that the psychotic component of schizophrenia was due to a combination of both excessive 5-HT2A and D2 receptor stimulation.
“We found that the ‘atypical’ drugs, which produced little or no motor side effects, were more potent serotonin 5-HT2A than D2 receptors,” says Dr. Meltzer. “Eventually, we showed that clozapine could be an effective antipsychotic and tolerable to patients with PD psychosis at very low doses, which did not block D2 receptors but could block 5-HT2A receptors.”
Dr. Meltzer’s discoveries contributed to a rush to develop a new class of atypical antipsychotics. These “sons of clozapine,” rather than clozapine, became the dominant treatments for schizophrenia and other disorders, because the severity of clozapine’s side effects was off-putting to many prescribers and patients. Additionally, Dr. Meltzer’s serotonin-dopamine hypothesis wasn’t universally accepted.
“No one doubted clozapine’s effectiveness at treating dopamine-based psychosis,” says Bryan L. Roth, MD, PhD, professor of pharmacology at the University of North Carolina, who joined Case Western as a junior faculty member in the early ‘90s specifically because of Dr. Meltzer’s well-regarded pre-clinical and clinical neuropharmacology program in schizophrenia. “But there was debate about whether it was the action of 5-HT2A or some other receptor.” Agrees Dr. Meltzer, “My theory met with some resistance. It wasn’t the only one advocated and was not immediately obvious the correct one.”
Then ACADIA called. The start-up company’s founder, scientist Mark Brann, believed that Dr. Meltzer was on to something good.
A RECEPTIVE AUDIENCE
“ACADIA had looked over the theories of schizophrenia and appropriate drug targets and thought that I had gotten it right with advocating for the role of the 5-HT2A,” recalls Dr. Meltzer, who in the summer of 1996 moved to Vanderbilt University as Douglas Bond Professor of Psychiatry and director of psychopharmacology in the Department of Psychiatry. His work with ACADIA led to the discovery of pimavanserin, a drug that holds much promise for the treatment of schizophrenia, bipolar disorder, and depression as well as the psychosis of Alzheimer’s disease.
So 24 years later, Dr. Meltzer has seen his hypothesis come to light in a novel compound, in part, due to his unflagging belief in serotonin receptors and their role in psychosis. “He has single-mindedly studied this once trendy area through its ups and downs,” says Dr. Roth, an expert in molecular neuropharmacology. “Without the vast amount of data he has generated and his devotion over the years, it is safe to say this drug would not exist.”
Advancing novel research findings that bring the next breakthrough drug to market requires substantial investment of capital. The investment can total as much as a billion dollars, by some industry estimates, when all is said and done. Clinical trials can cost as much as $150,000 per patient, and 600 subjects is the norm for a pivotal trial. Driven to pursue new knowledge, academia is full of people with great ideas. Interested in developing new therapeutics, pharmaceutical companies have the drug development and regulatory know-how, as well as the funding, to invest in ideas they believe will yield the best products. How academia and private industry come together isn’t an exact science but based on the successful collaboration of Dr. Meltzer and ACADIA, it is a relationship that can truly help to translate research into clinical practice.
“It’s critical to overcome the bias in academics and look for more ways to partner with industry,” says Dr. Meltzer, who plans to soon start conducting clinical trials for the use of pimavanserin in patients with schizophrenia. “If our medical center’s mission is to do the best for everyone, developing these types of relationships is the best way to achieve this goal.”
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Advancing schizophrenia treatment
Risperidone is a widely used antipsychotic drug for schizophrenia patients experiencing a relapse of psychosis. In 2012 Dr. Meltzer published a study showing the benefits of combining pimavanserin with a sub-effective dose of risperidone to restore full 5-HT2A receptor blockade. Used together, the two drugs are more effective at alleviating schizophrenia-related psychosis and produce much fewer side effects than the standard dose of risperidone.
Dr. Meltzer hopes to test this concept in a clinical trial in the very near future. Says Dr. Meltzer, “If successful, it will be another major milestone in our efforts to help people with severe mental illnesses.”
Dr Meltzer on Pima
http://bbrfoundation.org/brain-matters-discoveries/fda-expedites-new-psychosis-treatment-developed-by-scientific-council
FDA Expedites New Psychosis Treatment Developed by Scientific Council Member
May 13, 2013
Herbert Meltzer, M.D.
Brain & Behavior Research Foundation Scientific Council Member and NARSAD Distinguished Investigator Grantee, Herbert Meltzer, M.D., recipient of the Foundation’s Lieber prize for Outstanding Achievement in Schizophrenia Research, was instrumental in developing a new drug, pimavanserin, for the treatment of psychosis associated with Parkinson's disease. The US Food and Drug Administration (FDA), is expediting the approval of this innovative therapy, which could come as early as next year, because currently there are no approved treatments for this type of psychosis in the United States.
"This is a landmark study and will potentially bring a new treatment option to large numbers of individuals with psychotic-spectrum disorders," says Bryan Roth M.D., Ph.D., Michael Hooker Distinguished Professor of Pharmacology at the University of North Carolina School of Medicine.
Parkinson's disease psychosis is a debilitating psychiatric condition that develops in almost 60 percent of patients with Parkinson's disease. Traditionally, physicians would address this disorder by prescribing drugs that target dopamine signalling, because excess dopamine is thought to exacerbate psychosis. However, such treatments can produce serious side effects and often worsen the symptoms of Parkinson's disease.
What makes this treatment so effective is the fact that it does not interfere with dopamine signalling, but instead selectively blocks serotonin signalling. Dr. Meltzer, Professor of Psychiatry at the Northwestern Feinberg School of Medicine, developed pimavanserin together with the California-based company ACADIA Pharmaceuticals. This milestone represents a culmination of 25 years of research that Dr. Meltzer has spent designing more effective and safer drugs for the treatment of psychosis, with support from the Brain & Behavior Research Foundation, private donors, as well as the National Institute of Mental Health and ACADIA. A pivotal phase 3 clinical study demonstrated pimavanserin's effectiveness against psychosis in patients with Parkinson's disease and a separate study from Dr Meltzer and colleagues showed that this innovative therapy also enhanced treatment response with current second generation antipsychotic drugs in acutely psychotic patients with schizophrenia.
“This is the first major novel advancement in the treatment of psychosis in the last 25 years and can be expected to have a big impact shortly in the treatment of all types of psychosis, especially schizophrenia and psychotic mood disorders,” says Dr. Meltzer. It is extremely well tolerated, unlike other antipsychotic drugs used for Parkinson’s disease psychosis. Once this drug is approved, he expects it will be tested and used extensively to treat other forms of psychosis, including Alzheimer’s psychosis. “The FDA has taken the unprecedented step in this area to expedite the approval of this drug because it is first in its class for the treatment of Parkinson’s disease psychosis and there is no FDA-approved treatment for this debilitating condition which creates great suffering for patients and their caregivers. I believe it will be widely used within five years as augmentation for current antipsychotic medications to achieve full efficacy, perhaps more quickly, and with fewer side effects as I have already demonstrated for risperidone in a clinical trial and for all other atypical antipsychotic medications in basic research studies.”
Sovaldi Warehousing and Otezla Trends Continue UBS
Update on Sovaldi prescription data: TRx -6%, NRX -2% w/w
Scripts for Gilead's Sovaldi during the week ending July 18 were released this morning with total scripts of 7,551, down 6% from last week. New Rx were 2,889, down 2% w/w. The trend continues to suggest warehousing ahead of the ledipasvir / sofosbuvir combo expected in 4Q. A total of 19,461 scripts and 7,271 new scripts have been recorded in 3Q. Conservatively, we are tracking to $1.3bn for 3Q Sovaldi sales (current Bloomberg consensus is $2.4bn) if no additional patients are added for the rest of the quarter. We assume 95% complete therapy (97.5% refill in months 2 and 3 each), a 12% gross-to-net pricing (more conservative than Gilead comments imply), a 0.88 correction factor suggested by scripts vs. reported sales, and 10% of NRx are actually refills. Below, we include a plot of the launch thus far for Sovaldi, compared to the same period of the launches for Incivek and Victrelis.
Update on Otezla prescription data: TRx +4%, NRx +4% w/w
Scripts for Celgene's Otezla indicate TRx of 812 (up 4% w/w), and NRx of 605 (up 4% w/w) during the week ending July 18. Below, we include a plot of the launch thus far for Otezla, compared to the same period of the launch for Xeljanz. Launch-to-date, Otezla TRx is tracking 75% higher than Xeljanz’s launch, despite the fact that the Otezla Rx trends exclude the titration packs offered to patients to initiate therapy.
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