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I've shared it with a few elected officials and bureaucrats, yes. No, it didn't go anywhere because nobody wants to tackle drug pricing.
And yes, in that original article from 4 years ago I mention that we'd have to exempt "non-poor" countries. We'd pick a basket (G7, for example) of countries and work off of that. Then weight even that by GDP or income or something.
It's unsustainable for the US to pay for R&D by itself (or largely by itself). Frankly, some administration should bring it up as a WTO issue. While the WTO rules are more suited to tariffs or unfair local subsidies, the rules should work in the reverse situation of a restriction requiring US companies to charge LESS.
I tried that angle in my discussions, too. That got a little more interest, but nobody wants to get anywhere close to touching drug pricing after the "death panel" nonsense.
EXEL confirmed long time ago the total alpha to spend in COMET-1 is 0.05.
They have never said how they allocated it, though I would have to say I never detected any sense that they would be surprised if the trial went to the full analysis.
FWIW, here is what I've worked up over the years (at BSR and ABV) on COMET-1.
COMET-1 enrollment pattern
May “initiated trial” 280 international sites targeted.
July to December 2012 = 60 patients
February 2013: “50% of trial sites are activated”
May 2013: “Most COMET trial sites are activated”
January to September 2013 = 900 patients
“960 patients enrolled in 14 months”
Statistical assumptions
1*=OS
N=960
Randomized 2:1
Study arm 9.0 month OS assumption (cabozantinib monotherapy)
Control arm 7.0 month OS assumption (prednisone monotherapy)
90% power at HR=0.75, p=0.05
One interim analysis, originally disclosed as 387 patients (later as “2/3rds of total events”)
Final analysis confirmed at 578 events
Other
The 7-month baseline assumption was derived from the COU-AA-301 trial of abiraterone (Zytiga) and represents the duration of treatment on the Zytiga arm between the end of treatment (median time on drug) and death (median overall survival).
There is no SPA.
The trial was initiated May 30, 2013, but management said they enrolled the 960 patients in 14 months.
I expect the trial was enrolled mostly ex-US, particularly in Europe.
Hope everyone is doing well, been a long time since I dropped by.
David
It was in RVX's best interests to be really clear. Lots of potential partners were watching and the clarity paid off. Lots of new people to the table to take a look. We'll see if that pays off.
I think the headline numbers on the ALT elevations are worse than the actual fact. The ALTs are generally transient and resolve. There really isn't any way you can get at lipids without elevating ALTs - at least not any way that works. I keep pestering them to show ALT values over time. Maybe at the next oppy for presentation.
It's all about a deal at this point. Will one of the interested parties take a shot at the drug and the other, more potent cardio-focused bromodomain inhibitors in the RVX pipeline or not? I think the answer is yes, especially if their medicinal chemists can create a combo pill.
The fact there is such strong differential efficacy between Crestor and Lipitor actually makes the drug very much more interesting to AZN. They can use the same sales force to press RVX-208 as they do (soon to be generic) Crestor, gaining money from both.
My guess is any partner takes it into a large P2b trial to confirm the Crestor effect. No more IVUS because the variability gets too big when you get to the size of ASSURE or larger. Just a "simple" MACE endpoint. I'd expect a two-stage deal -- something modest to start and then a larger buy-in if the P2b is positive... which one would think it should be (understanding the appropriate caveats for chasing post-hoc data).
David
Clay sells only the options that are expiring or for tax purposes. He's been pretty clear about that.
OT: Just FYI for folks, alias change from BSR_David to AlpineBV_Miller. This should affect all my prior posts, too, if I undertand IH's policies in this regard.
Thanks much.
FWIW, probably changing my nickname on here so there isn't any confusion.
They have slides in the deck both for comparison against control and baseline. In both cases RVX-208 was superior in the target HDL population.
NCCN Guidelines for Patients - Prostate Cancer
Did anyone here save to their local drive a PDF of the **PRIOR** version of the NCCN Guidelines for Patients - Prostate Cancer?
I'm not looking for the current version (marked Version 1.2013).
I'm not looking for the Treatment Guidelines.
I'm looking for the prior version of the "NCCN Guidelines for Patients - Prostate Cancer"
If you have it, I'd appreciate you emailing it to me -- ddmiller@biotechmonthly.com
Thanks,
David
RVX --
RVX ---
One thing before I start quoting...
a1-HDL is not he majority of HDL in the measurement of HDL-C. In fact, a1-HDL is around 15% of HDL-C as noted by the measures in the 2004 Asztalos paper. You had stated before that a1-HDL made up the vast majority of HDL-C, so I just wanted to correct that.
RVX
Rosu and Ator won't get IVUs reductions in six months of dosing.
Cleveland Clinic designed this trial, not RVX. Worth keeping in mind. The primary is change from baseline, but there is a control arm to compare the changes in baseline. Recall the ETC-216 data didn't report a 4% difference from baseline in ETC-216. It reported a 4% difference between the growth in the placebo arm and the reduction in the control arm.
Last we talked on the subject, RVX management said they'd report the numbers both ways to reduce confusion.
As to your criticisms of the 2004 Asztalos paper and preference for the 1989 Gordon paper, there are a couple of things you should understand.
Gordon looked at overal HDL-C and not sub-fractions. The Gordon paper comes to the virtually the same conclusion as the later Asztalos paper -- every 1% rise in HDL-C creates a 2-3% decrease in CHD.
The Asztalos paper differs primarily in that his team looked specifically at sub-fractions. They concluded a 1% increase in a1-HDL generated a 26% decrease in CHD. This was supported internally by a1-HDL to HDL-C ratios having an even higher benefit -- which, to some extent, addresses the point that HDL-C measured by weight (which isn't how they measure it in modern studies) is largely a1-HDL.
As to the superiority/inferiority of the statistical methods, I won't argue there. Since the Gordon paper doesn't address a1-HDL at all, it's rather unfair to ding Resverlogix management for not using a1-HDL numbers from that paper. Again, note that overall HDL-C projections were essentially equivalent between both papers.
David
ETC-216 was actually a mimic of preß-HDL comprised of a synthetic version of apo-a1 Milano and a synthetic phospholipid. It was ultimately impossible to manufacture at commercial quantities.
In theory, the "increase in HDL" with ETC-216 would have been equal to the number of viable drug particles that survived the infusion process since preß-HDL counts as HDL.
If you want to talk about what the increase in the larger a1-HDL particles would be, it would likely be similar -- minus some completely unknown percentage for the number of ETC-216 particles that could not mature into a1-HDL due to lack of available mediators like LCAT.
RVX-208 attempts to back up one step further by spurring the liver into producing apo-a1, which they hope matures into preß-HDL via ABCA1 and other mediators.
It's clear the drug produces apo-a1. Whether it creates enough of it and/or whether the creation triggers the beneficial cascade that results in maturity to a1-HDL that can uptake fats and offload them into the liver is what ASSURE will tell us.
The Phase III trials will tell us whether that process converts into morbidity and mortaility benefits as the post-hoc, retrospective analyses of a generation of lipid trials suggest.
Resverlogix
Past the rant about "hiding" the liver tox seen in ASSERT, people are correct to be cautious here. SUSTAIN hasn't been reported out in full yet, though management has been clear with us at least the rise in enzymes was transient and disappeared.
RVX-208 is a NME and a novel mechanism. apo-a1 boosting had its heyday in the early part of the last decade with Esperion, which we covered and made a a lot of money off of. All the BS with these CETP-inhibitors, which we also predicted, has confused the apo-a1 story for many people and taken the bloom off the rose of HDL-directed therapy (which RVX-208 is not, but that's a longer conversation).
Management indeed has a history. Hell, they had a toxic convertible when we started covering them and argued it was not a threat (now Don tells me to have CEOs considering toxics to call them so he can straighten them out). In the past four years, however, they got smart quick. They've been responsive to our questions, listened to our criticisms, took our advice into account, and generally have made smart moves. The best example of this is bringing Cleveland Clinic on board. It shows they are serious about generating quality data.
Regardless of how much management has improved over the last four years or how refreshing I find their attitude and excitement about RVX-208, the ASSURE trial is one big-ass binary event. Since almost none of us have access to options, that makes the risk even higher.
While I seriously doubt pharma will ignore stellar ASSURE data for long, I can also see the argument that drugs like RVX-208 are not the rage they once were. And even if they are, the Phase III clinical trial program any pharma is likely to launch will be expensive enough that pharma will want to be DAMN sure they know what they are getting before signing a deal.
Unless everything we know about the Reverse Lipid Transport pathway is wrong, I think the drug will work. Could everything we know about RLT be wrong? Sure. Could there be trial quirks in ASSURE that prevent us from seeing the signal? Sure. There is clearly risk here.
The bottom line is if ASSURE fails, anyone invested in RVX is going to get VERY creamed and, as investors, we HAVE to respect that.
David
Nice to see, some 7 years later, the SEC is waking up to what two reporters figured out (without subpeona power) in 2005:
http://seattletimes.com/news/business/drugsecrets/
It's not the manufacturing that is issue, it is the logistics. Coordinating the entire supply chain is the magic in the manufacturing process. Nobody is going to get efficiencies on that -- well nobody except FedEx or UPS -- just by acquiring the company.
We did not use the word "scam", but the company's long history of claiming progress with no actual progress made was worrisome to us. Our view was they were finally running "put up or shut up" trials that would provide an answer to whether they had something or were simply experts at separating shareholders from their money to continue collecting a salary.
FWIW, I agree with Dew that was a very bad PR.
FWIW, it isn't just Dew. We worked up Peregrine back in June 2010 and passed on it because of insufficiency of their earlier trials. We thought the risk too high until after the current crop of Phase II data were in.
When we pass on a company we usualy don't write it up, but we did on this one.
Highlight of ASH was the MD Anderson guys presenting their institutions history with ruxo showing a survival advantage. They really went after the Mayo data. Was a hoot.
I'm not normally a fan of MDACC (see also Advexin), but it's nice to see someone having enough courage to call out (in a public, peer-reviewed format) crappy data from another institution. Much better than the silent backstabbing that usually goes on...
Poster today from Mayo Clinic experience shows no survival difference between the pts they enrolled on ruxo over the years and patients contemporaneously enrolled.
Not much info on the poster concerning whether they attempted to case match, but the OS curves are atop each other.
I'm assuming the survival data I previously tweeted about comes from INCY directly.
The data is a 3-step process CRO --> data analysis firm --> PYMX. All PYMX got was the four numbers. I'm more peeved at the fact they didn't give unblinded data like they said they would. There is no valid reason to preserve alpha in an exploratory Phase IIa dose-finding trial.
Since they also gave an average for the four arms, it can't be 87-87-87-100.
The trial isn't powered nor designed to show superiority. Antibiotics are approved on non-inferiority. Anything in the ballpark and no unknown safety signals are the bar at this stage of the game.
The trial also did not stratify for MRSA/MSSA between arms so inter-arm variability may have to do with different disease to a greater degree than drug.
@Dew -- OK, just wondered if there was something I was missing given the strength of your statement. I agree with you, especially for trials outside EU/NA.
@Thurly -- I'm aware of that. My question wasn't related to approval, more to overall trust in the data.
Just because he was at Genentech doesn't mean the drug will work or that the trial was designed properly.
Why do you object to asking the question?
Very smart people make this mistake all the time. More to the point, CROs make this mistake on behalf of smart people all the time.
It is actually rare in P2 randomized trials to randomize by center or even by country. Oncologists and management teams have a blind spot about cancer in that they think patients are all the same regardless of the country. Some realize this isn't the case, but not many.
We see small biotechs enroll outside NA/EU and then have their P3s run in the EU/NA blow up all the time. How many P2 trials run "cheaply" in Russia resulted in blown P3 trials run in the US?
Lots.
It's a good question to ask management.
Also a non-trivial question is how they did the randomization. If sutdy arm patients came from India and control-arm patients from elsewhere, the ORR difference shown would be boosted according to the data we looked at when we wrote this company up June 2010.
Randomization cures a lot of ills in Phase II trial designs for oncology products, but randomization doesn't automatically relieve investors of their job of being skeptics.
$MDVN has the UCLA lab cold on ARN509. Astellas, however, has the right of refusal on the compound as part of their existing deal with Medivation.
I think any change in price, but especially one upwards, would be distasteful. I agree with PGS on that one :)
Yes, but I doubt Dendreon will get there unless this issue persists into 2012 with little improvement. The problem is I'm not sure whether a $75,000 or $60,000 or even $45,000 price point will make a ton of difference to this cash flow problem. You'd get a bit of a boost simply because the practice could fit single-digit more patients per month into their existing cash flow/LOC situation, but then you'd be stuck right back at the same slow growth curve after a couple of months.
Dendreon will want to work through several ideas and strategies before resorting to a price cut. It chould be said I doubt urologists will WANT a price cut because it reduces the amount they get paid for Provenge.
There may be a demand issue, but what Dendreon is experiencing now has nothing to do with demand. End users who REALLY push their urologist are being referred out to academic centers and getting treated. The average patient accepts the urologist's claim he is being put on a waiting list.
Expect Dendreon to partner with certain practices to create "Provenge - No Waiting" ads in select markets, or the practices to do it themselves.
We can argue about whether the market demand exists, but saying "cost density" is a dmeand issue confuses an already confusing point.
There is actually a huge business opportunity here for a middleman to take on some of the risk. The middleman would evaluate patients and make a decision to guarantee payment based upon the patient profile. They guarantee to the doc they will pay if the MAC rejects the claim or delays payment.
Trick is I'm not sure some % of the $5800 provides enough money to create such a business. Not sure you could take a piece of DNDN's $93,000 for the service as your guarantee program could muck up the laws against DNDN doing this.
I think there is a lot of Monday-morning quarterbacking going on here on this issue. How many people would believe that doctors would withhold access to a proven life-extending drug because of cash flow issues at their practice? Remember, these urologists could simply refer these patients to a larger practice or an academic center and they could get treated. Instead, they are just sitting on them.
Prostate cancer is way more complicated than it appears. I've been ear-deep in this sector for over a decade now and I learn new things about the disease -- not so much scientifically, but how it is treated -- every year.
Despite being one of the bigger killers of men, it is not very well understood by doctors. With no survival-extending therapy until chemo in 2004, docs just aren't used to treating these patients. Add to that a relatively unique split treatment system where uros handle the surgery and oncs handle late-stage disease, you have a boatload of moving parts that make the sector daunting for someone who doesn't spend a **lot** of time on it.
Yes, but not like this. One could readily see orphan genetic conditions drugs as having the asme problem, but these are almost all young people's diseases (to start) and reimbursed largely by private insurers who will pre-approve treatment.
This is really a fairly unique combination of high expense inside one month in a Medicare population.
If Cardinal or one of the other common practice funders allows a $3M line of credit for Provenge and the onc practice puts 15 patients on this month and 15 on in the second month, that's the $3M right there. If the MAC is on a 60-day pay because of a paper generic code system and a funky interpretation of eligibility, that practice can't sell ANY cancer drug - much less Provenge -- in month 3.
This is why the Q-code and the NCD should make a difference. The NCD eliminates the funky criteria and the Q-code makes reimbursement requests electronic.
Remember, CMS doesn't administer Medicare at the doctor/patient level. 15 private companies do. Each has different procedures and is better or worse about payment speed. Each has different ideas of "fast" reimbursment and customer service. None will pre-approve a treatment. Makes for odd side effects...
Because of a stupid decision a few years back to whack their R&D, DNDN essentially has no pipeline. Their trp-m8 drug has been in Phase I trials for most of two years with no data. Neuvenge was supposed to start a trial last year and we'd be lucky to see it start this year. This is one more hazard of Dendreon not signing at least an ex-US partnership -- lack of management bandwidth to focus on their pipeline.
In theory, the should be able to use already licened antigen targets to duplicate Provenge success. The cassette technology, monoantigen focus, and semi-autologous approach should translate well to other tumors with a history of response to immune therapy. Bladder is a good first choice, though some question whether her2-neu is the best target.