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Metal protein attenuating compounds for the treatment of Alzheimer's dementia.
Sampson EL, Jenagaratnam L, McShane R.
Author information
Abstract
BACKGROUND:
Alzheimer's dementia (AD) may be caused by the formation of extracellular senile plaques comprised of beta-amyloid (Aß). In vitro and mouse model studies have demonstrated that metal protein attenuating compounds (MPACs) promote the solubilisation and clearance of Aß.
OBJECTIVES:
To evaluate the efficacy of metal protein attenuating compounds (MPACs) for the treatment of cognitive impairment due to Alzheimer's dementia.
SELECTION CRITERIA:
Randomised double-blind trials in which treatment with an MPAC was administered to participants with Alzheimer's dementia in a parallel group comparison with placebo were included.
DATA COLLECTION AND ANALYSIS:
Three review authors (RM, LJ, ELS) independently assessed the quality of trials according to the Cochrane Handbook for Systematic Reviews of Interventions.The primary outcome measure of interest was cognitive function (as measured by psychometric tests). The secondary outcome measures of interest were in the following areas: quality of life, functional performance, effect on carer, biomarkers, safety and adverse effects, and death.
MAIN RESULTS:
Two MPAC trials were identified. One trial compared clioquinol (PBT1) with placebo in 36 patients and 32 had sufficient data for per protocol analysis. ***There was no statistically significant difference in cognition (as measured on the Alzheimer's Disease Assessment Scale - Cognition (ADAS-Cog)) between the active treatment and placebo groups at 36 weeks. ****The difference in mean change from baseline ADAS-Cog score in the clioquinol arm compared with the placebo arm at weeks 24 and 36 was a difference of 7.37 (95% confidence interval (CI) 1.51 to 13.24) and 6.36 (95% CI -0.50 to 13.23), respectively.***There was no significant impact on non-cognitive symptoms or clinical global impression.***One participant in the active treatment group developed neurological symptoms (impaired visual acuity and colour vision) which resolved on cessation of treatment and were possibly attributable to the drug.
In the second trial a successor compound, PBT2, was compared with placebo in 78 participants with mild Alzheimer's dementia; all were included in the intention-to-treat analysis.
**There was no significant difference in the Neuropsychological Test Battery (NTB) composite, memory or executive scores between placebo and PBT2 in the least squares mean change from baseline at week 12. **
However, two executive function component tests of the NTB showed significant improvement over placebo in the PBT2 250 mg group from baseline to week 12: category fluency test (2.8 words, 95% CI 0.1 to 5.4; P = 0.041) and trail making part B (-48.0 s, 95% CI -83.0 to -13.0; P = 0.009).
[ this test is made up of 9 outcomes. Finding one or 2 that are significant by chance is fairly likely ]
**There was no significant effect on cognition on Mini-Mental State Examination (MMSE) or ADAS-Cog scales. PBT2 had a favourable safety profile.**
AUTHORS' CONCLUSIONS:
There is an absence of evidence as to whether clioquinol (PBT1) has any positive clinical benefit for patients with AD, or whether the drug is safe. We have some concerns about the quality of the study methodology; there was an imbalance in treatment and control groups after randomisation (participants in the active treatment group had a higher mean pre-morbid IQ) and the secondary analyses of results stratified by baseline dementia severity. The planned phase III trial of PBT1 has been abandoned and this compound has been withdrawn from development. The second trial of PBT2 was more rigorously conducted and showed that after 12 weeks this compound appeared to be safe and well tolerated in people with mild Alzheimer's dementia. Larger trials are now required to demonstrate cognitive efficacy.
http://www.ncbi.nlm.nih.gov/pubmed/22592705
Management leak huh?
There is zilch promising about PBT2.
Seriously? Yikes. Still not sure what they see in the RA program. Why are they afraid to stick with CF and inlicense some other orphans?
Re discount to Sovaldi regimen
What amount would not be enormous? 10, 15, or 20%? I expect it to be about $10-15k cheaper.
We are lowering our hepatitis-C (HCV) pipeline sales estimates by 40% and reducing our PT from $57 to $47. We see a balanced risk-reward. Dividend yield of approx. 3.5% should offer some support, unless interest rates step higher.
We reduced HCV sales projections for ABBV by 40% because management stated on Jan. 15 at a competitor’s conference that the company does not plan to compete on price with Gilead (GILD, not covered). We cut our 2015E HCV sales projection from $1.7B to $1.0B and our ‘15E EPS by 10% from $4.00 to $3.62. We continue to model HCV sales peaking late decade and then rolling over. Our previous 2020E HCV sales est of $2.5B was 30% of total pipeline sales and 11% of total company sales.
Our new 2020E HCV sales est. of $1.5B is 20% of total pipeline sales and 7% of total company sales.
GILD’s regimen is much simpler and the treatment duration much shorter than ABBV’s, but with comparable efficacy. As a reminder, GILD showed 94% SVR (cure rate) in treatment-nai¨ve GT1 with its one-pill (sofosbuvir + ledipasvir), once daily, eight-week long, sans ribavirin regimen, compared to ABBV’s 96% SVR with its six-pills, twice daily (four in AM, two in PM), 12-week long, with ribavirin regimen. See pp. 3–4 for dosing regimens graphic and Ph. 3 data summary.
An upside risk to our PT is that ABT-126 surprisingly succeeds in schizophrenia in mid-14. Expectations for ABT-126 are low because it already failed in Alzheimer’s and a competitor drug with a similar mechanism had failed in schizophrenia. We assume 10% odds of success and our 2020E odds adjusted sales of $200M imply unadjusted sales of $2B.
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Given GILD’s very strong Phase 3 HCV data, ABBV’s regimen may be held for GILD treatment failures unless it is discounted
GILD showed 94% SVR (cure rate) in treatment-nai¨ve GT1 with its one-pill (sofosbuvir + ledipasvir), once daily, eight-week long, sans ribavirin regimen, compared to ABBV’s 96% SVR with its six-pills, twice daily (four in AM, two in PM), 12-week long, with ribavirin regimen. See next page for data summary and graphical dosing regimens.
Note ABBV mgmt stated at the JPM Conference on Jan. 15 that it does not plan to discount its hep-C regimen relative to Gilead’s when it launches.
Given GILD’s very strong Phase 3 HCV data, ABBV’s regimen may be held for GILD treatment failures unless it is discounted
GILD showed 94% SVR (cure rate) in treatment-nai¨ve GT1 with its one-pill (sofosbuvir + ledipasvir), once daily, eight-week long, sans ribavirin regimen, compared to ABBV’s 96% SVR with its six-pills, twice daily (four in AM, two in PM), 12-week long, with ribavirin regimen. See next page for data summary and graphical dosing regimens.
Note ABBV mgmt stated at the JPM Conference on Jan. 15 that it does not plan to discount its hep-C regimen relative to Gilead’s when it launches.
ABBV’s regimen is four pills in AM and two in the PM for 12 weeks; Gilead’s is one pill a day for eight weeks
Pipeline readouts in 2014, beyond ABT-126, should be positive, but are mostly partnered-products
Data readouts for daclizumab (multiple sclerosis), elagolix (endometriosis), elotuzumab (multiple myeloma), ABT-199 (chronic lymphoid leukemia) are expected in 2014
Data from the Ph. 3 DECIDE study (NCT01064401; N=1,800) of daclizumab vs. Avonex in relapsing-remitting multiple sclerosis is expected in mid ‘14. ABBV is partnered with BIIB and earns 50% U.S. economics and ~40% ex-US.
Data from the Ph. 3 Violet PETAL study (NCT01620528; N=875) of elagolix (250mg arm and 150mg arm) vs. placebo in moderate-to-severe endometriosis pain is expected in 2H:14. We estimate that ABBV pays partner NBIX ~20% royalty on global sales.
We expect to see interim data from the single-arm Ph. 2 study (NCT01889186; N=100) of ABT-199 in relapsed/refractory CLL patients with 17p deletion in late ‘14. We will likely also see additional interim data in CLL and NHL from an ongoing Ph. 1 study (NCT01328626). ABBV and Roche are partnered and share profits/losses 50:50 in U.S. and ABBV books sales and pays Roche an undisclosed royalty on net sales ex-US.
We may also see data from the Ph. 3 ELOQUENT-2 study (NCT01239797; N=640) of Revlimid + dexamethasone +/- elotuzumab in relapsed or refractory multiple myeloma in 2014. ABBV is partnered with BMY for elotuzumab; we estimate ABBV gets ~25% of total economics, based on 30% share of U.S. profits and a tiered royalty on ex-US net sales.
I will post the report or a sizable snippet for you.
I do find it a little odd the ECYT hasnt disclosed what the "questions" the CHMP has for them. Seems material information isnt being disclosed.
Same joker who said AMRN was going to get bought 2 years ago
Hedging having to pay back AZN in the event the FDA wants another trial?
Company should do some preclinical studies up against Gazvya to prove their CEOs comments. in June'13, I asked him if they would do it (when Gazvya is approved) and he wouldn't give a straight answer.
If only you saw how much hair grease/gel he uses...
Re RNA/GSK
Still not so certain the issues with drisa are design alone. The route of administration(subq vs IV) might also be something that needs to be addressed.
Re ICPT endpoint
From Adam at JPM14, "@adamfeuerstein: $GILD using hepatitic venous pressure as NASH clinical endpoint. Agreement with FDA. $ICPT #JPM14"
The first paper uses siRNA knockdown of Galectin-3, bit different than anything either company is doing and likely much more efficient as well.
Doesnt appear to knockdown Galectin-3 levels all that much.
http://ljpc.com/wp-content/uploads/2013/08/Corp-Presentation-August2013.pdf
Such small real dollars, hard to believe they have high confidence. Baker manages what, $5-6B? They own ~$5-10m in LJPC. I view this as their way of doing an OTM call option.
The cap structure of this is just awful for anyone buying into the company. Fully diluted is 871M O/S shares.
http://www.sec.gov/Archives/edgar/data/920465/000119312513377211/d603170dex101.htm
If you think fruit pectin will cure liver fibrosis, please show me the evidence supporting that assertion.
Fast Track Designation is pretty close to meaningless.
No real HC investors are involved in GALT. They know the backstory. Adam described them pretty well
http://www.thestreet.com/story/12100340/2/biotech-stock-mailbag-galectin-keryx-navidea-cytori.html
Spare me the criticism after you long history of DNDN nonsense.
LOL - I didnt short it. Stock way too thin for any retail trader to get shares anyways. Just found it odd to pre-announce the conference call for the data so far in advance.
A rumor from Bloomberg journalist, Drew Armstrong, yesterday
"@ArmstrongDrew: Good stuff from our analyst team: $BMY making a land grab on $GILD, trying to push two-company combo therapy in hep C."
GALT and LJPC are complete jokes.
Citi analyst called it the next ICPT. Bubbly
Also there were a number of rumors about M&A that sent the stock higher. Do wonder when this train loses steam. An awful lot of billion dollar biotech companies.
He is a master of the bet. Might own small positions in some stocks, but owns sizable positions in a number of stocks. Huge position in SRPT and AEGR early in their runs.
Actually my main point was that no reputable KOLs will want to be a part of these studies, especially with real immunotherapy candidates available(PD1/PD-L1 & Yervoy+Nivo, etc).
I was ASCO13, didnt see any legit KOLs hanging around the Bavi Ph2 poster pondering how great it was.
CEO is full of it. No one will partner for psoriasis based on a n=32 Phase 2 trial. Drug was originally supposed to go into lupus but neither here nor there.
Re CYTR
You should be able to download the poster here - http://www.slideshare.net/pslice84/aldoxorubicin-p2sts01-ctos-poster-103113
It's a cheaply written poster, since they use N's vs %'s through a good portion of the poster in places it matters.
Novartis is working on something to address part (d). Believe there was a slide on it in their investor day webcast
I asked CEO and he gave me some run around answer. I've looked into Alzheimer's a lot, I highly doubt they have something worthwhile.
Show me some proof their Alzheimer's diagnostic isn't a bunch of crap.
Agree. Hearing Sandoz account managers well informed on the status of generic Copaxone. I was told they believe it will launch on time. (Referencing when Copaxone patents expire)
Xofigo should do well in Europe, US will require more work. In time, I'd expect it to get approved in other indications.
Not anytime soon
Based on what criteria?
Do you disagree with peak projections on Nivolumab?
This is 100% paid research coverage. I've met CEO, would not be involved.
This sounds like PPHM trial conduct all over again
Sadly, I do think these results aren't much different than what's been reported. The fact they did a mixed population of add on and de novo makes the data kind of worthless to me. Notice they also give no demographic info on each treatment arm(like MMSE, mild/moderate etc). There is a substantial difference in response to treatment based on those 2 variables.
How convenient of the WSJ, must have a deal with companies to report it that way
Not sure how you come to this conclusion with over $500M sold in past 2 years, $344M of which is in past 12 months.
http://www.secform4.com/insider-trading/882095.htm
Re Gazyva vs. Rituxan
GA101 pretty much crushed Rituxan. OS premature, but still looking good.
"Updated results of the stage 1 analysis: Median observation time was 23 months. Confirming the primary stage 1 results, GClb or RClb compared with Clb alone was associated with statistically significant and clinically meaningful improvement in PFS (GClb vs. Clb: HR 0.18, CI 0.13-0.24, p<.0001, RClb vs. Clb: HR 0.44, CI 0.34-0.57, p<.0001). The updated median PFS in GClb, RClb and Clb were 26.7, 16.3 and 11.1 months, respectively.
Updated OS analysis demonstrated a benefit of GClb over Clb (HR 0.41, CI 0.23-0.74, p=0.002). OS analysis for RClb over Clb showed HR 0.66, CI 0.39-1.11, p=0.113. At the data cut-off, 9%, 15%, and 20% of the patients in the GClb, RClb, and Clb arms, respectively, had died. OS medians were not reached."
https://ash.confex.com/ash/2013/webprogram/Paper60276.html