There appears to be a widespread misconception on this board that PK/PD analysis should be a swift process in such a small trial as this one. In fact, PK/PD analysis is a complex and painstakingly slow process even for small trials. You can easily discover this reality just by doing a little research on the web, but to make it easier, just google Creating NONMEM Datasets and click on the first result, which is a paper that succinctly summarizes the "nightmare" timeline that standard PK/PD analysis presents. NONMEM, by the way, is the gold standard software for readying a PK/PD dataset.
Anavex is only collecting PK/PD data for analysis at Weeks 1, 12, and 26, so that helps explain why Week 5 data was able to be presented relatively swiftly, since no PK/PD data collection was undertaken at Week 5.
Sure, people with Alzheimer's who haven't been able to play piano for three years re-learn how to do it all the time. I think it's actually one of the major symptoms of late-stage Alzheimer's. After all, in the past we've seen dozens of Alzheimer's patients regain complex abilities like playing piano and painting and sustain them eight months after treatment, haven't we, despite the fact that in Alzheimer's trials the placebo effect is not seen beyond 12 weeks? Haven't we? I just can't seem to find the citations right now....
Of course not, and I need to correct myself slightly, because week 5 data did go through PK/PD analysis, but it was released after the safety and efficacy data. That was the dose-response analysis that was reported recently and showed statistically significant correlation between level of 2-73 dosage and MMSE/ERP scores.
Do more research, because PK/PD has lots to do with patient response. We have already seen this for 2-73 specifically in the company's January 11 PR, which reported that a PK/PD analysis of week five data (via linear regression analysis followed by bootstrap and Bayesian hierarchal analysis) showed statistically significant correlation between degree of improvement in MMSE and ERP scores and higher dosage of 2-73. The 30mg dose of 2-73 showed an 80% probability of boosting MMSE score by 2 points after just five weeks.
As Dr. Relkin puts it, "Evidence of a dose-response relationship is one of the factors taken into account by regulatory agencies when ultimately considering medications for approval."
One of the reasons you were not aware of the above is because Anavex did have the week five PK/PD analysis ready yet when it released week five data back in November 2015. By the time it did have the PK/PD data ready that debunked all the basher cries of placebo effect back in November, the spotlight was not nearly so bright. That is why this time Anavex will wait until week twelve PK/PD data is ready as well before it releases week twelve efficacy data.
Familiarize yourselves with PK/PD. It takes a long time regardless of the number of patients. Just google Creating Nonmem Datasets and click on the first result. Nonmem is the gold standard in PK/PD analysis, and as the abstract states, "It usually takes months to prepare the NONMEM dataset before the Pharmacokineticist feels it is ready for them to use."
Nothing else has even come close to the data Anavex has shown. The other high-profile attempts were just trying to help with symptoms: Biogen, Lilly, Prana, Roche, Axovant, etc. It's a graveyard. They all (except Prana) just keep beating their heads against the failed amyloid-plaque hypothesis.
With Anavex, we have significant improvement seen in all four trial measures: MMSE, ERP, Cogstate, and ADCS-ADL. Despite the trial not being powered for stat sig, 2-73 was so effective that it achieved stat sig anyway in several ERP and Cogstate measures. Then the dose-response PK/PD analysis showed a stat sig relationship between dosage level of 2-73 and degree of improvement in MMSE and ERP, debunking the arguments of placebo effect (would have been one heck of an unprecedented placebo effect!). Most impressive of all, the interim 12-wk data showed 11 of 14 patients improving their ADCS-ADL scores by a mean/median 3.21 points. No other drug has ever even come close to that kind of impact in the ADCS-ADL measure.
But I'm sure it was just an accident that patients and caregivers clamored for a two-year extension on 2-73 and that we are hearing about patients re-learning to play piano, paint, play golf, remembering how a granddaughter takes her coffee, how to get to the mall by themselves, and so on.
Nah, I'm sure all this is just a coincidence, right? I mean, why even bother developing drugs when the placebo effect is this effective? OK, so the placebo effect has never before achieved anything close to this kind of data in previous Alzheimer's trials, granted. But there's a first time for everything, right? Heck, maybe the placebo effect or a strong cup of coffee could even make me dunk like Michael Jordan. That'd be sweet.
When data unprecedented in prior Alzheimer's trials comes out, shorts say Oh it must be the mother of all placebo effects, or maybe it's the coffee. They have very strong coffee in Australia, you know.
The relevant, time-consuming complexity lies in the analysis performed via the NONMEM (and/or other) software, not in the data collected. While Part A complexity may make some difference, the NONMEM process takes months regardless of whether the data is from Part A or the more straightforward Part B.
Yes I initially overlooked that Week 1 of Part B would mark Week 6 of the trial overall, but then corrected myself. As we know, the company did undertake and report PK/PD analysis on the five-week results, but not until well after reporting week-five safety and efficacy data, at which time there was far less attention paid to the PK/PD data (which debunked the cries of placebo effect) than if it had all been released together. That is why the company is waiting until all the data are ready before releasing anything further for week 12 (which is actually week 17 of the trial as a whole). Of course we do have the interim ADCS-ADL data for week 12 already from the November data release.
I disagree that we need the Plus patent. We have the 2-73 patent and that is enough to protect the company's IP. The Plus patent would just be gravy.
Also, we already know from back in November that the 12-week data will be good, no matter when it comes. In that interim 12-wk data release, 11 of 14 patients improved their ADCS-ADL scores, with a mean/median (not sure which) improvement of over three points. That degree of improvement in ADCS-ADL has never before been seen in an Alzheimer's trial.
So no matter when the full release comes, even from that alone (in the unlikely event that the other measures somehow reverse their positive trend at wk 5), we already know the 12-wk data will be excellent.
2-73 has shown strong signals of efficacy in humans in the 2a trial. As yet LM11A-31 has not shown any signals of efficacy in humans since it has not yet begun its own phase 2a trial. That is slated to begin in summer 2016 and take two years, so 2-73 is well ahead on the path to FDA acceptance in terms of both timing and signals of efficacy in humans.
Not only is it credible, it is well established that PK/PD analysis takes a long time even for smaller trials. A little reading will show that.
Exactly. The last major scientific conference for Alzheimer's was Barcelona where week five data was released. The next major scientific conference for Alzheimer's is AAIC in late July, and that is where twelve week data will be released, not just efficacy data, but PK/PD data as well, which is the part that has taken so long to analyze: for week five, efficacy and PK/PD were released separately, with PK/PD coming out two months later. This time they are waiting for PK/PD data as well (and for the major platform that AAIC provides) so that there can be no credible complaints of placebo effect when the efficacy data is good, as we know it will be from the interim 12-week results for ADCS-ADL that were already released back in November.
Exactly -- several of the patients have not reached the 26-week milestone yet. March 12 will provide partial 26-wk data, while the May conference will provide full 26-week data (along with interim 38-week data most likely). All patients should have passed the 26-week milestone by mid-April.
The 379% return over the last year is very disappointing, yes. Barely beats the S&P, right?
Also, since you don't like factual positive info (such as the unprecedented Alzheimer's trial data released on Nov 9, which by the way came after the up listing), I'm curious what non-factual positive info you'd like to see. Maybe you want Missling to announce that AF took a dose of 2-73 and turned into a unicorn?
Maybe that would improve on our paltry 379% return over the last year?
I've read about this one. Unlike 2-73 it has yet to be tested for efficacy in humans. Company is hoping to initiate a phase 2a trial in summer 2016 and expects to complete the trial in two years. So 2-73 is well ahead on the timeline, particularly if it starts the phase 2b/3 trial in 2016 as planned. 2-73 has also demonstrated strong preliminary signals of efficacy in humans, whereas this Pharmatrophix drug (LM11A-31/C31) has so far only done so only in mice.
Yahoo doesn't allow links, but if you go to the Pharmatrophix website and click on "Contact" (weirdly), you'll see their timeline estimate for their 2a trial.
Amazing that BP just keeps going after the failed amyloid plaque hypothesis, time after time, after time. Meanwhile, article after article in academic journals keeps adding to support for the Anavex approach via the Sigma-1 receptor and for the general hypothesis that Alzheimer's stems from a confluence of factors -- inflammation, oxidative stress, mitochrondrial dysfunction, calcium imbalance, etc.