Anavex Life Sciences Corp (AVXL)

[Investor2014]

Let me try to cut out in cardboard the logic with example references.

1) In the first place - why would a company that claims their potentially pivotal P2b/3 trial met all endpoints be going for Accelerated Approval and a Confirmatory Trial, and not simply traditional approval based on amazing P3 trial results? That seems at odds with Message Board 'expert' claims!!!

2) Can the FDA suggest or a company proactively plan running a Confirmatory P3 trial in parallel with granting Accelerated Approval?

The answer is a resounding yes! P3 trials are confirming results of prior P2 trials all the time in hope of traditional approval and as well as in support of Accelerated Approval. Example:

Confirmatory Phase 3 Trial Needed Prior to Camidanlumab Tesirine BLA Submission for Accelerated Approval Path, FDA Says

Although camidanlumab tesirine has demonstrated promising efficacy in a phase 2 trial (NCT04052997) for relapsed/refractory Hodgkin lymphoma, the FDA has strongly recommended conducting a randomized confirmatory phase 3 trial, preferably with full enrollment, at the time of biologic license application (BLA) submission, according to a press release from developer ADC Therapeutics

There are many more such examples, I suggest taking some time to research this with an unbiased mindset. Then read this again:

Association Between Preapproval Confirmatory Trial Initiation and Conversion to Traditional Approval or Withdrawal in the FDA Accelerated Approval Pathway.

Even applying logic just to the headline, we can consider the question: How many Pre-approval P4 trial has ever been designed and initiated by companies vs. P3 trials - Correct answers is Zero P4 trials and loads of P3 examples just like the article provides the stats on.

It is called a P4 trial when requested and designed subsequently to an Accelerated Approval, which is not the best approach because then Clinical Research is lumped together with commercial sales and hence an unusual and likely unethical and potentially biased selection of patients paying to participate.

So this means that when Anavex says:

Alzheimer’s disease: Full data ANAVEX®2-73-AD-004, including newly available preliminary results of surrogate biomarkers of pivotal Phase 2b/3 clinical trial. The Company intends to discuss these findings with regulatory authorities in the context of the ongoing clinical development of ANAVEX®2-73 in this indication, with the goal of providing a much-needed treatment to the millions of patients living with Alzheimer’s disease with a convenient once-daily oral treatment. The Company plans to proceed in parallel with the initiation of a confirmatory Alzheimer’s disease study.

The company is referring to plans for proceeding in parallel with the initiation of a confirmatory Alzheimer’s disease P3, not a P4 study. Here "parallel" means to their intended discussion of biomarker findings and AA pathways with regulatory authorities.

Anavex will take the proactive P3 Confirmatory trial approach exactly because of the stats in the Jama paper and that e.g. lequembi, as you correctly point out, technically achieved AA out of a P2 study. However, Biogen/Eisai had proactively timed the their Confirmatory P3 trial ideally to complete pretty much coinciding with applying for AA. This approach cut out about 1 year and allowed commercial sales for Biogen/Eisai until the agency PDUFA action date of July 6, 2023, for the traditional full approval decision.

There is clearly, as the Jama article points out too, a timing spectrum for voluntarily and proactively initiating one or more Confirmatory P3 trials prior to applying for AA. In the best case a Confirmatory P3 trial has results when e.g. the FDA is about to make their AA decision or at minimum a Confirmatory P3 trial has been designed and initiated.

For the reasons mentioned in this article: Permitting patients to pay for participation in clinical trials: the advent of the P4 trial, separating Clinical Research from Commercial Sale of a drug is preferable. That is, achieve AA as above out of a P2 trial accompanied by a proactively launched P3 Confirmatory trial, where patients as usual do not pay, but may receive placebo. Everyone else can visit their doctor to potentially be prescribed the treatment under AA.

I think this is the best plan Anavex could have come up with. It will potentially results in Accelerated Approval in AD and can be neatly timed to occur just after potential approval in Rett from the EXCELLENCE study.

I don't know why folks are so attached to P4 trials and can't understand that commercialisation depends on clear Surrogate Endpoint Biomarker data leading to Accelerated Approval, NOT whether there is a 3 or 4 after P in the required Confirmatory Study.

Now I will rest the argument here for everyone's pontification and let time tell what actually will happen.