What UCB Pharma's development of Briviact can teach us about Anavex - my opinion only
I wanted to explain how UCB Pharma brought Briviact onto the market after nearly a decade of trials. The process that UCB went through may be what might be going on behind the scenes with Anavex.
When levetiracetam came on the market, it was a breakthrough epilepsy drug. It came into market in 1999 and it was the first drug racetam class of antiepileptic medications with a unique mechanism of action. Specifically, it has interaction with the SV2a protein (SV2a is a protein that is in neuronal synaptic vescicles). SV2A is believed to be involved in coordinating synaptic vescicle exocytosis and neurotransmitter release. Levetiracetam (Keppra) is now the most commonly prescribed antiepileptic medication on the market, recently surpassing phenytoin as the most popular antiepileptic medication (I have my own reservations and have fallen out of favor of levetiracetam due to some of the mood altering side effects that some patients have with it).
So Briviact is now on the market – it is the 2nd antiepileptic medication in the racetam class that has been approved for usage of partial onset seizures. Briviact is the result of a large rational discovery effort embarked upon by UCB pharma in an effort to find another SV2A ligand as a new addition to the racetam class. UCB wanted to developed another high-affinity SV2A ligand, distinct from levetiracetam, with antiepileptic properties (levetiracetam is a mild-moderate affinity SV2A ligand).
12,000 compounds were screened for higher affinity interaction with SV2A in vitro than levetiracetam. Of these 12,000 compounds, 900 were tested in an initial animal screening model of epilepsy. 30 of the most promising compounds of the 900 tested were then profiled in a broad range of animal models of seizures and epilepsy. The agents with an animal model profile similar to levetiracetam were not pursued through phase 3 clinical trials. UCB achieved its goal with the identification of Briviact, a new molecular entity of the racetam class of AEDs. Briviact is not an active metabolite or enantiomer of levetiracetam.
The Briviact Phase 3 trials ended up being the largest antiepileptic drug clinical development program in the history of antiepileptic drug development and UCB spent a tremendous amount of time, money and effort into getting Briviact approved by the FDA. There were 2 studies initially in the phase 3 trials using lower dosages of Briviact. Long story short, there were some discrepancies with the data in these trials especially for the cohort of patients who were receiving concomitant levetiracetam. Therefore, Briviact designed a 3rd study – specifically excluding patients who were on concomitant levetiracetam (a cohort of this group in the 3rd study had prior exposure to levetiracetam in the past, but was not on it at the time of the Briviact study). The 3rd study showed that patients who had prior exposure to levetiracetam had better reduction of seizures on Briviact than the cohort of patients who were never exposed to levetiracetam.
I think with Anavex, the cohort of patients who have never been exposed to donepezil but only 2-73 (7 patients) showed some possible benefit with 2-73 alone relative to the cohort of patients already on donepezil. Like UCB in its development of Briviact – further study by Anavex is needed for the cohort of patients not on concomitant donepezil however unlike UCB who was already undergoing a phase 3 trial when the data discrepancies became apparent, Anavex is doing what it can now to design a phase 3 trial to ensure that unexpected dead ends do not come up (leading to delay in end of study, increased cost, etc.)
Why do I bring up some of these points and how does it relate to Anavex? UCB pharma used the failures seen in some of the data from the first 2 studies in the phase 3 trials to design a 3rd study to lessen the risk of not meeting primary endpoints. UCB did everything it needed (the cost was astronomical) to get FDA approval for Briviact. Anavex is doing everything it needs to do now, before the start of a costly phase 3 trial – to ensure a higher likelihood for FDA approval for an AD indication and possibly other indications as well.
I believe that with the adaptive trial design Anavex has taken with a small sample size and no control group, data discrepancies that may ultimately lead to a failed phase 3 trial are being now being exposed. With the exposure of these data discrepancies, Anavex is going to use a “precision medicine” approach in designing a phase 3 trials. I believe that with all of the recent news and the “precision medicine” approach, the use of biomarkers, etc. with the unique statistical analytical methods employed by Ariana Pharma who will now collaborate with Anavex – Missling and his team are taking the patience and time to design a very well thought out phase 2/3 double blinded, placebo controlled, randomized control trial. Anavex, in essense, is using its “failures” to design a new trial to ensure some form of success.
The pieces will come together eventually and as I have always implied – patience is a virtue. Paradigm shifts in neurology take time and for the long investors who can be patient, I believe good outcomes will come forth.
As always, the above is my own opinion and analysis and you all should do your own due diligence before investing in a speculative, microcap biotech like Anavex.
AI
