There is something happening at the neurology department at the FDA.
AND IT IS A POSITIVE DEVELOPMENT FOR DRUG DEVELOPMENT IN A VERY HIGHLY DIFFICULT SEGMENT OF DRUG DEVELOPMENT: NEUROLOGY
It seems that FDA is becoming MORE FLEXIBLE WITH DRUG APPROVAL PROCESS – A MOVE THAT CAN BE VIEWED TO BE “LOWERING THE BAR” INCLUDING LEVERAGING “BIOMARKERS” FOR APPROVAL PATHWAY.
FDA Neurology is headed by Billy Dunn, M.D –
Below is the timeline of recent events that seem to suggest that neurology is becoming more receptive to taking more flexibility approach to drug development/approval in neurology.
July 26th 2022: FDA Accepts Biogen’s New Drug Application and Grants Priority Review of Tofersen for a Rare, Genetic Form of ALS
Tofersen is an antisense oligoneucleotide (ASO) targeting SOD1 and is being evaluated for the potential treatment of SOD1-ALS. SOD1 is a pathogenic protein that is deemed to cause ALS and tofersen treats SOD1-ALS by silencing the expression of SOD1 mutation and therefore stopping the production of SOD1 as shown below (source: the ALS association).
Given strong biological rationale, tofersen had high expectations, but unfortunately, tofersen had a negative phase 3 study – it missed the primary endpoint as shown below chart.
placebo are dotted lines and treatment arms are solid lines. Unfortunately, the curves did not separate between solid and dotted lines (blue is slow progressing and red is fast progressing).
With no clinical benefit, investors thought the drug was dead, but one day we found out that Biogen filed for tofersen and FDA ACCEPTED AND GRANTED PRIORITY REVIEW under accelerated approval pathway.
Given the OLE data where the curve began to separate with more time, FDA is now making a call that the drug would have been able to show benefit if there was more time in the original phase 3 study design. Biogen will be required to technically run a “confirmatory trial”, but it will not be easy to enroll patients in a randomized Phase 3 study – it is a ultra rare disease with patients rapidly progressing – nobody will enroll in the trial where there is change of not getting the drug (placebo controlled trial means some people will have to be put in placebo group) when there is an FDA approved therapy (100% change of getting the drug).
September 7, 2022: Amylyx Pharmaceuticals Announces FDA Advisory Committee Supports Approval of AMX0035 for the Treatment of ALS
This was a very controversial Adcom in many ways – it was the second AdCom that was requested by the FDA after the first AdCom went negatively. Also at the beginning of the second Adcom (during which we saw positive vote), head of FDA neurology department made comments that could have influence the vote.
Some of Billy Dunn’s comments really emphasized the regulatory flexibility in approving drugs for serious and life threatening diseases and are as follows:
“Our underlying legal authority is clear in not only allowing, but also endorsing and encouraging the application of regulatory flexibility in the setting of serious and life threatening diseases,”
“It is unquestionably relevant to ALS drug development in general and to our specific consideration of the data before us.”
Amylyx drug had a positive P2 study, but overall view was that the study was essentially too small to warrant FDA approval. P2 study only had ~140 patients (87 in treatment and 49 in placebo).
It is very rare to see such positive-biased comments from the FDA – to a point where many got the impression that FDA wanted to approve the drug.
However, FDA neurology department went beyond ALS to apply regulatory flexibility – its reach also expanded to neuromuscular disease.
July 29th 2022: Sarepta Therapeutics Announces Intent to Submit an Accelerated Approval Biologics License Application for its Gene Therapy SRP-9001 to Treat Duchenne Muscular Dystrophy
Sarepta also had a negative study on clinical endpoint on a trial that was expected to serve as basis for accelerated approval, but FDA is allowing Sarepta to file for accelerated approval on essentially “totality of data” that suggest clinical benefit across multiple studies.
WHY IS FDA DOING THIS?
I am a fan of driving innovation and giving hope to patients and I fully support FDA’s decision to apply some regulatory flexibility to accelerate market access for innovative medicine in neurology.
Neurology has been a graveyard of drug development because it is extremely challenging area for drug development for multiple reasons, including:
- Our understanding of neurology is still fairly nascent: it is very challenging to tell causation vs. correlation. Is the toxic protein causing the disease or is it just by-product of the disease?
- Neurological diseases tend to be multi-factorial : drugs often go after one target – meaning others remain intact to continue to impact disease.
- Neurological diseases can accumulate a long time and can take a long time for drug to have an effect: clinical trials may need to be VERY long to show benefit on hard endpoint, such as cognition.
With more approvals, neuroscience should become an investible space for many biotech investors. There are interesting neurology / neuromuscular developers that should benefit from this mega trend from the FDA – some that come to my mind are: $ACAD, $SRPT, $NBIX, $ION, $BIIB, $ALKS among others.
With aging population, keeping investment dollars flowing to neuroscience is more important than ever. Are you on this trend?
*not investment advice
