Praxis Interactive's essential tremor drug succeeded in Phase 3 despite an earlier data monitoring committee (DMC) recommendation to stop for futility. This rare outcome shows that interim analyses on a small fraction of patients can be misleading due to high variance, and continuing a trial against DMC advice can be a winning strategy.
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Analysts and Abivax's CEO believe the upcoming maintenance trial for its drug Obafazimod has a very high probability of success. This confidence is based on the historical rarity of drugs succeeding in the initial 'induction' phase but then failing in the longer 'maintenance' phase for ulcerative colitis.
Unicure's experience reveals a significant regulatory risk: the FDA can reverse its position on a pre-agreed Statistical Analysis Plan (SAP). Despite prior alignment on using a natural history control, the agency later told the company this approach was merely 'exploratory,' invalidating their filing strategy and shocking investors.
Novo Nordisk ran a nearly 4,000-patient Phase 3 Alzheimer's trial despite publicly stating it had a low probability of success. This strategy consumes valuable patient resources, raising ethical questions about whether a smaller, definitive Phase 2 study would have been a more responsible approach for the broader research ecosystem.
Unicure's setback with its Huntington's gene therapy demonstrates a new political risk at the FDA. A prior agreement on a trial's design can be overturned by new leadership, especially if the data is not overwhelmingly definitive. This makes past regulatory alignment a less reliable indicator of future approval.
Abivax's drug has a novel, not fully understood mechanism (miR-124). However, analysts believe strong clinical data across thousands of patients can trump this ambiguity for doctors and regulators, citing historical precedents like Revlimid for drugs that gained approval despite unclear biological pathways.
ProKidney made the tough call to stop its second Phase 3 study to save $150-170M. This strategic trade-off allowed them to focus resources on the primary US trial under its RMAT designation and crucially extend their cash runway past the 2027 data readout, a vital move for survival in a tough biotech market.
To save money, Rhythm's leadership considered canceling a clinical study because the prevailing scientific logic suggested their drug wouldn't work. The study's unexpected, resounding success became the company's pivotal turning point, highlighting the value of pursuing scientifically contrarian ideas.
The FDA's current leadership appears to be raising the bar for approvals based on single-arm studies. Especially in slowly progressing diseases with variable endpoints, the agency now requires an effect so dramatic it's akin to a parachute's benefit—unmistakable and not subject to interpretation against historical data.
Contrary to market convention, a trial delay can be a bullish signal. When an independent data monitoring committee (IDMC) recommends adding more patients, as with Bristol's ADEPT-2 study, it implies they've seen a therapeutic signal worth salvaging, potentially increasing the trial's ultimate chance of success.
The success of Praxis's small molecule for a genetic epilepsy presents a strategic alternative to cell and gene therapies. In an era where complex modalities face funding, safety, and commercial hurdles, advanced small molecules offer a viable and potentially more practical path for treating genetic disorders.
