The FDA's new pathway for rare disease drugs, based on causal biology, is scientifically promising. However, the name "plausible mechanism" is a critical flaw. The term sounds weak, creating doubt for patients and giving payers powerful leverage to deny coverage by implying a lower standard of evidence.

In a striking reversal from 2024, large European pharmaceutical companies secured 13 FDA approvals while their eight largest US counterparts received only four. No single US company had more than one new drug approval, highlighting a significant performance gap and a potential shift in R&D pipeline productivity between the two regions.

For its alpha-1 antitrypsin deficiency program, Beam aligned with the FDA on an accelerated approval pathway based on a surrogate endpoint: restored alpha-1 protein levels. This strategy allows for faster market entry, with a longer-term confirmatory trial measuring clinical outcomes like lung and liver function running in parallel.

A key tension is emerging in orphan drug development. While the FDA's approval standards appear to be rising and becoming more erratic, Congress has simultaneously created a powerful economic incentive by exempting orphan-only drugs from Medicare price negotiation, creating a complex strategic landscape.

A key trend in 2025's drug approvals is that "best-in-class" therapies are distinguished not just by efficacy, but by innovations in formulation and delivery that improve the patient experience. Examples include subcutaneous versions of IV drugs and new delivery methods that expand patient access.

Despite widespread concern about political disruption at the FDA, key metrics for innovation in new drug approvals—such as first-in-class drugs and new targets—were almost completely flat in 2025 compared to previous years. This suggests the core regulatory engine has remained consistent, for now.

The Orphan Drug Act successfully incentivized R&D for rare diseases. A similar policy framework is needed for common, age-related diseases. Despite their massive potential markets, these indications suffer from extremely high failure rates and costs. A new incentive structure could de-risk development and align commercial goals with the enormous societal need for longevity.

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.

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.