One of the FDA’s crowning achievements historically was its rejection of the not-ready-for-prime-time drug, thalidomide, in the 1950s, while their counterparts in Europe approved it to devastating results. That and other success stories of the US FDA’s risk-averse stance have dug the agency’s approach to drug approval firmly into the conservative side of things. But it’s a thankless job. The pressure is always there from the many public groups, notably patient groups, clamoring for effective treatments, and sometimes that pressure can be overwhelming.
That’s what one pundit felt happened with the approval of one of Sarepta therapeutics drugs a few years ago. Importantly, the rejection of Sarepta’s follow up drug this month was hypothesized to be payback for mistakenly bowing to that pressure back then. So what’s the deal here?
Well, the drugs in question are for the well known genetic disease Duchenne’s Muscular Dystrophy (DMD), which is incurable and common enough that the public has been clamoring for treatment for many years. DMD is caused by inherited mutations in the gene for the muscle protein dystrophin, and dystrophin malfunctioning causes progressive loss of muscle use until death.
Importantly, the disease usually involves complete loss of dystrophin in the affected muscle, so restoration of even a tiny fraction is theorized and believed to have an outsize beneficial effect on patient muscular function and quality and length of life. This led to drug treatment strategies involving tricking the gene-to-protein machinery in cells into letting a little bit of functioning dystrophin through the censoring filters of the cell to get this outsize effect. Basically, most or all cells have mechanisms to arrest production of or clear away abnormal proteins or their encoding gene product nucleic acids. So Sarepta, and other companies like PTC therapeutics, developed small molecule drugs that target those mechanisms to let some abnormal dystrophic through, because even if it is abnormal, it still might retain some or all of its function and have the outsize effect.
There are now quite a few competitors in this space and they all face the same challenge of getting these first in class drugs approved despite high potential toxicity (if it's letting dystrophin through, isn’t it letting other harmful abnormal proteins through?). Their advantage is the intense public pressure placed on the FDA by the patients who desperately want to use these drugs, even if they are unproven. That pressure was hypothesized to have led to Sarepta’s initial approval and the rebound was hypothesized to have led to the current rejection.
However, speculation about the politics aside, the rejection letter actually cited toxicity concerns in the skin and the kidney. So there was room for improvement in terms of the data package by addressing those adverse events. As with the similar story for PTC, could using tools like those being pioneered by GeneCentrix have allowed Sarepta to improve their data package by looking for their drug’s activity in the skin and kidney?