BioMarin Pharmaceutical (NASDAQ: BMRN) received a rejection letter from the FDA on August 19th, 2020 following interim results of its phase 3 trial of the gene therapy drug Valoctocogene Roxaparvovec. The letter was a ‘complete response letter’, or in other words final. That sent the drug company’s stock crashing down 35% following the news.

What happened? BioMarin submitted a marketing application using three years worth of data from a phase 1/2 study and interim data from a phase 3 study. What the FDA was looking for, which is reasonable, is the durability of treatment or in other words does it work over the long-term. The reason it was a surprise was because usually the FDA lets the drug companies know exactly what it wants to see for approval but in this case BioMarin says the FDA surprised them after the fact. Why couldn’t they use the phase 1 / 2 three years worth of data? Turns out it only enrolled 7 patients compared to the 134 in phase 3. 

This means that for now--the phase 3 trial results need to be measured for at least 2 years to show durability. This results in a November 2021 completion date.

Why is this important? Gene therapies have the potential to ‘cure’ genetic diseases by inserting functioning genes (where they weren’t functioning before) to produce the missing protein that caused the genetic disease in the first place. In the case of Hemophilia A, that happens to be a protein called factor VII which is a clotting protein. Without it, even the slightest trauma can cause life-threatening bleeding. Imagine a bruise (which is pooled blood) that just keeps getting bigger because it doesn’t clot after a period of time as with people who have sufficient clotting factors. This is problematic if the blood expands in tight spaces like joints or worse in the brain following head trauma. 

What’s the cost? Hemophilia A affects 1 in 10,000 folks and as with most things in life, the severity is on a spectrum with the severe cases able to only produce 1 percent or less of factor VIII. Today, these patients are treated with infusions of factor VIII. Treatment of Hemophilia costs on average about $270,000 a year per patient (2015 data) and can go up to $1 million per patient (when there are complications or emergency infusions). There are 20,000 people with the genetic disorder and one can imagine that if there was a single injection that would ‘cure’ this, drug manufacturers would be able to charge several million dollars and still achieve cost savings for the health system as a whole. More importantly, if it works, it would mean a completely different life for patients suffering from Hemophilia A.