FDA in-house review spotlights an issue with one of Horizon's endpoints but notes efficacy for lead drug
The FDA in-house review highlights a disagreement of investigators’ use of a key endpoint by Horizon Pharma in the late-stage trial for the top drug in its pipeline, but largely agreed that the antibody was effective.
Horizon submitted a BLA for thyroid eye disease (TED) drug teprotumumab in March, less than two years after they bought the drug (and the rest of a division) from Narrow River for $145 million upfront. With breakthrough status, priority review, orphan designation and in-house sales projections of up to $750 million, the one-time Roche reject became the marquee pipeline asset for a company that’s developed some of the world’s most expensive drugs.
Horizon submitted their application based on a Phase II and a Phase III study, touting positive results on primary endpoints in both trials. But the FDA rejected their primary endpoint in the Phase II and secondary endpoint in Phase III: Clinical Activity Score, or CAS. They noted that CAS compiles multiple forms of clinical activity and weighs them equally.
“FDA’s clinical team does not consider these factors to be of equal clinical weight either to the patients or to physicians treating these patients,” they wrote.
Rather, they focused on patients’ response in proptosis, or the dislocation of the eye from its orbit, arguing that this was the main symptom that afflicts TED patients. They noted an improvement by week 6 in both trials that continued through the treatment period, and that 60% of patients did not relapse in the year following treatment.
For patients, proptosis often leads to diplopia — more popularly called “double-vision” — and despite less than eye-popping results in patients’ subjective responses, the FDA said Horizon showed improvement.
The FDA had few warnings about adverse effects besides a slight increase in gastro-intestinal events, but noted the limited patient population. With less than 90 patients who received the treatment, they said, adverse effects can be expected to occur in up to 3% of patients without showing up in the trial.
TED is an autoimmune disorder that largely affects women in middle age and can lead to blindness if not treated with surgery early on. Horizon projects to treat around 15,000 to 20,000 people.
The PDUFA date is set for March 8. An approval would mark one end of a long road for the drug. It began at Genmab, before Roche licensed it as a treatment for solid tumors. It proved ineffective, and was later tested at Narrow River in diabetic macular edema — the antibody affects the insulin-like growth factor-1 receptor — before showing promise in TED.
In their latest earnings call on September 30, the company appeared to fully expect approval.
“We are aggressively preparing for the potential US launch with our teprotumumab commercial and medical teams fully in place,” CEO Timothy Walbert said.