BioMarin wilts as a big PhIII study disappoints investors, again

BioMarin says it hit the primary endpoint in its pivotal Phase III study of pegvaliase, another one of its rare disease drugs bound for a filing date with regulators later in the year. But the study also flubbed a key secondary endpoint for cognitive improvements, raising doubts about the drug's future and driving down its shares ($BMRN) by more than 4% Monday morning.

The study utilized a randomized discontinuation design for patients with phenylketonuria (PKU), an orphan disease where they lack an enzyme needed to eliminate Phe (phenylalaline) in the blood. Patients who initially respond to the daily injection are split between a drug--either a 20-mg or 40-mg dose--and placebo group and in this case have their Phe levels checked over 8 weeks.

Currently, Phe is managed by a strict diet, with patients on BioMarin's Kuvan often able to substantially rein it in. This new injectable, AKA PEG-PAL, is intended to eliminate the dietary element, possibly aiming at the most severe cases.

According to their preliminary results, the pegvaliase group demonstrated a 62% improvement in blood Phe compared to the placebo arm, hitting the primary. And that's good enough to take to the FDA for an approval, according to the biotech.

But there was no benefit in inattention or mood scores among the patients, which could pose a threat to their regulatory strategy. In fact, BioMarin R&D chief Hank Fuchs noted in a call with analysts that the level of inattention tracked in study was unfavorable to the drug arm, which is a clear setback. There was a "trend" toward cognitive improvement in patients in what BioMarin called an "exploratory sub study" in 9 patients. But that would likely prove to be a hard stretch in presenting it as the kind of cognitive trend that can convince the regulators.

Investigators also pointed to long-term evaluations that revealed an improvement in inattention scores among patients demonstrating the biggest drops in Phe, making a connection between the key biomarker for the disease and the kind of cognitive improvements the agency is looking for. Again, though, that kind of analysis has to be endorsed by the FDA and its experts.

Q1 2016 has been a rough stretch for BioMarin. Just weeks ago the rare disease biotech disappointed some analysts with its readout on a study for a type of Batten disease. And earlier the FDA rejected its Duchenne muscular dystrophy drug, a severe disappointment that left some observers wondering about the company's credibility on R&D. Pegvaliase was seen as a substitute for BioMarin's near-term DMD expectations.

OHSU's Cary Harding

"Treatment with pegvaliase has resulted in dramatic Phe decreases down to within normal levels which have not been achievable in the past with other PKU treatment options. We are grateful to the patients who participated in this important trial. Blood Phe reductions at this level have the potential to have a meaningful impact on the lives of PKU patients," said Dr. Cary Harding, professor of molecular and medical genetics and pediatrics at Oregon Health & Science University and investigator for the pegvaliase Phase III program.

- here's the release

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