Upcoming events – Biomarin’s rare disease approval and Probiodrug’s Alzheimer’s play

Welcome to your weekly digest of approaching regulatory and clinical readouts. Biomarin is looking for approval of its enzyme-replacement therapy Brineura in a rare condition called CLN2 disease, which leads to developmental deterioration in children. The US regulators will decide by April 27, but could announce an advisory meeting in the coming weeks.

Meanwhile Probiodrug is expected to report phase II data in early June with PQ912 in Alzheimer’s disease, a binary event for one of only a handful of companies using a small-molecule approach in this highly intractable disorder.

Rare disease

Biomarin’s Brineura contains the active ingredient cerliponase alfa, a recombinant human tripeptidyl peptidase 1 (rhTPP1) intended for treating children with CLN2 disease, a type of lysosomal storage disorder particularly affecting cells in the brain and eyes.

The disease is rapidly progressing with no approved treatments; most affected children lose the ability to walk and talk by approximately six years of age, with death by 12. It affects about 1,200 to 1,600 children worldwide.

The filing was initially based on 48-week data from a single-arm, open-label phase I/II trial. In 21 patients the average rate of decline in motor-language CLN2 score was -0.43 versus -2.09 from natural history, giving a p value of <0.0001.

A 300mg dose of Brineura was given every 14 days by intracerebroventricular infusion over around four hours. Given the invasive nature of delivery all patients experienced at least one adverse event, and in seven patients there were 10 drug-related severe events, though there were no discontinuations or dose reductions due to adverse events.

The approval date for Brineura was extended by three months to April 27 after an FDA request for efficacy data from an ongoing extension study, which was designated as a major amendment. 81-week data showed prolonged attenuation of disease progression.

The agency said it planned an advisory committee meeting, but no confirmed date has yet been given, though this could be announced in the coming weeks. Brineura has US orphan drug and breakthrough designations, and a regulatory decision in Europe, where Brineura also has orphan drug designation, is expected by the third quarter.

Sales are forecast to reach $252m by 2022, according to consensus from EvaluatePharma. Biomarin suffered last year with the failure of its Duchenne treatments, and will be hoping for a better 2017.

Targeting amyloid

With numerous high-profile setbacks in Alzheimer’s disease attention now turns to Probiodrug and its attempt to inhibit glutaminyl cyclase or QC, an enzyme it says is instrumental in catalysing the conversion of beta amyloid into pyroglutamate beta amyloid (pGlu-Abeta). The German company says this form of amlyloid is linked to the formation of soluble, toxic “pre-plaques” that lie behind Alzheimer’s progression.

The double-blind phase IIa Saphir study tests PQ912 against placebo in 120 treatment-naive patients with early Alzheimer’s, dosing 800mg orally twice a day for 12 weeks. The primary endpoint looks at adverse events, while secondary outcomes include mini-mental state examination, changes in Alzheimer’s-related biomarkers in the cerebrospinal fluid, and change in brain function measured by MRI and electroencephalography. Data are due by early June.

A phase I trial in 205 healthy volunteers showed that PQ912 was safe and well tolerated, with the most frequently reported adverse events being gastrointestinal disorders and headache.

Lilly is noteable for looking at a similar approach, but using an antibody to target pGlu-Abeta. Its MAb is coded LY3002813, and phase I data were reported on it at last year's Alzheimer's Association International Conference, showing 10mg/kg to reduce amyloid plaque load by 40%, although there were just six patients in this trial; still, analysts at Rx Securities said the results validated Probiodrug’s strategy. A second phase I trial of LY3002813 is ongoing.

Probiodrug completed its IPO on the Amsterdam Euronext back in 2014, and its shares are down 24% over the past year. The company has €21.9m ($23.4m) in cash, but a licensing deal could be on the cards if data impress. However, Alzheimer’s has eluded big pharma thus far, and PQ912 could prove to be just another nail in the coffin for the amyloid hypothesis.

Project Trial ID
Brineura NCT01907087 (Ph I/II)
NCT02485899 (Extension study)
PQ912 NCT02389413 (Saphir)

To contact the writer of this story email Joanne Fagg in London at joannef@epvantage.com or follow @ByJoFagg on Twitter

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