番茄社区

LONDON -- An investigational drug aimed at remyelinating damaged axons missed its primary endpoint in a phase IIb trial, researchers reported here.

In the SYNERGY study, there was an "inverted U-shaped dose-response" for the composite clinical endpoint among patients on one of four doses of opicinumab (anti-LINGO-1) instead of the linear trend that was expected, , of Biogen, at the .

Additionally, there was a far higher placebo response than expected, at 52% compared with the anticipated 40%, he said.

"This was a difficult study, and we have learned a lot. We believe we have identified the appropriate patient population, dose, and exposure, as well as endpoints to inform the next study."

Cadavid said the company is "in the process of evaluating the optimal study design ... and we welcome any insights or ideas as we try to interpret these data."

There was much excitement about anti-LINGO when results from the RENEW trial reported at last year's American Academy of Neurology annual meeting showed that the candidate remyelinating agent improved nerve signaling in acute optic neuritis. But hopes were dashed when Biogen released disappointing top-line results from SYNERGY earlier this summer.

The SYNERGY study enrolled both relapsing-remitting (80%) and secondary progressive (20%) MS patients who had some form of disability at baseline given that the "primary objective was to test something we believe had never been done before -- to use a remyelination strategy to treat pre-existing disability," Cadavid said.

Patients were randomized to placebo or to one of four doses of the drug -- 3 mg/kg, 10 mg/kg, 30 mg/kg, or 100 mg/kg -- and were also given interferon beta (Avonex) concurrently. Participants were treated for 72 weeks, with final follow-up at week 84. At that point, about 130 patients finished the trial, which limited its power, Cadavid noted.

"This was a learning trial to try to get critical information about the dose, the clinical endpoints that may move with remyelination, and the type of patients that could benefit," Cadavid said.

The primary endpoint was the percentage of patients with improvement in disability as measured by a composite endpoint of Expanded Disability Status Scale score, Timed 25-foot walk test, 9-hole peg test, and the 3-second Paced Auditory Serial Addition Test.

Cadavid reported that his team saw good pharmacokinetic data, with a linear dose-response increase.

Still, the drug failed to meet its primary endpoint, and the researchers instead saw the inverted U-shaped dose response, which was not significant for the linear trend test (P=0.8931).

For every individual outcome of the composite, there was also an inverted-U response, Cadavid reported.

In further analyses, the team found that the drug worked better for younger patients (those under age 40), those with relapsing-remitting disease, and those with a shorter disease duration (8 years or less). There was also an advantage among patients with less whole brain volume loss at baseline, he said.

The drug was generally well tolerated, although there were hypersensitivity reactions in the highest dose group, and weight gain with all drug groups -- "which looked real, and had been seen before in RENEW."

He concluded that sub-analyses revealed "biological markers that are valuable to informing future steps."

, of Hôpital de la Salpêtrière in Paris, who was not involved in the study, said that remyelinating therapies "are fascinating, but we crucially need markers to assess repair."

"Probably with the trial design we have at the moment, we are not in good condition to assess repair efficacy," Lubetzki said. "This would be my key concern."

Also commenting, , of Ohio Health, who also was not involved in the study, agreed that additional biomarkers are needed -- although that has been a challenge given that brain and spinal cord biopsies are not an option.

While learning the selection criteria for a future trial was helpful, it indicates a population very different from those who have a greater need for treatment: older patients and people with more progressive disease, she said.

"It was disappointing not to see a dose-response trend," Nicholas told 番茄社区. "I don't think it's surprising that younger patients and those with better brain volume at baseline tended to respond. I also think it was really striking how well the placebo group did.

I think this deserves another phase II trial," she added.

Comment