Escape velocity? Bioblast phase II could open door to remedy in rare OPMD

By Randy Osborne, Staff Writer

Bioblast Pharma Ltd. CEO Colin Foster told BioWorld Today “it would not be unreasonable to think” that regulators could deem pivotal the upcoming phase IIb trial with trehalose in oculopharyngeal muscular dystrophy (OPMD), but the company doesn’t count on that. “We’re looking forward, recognizing that we [probably] have to do a phase III study,” he said.

Shares of New Haven, Conn.-based Bioblast (NASDAQ:ORPN) closed Wednesday at $4.20, up $1.56, or 59 percent, having traded as high as $7.95 after the firm disclosed phase II data from its HOPEMD trial testing the disaccharide trehalose, known for its ability to stabilize intracellular and intranuclear proteins. The experiment aimed to learn about safety and tolerability – trehalose passed in those departments – but also included secondary endpoints to see if the drug improved, or at least prevented worsening, of markers in rare disease OPMD. It rang bells there, too.

An inherited myopathy, OPMD is characterized by dysphagia (difficulty in swallowing), eyelid drooping, or ptosis, as well as loss of muscle strength and weakness. Specifically, it’s a polyalanine-mutation disease with onset around middle age.

“On some highly consequential proteins associated with normal muscle homeostasis, you’ve got a particular protein that ends up having too many alanines stuck on the back,” Foster said, which “creates just a mess. It’s almost like a dust bunny under your bed.” Proteins can’t fold properly, leading to symptoms, and patients become emaciated because they are unable to eat normally.

“They’ve lost the reflex to get rid of food that goes down their windpipe,” he said, and suffer repeated bouts of aspiration pneumonia, which can lead to death.

“It’s an insidious, one-way disease,” Foster said. “For the muscle weakness, there’s nothing. You’re stuck with it.” Surgery may help swallowing. “Literally, [surgeons] seek to expand the size of your throat, allowing food to plop down more easily into the esophagus.” But the benefits only last about 15 months on average.

“That gives you an idea how accelerated this disease is, even on the dysphagia side,” he said, noting “a tremendous amount of apathy among the undiagnosed. They know what the future holds. I got a call from a guy on Long Island the other day” whose father is afflicted. The son “doesn’t want to be like that, but he’s already got symptoms that are going to set him on the same course as his dad. People are looking for solutions, for sure.”

In the open-label trial, data from which were reported Wednesday at Myology 2016, a muscle conference in Lyon, France, 25 patients with OPMD clinical dysphagia and muscle weakness were enrolled at two centers in Canada and Israel. All have completed 24 weeks of weekly treatment, and Bioblast reported improvements vs. baseline in multiple secondary efficacy endpoints related to dysphagia along with muscle strength and function.

POTENTIAL TAKEOUT: ANALYST

The dysphagia endpoints were the timed cold water drinking

test (80 mL) for all sites, the nectar (80 mL) and honey (80 mL) timed drinking tests at the Canadian site, and the Penetration Aspiration Score as measured by video fluoroscopy (VFS-
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PAS), a radiographic technique to determine the severity of swallowing difficulties and risk of aspiration. One patient- reported, swallowing quality-of-life questionnaire (SWAL-QOL) specifically developed for patients suffering from swallowing problems was employed to assess the degree to which patients felt that their swallowing capability improved with treatment.

A mean reduction in time to complete the cold water drinking test of 31.8 percent turned up vs. baseline (n=23). In the nectar and honey timed drinking tests, time to complete was reduced by 43.8 percent and 46.6 percent, respectively (n=11). Out of the 11 patients in Canada whose scores were evaluated in the per- protocol analysis of the VFS-PAS, six patients improved (54.5 percent), two showed stabilization (18.2 percent), and three deteriorated (27.2 percent). Due to deviations from protocol and deficient radiological procedures, the VFS-PAS tests from the Israel cohort were excluded from the final analysis. With respect to the SWAL-QOL questionnaire, there was a 12.7 percent (n=24) improvement vs. baseline with the mean total symptom severity score increasing from 43.2 to 48.7.

As measured quantitatively by a digital hand-held dynamometer, a mean increase was recorded in lower body-muscle strength compared to baseline in knee extension of 15 percent (n=22)

and foot dorsiflexion of 22.4 percent (n=22). Hip flexion did not materially change (1.3 percent deterioration, n=21). For the upper-extremity strength tests, arm (bicep) flexion increased on average 17.9 percent (n=22), and shoulder abduction by 11.4 percent (n=22).

The 30-second arm-lift test showed a 16 percent increase in the number of completed tasks (n=20) at 24 weeks of treatment vs. baseline, while the 30-second, sit-to-stand test showed a

16.6 percent increase (n=21). In a standard, four-stair climbing test, the results didn’t change much (1.5 percent deterioration, n=21).

“When we talk to our neurologists, they say [hip flexion] one of these things that’s going to be very difficult to change,” Foster said. The stair-climbing scores may not provide a good picture “because, in that particular test, you’re not really testing single- muscle strength performance” – a group of muscles is involved. Bioblast’s phase IIb trial is expected to start around mid-year, he said.

The long shot of approval based on the pair of phase II studies could pan out “if we design the study appropriately and execute well and have some very good data at the end of it, confirming the positive effect [or] perhaps even accentuating the positive effect, because people won’t be compared to baseline but to people who are on placebo,” he said, estimating the phase

IIb will enroll “between 40 and 80 patients. That’s sort of the realm. It’s a very manageable trial.”

Starting coverage in January and calling Bioblast “underrated,”

Rodman & Renshow analyst Raghuram Selvaraju estimated peak sales of trehalose in OPMD alone at $600 million. The drug is also in phase II development for spinocerebellar ataxia type 3. Merger-and-acquisition transactions “in the orphan sector involving firms with narrower pipelines than Bioblast have taken place at much higher valuations,” he wrote in a research report, pointing to the buyout of Lexington, Mass.- based Synageva Biopharma Corp., a single-product orphan drug company, by Alexion Pharmaceuticals Inc., of Cheshire, Conn., for $8.4 billion, which happened before Synageva won approval for its sole clinical asset, Kanuma (sebelipase alfa) for lysosomal acid lipase deficiency. (See BioWorld Today, May 7, 2015, and Dec. 9, 2015.)

OPMD is known to affect about 6,000 people in the U.S. “We fully expect, knowing how these things happen, there are probably two to three times that number who are undiagnosed, and frankly, some market research tells us the number could even be higher than that,” Foster said.

Efficacy and speed were two things that together made up “a little bit of a eureka moment,” in the currently reporting trial, he added, but Bioblast needs to “prove it the old-fashioned way” with the phase IIb, double-blind, placebo controlled study. “I’m feeling very good,” he said. “We’ve got something.” //

Escape velocity? Bioblast phase II could open door to remedy in rare OPMD

POTENTIAL TAKEOUT: ANALYST

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