• On October 27, post excellent reported interim results, Bio Blast announced the postponement of its phase 2 trial as redundant, and an early start of phase 3.
  • On December 9, ORPN changed its stance, rescheduled phase 3, and started a phase 2b trial.
  • Is this a cause of worry?


On Tuesday, via email, I asked Mr. Colin Foster, CEO of Bio Blast (NASDAQ:ORPN), why did you first postpone a phase 2 trial, plan an early phase 3 trial, then stop the phase 3 and go back to doing what you call a phase 2b trial?

In September, as part of an article, I had asked him the first part of this question, when the news of the stopped phase 3 was not out yet. Mr. Foster had given an interesting answer to the first part of that question; ORPN stopped phase 2 and went directly for the phase 3 because phase 2 provided excellent results at 25 patients and the company thought it would move the remaining patients to phase 3. He used the word "precious" when describing OPMD patients. It is a rare disease, and he didn't want to use up the few available patients in phase 2 when it had already done so well; he wanted to retain them for the phase 3.

So, now my question is, why did it change that position and return to a phase 2 (2b) again? Did the results somehow change, or did the FDA tell the company to complete that trial, or was it an internal decision?

About the abandoned phase 2 trial, Professor Bernard Brais, MD, M.Phil., PhD, FRCP(C), Professor, Department of Neurology and Neurosurgery and Human Genetics, Faculty of Medicine, McGill University, Co-director Rare Neurological Diseases Group at the Montreal Neurological Institute, was the Principal Investigator in the study.

What I understand is that, this was supposed to be an 18-month, 74-patient trial. After the company enrolled 25 patients, and six months into the trial, it did an interim analysis and found excellent results in various muscle group strength tests, functional muscle tests, drinking tests, and patients reported quality of life. Oculopharyngeal muscular dystrophy, or OPMD, if you recall, is a disease that sets in around 40, and is characterized by muscular weakness. It is quite rare in the general population, but is more prevalent in French Canadians and Bukhara Jews. So patients are hard to come by.

The unexpected good results, paraphrased from the press release:

Safety and Tolerability - Cabaletta was well tolerated and no patients discontinued the study.

Penetration Aspiration Score (VFS-PAS) - Out of 12 patients whose scores were evaluated by VFS-PAS, 10 patients (83.3%) showed stabilization (4 out of the 10) or improvement (6 out of the 10) in their VFS-PAS scores. Seven patients enrolled in Canada had a baseline and 24-week VFS-PAS score. Five of the 7 patients had stable (3 out of the 7) or improved (2 out of the 7) VFS-PAS scores while 2 patients deteriorated. Five patients enrolled in Israel who did not have a scheduled baseline score had an unscheduled VFS-PAS evaluation performed after being on treatment for varying amounts of time ranging from one to four months. The results of this unscheduled evaluation were compared to the results obtained after 24 weeks of therapy. All 5 patients enrolled in Israel were stable (2 out of 5) or improved (3 out of 5). Seven baseline VFS-PAS measurements recorded in Israel were uninterpretable due to faulty radiological procedure and were excluded from the interim data set.

Timed Drinking Test - There was a statistically significant 35.3% improvement versus baseline (p<0.0001) in the timed drinking test (80mL cold water), a test for swallowing dysfunction.

Swallowing Quality of Life (SWAL-QOL) - Demonstrated a statistically significant improvement in the mean reported symptom severity score from baseline through to 24 weeks. (p=0.0448, n=21).

Muscle Strength Tests - The composite score of three lower extremity muscle strength tests showed a statistically significant improvement over baseline of 13.4% (p=0.0059, n=19). 13.9% in knee extension (p=0.0058), 24.3% in foot extension (p=0.0381). Hip flexion did not achieve statistical significance but had a numerical improvement of 3.5% (p=0.4348).

The composite score of two upper extremity muscle strength tests (comprised of shoulder abduction and arm flexion) showed a numerical improvement of 12.9% versus baseline, but did not achieve statistical significance (p=0.0836, n=19).

Functional Muscle Tests - The 30 second arm-lift test showed a statistically significant improvement of 17.6% (p=0.0191, n=18) while the 30 second sit-to-stand test showed a numerical improvement of 14.1% versus baseline (p=0.0682, n=18). Notably, this latter test showed a statistically significant improvement in absolute numbers with a p=0.0160. In the standard 4-stair climbing test, importantly, no deterioration was observed but there was no statistically significant improvement.

That's a lengthy quote, and you don't need to go through the entire thing, but the basic point, as OPRN underscored, is that excellent results were obtained in relation to the key symptoms of OPMD, namely swallowing and muscle weakness. Both achieved statistically significant improvement. Here's a capsule of the data:

(click to enlarge)


So, although it is a little unusual, it does make some sense to decide to proceed directly to a phase 3 at this stage rather than wait 12 more months, double and triple verify the same good results, spend more investor money, "use up" patients in a rare disease, and then begin a phase 3.

Here's the statement the CEO made at the time, October 27 to be precise:

These results support our plan to move forward with a pivotal Phase 3 study in OPMD following pending meetings with regulatory authorities…Following these interactions and based on the open IND, Orphan Drug designation, and Fast Track designation we have been granted for this program, our goal is to advance with a Phase 3 study in the U.S. and in Canada.

Less than two months later, however, here's what was said in an apparent volte-face:

Based on the positive data from the HOPEMD study, the Company intends to conduct a double-blind, placebo-controlled, Phase 2b study to augment the existing data package for Cabaletta and to further guide the design of a future pivotal Phase 3 study. Therefore, at this time, and in advance of discussions with regulatory authorities, the Company does not anticipate commencing a Phase 3 Cabaletta clinical study in 2016 in either OPMD or spinocerebellar ataxia type 3 (SCA3) patients.

No wonder the stock plunged quite a few points in the aftermath. Being a micro-cap relatively unknown, the market, already plagued by a suffering biotech, assumed the worst.

However, looking at the excellent claimed results, I believe the change in strategy is a minor issue. Notably, it does not have anything to do with a reevaluation of the results, because, as we just saw, the interim results were quite convincing. The company also hasn't disclosed any guidance from the FDA as a cause of the strategy change. So, in my opinion and unless otherwise stated, it seems that this was an internal decision to follow the proper pathway to an NDA and not jump a step. I think somebody figured that the FDA would anyway tell the company to complete the phase 2, or 2b, whatever you want to call it - so why wait for it to tell that.

I only wish Mr. Foster would have clarified that for us.