Capricor Therapeutics Inc. CEO Linda Marbán told BioWorld that the anaphylaxis case that caused her firm to suspend dosing voluntarily in the blinded, pivotal Hope-2 trial with stem cell therapy CAP-1002 was "likely caused by something in the infusion solution. Because the timing of the reaction was so immediate – literally within one minute of the beginning of the infusion – the immunologists that we've consulted do not believe it was related to cells, even if the patient was on cells."

The reaction "was handled exactly correctly" and the patient went home the next day with no further problems, Marbán said. "We have a list of suspects and we're looking for the criminal," though such pinpointing is "very difficult in allergy situations," she noted. "Physicians are not worried about this. It happens a lot." Capricor disclosed the dosing hold in an 8-K filing.

CAP-1002 consists of allogeneic cardiosphere-derived cells that have been shown in previous experiments to provide immunomodulatory activity and stimulate cellular regrowth. Maxim analyst Jason McCarthy pointed out that it's unclear if the allergic reaction is related to CAP-1002 cells, placebo "or some other factor. Although we are not changing estimates as we are hopeful for a quick resolution, as of now, the timing of the delay and when/if the trial will resume is unknown." He lowered his rating to "hold" from "buy" and removed his price target.

Shares of the company (NASDAQ:CAPR) closed Thursday at 32 cents, down 4 cents.

Next comes a controlled unblinding of Hope-2 by scientists who will determine whether the patient was on active drug or placebo, Marbán said. Documentation of the anaphylaxis event has been submitted to the FDA, and a layout of the proposed mitigation strategy will follow "within the next week or so," she said, expecting about "a 60-day process from, 'Oh my gosh, this happened' to 'OK, let's infuse the next patient.'" Before taking part in the trial, patients could be treated with antihistamines or potentially steroids; regulators will have the final word.

Hope-2 is an 84-patient, randomized, double-blind, placebo-controlled study with a focus on non-ambulatory patients with DMD, using the intravenous route to deliver 150 million cells over four infusions in a year and deploying improvement on the Performance of the Upper Limb test as the primary endpoint, important because wheelchair-bound DMD patients need upper-arm muscles to stay mobile, eat and otherwise take care of themselves.

Capricor's holdup with Hope-2 cast a dark, albeit small, cloud over an encouraging meeting this month with the FDA. "We can't release our full clinical development plan until we get the minutes back, which will be in the next couple of weeks," Marbán said. "But what I can say is that the FDA is very supportive of the program."

The Hope-2 hitch came around the same time that Sarepta Therapeutics Inc., of Cambridge, Mass., finished the rolling NDA filing for golodirsen to treat exon 53 skip-amenable DMD. Leerink analyst Joseph Schwartz wrote in a report that, "with Exondys51 for exon 51 skip-amenable DMD on the market, and revenue guidance of $295 million to $305 million for fiscal year 2018, and [the company's] potentially curative microdystrophin gene therapy programs for DMD rapidly advancing in the clinic, the complete NDA submission of golodirsen places another drug candidate closer to commercial territory." He had previously raised his probability of U.S. success estimate to 90 percent from 75 percent in anticipation of the NDA filing's finish, and he continues to peg the chances at 45 percent in Europe. In early October, Sarepta made headlines with its gene therapy in DMD. Phase I/II data in four boys given AAVrh74.MHCK7.micro-dystrophin showed a good safety profile after nine months of follow-up. About a month after disclosing the data, Sarepta raised $500 million in a public offering. (See BioWorld, Oct. 5, 2018.)

Of show stoppers and 'nothing burgers'

Others have met with setbacks in DMD. At the end of August, New York-based Pfizer Inc. put the kibosh on a pair of phase II studies testing its DMD drug, domagrozumab, after finding the anti-myostatin candidate offered boys with DMD no more benefit than a placebo during a stair-climbing test. The prospect was one of 15 programs the company had identified as potential blockbuster medicines, and the company said it would keep an early stage gene therapy drug in development. Solid Biosciences Inc., of Cambridge, Mass., has a gene therapy in DMD, too: SGT-001, undergoing phase I/II testing.

The Pfizer fizzle raised phase II discontinuations in DMD to six across varied mechanisms of action, according to Cortellis Analytics Drug Attrition Rates data. Summit Therapeutics plc, of Oxfordshire, U.K., gave up on the small-molecule utrophin modulator ezutromid over lack of efficacy in June. San Rafael, Calif.-based Biomarin Pharmaceutical Inc. abandoned exon-skipping candidate Kyndrisa (drisapersen) in May 2016, as well as its follow-ons, rimigorsen (BMN-044), BMN-045 and BMN-053. And Shire plc, of Dublin, washed its hands of the Acceleron Pharma Inc.-sourced myostatin inhibitor ramatercept in May 2013. (See BioWorld Today, June 2, 2016, Aug. 31, 2018, and June 28, 2018.)

Still, optimism prevails in many quarters. Santhera Pharmaceuticals Holding AG, of Pratteln, Switzerland, recently beefed up its DMD franchise in an option deal to license rights to vamorolone, a new class of steroid drug designed to reduce side effects and allow for longer-term treatment than is possible with glucocorticoid therapy. Under the terms of a deal with Allschwil, Switzerland-based Idorsia Ltd., Santhera made an up-front cash payment of $20 million and issued Idorsia with 1 million new shares. An option included in the arrangement will be exercised – or not – when the ongoing phase IIb pivotal study of vamorolone reports around August 2020. (See BioWorld, Nov. 26, 2018.)

Other contenders include Cambridge, Mass.-based Wave Life Sciences Ltd., which this month rolled out phase I news with WVE-210201, a stereopure antisense oligonucleotide (ASO) shown to induce skipping of exon 51 of dystrophin pre-mRNA in preclinical studies and boasted "no significant safety finding [but] without any supporting data," H.C. Wainwright analyst Debjit Chattopadhyay said in a report. "However, this was a single ascending-dose (SAD) study in boys with a diagnosis of DMD amenable to treatment with an exon 51 skipping antisense oligonucleotide, hence we were not expecting any show stoppers." The study has been open to ambulant as well as non-ambulatory boys ages 5 to 18. The SAD study included five cohorts with an anticipated enrollment of eight patients per cohort, with some patients in each cohort randomized to placebo, "and the design closely mimics the drisapersen SAD study," he noted, adding that Wave's "press release indicated the selection of a phase II/III dose, which was the dose from the fourth cohort, where the data safety and monitoring committee [DSMC] has allowed enrollment into cohort five. This was confusing at first glance, but turned out to be a nothing burger and per protocol, in our view."

The full SAD data could spill at a medical conference during the first half of next year, including data from the fifth cohort, but "the more relevant read on the safety and differentiation of stereopure ASOs are likely to come from the ongoing open-label extension [OLE] study," he said. "Management indicated the decision not to divulge additional safety details, considering the fifth cohort's enrollment was recently initiated and in the ongoing OLE program, patients are being maintained at the dose from their respective cohorts. While we do not have a handle on the doses that were explored in the SAD study, we view the DSMC's decision to allow the exploration of highest planned doses as a positive."

In late November, Catabasis Pharmaceuticals Inc. disclosed that data from the phase I MoveDMD study edasalonexent (CAT-1004) were published in the Journal of Neuromuscular Diseases. The oral small molecule was well-tolerated in pediatric patients and the results showed that it inhibited NF-kB, a key link between loss of dystrophin and disease progression. MoveDMD is a multipart experiment including phase I, phase II and an on-going open-label extension study. Catabasis is enrolling the phase III study called PolarisDMD.