DUBLIN – Shares in Celyad SA fell 40 percent in Brussels Tuesday on news that its C-Cure stem cell therapy failed to reach the primary endpoint of a phase III trial in patients with congestive heart failure.
C-Cure comprises autologous bone marrow-derived stem cells that are reprogrammed ex vivo, using a proprietary cocktail of growth factors, to become cardiopoietic cells. The primary endpoint of the Chart-1 placebo-controlled study, which recruited 271 patients, was a composite measure based on mortality, worsening of heart failure events, quality of life, six-minute walk test performance, end systolic volume and ejection fraction.
The company, based in Mont-Saint-Guibert, Belgium, plans to report the full dataset at the European Society of Cardiology (ESC) Congress in Rome on Aug. 28. Because of the ESC embargo, CEO Christian Homsy was unable to comment on the performance of the therapy with respect to each of the individual elements of the endpoints.
The firm will also have to wait until the ESC meeting to unveil "potentially significant information," he told BioWorld Today, on whether all patients in the trial received an adequate dose of cells to the right area of the heart.
The company is, nevertheless, setting out its stall on the basis of a post-hoc analysis, which detected an efficacy signal in about 60 percent of the study population defined on the basis of their baseline End Diastolic Volume (EDV) readings. Patients within a specific range of EDV values exhibited either a statistically significant difference or a strong trend with respect to all the components of the primary endpoint, the company said. They represent about 20 percent of the wider heart failure patient population.
EDV is a measure of the volume of blood present in the heart ventricles immediately prior to systole or contraction. Patients' EDV readings have emerged in recent years as a widely accepted predictor of response to heart failure therapies, including drugs, cell therapies and devices. The Chart-1 protocol, which was prepared in 2012, did not include the measure prospectively, however. "We should have known better, to be frank," Homsy said.
The range of values that correlated with a positive response was identified on a post-hoc basis, but the stratification was internally consistent with other disease parameters, Homsy said. The company now wants to assess the significance of its observation prospectively, by amending the protocol of a U.S. phase III trial of C-Cure. That will not result in any major delay, Homsy said, as it simply involves adjustments to the study's inclusion and exclusion criteria. It will also seek breakthrough therapy designation from the FDA.
Homsy cited San Diego-based Celladon Corp.'s Cupid 2 trial in 25 patients – the program was ultimately unsuccessful – as a precedent. "We have north of 160 patients showing responses, so I think that's doable," he said.
The company also plans to seek conditional approval in Europe, on the basis of the Chart-1 study. "We are not confident, but we are hopeful that we can convince the regulator that some patients suffering from heart failure respond to this therapy," Homsy told a conference call audience. Whether that is a realistic avenue to explore will soon become apparent. "We expect to have that guidance in the next three to four months, as soon as we've had a meeting with the European Medicines Agency," he said.
The company does not plan to conduct any further trials itself, however, so the therapy will only advance into a second phase III study if Celyad succeeds in landing a partner. Talks with potential partners have been ongoing – and the company is also considering a spinout with a prospective investor, a move that would enable it to concentrate fully on immuno-oncology, an area it entered last year through its acquisition of Oncyte, the immuno-oncology arm of Lebanon, N.H.-based Celdara Medical LLC.
Trading in Celyad shares (Brussels:CYAD) was halted during the conference call, but the stock plummeted on resumption. It ended the day at €23.52 (US$25.98), a loss of €15.955.
Heart failure has been unhappy territory for a clutch of cell and gene therapy developers. Celyad's news followed a recent move by Teva Pharmaceutical Industries Ltd. to return rights to MPC-150-IM, a mesenchymal precursor cell therapy, to its developer Mesoblast Ltd. Shortly before that, Celladon's Mydicar (AAV1/SERCA2a) gene therapy also missed in the phase IIb Cupid 2 trial. (See BioWorld Today, April 28, 2016, and June 15, 2016.)
Meanwhile, there was more positive news for another European cell therapy developer, as Milan, Italy-based Molmed SpA received a positive recommendation late last week from the EMA's Committee for Human Medicinal Products for Zalmoxis, a method for improving the safety of allogeneic, haploidentical hematopoietic stem cell transplants.
The approach involves the ex vivo engineering of donor T cells to express a suicide gene encoding the herpes simplex virus thymidine kinase. Should graft-vs.-host disease develop, that allows doctors to eliminate the transferred T cells with the antiviral drug ganciclovir.
Molmed has gained a recommendation for conditional approval on the basis of clinical studies in which 45 patients who received Zalmoxis had a survival rate of 49 percent vs. 37 percent for external controls who had undergone a similar procedure without Zalmoxis.