Acer Therapeutics’ Edsivo (celiprolol) is not expected to win approval from the US Food and Drug Administration (FDA) for vascular Ehlers-Danlos syndrome (vEDS), as the registrational trial was too small and not well-controlled, according to experts.

Ehlers-Danlos syndrome treatment

EDS is a group of rare inherited conditions that affect connective tissue, of which vEDS is a rare type that is often considered to be the most serious. It affects the blood vessels and internal organs, which can cause them to split open and lead to life-threatening bleeding, according to the National Health Service.

An analyst report was optimistic about Edsivo’s FDA approval. It noted the previous data, as well as the fact that the drug is used as an off-label treatment in Europe and there is an unmet need in the US.

Celiprolol is approved as a beta-blocker for hypertension. However, while one expert interviewed expressed hope for approval based on off-label use and unmet need, she declined to comment on the data’s validity.

Trial size too small

Other experts interviewed said that given the trial comprised of 53 patients, the Phase IV trial (NCT00190411) was too small even for a rare disease like vEDS.

Furthermore, far fewer patients were recruited than the initial number needed to power the trial appropriately, said one of the experts.

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Additionally, many more patients with the collagen 3A1 (COL3A1) gene mutation was in the control group with no beta blockers rather than the Edsivo group, said the experts.

The COL3A1 mutation defines patients with vEDS, and thus non-vEDS patients may also have been included in the trial, one of the experts noted.

In terms of safety, while all the experts agreed that the trial results showed no red flags, two pointed to recently presented mouse data showing that Edsivo may increase death. While the data gave one of them pause, another expert cautioned on translating those results to humans.

Acer submitted a New Drug Application (NDA) to the FDA in October 2018 and has requested priority review for Edsivo, which could result in a late second quarter 2019 FDA review date, according to a company press release.

Sales are predicted to reach $400 million, according to the analyst report. Acer’s market capitalisation is $239 million. Acer declined an invitation to comment for this article.

Efficacy data not robust enough

The study that the approval of Edsivo would be based on was not well-designed, with an overall small trial size, said vEDS expert Dr Harry Dietz, Co-director of the Medical Genetics Fellowship Training Programme and Professor of Paediatrics at The Johns Hopkins Hospital, Baltimore, Maryland, US.

Only 53 patients were enrolled in the trial, indicating recruitment was likely to have been challenging, said Dietz, pointing out the trial was almost half the size that was initially targeted.

Lancet paper findings

The trial powering was based on enrolling at least 50 vEDS patients in each group, as 40 primary events were needed to achieve a power of 80% as cited in the Lancet paper where the study is published (Ong, K. et al. 2010 Oct 30; 376 (9751): 1476-84).

Additionally, the number of patients with vEDS is very low, which may have been the reason why so few patients were enrolled in the study, said Dr Paul Grossfeld, Pediatric Cardiologist with the Rady Children’s Hospital, San Diego, California and Francesca Cortini, PhD, Research Fellow at the University of Milan, Italy.

The Lancet paper stated that there were 87 individuals eligible for the study but 12 refused to participate and four were unable to move.

Eighteen subjects who were previously treated with beta blockers were included in the follow-up cohort. The frequency of vEDS is estimated to be 1 in 50,000 to 1 in 200,000 (Am J Med Genet C Semin Med Genet. 2017 Mar; 175 (1): 40-47).

While the major adverse cardiovascular events (MACE) primary measure is clinically significant, it can pose difficulties in recruiting patients, as an aortic dissection over five years is difficult to find, said Dr Grossfeld.

The MACE outcome measure in the clinical trials is a composite of clinical events that occur in patients. The Lancet paper stated that the reduction in the MACE primary outcome measure at a five-year follow-up was reached by five (20%) in the Edsivo group and by 14 (50%) controls (hazard ratio [HR] 0.36; 95% confidence interval [CI]; p=0.04), which is not a sufficient set of data to gain FDA approval, according to Dr Dietz and Dr Grossfeld.

The results indicate there were more patients on the placebo arm who had aortic rupture than the Edsivo arm, the expert added.

Besides the low patient figures, the imbalance between the experimental and control arms in terms of patients with the COL3A1 mutation means the results are also insufficient for FDA approval, said Dr Dietz and Dr Grossfeld.

Another study with the same number of patients with the mutation in each group or higher for both groups would be needed to identify the true Edsivo effects.

In the treatment group, 53% of the 25 patients in the Edsivo group had the mutation, while in the placebo group, 71% out of 28 patients had the mutation, the Lancet paper reported.

A trial that compares only patients with the COL3A1 mutation to placebo patients can best identify any clinically significant benefit with Edsivo, said Dr Grossfeld.

Furthermore, when patients do not have the COL3A1 mutation but exhibit similar symptoms, then they may have another disorder such as Loeys-Dietz syndrome. Therefore, some of the trial’s patients may have not even had vEDS.

In its press releases, Acer has not indicated another trial would be run; rather it says the data in the Lancet paper, with an Acer-sponsored retrospective source verified analysis of the trial data and manufacturing, non-clinical and other components of the regulatory package, will go into the NDA.

While Ms Cortini did not comment on the results’ potential to trigger FDA approval, she said she hoped Edsivo would be approved, as it has been used in Europe as an off-label treatment. In fact, she noted, it is the standard of care for vEDS in France.

Mouse safety data triggers debate

Although no safety concerns were identified in the clinical study, a recent mouse study for Edsivo showed an increase in death, said Dr Grossfeld.

The study, presented at the American Society of Human Genetics meeting in San Diego in October 2018 (presentation number 271), found that treating mice with Edsivo was associated with a significant acceleration of dissection and death in both vEDS models.

The result may have been caused by the mice’s genetic mutation, as it may not have been the same as those seen in clinical trial patients, said Dr Grossfeld.

The mouse data can thus be difficult to translate into human data, he and Cortini noted. Although the mouse genome is almost 80% the same as that of humans, there are also allelic differences in the COL3A1 gene, said Grossfeld.

The study used two knock-in mouse models of vEDS (Col3a1 G209S/+ and Col3a1 G772D/+).

The Lancet paper reported that adverse events were severe fatigue in one patient after starting 100mg Edsivo and mild fatigue in two patients related to dose uptitration.