The Marfan Foundation Statement on Celiprolol

On June 25, 2019, the FDA announced that it has rejected Acer Therapeutics’ application for exclusive use of the third generation beta blocker celiprolol in the US for the treatment of people with vascular Ehlers-Danlos syndrome (vEDS). This is a rare (about 1/50,000 in the US) genetic condition that results from mutations in one copy of the COL3A1 gene (which encodes type III collagen) and is complicated by arterial aneurysm, dissection, and rupture which can lead to premature death.wisepoqder Celiprolol powder

The Marfan Foundation, as well as representatives of its Professional Advisory Board, have reviewed the underlying studies of the drug and agree that celiprolol does not warrant designation as a sole approved drug for the treatment of people with vEDS (see background below). The Foundation recommends that registries of affected individuals with COL3A1 mutations be assembled quickly to facilitate informative clinical trials.

Patients should be aware that there are similar third generation beta-blockers, such as carvedilol, nebivolol, and labetalol, available in the US that are being prescribed off-label for this condition. Both carvedilol and labetalol are generic; therefore, they are very low in cost, and nebivolol will soon come off patent. However, there are no trials or long-term studies utilizing these drugs investigating protective effects in this population.

We suggest that optimal future trial design require molecular confirmation of diagnosis and take into account the type of mutation in a given patient as well as prior medical and surgical history, including vascular events and interventions. The outcomes need to be rigorously defined and ascertained by individuals who are unaware of treatment status in order to avoid bias. The assignment of an individual to the celiprolol or control (no or alternative treatment) group needs to occur at random and be maintained throughout the study.

This proposed prospective, randomized, placebo-controlled, double-blinded, and intention to treat study design is standard in the field and is the most powerful and definitive way to assess for benefit or absence of benefit for celiprolol in vEDS. It is also essential that the study be of sufficient size to reach robust conclusions – including both the number of individuals treated with celiprolol and those receiving placebo or alternative therapy. Alternative medications for testing might include other beta-blockers that are currently available in the US and are inexpensive or other medications that have demonstrated protective effects in animal models. The costs for the trial will be significant, given the nature of surveillance that will probably be needed, and support from multiple sources will have to be obtained.

The Marfan Foundation is eager to assist in protocol design, generation of funds, patient recruitment, and education of both patients and their healthcare providers, as it did with the Pediatric Heart Network Study of the angiotensin-receptor blocker losartan in Marfan syndrome.

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