Celiprolol May Be Protective in COL3A1-positive Vascular EDS

The therapy celiprolol may have a protective effect in COL3A1-positive patients with vascular Ehlers-Danlos syndrome (vEDS), according to results of a long-term study.

The data were published in the European Journal of Vascular & Endovascular Surgery, in the article “Celiprolol Treatment in Patients with Vascular Ehlers-Danlos Syndrome.”

Considered the most severe form of EDS, vEDS is marked by impaired production of the tissue’s structural protein collagen, often due to mutations in the COL3A1 gene. Patients with vEDS can experience ruptures, such as colonic perforation (when the tissue of the colon tears) or arterial rupture (when the wall of an artery tears). The disease has no approved treatment options.

Acer Therapeutics is developing a therapy called Edsivo (celiprolol) for the treatment of vEDS. Celiprolol is used to treat hypertension (high blood pressure), and it is thought to benefit vEDS patients by reducing blood pressure in vessels most prone to dissection and rupture, and by promoting normal collagen synthesis in blood vessels.

At the end of 2018, Acer submitted a new drug application (NDA) for Edsivo as a vEDS treatment, after being granted orphan drug designation by the U.S. Food and Drug Administration (FDA) in 2015. However, in June 2019, the FDA issued a complete response letter denying the application.

At the end of 2019, Acer issued a Formal Dispute Resolution Request (FDRR), a formal appeal of the FDA’s initial denial. In March 2020, the FDA responded to the FDRR and the agency reaffirmed its earlier decision that further clinical trial data supporting the therapy’s effectiveness were needed before Edsivo could be approved for vEDS.

“Since our meeting with the FDA’s Office of New Drugs (OND) last February, we have been working diligently to evaluate various forms of confirmatory evidence needed to meet the substantial evidence standard (…) We intend to submit a request to the FDA in the next several weeks for a meeting to discuss the appropriateness of our approach,” Chris Schelling, CEO and founder of Acer Therapeutics, said in a press release.

In 2010, the French/Belgian Beta Blockers in Ehlers-Danlos Syndrome Treatment (BBEST) trial (NCT00190411), evaluating the protective effect of celiprolol on cardiovascular events, reported that the number of serious vascular events could be halved by treating vEDS patients with celiprolol.

Now, researchers at Uppsala University Hospital, a national referral center for vEDS patients in Sweden, described the long-term outcomes of celiprolol treatment in a group of 40 vEDS patients (60% female, mean age 43.5 years), from 2011 to 2019. Median follow-up was 22 months (ranging from 1 to 98 months). All patients had disease-causing mutations in the COL3A1 gene.

Patients received celiprolol twice daily (titrated up by 100 mg steps to a maximum of 400 mg daily) and were clinically monitored by a multidisciplinary team. Family history, clinical events, medication, and side effects were registered. Data was analyzed using appropriate statistical models.

Most of the patients had either a strong family history of genetically verified vEDS (26 patients, 65%), or first-degree relatives with suspected vEDS (14 patients, 35%).

Some patients were treated separately or in combination with other medications — namely, angiotensin-converting enzyme inhibitors, angiotensin II inhibitors, beta blockers, calcium channel blockers, and diuretics.

Before the start of treatment with celiprolol, 16 patients (40%) had one or more vascular manifestations, such as arterial dissections or spontaneous bleeding.

At the end of follow-up, 26 patients (65%) reached the target dose of 400 mg daily. Eight patients did not achieve maximum dose, either because of side effects (six patients) or short follow-up time (two patients). One patient died before reaching the maximum dose and five discontinued treatment.

Side effects were experienced by 14 patients. The most common being dizziness, abnormal tiredness, headache, and nausea. Most of the side effects were temporary and improved after dose reduction.

Major vascular events occurred in five patients during treatment, four of which were fatal.

The annual risk of a major vascular event was 4.7% in this group, similar to that observed in the celiprolol treatment group of the BBEST2 trial (5%) and lower than in the BBEST trial control group (12%). No significant predictor of vascular events was identified.

Researchers noted some limitations to the Swedish study, including the low number of patients.

Nonetheless, the team concluded that “treatment with celiprolol is well tolerated in most patients with vEDS” and suggested that “celiprolol has a protective effect in patients with vEDS.”

“The results from this long-term registry study and the increasing length of follow-up provide further evidence of celiprolol’s potential protective effect in COL3A1-positive vEDS patients,” said Martin Björck, MD, PhD. Björck is the study’s senior author and professor emeritus of vascular surgery, Department of Surgical Sciences at Uppsala University.

“Dr. Björck is an incredibly well-respected vascular specialist in Europe. We are encouraged by his team’s results that add to the growing body of evidence in support of celiprolol’s potential benefit in treating COL3A1-positive vEDS patients,” Schelling added.