EDSIVO™ (celiprolol) for Vascular Ehlers-Danlos Syndrome (vEDS)

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Ehlers-Danlos syndrome (EDS) is an autosomal inherited disorder caused by mutations in the genes responsible for the structure, production, or processing of collagen, an important component of the connective tissues in the human body, or proteins that interact with collagen. EDS is a spectrum disorder where patients present with various forms, the most serious of which is vEDS, also known as vEDS type IV, which is generally caused by a mutation in the COL3A1 gene resulting in reduced collagen levels. vEDS causes abnormal fragility in blood vessels, which can give rise to aneurysms, abnormal connections between blood vessels known as arteriovenous fistulas, arterial dissections, and spontaneous vascular ruptures, all of which can be potentially life-threatening. Gastrointestinal and uterine fragility or rupture also commonly occur in vEDS patients. Spontaneous arterial rupture has a peak incidence in the third or fourth decade of life in vEDS patients but may occur earlier and is the most common cause of sudden death in vEDS patients. Arterial rupture or dissection events occur in about 25% of patients before the age of 20 but increase to roughly 90% of patients by the age of 40. The median survival age of vEDS patients in the U.S. is 51 years, with arterial rupture being the most common cause of sudden death.1 Pregnancy-related complications also occur in women with vEDS and include arterial dissection or rupture, uterine rupture, hemorrhage, premature rupture of membranes, lacerations, and complications during and after surgery.

Based on an analysis of diagnosed vEDS patients from the Truven MarketScan® database and U.S. population data, Acer projects the total COL3A1-positive vEDS patient prevalence in the U.S. could be as high as 7,000 patients.

Current Treatment Options for vEDS and Rationale for EDSIVO™ in vEDS
Currently, there are no approved pharmacologic therapies anywhere in the world for vEDS. However, celiprolol, off label, has become the standard of care therapy for vEDS in Europe.2 Medical intervention for vEDS focuses on surgery, symptomatic treatment, genetic counseling, and prophylactic measures, such as avoiding intense physical activity, scuba diving, and violent sports. Arterial, digestive, or uterine complications in vEDS patients typically require immediate hospitalization, observation in an intensive care unit, and sometimes surgery. Pregnant women with vEDS are considered to be at risk and receive special care.

While vEDS patients are encouraged to take steps to minimize the chances of an arterial rupture or dissection, there are no pharmacologic options to reduce the likelihood of such an event, and accordingly current treatments for vEDS focus on the repair of arterial ruptures or dissection. Therefore, patients must adopt a “watch and wait” approach following any confirmed diagnosis. Unfortunately, many of these arterial events have high mortality associated with them, and thus, a pharmacologic intervention that reduces the rate of events would be clinically meaningful.

EDSIVO™ (celiprolol) is a new chemical entity (NCE) currently in Phase 3 development for the treatment of COL3A1-positive vEDS patients to potentially reduce the risk of arterial and other hollow organ clinical events. In October 2010, data was published in the Lancet from the BBEST trial designed to assess the preventative effect of celiprolol for major cardiovascular events in patients with vEDS via a multicenter, prospective, randomized, open trial with blinded evaluation of clinical events.3 In addition, data from long-term observational studies of patients treated with celiprolol in France and Sweden were published in the Journal of the American College of Cardiology (JACC)4 in April 2019 and in the European Journal of Vascular and Endovascular Surgery (EJVES) in November 20205, respectively. Data from these and other publications can be found at www.acertx.com. Acer’s original NDA was submitted based on data obtained from the BBEST trial and accepted for filing in October 2018 with priority review. Following FDA review, Acer received a Complete Response Letter (CRL) in June 2019 stating that it will be necessary to conduct an adequate and well-controlled trial to determine whether EDSIVO™ reduces the risk of clinical events in patients with vEDS. In April 2022, FDA granted celiprolol Breakthrough Therapy designation in the U.S. for the treatment of patients with COL3A1-positive vEDS. In May 2022, Acer reached agreement with FDA under an SPA for its Pivotal Phase 3 clinical trial of EDSIVO™ (celiprolol) for the treatment of patients with COL3A1-positive vEDS. Agreement on our Phase 3 trial design indicates concurrence by FDA with the adequacy and acceptability of specific critical elements of the overall protocol design that could support a future regulatory submission and marketing application if the trial results meet the agreed-upon criteria. For more information on Special Protocol Assessments, please visit: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/special-protocol-assessment-guidance-industry.6 Celiprolol received FDA Orphan Drug Designation for the treatment of vEDS in 2015.

In June 2022, we announced the initiation of patient screening in our Phase 3 DiSCOVER (Decentralized Study of Celiprolol on vEDS-related Event Reduction) clinical trial of EDSIVO™ (celiprolol) for the treatment of patients with COL3A1-positive vEDS. The DiSCOVER trial is a prospective, Phase 3, randomized, double-blind, placebo-controlled efficacy trial designed to evaluate EDSIVO™ (celiprolol) in patients with genetically confirmed COL3A1-positive vEDS using a decentralized clinical trial design and an independent adjudication committee. The primary objective of the trial is to determine whether EDSIVO™ (celiprolol) reduces the occurrence of vEDS-related clinical events requiring medical attention, including fatal and non-fatal cardiac or arterial events, uterine rupture, intestinal rupture, and/or unexplained sudden death, relative to placebo as measured by time to event. We plan to enroll approximately 150 COL3A1-positive vEDS patients, all in the U.S., randomized 2:1 to receive either EDSIVO™ (celiprolol) or placebo, respectively. Individuals seeking more information on the EDSIVO™ (celiprolol) pivotal clinical trial are invited to visit www.discoverceliprolol.com.

Once the trial is fully enrolled, the duration of the DiSCOVER trial is currently estimated to be up to approximately 3.5 years to completion (based on statistical power calculations and number of primary events), which will require additional capital beyond Q3 2022. One interim analysis (based on number of primary events) is also planned at approximately 24 months after full enrollment.

EDSIVO™ (celiprolol) is an investigational product candidate which has not been approved by the FDA. There is no guarantee that this product candidate will receive regulatory authority approval or become commercially available for any indications in the U.S.

References

  1. Pepin, et al. Survival is affected by mutation type and molecular mechanism in vascular Ehlers–Danlos syndrome (EDS type IV). Genet Med. 2014 Dec;16(12):881-8.
  2. FightvEds.org
  3. Ong KT, et al. Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective andomized, open, blinded-endpoints trial. Lancet. 2010;376(9751):1476-1484
  4. Frank M, et al. Vascular Ehlers-Danlos Syndrome: Long-Term Observational Study. J Am Coll Cardiol. 2019 Apr, 73 (15) 1948–1957
  5. Björck M, et al. Celiprolol Treatment in Patients with Vascular Ehlers-Danlos Syndrome. European Journal of Vascular and Endovascular Surgery. November 20, 2020.
  6. S. Food and Drug Administration (FDA). Special Protocol Assessment. https://www.fda.gov/media/97618/download Updated April 2018. Accessed April 3, 2022
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