Ehlers-Danlos Syndrome (EDS) is a group of hereditary disorders of connective tissue. vEDS is the most severe subtype where patients suffer from life-threatening arterial dissections and ruptures, as well as intestinal and uterine ruptures. The median age of death in the U.S. is 51 years.1 An Acer-commissioned patient-finder study phenotypically identified 4,169 vEDS patients in the U.S. from an analysis of a commercially available patient claims database with data of approximately 190 million unique patient lives. Based on that information, Acer estimates the prevalence of phenotypically-defined vEDS in the U.S. could be greater than 1 in 45,000. Currently, there are no FDA-approved therapies for vEDS.
Acer is advancing EDSIVO™, a new chemical entity (NCE), for the treatment of COL3A1-positive vEDS based on published results from a randomized controlled clinical trial of celiprolol (BBEST).2 In addition, long-term data has now been published from separate French3 and Swedish4 vEDS patient registries.
We submitted our NDA for EDSIVO™ in October 2018 and it was accepted for filing and substantive review by the FDA in December 2018, with priority review status. In June 2019, we received a Complete Response Letter (CRL) from the FDA regarding our NDA for EDSIVO™ for the treatment of vEDS using the data obtained from the BBEST trial2 as the basis of approval. The CRL stated that it will be necessary to conduct an adequate and well-controlled trial to determine whether celiprolol reduces the risk of clinical events in patients with vEDS. In December 2019, we submitted a Formal Dispute Resolution Request to the FDA’s Office of New Drugs appealing the FDA’s decision as outlined in the CRL. In March 2020, we received a response to our Formal Dispute Resolution Request from the Office of New Drugs of the FDA stating that it had denied our appeal of the CRL. In its Appeal Denied letter, the OND described possible paths forward for Acer to explore that could provide the substantial evidence of effectiveness needed to support a potential resubmission of the EDSIVO™ NDA for the treatment of patients with vEDS with a confirmed COL3A1 mutation. The OND referred to the FDA Guidance document issued in December 20195, where substantial evidence of effectiveness can be provided by two or more adequate and well-controlled studies demonstrating efficacy, or a single positive adequate and well-controlled study plus confirmatory evidence.
We believe we have identified a plan to collect additional data that supports the results from the COL3A1-positive analysis from the BBEST trial and could help meet the standard set forth in the FDA Guidance document issued in December 2019. A Type B meeting is scheduled in the second quarter of 2021 with the FDA to discuss Acer’s proposed plan to provide sufficient confirmatory evidence. If successful, we believe that data provided under our proposal could potentially satisfy the additional confirmatory evidence needed to support a resubmission of our NDA, assuming the additional data analysis is positive. There can be no assurance that FDA will accept our plan or, if accepted, that the resulting data would be adequate to support resubmission, filing or approval of our NDA. We may also conclude at any point that the cost, risk and uncertainty of obtaining that additional data does not justify continuing with the development of EDSIVO™. Additional information on the EDSIVO™ program can be found in our current corporate presentation.
EDSIVO™ is an investigational drug in the U.S. and is not currently FDA approved for any indication.
- Pepin M, et al. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med. 2000; 342:673-80
- Ong KT, et al. Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial. Lancet. 2010;376(9751):1476-1484
- Frank M, et al. Vascular Ehlers-Danlos Syndrome: Long-Term Observational Study. J Am Coll Cardiol. 2019 Apr, 73 (15) 1948–1957
- Baderkhan, H, et al. Celiprolol Treatment in Patients with Vascular Ehlers-Danlos Syndrome. European Journal of Vascular and Endovascular Surgery. November 20, 2020.
- FDA guidance “Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products”, December 2019