RELIEF THERAPEUTICS Holding SA (SIX: RLF, OTCQB: RLFTF, RLFTY) (Relief), and its collaboration partner, Acer Therapeutics Inc. (Nasdaq: ACER) (Acer), today announced that the European Commission has granted orphan medicinal product designation in the EU to ACER-001 (sodium phenylbutyrate) for the potential treatment of patients with Maple Syrup Urine Disease (MSUD). ACER-001 was granted orphan drug designation by the U.S. Food and Drug Administration (FDA) in the U.S. for MSUD in 2014.
Orphan designation by the European Commission is another important milestone for the ACER-001 program that provides further validation of the important role we believe ACER-001 will play in the potential treatment of multiple rare diseases, stated Raghuram (Ram) Selvaraju, Ph.D., Chairman of the Board of Directors of Relief. We look forward to the continued advancement of ACER-001 in MSUD and Urea Cycle Disorders.
We are very pleased to receive orphan medicinal product designation in both the U.S. and now the EU, underscoring the urgent need for an approved treatment for MSUD, said Adrian Quartel, MD, FFPM, Chief Medical Officer of Acer. Currently, the only treatment option for patients with MSUD is a lifelong, protein-restricted diet, however, they still remain at serious risk for a wide range of life-threatening complications.
Orphan drug designation is granted to medicines that treat or prevent a life-threatening or chronically debilitating rare disease, with a prevalence in the EU of not more than 5 in 10,000, and with either no currently approved method of prevention or treatment, or with significant benefit to those affected by the disease. The designation potentially provides certain benefits to ACER-001, including the potential for up to 10-year EU market exclusivity upon regulatory approval, if received, reductions in EMA application fees, and access to study protocol assistance.
Rationale for ACER-001 Treatment in MSUD
Multiple investigational trials evaluating sodium phenylbutyrate in urea cycle disorder (UCD) patients suggest treatment with sodium phenylbutyrate is associated with selective reduction in branched chain amino acids (BCAA) despite adequate restricted dietary protein intake.1,2,3,4 Analysis of data from a longitudinal multicenter study of 553 UCD patients treated with sodium phenylbutyrate demonstrated that sodium phenylbutyrate decreased plasma BCAA in patients with UCDs and could serve as a therapy in maple syrup urine disease and other common complex disorders with dysregulation of BCAA metabolism.2
Based on this clinical observation, investigators at Baylor College of Medicine explored the potential of sodium phenylbutyrate treatment to lower BCAA and corresponding branched-chain ?-ketoacid (BCKA) levels in both healthy subjects and patients with MSUD. The investigators found that sodium phenylbutyrate, when dosed over three days, showed a statistically significant reduction of leucine in all three healthy subjects and in three out of the five MSUD patients who participated in the trial.5
In November 2020, study results evaluating the effect of sodium phenylbutyrate in the management of acute metabolic decompensation in pediatric MSUD patients (n=10) were published by investigators from Istanbul University-Cerrahpasa Medical Faculty in the peer-reviewed Journal of Pediatric Endocrinology and Metabolism showing a significant reduction in leucine levels in MSUD patients experiencing an acute attack.6 The results suggested that sodium phenylbutyrate could be safely administered in combination with emergency protocol using other active pharmaceuticals and supports additional investigation of potential clinical benefit beyond emergency protocol alone.
MSUD is a rare inherited disorder caused by a deficiency of branched-chain alpha-keto acid dehydrogenase complex, resulting in elevated blood levels of the (BCAA) leucine, valine, and isoleucine, as well as the associated (BCKA) in a patients blood. Left untreated, this can result in neurological damage, mental disability, coma, or death. The most severe presentation of MSUD, known as classic MSUD, accounts for 80% of cases and can result in neonatal onset with encephalopathy and coma. Although metabolic management of the disease is possible via a highly restrictive diet, the outcome is unpredictable, and a significant portion of affected individuals are mentally impaired or experience neurological complications.
MSUD is typically diagnosed at birth via newborn screening and incidence is estimated at 1 in 185,000 people worldwide and 1 in 220,000 people in the United States.7 The disorder occurs more frequently in the Old Order Mennonite population, with an estimated incidence of about 1 in 380 newborns, and the Ashkenazi Jewish population, with an estimated incidence of 1 in 26,000.8
ACER-001 (sodium phenylbutyrate) is being developed for the treatment of various inborn errors of metabolism, including UCDs and Maple Syrup Urine Disease (MSUD). ACER-001 (sodium phenylbutyrate) is an immediate-release, polymer coated, multi-particulate formulation of sodium phenylbutyrate for oral administration via suspension, that is designed to improve palatability. ACER-001 (sodium phenylbutyrate) has been granted orphan drug designation by the FDA for MSUD. In July 2022, the FDA accepted Acers NDA resubmission (Class 2) and assigned a Prescription Drug User Fee Act (PDUFA) target action date of January 15, 2023. This investigational product candidate has not been approved by FDA, the European Medicines Agency (EMA), or any other regulatory authority. There can be no assurance that the resubmitted ACER-001 NDA for UCDs will be approved by the FDA, or that ACER-001 (sodium phenylbutyrate) will otherwise be approved for any indication.
About RELIEF THERAPEUTICS Holding SA
Relief is a Swiss, commercial-stage, biopharmaceutical company focused on identification development and commercialization of novel, patent protected products intended for the treatment of metabolic, dermatological and pulmonary rare diseases with a portfolio of clinical and marketed assets that serve unmet patient needs. Relief has a Collaboration and License Agreement with Acer Therapeutics for the worldwide development and commercialization of ACER-001 (sodium phenylbutyrate) for the treatment of various inborn errors of metabolism, including UCDs and Maple Syrup Urine Disease (MSUD). Relief also continues to develop aviptadil for several rare pulmonary indications; Relief's 2021 acquisitions of APR Applied Pharma Research SA and AdVita Lifescience GmbH brought to Relief a diverse pipeline of marketed and development-stage programs.
RELIEF THERAPEUTICS Holding SA is listed on the SIX Swiss Exchange under the symbol RLF and quoted in the U.S. on OTCQB under the symbols RLFTF and RLFTY. For more information, visit www.relieftherapeutics.com Follow Relief on LinkedIn.
About Acer Therapeutics Inc.
Acer is a pharmaceutical company focused on the acquisition, development and commercialization of therapies for serious rare and life-threatening diseases with significant unmet medical needs. Acers pipeline includes four investigational programs: ACER-001 (sodium phenylbutyrate) for treatment of various inborn errors of metabolism, including urea cycle disorders (UCDs) and Maple Syrup Urine Disease (MSUD); ACER-801 (osanetant) for treatment of induced Vasomotor Symptoms (iVMS); EDSIVO (celiprolol) for treatment of vascular Ehlers-Danlos syndrome (vEDS) in patients with a confirmed type III collagen (COL3A1) mutation; and ACER-2820 (emetine), a host-directed therapy against a variety of viruses, including cytomegalovirus, Zika, dengue, Ebola and COVID-19. For more information, visit www.acertx.com .
References Muelly 2011 Neuropsychiatric and Neurochemical Sequelae of MSUD.L.C. Burrage, et al., Sodium phenylbutyrate decreases plasma branched-chain amino acids in patients with urea cycle disorders, Mol. Genet. Metab. (2014)Scaglia F. New insights in nutritional management and amino acid supplementation in urea cycle disorders. Mol Genet Metab. 2010;100 Suppl 1(Suppl 1):S72-6.Hberle, J., Boddaert, N., Burlina, A. et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis 7, 32 (2012)Brunetti-Pierri et al. Phenylbutyrate therapy for maple syrup urine disease. Hum Mol Genet. 2011 February 15; 20(4): 631640.Zubarioglu T, et al. Impact of sodium phenylbutyrate treatment in acute management of maple syrup urine disease attacks: a single-center experience. J Pediatr Endocrinol Metab. 2020 Nov 11;34(1):121-126.Chapman, K, et al. (2018). Incidence of maple syrup urine disease, propionic acidemia, and methylmalonic aciduria from newborn screening data. Molecular Genetics and Metabolism Reports. 15. 106-109.Strauss KA, et al. Maple Syrup Urine Disease. In: Pagon RA, Adam MP, Ardinger HH, al. e, eds. GeneReviews [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK1319/: University of Washington, Seattle; 2006. Accessed March 22, 2017