In March 2021, we announced that Acer and Relief entered into a Collaboration and License Agreement (CLA) for worldwide development and commercialization of ACER-001. ACER-001 (sodium phenylbutyrate) is a nitrogen-binding agent being developed for the treatment of various inborn errors of metabolism, including UCDs and MSUD.
MSUD is a rare, life-threatening metabolic disorder caused by a deficiency in an enzyme complex that metabolizes branched chain ketoacids, the breakdown products of the three branched-chain amino acids (BCAAs), leucine, valine, and isoleucine. Left untreated, MSUD leads to elevated plasma concentrations of these amino acids, which can lead to chronic and acute neurological damage, ranging from developmental delays in children, seizures, cognitive challenges, and in some cases death.
Current Treatment Options in MSUD and Rationale for ACER-001 Treatment in MSUD
Currently, the only treatment option for patients with MSUD is a life-long, protein-restricted diet to limit the intake of BCAA, with aggressive medical interventions when blood levels of BCAA or BCKA become elevated.
Multiple investigational trials evaluating sodium phenylbutyrate in urea cycle disorder (UCD) patients suggest treatment with sodium phenylbutyrate is associated with selective reduction in BCAA despite adequate 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 α-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 may provide additional clinical benefit beyond emergency protocol alone.
ACER-001 Registration Plan (MSUD)
On July 28, 2022, we announced the submission of an Investigational New Drug (IND) application to the FDA to evaluate the efficacy and safety of ACER-001 (sodium phenylbutyrate) for the potential treatment of patients with MSUD. The proposed initial Phase 2a, open-label dose-ranging trial is designed to evaluate the effect of different doses of ACER-001 (sodium phenylbutyrate) on blood leucine and other branched-chain amino acid (BCAA) levels in MSUD patients.
ACER-001 was granted orphan drug designation by the FDA in the U.S. for MSUD in 2014, and Acer announced in August 2022 that the European Commission granted orphan medicinal product designation in the EU to ACER-001 for MSUD.
If the required clinical studies are successful, we plan to seek FDA approval to market ACER-001 for the treatment of MSUD in the U.S. by submitting a 505(b)(2) NDA incorporating data from BUPHENYL’s® NDA (the reference listed drug) while supplementing our intended NDA for ACER-001 with additional PK, PD, efficacy and safety data specifically in the MSUD population. Additional information on the ACER-001 program can be found in our current corporate presentation.
ACER-001 is an investigational product candidate which has not been approved for any indication by FDA, the European Medicines Agency (EMA), or any other regulatory authority.
- Muelly 2011 Neuropsychiatric and Neurochemical Sequelae of MSUD.
- 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.
- Häberle, 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): 631–640.
- 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.