ACER-001 for Urea Cycle Disorders (UCDs)


ACER-001 is a powder formulation of sodium phenylbutyrate (NaPB) for oral suspension. The formulation is designed to be both taste-masked and immediate release. ACER-001 is being developed using a microencapsulation process for the treatment of various inborn errors of metabolism, including UCDs and MSUD. ACER-001 microparticles consist of a core center, a layer of active drug, and a taste-masking coating that quickly dissolves in the stomach, allowing taste to be neutralized while still allowing for rapid systemic release. NaPB has been found to help control blood ammonia levels in conjunction with a restricted diet for people with UCDs.1,2 However, non-compliance with treatment is common. Reasons given for non-compliance include the unpleasant taste associated with available medications, the frequency with which medication must be taken and the high cost of the medication.

For the treatment of UCDs, NaPB is a prodrug that metabolizes quickly to become phenylacetate. Phenylacetate then binds to glutamine via acetylation to become phenylacetylglutamine. Phenylacetylglutamine is similar to urea in that it contains two moles of nitrogen and is excreted by the kidneys. Through this process, NaPB is an alternate way to excrete excessive nitrogen created by ineffective processing of ammonia during the urea cycle.3

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We believe that if ACER-001 is approved, its taste-masked properties will make it a compelling alternative to existing NaPB-based treatments, as the unpleasant taste associated with NaPB is cited as a major impediment to patient compliance with those treatments.4

ACER-001 Bioequivalent to BUPHENYL® in Healthy Volunteer Trial Under Fasted Conditions

In February 2020, we reported the successful completion and final data from Part B of our trial evaluating the bioavailability and bioequivalence of ACER-001 to BUPHENYL® (NaPB) under fasted conditions. Consistent with observations from Part A of the trial, data from Part B showed ACER-001 to be bioequivalent to BUPHENYL® and were within the parameters recommended by the FDA’s Guidance for Industry, “Statistical Approaches to Establishing Bioequivalence.” The ACER-001 trial design consisted of two parts. Part A was a single-center, single-blind, randomized, single-dose crossover trial designed to evaluate the relative bioavailability of three different oral suspension formulations of ACER-001 compared to BUPHENYL® in 20 healthy adult subjects. Results from Part A of the trial, along with results from a concurrent taste assessment trial evaluating palatability of the three formulations of ACER-001 compared to BUPHENYL®, informed Acer’s selection of the single, optimal formulation of ACER-001 that was evaluated in Part B. Part B of this trial was a single-center, single-blind, randomized, single-dose crossover study designed to show bioequivalence of ACER-001 compared to BUPHENYL® in 36 healthy adult subjects. As described above, results from Part B were announced in February 2020.

ACER-001 in a Fasted State Increased Systemic Exposure of Phenylbutyrate (PBA)

The bioequivalence (BE) trial completed in February 2020 also included a food effect study, which evaluated the pharmacokinetics (PK) of sodium phenylbutyrate (NaPB) showing that administration of ACER-001 in a fasted state achieved more than two times the maximum concentration (Cmax) of PBA compared to administration of the same dose of ACER-001 in a fed state. These results are consistent with previously published data by Nakano, et al5 that evaluated PK of NaPB in patients with progressive familial intrahepatic cholestasis, also demonstrating that administration of NaPB in a fasted state significantly increased PBA peak plasma concentration compared to administration of NaPB in a fed state.

Currently approved therapies for UCDs, including BUPHENYL®6 and RAVICTI®7 (glycerol phenylbutyrate), are required to be administered with food. BUPHENYL® is required to be administered in a fed state due to its aversive odor and taste, with side effects including nausea, vomiting and headaches, which often lead to discontinuation of treatment.8 Additionally, prescribing information states that BUPHENYL® food effect is unknown. RAVICTI® PK and pharmacodynamic (PD) properties were determined to be indistinguishable in fed or fasted states.9 ACER-001 is uniquely formulated with its multi-particulate, taste-masked coating to allow for fasted, or pre-meal, administration while still allowing for rapid systemic release.

Based on the results from the food effect study within the ACER-001 BE trial, we commissioned Rosa & Co. LLC to create a PhysioPD® PK model to evaluate the potential food effect on exposure, tolerability and efficacy of ACER-001 in UCDs patients. Results from this in silico model suggest that administration of ACER-001 in a fasted state required approximately 30% less PBA to achieve comparable therapeutic benefit in a fed state. In addition, the model predicted that administration of ACER-001 in a fasted state compared to administration of BUPHENYL® or RAVICTI® (same amounts of PBA) in their required fed states is expected to result in higher peak blood PBA, PAA and PAGN concentrations, predicting a 43% increase in urinary PAGN levels (a negative correlation between blood ammonia area under the curve and 24-hour urinary PAGN amount has been demonstrated10).

ACER-001 Regulatory Pathway

In August 2020, the FDA provided further clarity on our proposed regulatory paths forward for administration of ACER-001 under fed, or pre-meal, conditions. In its feedback, the FDA advised that because BUPHENYL® is labeled for administration with food and a food effect has been observed with ACER-001 we conduct a BE trial comparing the pharmacokinetics of BUPHENYL® and ACER-001, both under fed conditions. In December 2020, we completed enrollment of approximately 36 healthy adults in this trial and expect topline results in the first quarter of 2021. The results of the BE fed trial will be included as a part of the Company’s planned NDA submission under the Section 505(b)(2) regulatory pathway for ACER-001 in the treatment of UCDs, where ACER-001 is administered with food. We anticipate holding a pre-NDA meeting with FDA in the second quarter of 2021, assuming successful and timely completion of the ongoing development activities (including the BE fed trial, nonclinical work, and evaluation of long-term product stability data) and subject to additional capital. We intend to submit an NDA for ACER-001 under fed conditions in UCD patients in mid-2021, subject to a successful pre-NDA meeting and additional capital.

In parallel or after initial potential FDA approval under fed conditions, we also plan to evaluate potential development of ACER-001 for administration under fasted or pre-meal conditions, which would require additional clinical pharmacokinetic, safety and efficacy studies, and potentially other clinical and nonclinical studies, in order to provide the necessary evidence of safety and efficacy of ACER-001 to be considered for FDA approval for administration under fasted or pre-meal conditions.

More information on ACER-001 and our other programs can be found in our current corporate presentation.


  1. Ah Mew N, Lanpher BC, Gropman A, Chapman KA, al. e. Urea cycle disorders overview. Gene Reviews. Seattle, Washington: University of Washington, Seattle; 1993.
  2. Sirrs SM, et al. Barriers to Transplantation in Adults with Inborn Errors of Metabolism. JIMD Rep. 2013;8:139-144.
  3. Brusilow SW, Maestri NE. Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr. 1996;43:127-170.
  4. Shchelochkov OA,et al. Barriers to drug adherence in the treatment of urea cycle disorders: Assessment of patient, caregiver and provider perspectives. Mol Genet Metab. 2016;8:43-47.
  5. Nakano S, et al. Effect of food on the pharmacokinetics and therapeutic efficacy of 4-phenylbutyrate in progressive familial intrahepatic cholestasis. Sci Rep 9, 17075 (2019).
  8. Pena-Qintana L, et al. Profile of sodium phenylbutyrate granules for the treatment of urea-cycle disorders: patient perspectives. Patient Preference and Adherence Volume 11:1489-1496, September 2017.
  9. United States Patent number US8642012B2.
  10. Lee et al. Phase 2 Comparison of A Novel Ammonia Scavenging Agent With Sodium Phenylbutyrate In Patients With Urea Cycle Disorders: Safety, Pharmacokinetics And Ammonia Control. Mol Genet Metab. 2010 July; 100(3): 221–228.