ACER-001 for Maple Syrup Urine Disease (MSUD)

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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 inherited disorder caused by defects in the mitochondrial branched-chain ketoacid dehydrogenase complex, which results in elevated blood levels of the branched-chain amino acids (BCAA), leucine, valine, and isoleucine, as well as the associated branched-chain ketoacids (BCKA) in a patient’s blood.

Current Treatment Options in MSUD and Rationale for ACER-001 Treatment in MSUD
There are currently no approved pharmacologic therapies in the U.S. or the EU for MSUD. Treatment of MSUD consists primarily of a severely restricted diet to limit the intake of BCAA, with aggressive medical interventions when blood levels of BCAA or BCKA become elevated.

Therapy with NaPB in UCD patients has been associated with a selective reduction in BCAA despite adequate dietary protein intake.1 Based on this clinical observation, investigators at Baylor College of Medicine (BCM) explored the potential of NaPB treatment to lower BCAA and corresponding BCKA in patients with MSUD. The investigators found that BCAA and BCKA were both significantly reduced following NaPB therapy in control subjects and in patients with MSUD, although there was no simple correlation between the patients’ levels of residual enzymatic activity with the response of plasma BCAA and their BCKA to NaPB. NaPB demonstrated 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. The reduction in leucine, the most toxic of the BCAAs, in the three responsive MSUD patients ranged between 28-34%, which is considered by clinicians to be a meaningful response.

Investigators at BCM further explored the mechanistic rationale why NaPB lowered BCAA/BCKA levels. NaPB was found to be an allosteric inhibitor of the branched-chain keto acid dehydrogenase complex kinase (BCKD-kinase), and enzyme that regulates the activity of the branched-chain keto acid dehydrogenase complex (BCKDC) enzyme that is responsible for the normal metabolism of BCKAs.2 By inhibiting the BCKD-kinase, the BCKDC is constitutively activated, thus the increased activity results in a reduction in the plasma levels of BCAA and BCKA in all people, including those with MSUD,3 suggesting that NaPB may be an effective treatment for people with MSUD, who experience elevated BCAA levels.1,3

In November 2020, study results evaluating the effect of NaPB in the management of acute MSUD attacks in pediatric patients (n=10) were published in the Journal of Pediatric Endocrinology and Metabolism showing a significant reduction in leucine levels in MSUD patients experiencing an acute attack.4 The results suggested that NaPB can be safely administered in combination with emergency protocol and may provide additional clinical benefit beyond emergency protocol alone. However, verifying this outcome would require additional validation in a controlled trial. If ACER-001 is approved for the treatment of chronic MSUD, we believe patients will not be required to interrupt their therapy in the event of an acute crisis.

ACER-001 Registration Plan (MSUD)
We anticipate initiation of a clinical study evaluating ACER-001 in MSUD to occur in the second half of 2022, subject to additional capital. If these 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 drug in the U.S. and is not currently FDA approved for MSUD.

References

  1. Muelly 2011 Neuropsychiatric and Neurochemical Sequelae of MSUD.
  2. Danner DJ, et al. Molecular genetic basis for inherited human disorders of branched-chain alpha-keto acid dehydrogenase complex. Ann N Y Acad Sci. 1989;573:369-377.
  3. Tanyel Zubarioglu, et al. “Impact of sodium phenylbutyrate treatment in acute management of maple syrup urine disease attacks: a single-center experience” https://doi.org/10.1515/jpem-2020-0356
  4. Zubarioglu T, et al. “Impact of sodium phenylbutyrate treatment in acute management of maple syrup urine disease attacks: a single-center experience” https://doi.org/10.1515/jpem-2020-0356
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