We at Acer Therapeutics (www.acertx.com) are delighted to have the opportunity to inform the MSUD Community about our work in development of a pharmacologic therapy for MSUD.
I am pleased to have been invited to discuss our work at the 18th BIENNIAL MSUD SYMPOSIUM in Raleigh, North Carolina in June. We look forward to continuing collaboration with the MSUD Family Support Group. Our success at Acer is dependent in part on our responsiveness to the MSUD patient and physician community’s needs. Strong advocacy support from clinicians, patients, families, and patient advocacy groups is critical to the success of companies like ours.
I will begin with a quick introduction to our company and who we are. Acer is a specialty orphan pharmaceutical company. Our strategy is to develop therapies for the treatment of serious, ultra-rare diseases with critical unmet medical need. The medicines we are developing have some degree of established safety data from animal (pre-clinical) and human (clinical) studies undertaken previously. Typically, clinical proof-of-concept studies have already been completed prior to our involvement. This approach reduces development risk, timelines and cost. Acer’s headquarters are in Cambridge, MA. We have a very experienced management team including:
- Chris Schelling, CEO, Founder and Director who has 17 years of biotech/pharma strategic and orphan drug expertise; Chris was previously at BioMarin
- Jeff Davis, Head of Corporate Development who has 25+ years of drug discovery, business and corporate development expertise; Jeff was previously at Genzyme
- Harry Palmin, Acting CFO spent 15 years as President, CEO and Board Director at Novelos Therapeutics, oversaw 10 clinical studies in oncology and infectious diseases; previously at Lehman Brothers and Morgan Stanley
- Ben Dewees, Vice President, Regulatory & Manufacturing, who has 20 years of orphan drug regulatory and manufacturing expertise at BioMarin and Biogen Idec
- Robert Steiner, MD, Chief Medical Officer, who has 20+ years orphan disease treatment and research experience including MSUD. Bob is Clinical Professor at the University of Wisconsin, having previously held positions at Marshfield Clinic and Oregon Health & Science University (OHSU)
Acer currently has two drugs in the pipeline, for three orphan diseases. ACER-002 is being developed for vascular Ehlers Danlos Syndrome (vEDS) and will not be considered further here. ACER-001 is being developed for Maple Syrup Urine Disease (MSUD) and also Urea Cycle Disorders (UCD). ACER-001 is a tastemasked, immediate-release formulation of sodium phenylbutyrate (NaPB). As some of you may know, NaPB is a pretty horrible tasting drug! So, we have spent a couple of years developing a formulation of NaPB that has very little, or no taste at all. This is important, because we want patients to take all of their medicine, and that may be difficult to do if the drug tastes bad.
NaPB was originally approved by the Food and Drug Administration (FDA) in 1996 to treat UCD. UCD are life threatening disorders of amino acid metabolism, not unlike MSUD (1). Acer is currently collaborating closely with Dr. Brendan Lee and Baylor College of Medicine, where NaPB is currently being studied for treatment of patients with Maple Syrup Urine Disease (MSUD). As the readership of this newsletter knows, MSUD is an inborn error of amino acid metabolism (1). There are currently no approved medication treatment options and dietary therapy alone is not optimal. Patients may suffer chronic neurological damage and life-threatening metabolic decompensation. Our goal at Acer is to develop ACER-001 to be used in addition to dietary therapy in treatment of MSUD. It was noted by physicians at Baylor College of Medicine (BCM) and elsewhere several years ago that NaPB reduces branched-chain amino acid levels (2). Leucine (Leu) is a branched-chain amino acid that accumulates in patients with MSUD and is responsible for complications. Lowering Leucin MSUD is beneficial. Brendan Lee and colleagues at BCM identified the novel mechanism of action of NaPB in MSUD – NaPB inhibits the branched-chain ketoacid dehydrogenase kinase that, in turn, activates the branched-chain ketoacid dehydrogenase complex – which is the enzyme deficient in MSUD – thereby potentially increasing the effectiveness of the MSUD enzyme (3). A clinical proof-of-concept study in MSUD with NaPB carried out at BCM showed statistically significant decreases in Leu (3). 5 MSUD patients received 3 days of a steady-state protein diet followed by 3 days of NaPB plus diet. The results showed a statistically significant decrease in Leucin 3 of 5 MSUD patients (p< 0.05 in responders). Leucine levels fell approximately 30% (28-34%) in responders. Clinicians consider a 20-30% decrease in blood Leucine levels as clinically meaningful.
A second trial of NaPB in MSUD is underway at BCM. We at Acer are planning a Phase 2 study of ACER-001 in which we will evaluate the degree and frequency of response to ACER-001 treatment as demonstrated by reduction in blood Leucine levels among MSUD patients with elevated blood Leucine levels. We will evaluate the safety of ACER-001 treatment in MSUD patients, identify individuals with MSUD who respond to ACER-001 with a clinically-meaningful reduction in blood Leucine, and evaluate the correlation between blood Leucine levels and branched-chain α-ketoacid dehydrogenase (BCKD) gene mutations. Current enrollment plans (which are subject to change) include pediatric and adult MSUD patients with elevated Leucine levels. Approximately 60 patients will be enrolled. Safety is assessed by medical history, monitoring adverse events and vital signs, physical examinations, lab tests (e.g. amino acids, chemistry, hematology, and urinalysis). Approximately 10-15 sites will be needed, chosen from clinics in around the US with experienced MSUD clinicians.
In summary, Acer Therapeutics (www.acertx.com) is a specialty orphan pharmaceutical company whose strategy is to develop therapies for the treatment of serious, ultra-rare diseases with critical unmet medical need. We are developing a new taste-masked, immediate release formulation of sodium phenylbutyrate (ACER-001) for treatment along with diet of MSUD. We very much look forward to partnering with the MSUD medical, scientific and patient communities in development of this new, exciting therapy.
- Rice GM, Steiner RD. Inborn Errors of Metabolism (Metabolic Disorders). Pediatric Rev. 37:3-17. 2016
- Burrage LC et al. Mol Genet Metab. 113:131-5. 2014
- Brunetti-Pierri N et al. Hum Mol Genet. 20:631-40. 2011