Identification of 2,2-Dimethylbutanoic Acid (HST5040), a Clinical Development Candidate for the Treatment of Propionic Acidemia and Methylmalonic Acidemia

Abstract

Propionic acidemia (PA) and methylmalonic acidemia (MMA) are rare autosomal recessive disorders of propionyl-CoA (P-CoA) catabolism, caused by a deficiency in the enzymes P-CoA carboxylase and methylmalonyl-CoA (M-CoA) mutase, respectively. PA and MMA are classified as intoxication-type inborn errors of metabolism because the intramitochondrial accumulation of P-CoA, M-CoA, and other metabolites results in secondary inhibition of multiple pathways of intermediary metabolism, leading to organ dysfunction and failure. Herein, we describe the structure–activity relationships of a series of short-chain carboxylic acids which reduce disease-related metabolites in PA and MMA primary hepatocyte disease models. These studies culminated in the identification of 2,2-dimethylbutanoic acid (10, HST5040) as a clinical candidate for the treatment of PA and MMA. Additionally, we describe the in vitro and in vivo absorption, distribution, metabolism, and excretion profile of HST5040, data from preclinical studies, and the synthesis of the sodium salt of HST5040 for clinical trials.

Mitochondrial disease, mitophagy, and cellular distress in methylmalonic acidemia

“…Alternatively, using primary hepatocyte disease models, a group of scientists from HemoShear Therapeutics have shown that supplementation with disodium citrate partially rebalances the concentration of TCA cycle intermediates [ 138 ], while supplementation with a short-chain carboxylic acid (2,2-dimethylbutanoic acid) is able to reduce intracellular concentrations of metabolites related to propionyl-CoA and methylmalonyl-CoA [ 155 , 156 ]. This latter molecule is now part of a therapeutic clinical trial (NCT04732429) for MMA.…”

Relief of CoA sequestration and restoration of mitochondrial function in a mouse model of propionic acidemia

“…PA patients have impaired neurocognitive development, 72 and as a small molecule that penetrates the brain, BBP‐671 has the potential to correct CoASH sequestration and defective TCA cycles in the brain and other affected tissues. Another small molecule approach to PA is treatment with 2,2‐dimethylbutyrate (HST5040), which enters cells and is converted to its CoA thioester derivative 38,39 . This treatment reduces C3‐CoA and its downstream metabolites by sequestering CoASH as the HST5040 thioester.…”

“…Another small molecule approach to PA is treatment with 2,2‐dimethylbutyrate (HST5040), which enters cells and is converted to its CoA thioester derivative. 38 , 39 This treatment reduces C3‐CoA and its downstream metabolites by sequestering CoASH as the HST5040 thioester. However, there are animal toxicities that arise from exposure to xenobiotic carboxylic acids, notably valproic acid, that are directly attributed to CoASH sequestration into non‐metabolizable thioesters, 62 , 73 , 74 , 75 , 76 , 77 and the utility of HST5040 remains to be tested in a PA mouse model.…”

“…Gene or RNA therapies under active development reduce the concentrations of PA biomarkers in mouse models 33–37 . Small molecule therapeutic strategies are also under exploration 38,39 . PANK activity is potently inhibited by C3‐CoA and this inhibition is reversed by PZ‐3022, a representative member of a drug‐like series of allosteric PANK activators, called pantazines, that elevate tissue CoA, 40,41 attenuate the inhibition of PANK activity by C3‐CoA and improve mitochondrial function in a PA mouse model 7 .…”

“… 33 , 34 , 35 , 36 , 37 Small molecule therapeutic strategies are also under exploration. 38 , 39 PANK activity is potently inhibited by C3‐CoA and this inhibition is reversed by PZ‐3022, a representative member of a drug‐like series of allosteric PANK activators, called pantazines, that elevate tissue CoA, 40 , 41 attenuate the inhibition of PANK activity by C3‐CoA and improve mitochondrial function in a PA mouse model. 7 BBP‐671 is a pantazine that has been chemically optimized for pharmaceutical use and is under investigation in a clinical trial as a potential therapy for PA and methylmalonic acidemia ( ClinicalTrials.gov Identifier: NCT04836494).…”