Molecules on the Move: Reversible BTKi in MS, THR-beta Agonist in NASH, and More

This article compiles recent high-profile clinical readouts and related news with small molecules of general interest and structures where they are available. Targets and indications discussed in this article include BTK for MS, Axl, TYRO3, and Mer for oncology, HIF prolyl-hydroxylase in anemia, ET/AT in nephrology, a JAK2 inhibitor for myelofibrosis, and THR-beta in NASH.

A Tetrahydrobiopterin Precursor with Positive Ph. III in Phenylketonuria

sepiapterin (PTC923, CNSA-001)
oral BH4 precursor 7.5-60mg/kg QD
reduced phenylalanine levels in Ph. III

PTC Therapeutics’ sepiapterin met its primary endpoint in a Ph. III trial (NCT05099640; n=98, 7.5-60mg/kg QD) of the rare inherited disorder phenylketonuria, in which patients cannot break down the amino acid phenylalanine. Sepiapterin (synthetic) is a precursor of tetrahydrobiopterin (BH4), which is essential for degradation of phenylalanine. The compound reduced blood levels of phenylalanine by 63% in the overall study population. Of note, sepiapterin might be a treatment option for patients who don’t typically respond to BioMarin’s sapropterin (Kuvan), as a phenylalanine reduction of 69% was seen in patients with classic phenylketonuria. Unlike sapropterin, sepiapterin is more active in cells and is also brain-penetrant.

The program is notable as it’s a success for PTC outside of RNA splicing modulation, for which it has recently become famous thanks to the success of risdiplam and its emerging Huntington’s disease program.

Another THR-Beta Positive Readout in NASH