Toxic accumulation of phenylalanine underlies the neurological deficits and morbidity in phenylketonuria (PKU). Despite availability of treatment options for PKU patients, high unmet need remains for safe and convenient therapies that work across a broad cross section of PKU patients and allow for diet normalization.
SLC6A19 is the principal transporter for the (re-)absorption of neutral amino acids (AAs), including Phe, in the intestine and kidney and is a potential therapeutic target for PKU. Leveraging a novel chemoproteomic platform, we identified small molecules that inhibit SLC6A19 transport function. We demonstrated that pharmacological inhibition of SLC6A19 in PKU mice increases urinary excretion of Phe and reduction in pathogenic plasma levels of this amino acid.
Administration of JNT-517, a first-in-class investigational oral SLC6A19 inhibitor, in a randomized, placebo-controlled study in healthy participants, was found to be safe and well tolerated and led to rapid, sustained and dose-related increases in excretion of SLC6A19 AA substrates, including Phe.
In a 28 day randomized, double-blind, placebo-controlled trial in individuals with PKU (average blood Phe level of >600µM). JNT-517 led to a statistically significant (p=0.0019 vs. placebo) mean blood Phe reduction from baseline of 51% at day 28. A high response rate was seen where seven of eight (88%) treated participants achieved >30% reduction in blood Phe from baseline; five of eight (63%) achieved >45% reduction; and two of eight (25%) achieved >65% reduction. JNT-517 was safe and well tolerated with no serious adverse events and no clinically significant changes in laboratory parameters.
Taken together, these data provide compelling evidence that pharmacological inhibition of SLC6A19 represents a novel approach for PKU.
As the Head of Development at Jnana Therapeutics, Dr John Throup leads all clinical development programs within the organization and is responsible for building out a cross functional development organization capable of progressing programs from GLP tox to NDA/MAA submission. Prior to joining Jnana in January 2022, John was most recently Vice President and Development Lead at Bristol Myers Squibb (BMS) where he was responsible for leading the development of assets in the Immunology pipeline across early and late development. Most recently, Dr Throup led the development of the TYK2 inhibitor, deucravacitinib (Sotyktu®), from preclinical through development to approval. Before joining BMS in 2014, Dr Throup spent 15 years at GlaxoSmithKline (GSK) in operational and strategic leadership roles across the R&D organization. Dr Throup received his PhD in molecular microbiology from the University of Nottingham, UK.