PKU is a rare inherited metabolic disease caused by a deficiency in the enzyme required to metabolize phenylalanine (Phe), an amino acid found in virtually all protein-containing foods. In individuals with PKU, Phe accumulates to abnormally high levels in the blood which, if left untreated, results in progressive and severe neurological impairment and neuropsychological complications. There remains a high unmet medical need for new and effective therapeutic approaches for PKU. The solute carrier transporter SLC6A19 has emerged as a highly validated, but historically

 

The goal of PKU treatment is to consistently lower blood phenylalanine (Phe) concentrations to avoid neurocognitive and psychological morbidities. First-line treatment for patients with PKU is a low Phe diet that lacks many protein-containing foods and is supplemented by Phe-free medical foods. The diet is very restrictive and requires careful planning and calculation of protein intake. There are two approved treatments for patients with PKU: Kuvan (sapropterin dihydrochloride) and Palynziq (pegvaliase). Kuvan is tetrahydrobiopterin/BH4, the cofactor for the PAH enzyme that is mutated in PKU, and acts as a molecular chaperone to restore PAH activity. Palynziq is an injectable enzyme substitution therapy. There remains a high unmet medical need for new therapeutic approaches for the treatment of PKU. Jnana Therapeutics is developing JNT-517, an oral small molecule inhibitor of Solute Carrier Family 6 Member 19 (SLC6A19) that blocks renal Phe reabsorption and facilitates its excretion, to lower blood Phe levels in PKU patients irrespective of age or background genotype. Preclinical studies in the Pahenu2 PKU mouse model with a tool inhibitor (JNT-170) have demonstrated that small molecule inhibition of SLC6A19 can reduce plasma Phe levels. IND-enabling studies to date provide a clear path to the clinic for JNT-517.

 

JNT-517 is a small molecule inhibitor of the phenylalanine transporter SLC6A19 and is in development as a potential first-in-class oral treatment for phenylketonuria (PKU), a rare inherited metabolic disease 1. Jnana Therapeutics, a biotechnology company, has selected JNT-517 as a development candidate and plans to initiate a Phase 1 clinical study with JNT-517 later this year 1. The company’s proprietary inhibitors, identified using its RAPID platform, bind the target in a cryptic allosteric site 1. The discovery of JNT-517 is based on Jnana’s pioneering research and was enabled by RAPID, the company’s high-throughput screening-enabled chemoproteomic platform 1.

 

According to the results of Jnana Therapeutics’ Phase 1a clinical trial, JNT-517 was safe and well-tolerated at all dose levels studied, with no serious adverse events 12. The study also demonstrated compelling proof of mechanism for JNT-517, which confirms that blockade of SLC6A19 can dramatically increase excretion of Phe 1. The ongoing Phase 1b study will assess the impact of JNT-517 on plasma Phe levels in individuals with PKU 1. （NCT05781399）