SRW101

A First-In-Class Treatment for MCT8 Deficiency (ADHS)

AHDS is caused by mutations in the SLC16A2 gene located on the X-chromosome, resulting in a defective or absent thyroid hormone (TH) transporter, MCT8. MCT8 is required to transport the thyroid hormone T3 into cells in the brain and some other vital organs, but not all. An increased level of T3 in circulation results in increased metabolism in those tissues that are not dependent on MCT8 resulting in an inability to gain weight, while a decreased level of T3 in cells in the brain results in neuromuscular symptoms and intellectual disability seen in patients with AHDS.

SRW101, formerly known as DITPA (diiodothyropropionic acid), is a small molecule, synthetic T3 analog in development as an oral formulation with planned dosing of three times per day. Leading physicians in the study and treatment of AHDS, Drs. Refetoff and Weiss, identified SRW 101 as a possible treatment for AHDS. Following numerous pre-clinical studies, four AHDS patients were treated under Compassionate Use with beneficial results that were published in 2012 by Verge et al. (1)

Mechanism of Action

In its therapeutic approach, SRW101 crosses the blood-brain barrier through alternate transporters to partially correct the low levels of T3 (2). As in the case of T3, SRW101 (DITPA) binds to both alpha and beta thyroid hormone nuclear receptors (3) exerting a genomic effect by regulating the expression specific gene (4). DITPA also exerts a cytosolic or non-genomic effect (5). The reduction of circulating T3 as a consequence of DITPA is in part mediated through decreasing the enzyme deiodinases type 1 (6,7) thereby diminishing the generation of T3 from T4 in peripheral body tissues. Thus, importantly, SRW101 lowers the levels of T3 in the serum of MCT8 deficient patients, reducing the increased metabolism (6). As a consequence of the lower metabolism caloric requirements are reduced resulting in maintenance of weight and even causing weight gain.

MCT8 Deficiency

SRW as a
Therapeutic Approach

Orphan Drug and Rare Pediatric Disease Designations

SRW101 has been granted Orphan Drug Designation by the FDA as a drug or biological product to treat a rare disease or condition. Orphan drug designation qualifies PriZm Therapeutics for various development incentives.

SRW101 has also received Rare Pediatric Disease Designation from the FDA qualifying it to receive a Priority Review Voucher (PRV) from the FDA upon approval. The PRV entitles a company to FDA regulatory review of a drug in six months rather than the standard ten months. PRV’s are transferrable and may be sold. Sales prices of PRV’s from 2017-2020 have averaged ~$100 million.

Publications

References Related to SRW101 (DITPA) in MCT8D Deficiency and the Mechanism of Action