Mechanism of Action of SYNB1353 to Treat Homocystinuria
Can Ficicioglu, MD, PhD, Clinical Director of the Metabolic Disease Program at Children’s Hospital of Philadelphia, discusses positive top-line data from the phase 1 clinical trial in homocystinuria, confirming proof of mechanism of the drug candidate SYNB1353.
Homocystinuria is a rare congenital metabolic disease characterized by extremely elevated levels of homocysteine and its precursor, methionine. Homocystinuria is caused by an inherited deficiency in the enzyme, cystathionine beta-synthase. When cystathionine beta-synthase is absent, homocysteine and methionine build up in the blood and urine, putting patients at risk of multisystem complications, including acute thromboembolic events, optical damage from lens dislocation, skeletal deficiencies, and neurocognitive impairments.
As Dr. Ficicioglu explains, SYNB1353 is a novel, orally administered, non-systemically absorbed medication designed to lower homocysteine levels in patients with homocystinuria. SYNB1353 works by consuming methionine, a precursor to homocysteine, in the gastrointestinal tract. The U.S. Food and Drug Administration (FDA) granted Fast Track designation and Orphan Drug Designation to SYNB1353 for the potential treatment of homocystinuria.
The FDA’s decision to grant both designations is supported by recently released top-line results from the double-blind, dose-escalation, randomized, placebo-controlled, multiple-ascending dose phase 1 study evaluating the safety and tolerability of SYNB1353 in healthy volunteers.
Synlogic has completed dosing of 30 total subjects over four cohorts which evaluated 3 different dose levels (3×1011, 6×1011 and 1×1012 live cells) and two different formulations at the 1×1012 dose. In each cohort, subjects were randomly assigned to receive either SYNB1353 or a placebo (6 active/2 placebo per cohort). A methionine loading study was performed on day -1 and day 7 after an overnight fast, followed by a 24-hour collection period for the AUC assessments. Subjects were followed in the study for at least 28 days after the last dose.
At the 1×1012 dose, SYNB1353 decreased plasma methionine levels, as measured by the change in AUC from baseline, by -24.8% and -26.2% for the two different SYNB1353 formulations, compared to -2.1% in the placebo group.
There were no serious adverse events (AEs). One subject discontinued dosing due to an AE. In general, AEs were mild to moderate, transient and predominantly GI in nature. Frequency and severity of GI-related AEs were similar in the SYNB1353 and placebo groups (7/22 SYNB1353 vs 3/8 placebo subjects had one or more GI-related AE). All subjects completing the 28-day analysis cleared SYNB1353 in feces.
Overall, SYNB1353 was generally well tolerated, and AEs were all mild to moderate, transient, and predominantly gastrointestinal in nature.
To learn more about homocystinuria and other rare metabolic disorders, visit checkrare.com/diseases/metabolic-disorders/
