According to a press release from Synlogic Therapeutics, the Company recently halted development of its investigational hyperammonemia treatment SYNB1020 after an unsuccessful phase 1/2 clinical study.
Hyperammonemia is a metabolic condition characterized by increased levels of ammonia in the blood. Over time, elevated ammonia levels are associated with heightened risk for certain neurological and metabolic disorders including hepatic encephalopathies (decline in brain function associated with severe liver disease), Reye syndrome, and other serious liver diseases.
Notably, ammonia is the substance our body converts to the less-toxic urea. Most cases of hyperammonemia are therefore managed by nutritional management combined with drugs that enhance the body’s nitrogen-flushing capabilities. In particularly serious cases, physicians may encourage a full liver or liver cell transplant to correct the metabolic irregularities that leave blood ammonia levels dangerously high.
SYNB1020 was an engineered E. coli Nissle. Yes, it is a strain of E. coli, but most strains of this type of bacteria are harmless, and Nissle in particular has been well-researched for its potential as a probiotic.
In theory, researchers believed that an orally-administered SYNB1020 would respond to the high ammonia levels of the patients’ gastrointestinal tracts and begin to convert excess ammonia to the comparatively harmless amino acid arginine.
In a phase 1/2 study of SYNB1020, Synlogic recruited 23 patients with liver scarring and elevated blood ammonia levels. The drug was found to be safe and tolerable in early phases of the study, but evidence for the biologic’s effectiveness was quickly found lacking.
In the second phase of the study, 17 patients with consistently elevated blood ammonia levels were sorted into control and active groups. Eight participants received a placebo, the rest received SYNB1020 — for a period of six days. At that point, patients’ blood ammonia levels would be assessed, along with other inflammatory markers.
While patients who received SYNB1020 did show increased nitrogen levels in their urine (which would seemingly suggest more effective ammonia scrubbing in the body), unfortunately, no changes in blood ammonia levels or any of the secondary inflammatory endpoints were detected. It was a dud.
The failure of SYNB1020 is not at all unusual. The vast majority of clinically studied drugs fail before approval — recent data suggests that only about 15% of all drugs that enter phase 2 study ever gain market approval from the US Food and Drug Administration. Trial and error can be an important part of therapy development, and things learned in a “failed” study may still be useful in later work.
As Edison said, apocryphally, when struggling to create his lightbulb — “I didn’t fail, I learned 2,000 ways not to make a lightbulb.”
It can be discouraging for everyone involved when clinical studies fail. How do you think researchers should respond to such failures? Share your thoughts with Patient Worthy!