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SYNB8802 passes proof of concept in Dietary Hyperoxaluria study

Thu, 03/25/2021 - 16:04
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Synlogic's SYNB8802 has achieved proof of mechanism in a Dietary Hyperoxaluria study in which healthy volunteers on a high oxalate and low calcium diet were treated with multiple ascending doses of SYNB8802. The company has initiated Part B of the study and will assess the urinary oxalate lowering potential of SYNB8802 in patients with Enteric Hyperoxaluria following Roux-en-Y gastric bypass surgery. Data is expected in the second half of 2021.

SYNB8802 is an investigational oral drug for the treatment of Enteric Hyperoxaluria composed of an engineered Synthetic Biotic designed to lower urinary oxalate levels by consuming oxalate in the GI tract, potentially reducing kidney damage due to Enteric Hyperoxaluria. Synlogic is conducting a Phase 1 clinical study to evaluate the safety, tolerability, and potential for urinary oxalate lowering of SYNB8802 in healthy volunteers and patients.

The study has two parts: Part A is a multiple ascending dose study in healthy volunteers; Part B is a placebo controlled, cross-over design study in patients with Enteric Hyperoxaluria following Roux-en-Y gastric bypass surgery which provides an opportunity to demonstrate proof of concept.

In the study's efficacy analysis, the percent change from baseline urinary oxalate levels were -28.6% (90% CI: -42.4 to -11.6), compared to placebo, at the 3e11 live cell dose. This dose was well tolerated and will be used in Part B of the study.

"Enteric Hyperoxaluria is a debilitating condition with no approved treatment options," said Dr Richard Riese, Synlogic's Chief Medical Officer. "Lowering dangerously high levels of urinary oxalate is the only way to reduce the risk of disease progression and irreversible kidney damage. We are pleased that SYNB8802 has demonstrated meaningful lowering of urinary oxalate levels in healthy volunteers with induced Dietary Hyperoxaluria. We are advancing the programme rapidly into patients and will provide additional data this year."

The primary outcome of Part A of the Phase 1 study was safety and tolerability, with results used to select a dose for further study in patients with Enteric Hyperoxaluria in Part B of the trial. Synlogic has completed dosing of five cohorts in part A, 45 total subjects. Findings include:

  • SYNB8802 was generally well tolerated in healthy volunteers. There were no serious or systemic adverse events. The most frequent adverse events were mild or moderate, transient, and GI-related. Dietary Hyperoxaluria was successfully induced in Healthy Volunteers.
  • Subjects placed on 600 mg of daily dietary oxalate had urinary oxalate levels of 44.8 mg/24h at baseline.
  • Dose responsive changes in urinary oxalate levels were observed with a significant reduction in urinary oxalate relative to placebo across three dose levels.
  • A dose of 3e11 live cells administered three times daily with meals was selected as the dose for part B of the study.
  • This dose was well-tolerated and resulted in a change from baseline urinary oxalate reduction of 28.6% (90% CI: -42.4 to -11.6), compared to placebo.
  • At the end of dosing, the mean 24-hour urinary oxalate level was 40.1 mg for subjects treated with SYNB8802 3e11 live cells, compared to 58.1 mg for placebo subjects.
  • Upper limit of normal urinary oxalate levels are 45 mg per 24 hours.

Full results of the study will be presented at a future medical meeting.

Enteric Hyperoxaluria is an acquired metabolic disorder caused by increased absorption of dietary oxalate, which is present in many healthy foods, making it almost impossible to control with diet alone. Enteric Hyperoxaluria often occurs as a result of a primary insult to the bowel, such as inflammatory bowel disease, short bowel syndrome, or as a result of surgical procedures such as Roux-en-Y bariatric weight-loss surgery. Enteric Hyperoxaluria results in dangerously high levels of urinary oxalate, which causes progressive kidney damage, kidney stone formation, and nephrocalcinosis. There are no approved treatment options.

"At Synlogic, we are building a portfolio of Synthetic Biotic medicines that consume toxic metabolites to provide new treatment approaches for patients struggling to manage their disease," said Aoife Brennan, Synlogic's President and Chief Executive Officer. "Only 15 months after we nominated SYNB8802 as a programme, we are moving into a proof-of-concept patient study, demonstrating the speed and power of the Synthetic Biotic platform. We look forward to advancing additional metabolic product candidates to provide new treatment options for patients."