SAN FRANCISCO—Last August, Synlogic pulled the plug on its lead program: a “synthetic biotic,” or living microbe medicine, aimed at lowering ammonia levels in the intestine. Now, CEO Dr. Aoife Brennan is sharing what the company learned from that failure and what it means for Synlogic’s future.
Synlogic was developing the treatment, known as SYNB1020, for patients with hyperammonemia who lack the enzymes needed to break down ammonia and so have elevated levels of the compound. Treatment usually involves consuming less ammonia in the diet or taking drugs that block its absorption into the intestine. Synlogic’s idea was to engineer a strain of Escherichia coli bacteria to consume ammonia in patients’ guts.
It didn’t work. Synlogic ended the program, and its stock took a tumble. But the experience made the Cambridge, Massachusetts-based biotech think about how it chooses the diseases it goes after, Brennan said at the annual J.P. Morgan Healthcare Conference.
“We had started the company on the basis that we can fundamentally change the way drugs are developed and how we think about therapies by applying engineering principles to probiotic bacteria to make therapies designed specifically with potency to intercept the mechanisms of disease,” she said.
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It started with engineering bacteria because they’re simple, single-cell beings the genetics of which are mostly known. The ammonia experience taught Synlogic that it should keep the biology it goes after simple, too.
“The really important thing is we don’t take on too much biological risk for these early programs and that informed our next wave of programs to be really focused on disease where we know that if you can exclude a certain substrate from diet, it can have a clinical impact on disease,” Brennan said.
For example, a recently announced preclinical program aims at hyperoxaluria, in which excess oxalate in the body can lead to kidney failure.
“We know we all consume about 300 mg of oxalate in our diet every day. I those patients with hyperoxaluria, if we can lower that dietary oxalate by half, we can have an important clinical benefit,” Brennan said. “We can calculate how much oxalate the bacteria need to consume in vivo. It’s simple logic—it takes some complexity off the table.”
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“We didn’t have that same line of sight with the ammonia program,” she added. “Hyperammonemia had more complex biology than other programs we have had as opportunities.”
SYNB1020 also helped in another regard: paving the way for a new type of medicine. The company didn’t rely on previously trod paths, keeping or discarding elements that applied or didn’t apply.
“Our approach very much let us look at the regulatory path for a biologic or a small molecule. For each of those, quality attributes, we figure out how much that matters for our platform,” Brennan said. “Instead of saying sterility is irrelevant—because we’re using bacteria—we said, if you’re taking a dose of bacteria, the only bacteria you’re getting is ours. We exclude contamination with other bacteria, for instance.”
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In 2020, Synlogic will focus on getting its phenylketonuria (PKU) program, SYNB1618, into phase 2, and report data from its oncology program SYNB1891, which it’s testing on its own as well as in tandem with Tecentriq. The PKU treatment is engineered to consume phenylalanine, an amino acid that people with the condition cannot process, and the cancer treatment is designed to produce a STING agonist in the tumor microenvironment, said Chief Medical Officer Richard Riese, M.D., Ph.D. Synlogic is testing it in solid tumors and lymphoma. It also plans to reveal preclinical data for the hyperoxaluria program as well as from a treatment for maple syrup urine disease.
A year from now, according to interim Chief Financial Officer Gregg Beloff, Synlogic will be “consuming metabolites in the gut and showing the principles of ‘synthetic biotics’ are working in a number different clinical capacities.”