Proof of concept for the Genetically Engineered Microbial Medicines (GEMM) platform came in a recent first-in-human, Phase I trial.
Novome CEO Blake Wise/Courtesy of Novome Biotechnology
Engineered cell therapy rarely uses bacteria, and bacterial therapies are rarely engineered. Novome Biotechnologies, however, is engineering a class of microbes as therapeutics and engrafting them into the gut, where they grow until they are no longer needed.
“There are very few companies exploring the engineering of microbes for therapeutic activities, and we’re the only company engrafting them in the gut so they grow there,” Novome CEO Blake Wise told BioSpace. These engineered bacteria need to colonize the gut and grow there for their numbers to become sufficient to be therapeutically effective. In contrast, competing companies take a dose approach to bacteria delivery, in which beneficial bacteria are passed through the gut but do not colonize the space.
Novome’s engineered bacteria are a type of Bacteroides, a gram-negative, anaerobic bacteria. “These are the most highly-abundant genus of bacteria in the gut, making up 50% of the average human gut. A single species makes up to 5% to 10% of the gut bacteria naturally,” Wise said.
The lead indication, enteric hyperoxaluria, is a metabolic disorder characterized by elevated urinary oxalate levels that are associated with recurrent kidney stones, chronic kidney disease and other kidney diseases. It affects approximately 250,000 patients in the U.S.
NOV-001, which is designed to treat enteric hyperoxaluria, comes in two parts: one dose of the engineered bacteria (NB1000S, a proprietary microbial strain), and a daily 0.5-to-10-gram dose of NB2000P, a prebiotic control molecule that is the engineered bacteria’s food source. In this case, the food source is porphyran, a fiber-like seaweed extract.
Engineering changes the bacteria in three ways. It contains:
- A gene cassette for the therapeutic function (a payload)
- A gene cassette to consume the seaweed extract
- A kill switch
“When we deliver the porphyran (a polysaccharide), this bacterium (proliferates and) has constituted up to 5% of the total microbial load in the gut,” Wise said. When that specific food source is removed, the bacteria die and wash out of the gut.
Currently, he continued, “The bacterial strain is a liquid formulation and the porphyran is a powder. Each is mixed with water before consumption. Ultimately, both components will be co-formulated in a pill or capsule.” The dosage can be tuned by adjusting the quantity of the food source since the bacteria proliferate faster when there is ample food and slowly when food becomes scarce.
Proof of concept for the Genetically Engineered Microbial Medicines (GEMM) platform came in a recent first-in-human, Phase I trial. That 14-day, 24-person study showed that NOV-001 safely colonized in the human gut and that its proliferation could be controlled by once-daily dosing of the prebiotic control molecule. At the highest dose of NB2000P (10 grams), NB1000S was present at an average of 10 trillion cells per gram of stool.
Importantly, NOV-001 did not appear to disrupt the native gut microbiota. The diversity of flora was maintained during the treatment and, when it ended, the engineered bacteria appeared to leave participants’ systems.
In 2022, Novome plans to launch a Phase II A trial to assess the safety, tolerability and early efficacy of NOV-001 for patients with enteric hyperoxaluria. When this prospective, randomized, single-blinded placebo-controlled study begins, “This will be the first time the GEMM platform will be used on actual patients because the Phase I trial was conducted on healthy volunteers,” Wise noted.
“In healthy people, oxalate is processed out, but if there are underlying gastrointestinal (GI) disorders – such as bariatric surgery or inflammatory bowel syndrome (IBD) – oxalate may be over-absorbed and form kidney stones,” he said. Eventually, it may lead to kidney disease or kidney failure. “To treat enteric hyperoxaluria, we break it down before it can be absorbed.”
The therapy has the potential to fill a significant unmet need. “There’s no FDA-approved therapy for enteric hyperoxaluria,” Wise said. “Doctors tell their patients to avoid oxalate, but a healthy diet is largely made up of foods with oxalate.” The substance is found in leafy greens, almonds, soy, potatoes, beets, dates, raspberries and even chocolate.
“From a platform perspective, to break down oxalate, we want to ramp up our strain as high as possible.” This approach appears quite safe since the unengineered bacteria occurs naturally in the human body. “The FDA required no toxicologic studies for our human trials, which is rare,” Wise pointed out.
In other areas, Genentech is working with Novome to develop this approach as a treatment for IBD, which affects approximately 1.6 million people in the United States.
“We’re really excited about this collaboration,” Wise said. “Genentech has a lot of experience in the IBD space and are interested in using our platform to deliver a therapeutic payload.”
