For gout pain that does not respond to conventional therapies, patients’ only remaining option is a drug from Amgen. But this biologic medicine introduces the same problem facing every therapeutic protein: The body can see the engineered protein as foreign, prompting an immune response that renders the treatment ineffective. The technology of GRO Biosciences engineers proteins that the immune system sees as belonging to the body. The biotech startup aims to overcome the immune response limitation of the Amgen drug and it has raised $60 million for its technology’s first test in humans.
The Series B financing announced Friday was co-led by Atlas Venture and Access Biotechnology, both new investors in Cambridge, Massachusetts-based GRObio.
When it comes to designing therapeutic proteins, scientists have worked with what Mother Nature provides — 20 standard amino acids. GRObio develops proteins employing amino acids that aren’t used by nature to make proteins. These non-standard amino acids (NSAAs) enable the design of proteins with better properties, such as a more durable effect or precise control of the immune system, CEO Dan Mandell said. This approach has potential applications to autoimmune and inflammatory disorders. GRObio has selected gout as its lead indication.
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Gout is a form of arthritis that develops when high levels of uric acid in the blood lead to the formation and accumulation of uric crystals in joints, causing inflammation and pain. Treatment options include anti-inflammatory medications, such as corticosteroids, and URAT1 inhibitors, a class of drugs that reduces uric acid levels in the blood.
Uricase, the enzyme that breaks down uric acid, is not found in humans. If introduced into the human body, the immune system will produce antibodies against it. Amgen’s gout drug, Krystexxa, is an engineered version of uricase that’s attached to polyethylene glycol (PEG), a non-toxic and non-immunogenic polymer. A PEG reduces the immune response to a biologic therapy, an approach that has been employed in other drugs. Krystexxa helps gout patients initially. But clinical testing showed many Krystexxa-treated patients went on to develop anti-drug antibodies. Those antibodies cleared the engineered enzyme from circulation so it no longer works.
GRObio’s gout drug, called ProGly-Uricase, is also an engineered version of uricase, but it uses something of a trick to avoid an immune response. The immune system distinguishes between native proteins and foreign ones through glycans, sugar molecules on a protein’s surface. GRObio covers its engineered proteins with glycans that signal to the immune system that the protein belongs to the body. In preclinical research, GRObio said its ProGly (short for programmable glycosylation) enzyme led to “a dramatic reduction” in antibody drug antibodies compared to Krystexxa.
“We can control not only where these glycans appear on the surface of a protein, we can also control their composition,” Mandell said. “That means we can control how the immune system responds to a protein.”
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GRObio emerged in 2021, backed by $25 million in Series A financing. Its science stems from the lab of George Church, a Harvard University geneticist whose research has led to the founding of many biotech companies. Mandell was a research fellow in Church’s lab. “GRO” stands for genomically recoded organisms; the startup uses recoded E. coli bacteria to produce its NSAA proteins.
Gout makes sense as a lead indication because the clinical development pathway is relatively fast, Mandell said. Measuring uric acid levels in the blood offers a biomarker and clinical trial endpoint that is straightforward and clear. Also, because measuring those levels makes it possible to show proof-of-concept in Phase 1, success in an early-stage study can proceed directly to a Phase 3 registrational study.
“We’re able to take advantage of the clinical development pathway that was blazed by Krystexxa,” Mandell said. “Now there’s precedent for obtaining the efficacy data in Phase 1, which is unusual, and being able to get approval based on a biomarker in Phase 3.”
Krystexxa was developed and commercialized by Horizon Therapeutics, which Amgen acquired last year for $28 billion. Before the deal closed, Horizon reported $431.2 million in Krystexxa sales in the first half of 2023, a 39% increase compared to the same period in 2022. Gout competition could be coming soon from Swedish Orphan Biovitrum, whose enzyme therapy is under FDA review.
GRObio says its funding total now tops $90 million. The new round includes participation of earlier investors Leaps by Bayer, Redmile Group, Digitalis Ventures and Innovation Endeavors. Mandell isn’t offering any timelines for GRObio’s clinical trial plans, but he said the financing enables the startup to begin clinical scale manufacturing of the gout drug and proceed with activities to support an investigational new drug application.
The next program in the pipeline is a potential treatment for myasthenia gravis, a rare muscle disease driven by autoantibodies. While FDA-approved drugs from UCB and Argenx provide new treatment options for myasthenia gravis patients, the standard of care has been mainly drugs that have a broadly immunuosuppresive effect. Mandell said GRObio’s preclinical research showed its technology was able to induce the production of regulatory T cells. These cells suppressed the immune response to the specific antigen driving myasthenia gravis while leaving other antibodies in the animals untouched. GRObio is looking for pharmaceutical partners for the myasthenia gravis program specifically, and for the company’s platform technology broadly.
The startup will also apply the funding toward expansion of its technology platform. Mandell said it’s relatively straightforward to put many copies of a single NSAA into a protein. What’s more challenging is putting two or three different NSAAs into a protein at the same time, each one offering a different function. This capability could be applicable to the therapeutic drug class known as antibody drug conjugates, or ADCs. The GRObio technology not only makes the incorporation of multiple NSAAs into a single protein possible, it also makes producing these therapeutic proteins scalable. These therapies could find applications in cancer, joining a growing field of ADCs in development. But Mandell added that ADCs developed with the GRObio platform could also find use treating autoimmune diseases.
Photo by GRO Biosciences