Frank Vinluan , 2025-04-17 00:04:00
The journey of rare disease patients and their families can be a long one marked by misdiagnoses, and so it is for those who have the ultra-rare disorder with the abbreviated name PMM2-CDG. This enzyme deficiency leads to muscle problems and developmental delays that are often mistaken for other diseases, said Steven Axon, CEO of startup Glycomine.
PMM2-CDG is genetic, but it’s not currently part of newborn screening. The disease can be diagnosed with a genetic test, but a doctor needs to know to test for it. If a patient does not see a clinician familiar with PMM2-CDG, the journey to a diagnosis can be a year or longer. The most common misdiagnosis is cerebral palsy.
“If they were born before 1995, they still may believe they have cerebral palsy because this is when the PMM2 protein was identified as the culprit for this disorder,” Axon said. “But for other patients, they’ll have all sorts of challenges early on, so they’ll have challenges with their liver, they’ll have elevated liver enzymes, they’ll have this failure to thrive. So they’ll be seeing specialists and trying to understand.”
Deficiency of the disease’s namesake enzyme leads to problems throughout the body. The most common cause of death is organ failure. Other than supportive care, PMM2-CDG has no drug treatments. Glycomine is developing a drug that takes a novel approach to the enzyme deficiency. On Wednesday, the San Carlos, California-based biotech announced $115 million in new financing for mid-stage clinical testing.
PMM2-CDG is short for phosphomannomutase 2-congential disorder of glycosylation. Deficiency of the PMM2 enzyme stems from PMM2 gene mutations that disrupt glycosylation, the process in which sugar chains are attached to proteins. PMM2 enzyme is needed to convert a certain chemical compound into mannose-1-phosphate, a compound that’s essential to this process.
Glycoproteins formed by glycosylation are key to the function of various tissues and organs throughout the human body. Humans have around 10,000 glycosylated proteins, all of which can be affected by PMM2-CDG, Axon said. Ataxia, the loss of muscle coordination, is the most common presentation of PMM2-CDG. Seizures, developmental delays, and cognitive challenges are all common in the disease, which Glycomine estimates affects between 10,000 and 15,000 people in the U.S. and Europe.
For many rare enzyme deficiencies, treatment is typically enzyme replacement therapy. But Glycomine isn’t trying to replace PMM2 enzyme. The company’s drug candidate, code-named GLM101, is a replacement for mannose-1-phosphate. The reason for this approach is the nature of the disease, Axon said. Enzyme replacement is typically used for lysosomal storage disorders, diseases where the enzyme is needed to clear away something toxic. That’s not the case with PMM2-CDG. Therefore, it’s a lot easier to provide mannose-1-phosphate than it is to provide the deficient enzyme.
The challenge is delivering mannose-1-phosphate in the body. Without protection, the body breaks down the molecule in about five minutes — not enough time for it to get to where it’s needed to be of any help, Axon said. Glycomine encapsulates mannose-1-phosphate in a lipid nanoparticle, extending the circulating half-life of its drug to about 80 hours. It’s administered weekly via an intravenous infusion that takes around three hours, though the company is making changes that could shorten the dosing time.
“We deliver that weekly because a lot of the proteins that we’re interested in, they turn over in days,” Axon said. “We have this extended half-life, but by the time you get to the end of the week of the drug, we are below the exposure level we want to be at and so we need to replenish that.”
The science behind GLM101 was developed within Glycomine, a startup formed by Bay Area scientists in 2014 and backed by friends and family and seed money, said Axon, a biopharmaceutical industry veteran who joined the company in 2022. In 2016, Glycomine unveiled its PMM2-CDG drug candidate in preclinical development along with $12 million in Series A funding led by Sanderling Ventures. Five years later, Glycomine closed its $68 million Series B round to advance to the clinic.
So far, Glycomine has tested GLM101 in 10 patients in an open-label Phase 2 study. To date, data from four adults and five adolescents at six months show statistically significant and clinically meaningful improvement in ataxia according to rating scale used to assess this symptom. Furthermore, the drug appears to be safe and well tolerated.
With the encouraging early results, Glycomine is proceeding to a six-month placebo-controlled Phase 2b test designed to enroll between 40 and 50 participants age 4 and older. Like the open-label study, assessing ataxia will also be the goal of the placebo-controlled clinical trial. But after six months, those who received placebo will cross over to a treatment arm and all patients will be followed in a long-term extension study. Axon expects Phase 2b enrollment will start in the middle of this year; preliminary data could come in mid-2026. He added that the study is designed to potentially support a regulatory submission, but that determination still needs the FDA’s sign-off.
Axon said GLM101 could be used to treat other glycosylation disorders, but those diseases, even rarer than PMM2-CDG, affect handfuls of patients, which makes development difficult. Glycomine hasn’t pursued those indications. But the approach of using a lipid nanoparticle to deliver a payload with broad distribution throughout the body could apply to other diseases. Glycomine is exploring such applications, but the disease targets remain undisclosed.
Glycomine isn’t the only company developing a PMM2-CDG treatment. This rare disease is one of the targets for Applied Therapeutics’ lead drug candidate, govorestat. But that biotech is currently focusing the development of this drug for galactosemia, a different rare disease with no FDA-approved treatment. Last fall, the FDA turned down Applied’s application seeking regulatory approval in this indication. In PMM2, the Applied small molecule has been tested in a single patient in an investigator-initiated clinical trial, according to company regulatory filings.
Glycomine’s Series C financing announced Wednesday was led by CTI Life Sciences Fund, funds managed by abrdn Inc., and Advent Life Sciences. Those investors were joined by earlier investors Sanderling, Novo Holdings, Sanofi Ventures, Abingworth, RiverVest Venture Partners, Chiesi Ventures, Remiges Ventures, and Asahi Kasei Ventures.
Photo: Bulat Silvia, Getty Images