The Sugar Fix: A New Approach to Treating a Rare Glycosylation Disorder

/ EXPERT INSIGHTS

The Sugar Fix: A New Approach to Treating a Rare Glycosylation Disorder

GLM101 is in Phase 2 Clinical

Trials for PMM2-CDG

(MAY 2025)

The human body is a vast and intricate network of biological systems and processes in which countless molecular interactions work in coordination to maintain health and respond to disease. When something goes wrong with one of these processes, it can be catastrophic to the system and life-altering for the person. Disruptions in glycosylation, for example, can lead to life-threatening disorders that can be maddeningly difficult to diagnose and even harder to treat.

In recognition of World CDG Day, RiverVest is spotlighting the critical role of glycosylation in human health, what happens when it’s disrupted, and what a novel sugar replacement therapy now in clinical trials could mean for patients with a rare congenital disorder of glycosylation — PMM2-CDG.

When Something Feels Off

At first, everything seems “normal.” The baby is born full-term, the delivery goes smoothly, and the infant goes home with a typically anxious new parent. Newborns are fussy and floppy and spit up after eating. Perhaps it’s just colic. But this baby isn’t gaining weight or holding up her head. Her eyes are crossed, and she isn’t rolling over.

Something feels off. A diagnosis is proposed: cerebral palsy, epilepsy, autism… but none of them fit. The family embarks on a rare disease diagnostic journey that can last months, years, or even decades. The human body, after all, is incomprehensibly complex, with millions of biochemical reactions happening inside trillions of cells every second.

A genetic diagnosis is finally made, and it is a mouthful: phosphomannomutase 2 congenital disorder of glycosylation (PMM2-CDG).

But what does that even mean?

Image Courtesy of Glycomine, Inc.

Glycosylation: Hardy Proteins with Sugar on Top

Glycosylation is a complex biological process in which glycans — chains of sugars — are added to proteins, helping guide their structure, function, and cellular destination. It’s a process that’s essential for everything from immune defense to brain development.

“We all are familiar with DNA, proteins, and fats, but one of the overlooked building blocks of life is sugar,” explains Niall O’Donnell, Ph.D., a biochemist and managing director of RiverVest Venture Partners. “And I don’t mean the kind you put in your coffee. I’m talking about complex sugar chains called glycans that control and regulate how proteins are built, modified, and directed inside the body — helping them fold into the right shape, tagging them for delivery to the right place, and fine-tuning how they function.”

“One of the overlooked building blocks of life is sugar, and I don’t mean the kind you put in your coffee.”

NIALL O’DONNELL, PHD

Biochemist and Managing Director

RiverVest Venture Partners

Protein folding is critically important because a protein’s shape determines its function. When proteins are made, they start as long chains of amino acids. To work properly, they must fold into a precise three-dimensional shape. Glycans added during glycosylation can stabilize intermediate forms of a protein as it folds, guiding the protein toward its proper three-dimensional shape.

Protein tagging is a critical part of the cellular transportation system, which is a complex, coordinated process that ensures proteins are delivered to the correct location. Glycans added during glycosylation act like shipping labels, directing proteins to their intended destination — the cell surface, for example, where they act as receptors or channels, or to lysosomes, which are the cell’s waste-processing centers.

Protein performing is what the proteins do once they reach their destination. Glycosylation plays a critical role in functions such as:

Cell signaling. Glycoproteins on the surface of immune cells help them detect signals from their environment, interact with one another, and coordinate complex biological processes like growth, differentiation, and repair.

Immune system regulation. Antibodies (immunoglobulins), for instance, are glycosylated in ways that affect how they recognize and bind to antigens and recruit other immune cells. These glycan modifications help fine-tune immune strength, balance inflammation, and ensure the body responds appropriately to threats.

Neural development and coordination: Glycosylation also plays a critical role in the development and function of the nervous system, especially the cerebellum, which controls coordination and balance. Glycans influence how neurons grow, form connections, and communicate.

Disordered Glycosylation: When Mutated Genes Stymie the System

Glycosylation depends on the coordinated activity of many different genes, most of which encode enzymes that build and attach glycans to proteins. When a genetic mutation impairs one of these enzymes, the glycosylation process breaks down, leading to proteins that are misfolded, misrouted, or nonfunctional. The resulting problems can affect almost any organ system, causing serious problems such as developmental delays, neurological impairment, liver dysfunction, immune deficiencies, and more.

Congenital disorders of glycosylation (CDGs) is the umbrella term for a large and diverse group of rare genetic diseases caused by defects in glycosylation. As of May 2024, scientists have linked CDGs to mutations in 189 different genes, resulting in over 200 distinct subtypes.

Because CDGs are rare — some affecting only a handful of individuals worldwide — and share symptoms with more common conditions, they are often misdiagnosed as cerebral palsy, mitochondrial disease, autism spectrum, and other disorders. This underscores the complex and difficult journey of diagnosing rare diseases.

While symptoms and severity vary widely depending on the specific genetic variant, CDGs typically affect multiple organ systems, present with overlapping clinical features, and almost always include a neurological component.

PMM2-CDG: A Life-Threatening Disorder in Need of Repair

The most common congenital disorder of glycosylation is PMM2-CDG, caused by mutations in the phosphomannomutase 2 (PMM2) gene. PMM2-CDG accounts for roughly 60 percent of documented CDG patients. Although there are over 2,300 confirmed cases of PMM2-CDG, the true number of affected individuals may be as high as 20,000 when accounting for missed or incorrect diagnoses.

PMM2-CDG is inherited in an autosomal recessive pattern. Individuals who inherit one faulty copy of the PMM2 gene are carriers and typically show no symptoms. Those who inherit two faulty copies — one from each parent — are expected to be affected. The condition affects individuals of all racial and ethnic backgrounds and typically presents in infancy.

Common early signs of PMM2-CDG include hypotonia (reduced muscle tone), strabismus (misaligned eyes), inverted nipples, developmental delays, and failure to thrive. Many affected infants also have an underdeveloped cerebellum, which can impair coordination and movement. Additional symptoms may include elevated liver enzymes, seizures, pericardial effusion (fluid around the heart), and blood clotting abnormalities.

There is currently no approved treatment for this devastating condition, which claims the lives of 10 percent of affected infants before they reach their first birthday and 20 percent before age 5 due to organ failure.

GLM101: Fuel to Make the Glycosylation Engine Go!

To address the unmet need of PMM2-CDG, biopharma startup Glycomine is developing GLM101, a first-in-class mannose-1-phosphate (M1P) replacement therapy. Its approach is elegantly simple in concept: deliver the sugar (M1P) that a functional PMM2 enzyme would normally produce, restoring the glycosylation process and allowing essential proteins to function properly.

Peter McWilliams, Ph.D., CBO at Glycomine, likens the missing M1P to a car that’s out of gas: “You’ve got the machinery needed to run the car, but without the gas, it’s not going anywhere. That’s what it’s like with glycosylation. The body has the machinery needed to build the glycans. It just needs the sugar.”

The challenge is that M1P is too unstable to be taken orally or injected directly. Glycomine’s solution is to encapsulate the M1P in a lipid nanoparticle — a tiny fat-based sphere that protects the sugar and allows it to circulate throughout the body and reach multiple organs. This delivery system is critical for addressing PMM2-CDG’s systemic nature.

“What Glycomine has done that’s so novel is to put a phosphorylated sugar into a lipid nanoparticle. That’s where we get these interesting results, and they’re not just happening in the lab. We’ve been able to translate these results into patients.”

Peter McWilliams, Ph.D., describes Glycomine’s approach to treating PMM2-CDG

GLM101 In The Clinic

Glycomine has enrolled more than 20 adults and adolescents across Europe and the U.S. in an ongoing Phase 2 open-label study of GLM101, and has recently begun dosing pediatric patients as young as age three. Early data are promising: among nine adult and adolescent patients, GLM101 led to an average 11.9-point improvement on the ICARS (International Cooperative Ataxia Rating Scale) over 24 weeks — a meaningful gain for patients struggling with ataxia, a key driver of PMM2-CDG disability that impacts walking, talking, and using fine motor skills.

“The first report that made us think this might be working was a patient in Barcelona who said they could walk better on sand,” said McWilliams. “We’ve had parents tell us that for the first time, their child can look them in the eye and engage in a longer conversation. And we’ve had patients who can spend more time with their assisted walking device, rather than relying solely on their wheelchair.”

Building on this momentum, Glycomine recently raised $115 million in a Series C financing to fund a Phase 2b clinical trial of GLM101. Like the open-label study, this randomized, placebo-controlled trial will evaluate improvements in ataxia using ICARS as its primary endpoint. The study will include 40 to 50 patients at 10 to 14 sites across the U.S. and Europe, with 24 weeks of placebo-controlled dosing, followed by 24 weeks of open-label treatment. Patient enrollment is expected to begin in mid-2025, with interim results anticipated in mid-2026.

“We’ve had parents tell us that for the first time, their child can look them in the eye and engage in a longer conversation.”

PETER MCWILLIAMS, PHD

Chief Business Officer

Glycomine, Inc.

Image Courtesy of Glycomine, Inc.

What Does This Mean For Patients With PMM2-CDG?

Reducing ataxia could significantly enhance quality of life for individuals with PMM2-CDG and ease the burden on their families. Better coordination and mobility might reduce the number of needed caregivers from several to one, for example. It could also foster greater independence and social engagement with family and friends. That might look like a child getting up on their own in the morning, brushing their teeth, getting dressed, and attending school.

Recognizing the urgency for an effective therapy for PMM2-CDG, the U.S. Food and Drug Administration (FDA) granted Fast Track Designation for GLM101 in September 2024. If GLM101 is approved, patients should expect to undergo weekly intravenous infusions of the M1P substrate replacement. For glycosylation to proceed effectively, the body will need a steady supply of the replacement sugar. Thus, GLM101 is intended to be a lifelong therapy.

Glycomine is exploring additional indications for its novel lipid nanoparticle carrier, perhaps other CDGs and related diseases. “We’ve learned a lot about that carrier over the years as we’ve manufactured it and scaled it up,” said McWilliams. “We understand the biology and we understand how to make it, but we’re also looking at different lipid nanoparticles and related technologies that can deliver different payloads, maybe other small molecules or mRNA.”

For now, the company is focused on completing enrollment and conducting the Phase 2b clinical study.

About Glycomine

Glycomine is a clinical-stage biotechnology company that is advancing treatments for serious rare diseases for which no other therapeutic options exist. The Company’s lead investigational drug candidate GLM101 is a mannose-1-phosphate replacement therapy in development to treat PMM2-CDG. GLM101 is designed to deliver mannose-1-phosphate into cells and thereby bypass disease-causing PMM2 mutations to restore pathway function. GLM101 has received Orphan Drug Designation in the U.S. and E.U. and Rare Pediatric Disease Designation and Fast Track Designation in the U.S. The company is based in San Carlos, California, and supported by leading international life sciences investors.

About RiverVest

RiverVest Venture Partners is a leading venture capital firm building life science companies to address significant unmet needs of patients and deliver consistently strong returns to investors. With headquarters in St. Louis and offices in San Diego and Cleveland, RiverVest accesses forward-thinking research and clinical expertise at leading institutions across the country to found and fund biopharma and medical device companies.