The journey of uncommon illness sufferers and their households could be a lengthy one marked by misdiagnoses, and so it’s for individuals who have the ultra-rare dysfunction with the abbreviated identify PMM2-CDG. This enzyme deficiency results in muscle issues and developmental delays which might be typically mistaken for different ailments, mentioned Steven Axon, CEO of startup Glycomine.
PMM2-CDG is genetic, but it surely’s not at present a part of new child screening. The illness could be recognized with a genetic take a look at, however a health care provider must know to check for it. If a affected person doesn’t see a clinician conversant in PMM2-CDG, the journey to a prognosis could be a yr or longer. The most typical misdiagnosis is cerebral palsy.
“In the event that they have been born earlier than 1995, they nonetheless could consider they’ve cerebral palsy as a result of that is when the PMM2 protein was recognized because the offender for this dysfunction,” Axon mentioned. “However for different sufferers, they’ll have all types of challenges early on, in order that they’ll have challenges with their liver, they’ll have elevated liver enzymes, they’ll have this failure to thrive. In order that they’ll be seeing specialists and making an attempt to know.”
Deficiency of the illness’s namesake enzyme results in issues all through the physique. The most typical explanation for loss of life is organ failure. Apart from supportive care, PMM2-CDG has no drug remedies. Glycomine is creating a drug that takes a novel method to the enzyme deficiency. On Wednesday, the San Carlos, California-based biotech introduced $115 million in new financing for mid-stage scientific testing.
PMM2-CDG is brief for phosphomannomutase 2-congential dysfunction of glycosylation. Deficiency of the PMM2 enzyme stems from PMM2 gene mutations that disrupt glycosylation, the method through which sugar chains are hooked up to proteins. PMM2 enzyme is required to transform a sure chemical compound into mannose-1-phosphate, a compound that’s important to this course of.
Glycoproteins shaped by glycosylation are key to the operate of varied tissues and organs all through the human physique. People have round 10,000 glycosylated proteins, all of which could be affected by PMM2-CDG, Axon mentioned. Ataxia, the lack of muscle coordination, is the commonest presentation of PMM2-CDG. Seizures, developmental delays, and cognitive challenges are all frequent within the illness, which Glycomine estimates impacts between 10,000 and 15,000 individuals within the U.S. and Europe.
For a lot of uncommon enzyme deficiencies, remedy is often enzyme substitute remedy. However Glycomine isn’t making an attempt to exchange PMM2 enzyme. The corporate’s drug candidate, code-named GLM101, is a substitute for mannose-1-phosphate. The explanation for this method is the character of the illness, Axon mentioned. Enzyme substitute is often used for lysosomal storage issues, ailments the place the enzyme is required to clear away one thing poisonous. That’s not the case with PMM2-CDG. Subsequently, it’s rather a lot simpler to supply mannose-1-phosphate than it’s to supply the poor enzyme.
The problem is delivering mannose-1-phosphate within the physique. With out safety, the physique breaks down the molecule in about 5 minutes — not sufficient time for it to get to the place it’s wanted to be of any assist, Axon mentioned. 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 by way of an intravenous infusion that takes round three hours, although the corporate is making modifications that might shorten the dosing time.
“We ship that weekly as a result of numerous the proteins that we’re all in favour of, they flip over in days,” Axon mentioned. “Now we have this prolonged half-life, however by the point you get to the tip of the week of the drug, we’re under the publicity degree we wish to be at and so we have to replenish that.”
The science behind GLM101 was developed inside Glycomine, a startup shaped by Bay Space scientists in 2014 and backed by family and friends and seed cash, mentioned Axon, a biopharmaceutical trade veteran who joined the corporate in 2022. In 2016, Glycomine unveiled its PMM2-CDG drug candidate in preclinical improvement together with $12 million in Sequence A funding led by Sanderling Ventures. 5 years later, Glycomine closed its $68 million Sequence B spherical to advance to the clinic.
Up to now, Glycomine has examined GLM101 in 10 sufferers in an open-label Section 2 examine. So far, information from 4 adults and 5 adolescents at six months present statistically important and clinically significant enchancment in ataxia in line with score scale used to evaluate this symptom. Moreover, the drug seems to be protected and nicely tolerated.
With the encouraging early outcomes, Glycomine is continuing to a six-month placebo-controlled Section 2b take a look at designed to enroll between 40 and 50 contributors age 4 and older. Just like the open-label examine, assessing ataxia can even be the aim of the placebo-controlled scientific trial. However after six months, those that obtained placebo will cross over to a remedy arm and all sufferers might be adopted in a long-term extension examine. Axon expects Section 2b enrollment will begin in the midst of this yr; preliminary information may are available in mid-2026. He added that the examine is designed to doubtlessly assist a regulatory submission, however that willpower nonetheless wants the FDA’s sign-off.
Axon mentioned GLM101 might be used to deal with different glycosylation issues, however these ailments, even rarer than PMM2-CDG, have an effect on handfuls of sufferers, which makes improvement troublesome. Glycomine hasn’t pursued these indications. However the method of utilizing a lipid nanoparticle to ship a payload with broad distribution all through the physique may apply to different ailments. Glycomine is exploring such functions, however the illness targets stay undisclosed.
Glycomine isn’t the one firm creating a PMM2-CDG remedy. This uncommon illness is among the targets for Utilized Therapeutics’ lead drug candidate, govorestat. However that biotech is at present focusing the event of this drug for galactosemia, a special uncommon illness with no FDA-approved remedy. Final fall, the FDA turned down Utilized’s utility in search of regulatory approval on this indication. In PMM2, the Utilized small molecule has been examined in a single affected person in an investigator-initiated scientific trial, in line with firm regulatory filings.
Glycomine’s Sequence C financing introduced Wednesday was led by CTI Life Sciences Fund, funds managed by abrdn Inc., and Creation Life Sciences. These traders have been joined by earlier traders Sanderling, Novo Holdings, Sanofi Ventures, Abingworth, RiverVest Enterprise Companions, Chiesi Ventures, Remiges Ventures, and Asahi Kasei Ventures.
Photograph: Bulat Silvia, Getty Photos
