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 can be usually mistaken for different ailments, mentioned Steven Axon, CEO of startup Glycomine.
PMM2-CDG is genetic, but it surely’s not at the moment a part of new child screening. The illness might be identified with a genetic check, however a physician must know to check for it. If a affected person doesn’t see a clinician accustomed to PMM2-CDG, the journey to a prognosis could be a yr or longer. The commonest 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 attempting to know.”
Deficiency of the illness’s namesake enzyme results in issues all through the physique. The commonest explanation for demise is organ failure. Apart from supportive care, PMM2-CDG has no drug therapies. Glycomine is growing 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 wherein 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 perform of varied tissues and organs all through the human physique. People have round 10,000 glycosylated proteins, all of which might be affected by PMM2-CDG, Axon mentioned. Ataxia, the lack of muscle coordination, is the most typical 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, therapy is usually enzyme alternative remedy. However Glycomine isn’t attempting to exchange PMM2 enzyme. The corporate’s drug candidate, code-named GLM101, is a alternative for mannose-1-phosphate. The rationale for this method is the character of the illness, Axon mentioned. Enzyme alternative is usually used for lysosomal storage problems, ailments the place the enzyme is required to clear away one thing poisonous. That’s not the case with PMM2-CDG. Due to this fact, it’s so much 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 would shorten the dosing time.
“We ship that weekly as a result of lots of the proteins that we’re eager about, they flip over in days,” Axon mentioned. “We’ve this prolonged half-life, however by the point you get to the top 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 business veteran who joined the corporate in 2022. In 2016, Glycomine unveiled its PMM2-CDG drug candidate in preclinical improvement together with $12 million in Collection A funding led by Sanderling Ventures. 5 years later, Glycomine closed its $68 million Collection B spherical to advance to the clinic.
To this point, Glycomine has examined GLM101 in 10 sufferers in an open-label Section 2 examine. Up to now, knowledge from 4 adults and 5 adolescents at six months present statistically important and clinically significant enchancment in ataxia in keeping with ranking scale used to evaluate this symptom. Moreover, the drug seems to be secure and effectively tolerated.
With the encouraging early outcomes, Glycomine is continuing to a six-month placebo-controlled Section 2b check designed to enroll between 40 and 50 members age 4 and older. Just like the open-label examine, assessing ataxia may also be the purpose of the placebo-controlled scientific trial. However after six months, those that acquired placebo will cross over to a therapy arm and all sufferers can be adopted in a long-term extension examine. Axon expects Section 2b enrollment will begin in the course of this yr; preliminary knowledge may are available mid-2026. He added that the examine is designed to probably assist a regulatory submission, however that dedication nonetheless wants the FDA’s sign-off.
Axon mentioned GLM101 could possibly be used to deal with different glycosylation problems, however these ailments, even rarer than PMM2-CDG, have an effect on handfuls of sufferers, which makes improvement tough. 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 growing a PMM2-CDG therapy. This uncommon illness is among the targets for Utilized Therapeutics’ lead drug candidate, govorestat. However that biotech is at the moment focusing the event of this drug for galactosemia, a distinct uncommon illness with no FDA-approved therapy. Final fall, the FDA turned down Utilized’s software searching for 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 keeping with firm regulatory filings.
Glycomine’s Collection 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 Photographs
