a study to assess the efficacy and safety of weekly doses of glm101 in participants with pmm2-cdg

Conditions: Phosphomannomutase 2 Deficiency; PMM2-CDG

Summary: this study is evaluating the safety, effectiveness, and how the body absorbs, distributes, and eliminates glm101, for participants with pmm2-cdg, including children, adolescents, and adults. researchers will compare participants receiving glm101 to those receiving a placebo to see if glm101 improves symptoms of pmm2-cdg. the study includes two treatment parts: a 24-week double blind placebo-controlled treatment period (part a), and a 24-week open-label phase where every participant will receive glm101(part b).

this phase 2b, multicenter, randomized, double-blind, placebo-controlled clinical study is designed to evaluate the efficacy, safety, and pharmacokinetics (pk) of glm101 in adult, adolescent, and pediatric participants with pmm2-cdg. the study is structured into: a 4-week screening period, a 24-week double-blind treatment period (part a) to assess primary efficacy, a 24-week open-label extension period (part b), and a safety follow-up visit conducted 4 weeks after the last infusion. in part a, participants will be randomly assigned to receive weekly intravenous infusions of either glm101 at 30 mg/kg or a placebo for 24 weeks. after the end of part a, participants will transition into part b, a 24-week open-label extension where all participants will receive glm101. the primary objective of the trial is to identify changes from baseline in coordination and muscle movement (ataxia) using the international co-operative ataxia rating scale (icars) after 24 weeks of taking glm101 compared to a placebo in pmm2-cdg patients.

Eligibility criteria:
inclusion criteria: participant is eligible for participation in the study if all of the following apply: * participant is aged ≥ 4 years old at the time of signing the consent. * participant with molecular diagnosis of pmm2-cdg. diagnosis is defined as biallelic pathogenic and/or likely pathogenic variants, or, in the case of variants of uncertain pathogenicity, demonstration of biallelic variants and pmm2 enzyme activity consistent with a diagnosis of pmm2-cdg. diagnosis with laboratory report(s) on file is required. * participant is willing and capable of completing the icars in its entirety without any assessment deemed as "not evaluable". * participant screening total icars score is ≥ 20 and ≤ 80 . * male or female participant has appropriate measures in place to prevent pregnancy: * if the participant is a woman of childbearing potential, i.e., fertile, following menarche and until becoming postmenopausal unless permanently sterile (permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy), she must not be pregnant (confirmed by a negative serum pregnancy test), is using a medically accepted method of contraception (abstinence, a hormonal contraceptive associated with inhibition of ovulation in conjunction with a barrier method, or use of an intrauterine device), and must agree to continue using this method for 50 days after the last infusion. note: sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the participant. periodic abstinence (calendar, symptothermal, post-ovulation methods) is not an acceptable method of contraception. * if the participant is a female of non-childbearing potential, she must be premenarchal, surgically sterile, or must have an ovarian dysfunction confirmed by a follicle stimulating hormone \> 40 iu/ l (or higher per local institutional guidelines) and absence of menses for 12 months after last menstrual bleeding without an alternative medical cause. * if the participant is a sexually active male with female partners, the participant agrees to use a medically acceptable method of contraception (abstinence, the partner taking a hormonal contraceptive in conjunction with male participant using male condom, or use by the partner of an intrauterine device with a male participant using male condom) and agrees to continue using this method for 50 days after the last infusion. * if the participant is male, he must agree to refrain from donating sperm during the study and 50 days after the last infusion. * the participant is willing and able to provide informed consent/assent, directly or through his/her legally authorized representative. * the participant has a caregiver who is willing and able to complete questionnaires and provide informed consent. exclusion criteria: participant will be excluded from participation in the study if any of the following criteria apply: * has uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, endocrine, metabolic, ophthalmologic, immunologic, psychiatric or other significant disease based on the investigator judgment. * diagnosis of congenital disorder of glycosylation (cdg) other than pmm2; diagnosis is defined as biallelic pathogenic and/or likely pathogenic variants, or, in the case of variants of uncertain pathogenicity, demonstration of biallelic variants and the defined cdg enzyme activity consistent with a diagnosis of the cdg other than pmm2 cdg. * has a history of liver transplant. * has an active infection requiring parenteral antibiotics, antivirals, antifungals or treatment with systemic steroids within 7 days prior to screening. * has a history of drug or alcohol use disorder within 12 months prior to screening. * has had a major surgical procedure within 30 days prior to screening or an upcoming planned major surgery. * previous history of glm101 administration. * is currently participating in another interventional clinical study or has completed another clinical study with an investigational drug or device within 30 days or 5 half-lives (whichever is longer) before enrollment. * have consumed products or supplements containing mannose or biotin within 2 weeks prior to screening. * elevated liver function tests: alanine aminotransferase or aspartate aminotransferase \> 3 × upper limit of normal (uln) or total bilirubin \> 2 × uln or international normalized ratio \> 1.5. * has screening laboratory value(s) considered clinically significant and not related to pmm2-cdg based on the investigator judgment. * has serology positive for hepatitis b surface antigen or hepatitis c antibody during screening. * has a qt interval by fridericia (qtcf) ≥ 450 ms, or other electrocardiogram abnormalities judged as clinically significant by the investigator. * has history or presence, upon clinical evaluation, of any illness that might impact the safety of glm101 infusion or evaluability of drug effect based on the investigator's and sponsor's medical monitor's discretion. * participant weighs above 75 kg. * participant has a known or suspected hypersensitivity to glm101 or any components of the formulation used. * any other reason for which, in the investigator's opinion, makes the participant unsuitable for study participation.

Keywords: glm101 cdg cdg 1a pmm2 ataxia