PGN-EDODM1 for Muscular Dystrophy
(FREEDOM2-DM1 Trial)
Recruiting in Palo Alto (17 mi)
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: PepGen Inc
Must not be taking: Myotonia medications
Disqualifiers: Congenital DM1, Abnormal labs, others
Prior Safety Data
Trial Summary
What is the purpose of this trial?The purpose of this study is to learn about the effects of an investigational medicine, PGN-EDODM1, to see how safe and tolerable multiple administrations of PGN-EDODM1 are for people with myotonic dystrophy type 1 (DM1) compared to placebo.
Will I have to stop taking my current medications?
The trial requires that you stop taking medications specifically for the treatment of myotonia at least 2 weeks before screening. For other medications, the protocol does not specify, so it's best to discuss with the study team.
What data supports the effectiveness of the drug PGN-EDODM1 for Muscular Dystrophy?
Research on similar treatments, like eteplirsen, shows that increasing dystrophin production can help slow down muscle decline in Duchenne muscular dystrophy. Additionally, studies on utrophin modulation suggest that enhancing related proteins can improve muscle function and stability, which might be relevant for PGN-EDODM1.
12345How is the drug PGN-EDODM1 different from other treatments for muscular dystrophy?
PGN-EDODM1 is unique because it targets the prostaglandin D2 (PGD2) pathway, which is involved in muscle necrosis in Duchenne muscular dystrophy (DMD). This approach is different from other treatments that focus on gene therapy or exon skipping, as it aims to reduce inflammation and muscle damage by inhibiting the enzyme responsible for PGD2 production.
678910Eligibility Criteria
This trial is for people with myotonic dystrophy type 1, who have myotonia and a confirmed genetic diagnosis. Participants should be able to move their tibialis anterior muscles against moderate pressure and have a BMI of less than 32 kg/m2.Inclusion Criteria
I can move my lower legs fully and resist some pressure.
Body Mass Index (BMI) of < 32.0 kg/m^2
I have been diagnosed with DM1 with a specific genetic marker.
+1 more
Exclusion Criteria
I was born with myotonic dystrophy type 1.
Known history or presence of any clinically significant conditions that may interfere with study safety assessments
Abnormal laboratory tests at screening considered clinically significant by the Investigator
+3 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive either PGN-EDODM1 or placebo once every 4 weeks for 12 weeks
12 weeks
3 visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The study tests PGN-EDODM1, an experimental drug for DM1. It will compare the safety and tolerability of multiple doses of PGN-EDODM1 against a placebo in participants.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: PGN-EDODM1Experimental Treatment1 Intervention
Participants will be randomized to receive ascending doses of PGN-EDODM1, once every 4 weeks (Q4W) for 12 weeks
Group II: PlaceboPlacebo Group1 Intervention
Participants randomized to the placebo arm will receive doses of saline (0.9% NaCl), once every 4 weeks (Q4W) for 12 weeks
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
CIUSSS du Saguenay-Lac-Saint-JeanChicoutimi, Canada
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Who Is Running the Clinical Trial?
PepGen IncLead Sponsor
References
Eteplirsen treatment for Duchenne muscular dystrophy: Exon skipping and dystrophin production. [2019]To describe the quantification of novel dystrophin production in patients with Duchenne muscular dystrophy (DMD) after long-term treatment with eteplirsen.
Open-Label Evaluation of Eteplirsen in Patients with Duchenne Muscular Dystrophy Amenable to Exon 51 Skipping: PROMOVI Trial. [2022]BackgroundEteplirsen received accelerated FDA approval for treatment of Duchenne muscular dystrophy (DMD) with mutations amenable to exon 51 skipping, based on demonstrated dystrophin production.ObjectiveTo report results from PROMOVI, a phase 3, multicenter, open-label study evaluating efficacy and safety of eteplirsen in a larger cohort.MethodsAmbulatory patients aged 7-16 years, with confirmed mutations amenable to exon 51 skipping, received eteplirsen 30 mg/kg/week intravenously for 96 weeks. An untreated cohort with DMD not amenable to exon 51 skipping was also enrolled.Results78/79 eteplirsen-treated patients completed 96 weeks of treatment. 15/30 untreated patients completed the study; this cohort was considered an inappropriate control group because of genotype-driven differences in clinical trajectory. At Week 96, eteplirsen-treated patients showed increased exon skipping (18.7-fold) and dystrophin protein (7-fold) versus baseline. Post-hoc comparisons with patients from eteplirsen phase 2 studies (4658-201/202) and mutation-matched external natural history controls confirmed previous results, suggesting clinically notable attenuation of decline on the 6-minute walk test over 96 weeks (PROMOVI: -68.9 m; phase 2 studies: -67.3 m; external controls: -133.8 m) and significant attenuation of percent predicted forced vital capacity annual decline (PROMOVI: -3.3%, phase 2 studies: -2.2%, external controls: -6.0%; p
The 6-minute walk test and other endpoints in Duchenne muscular dystrophy: longitudinal natural history observations over 48 weeks from a multicenter study. [2022]Duchenne muscular dystrophy (DMD) subjects ≥5 years with nonsense mutations were followed for 48 weeks in a multicenter, randomized, double-blind, placebo-controlled trial of ataluren. Placebo arm data (N = 57) provided insight into the natural history of the 6-minute walk test (6MWT) and other endpoints.
Second-generation compound for the modulation of utrophin in the therapy of DMD. [2022]Duchenne muscular dystrophy (DMD) is a lethal, X-linked muscle-wasting disease caused by lack of the cytoskeletal protein dystrophin. There is currently no cure for DMD although various promising approaches are progressing through human clinical trials. By pharmacologically modulating the expression of the dystrophin-related protein utrophin, we have previously demonstrated in dystrophin-deficient mdx studies, daily SMT C1100 treatment significantly reduced muscle degeneration leading to improved muscle function. This manuscript describes the significant disease modifying benefits associated with daily dosing of SMT022357, a second-generation compound in this drug series with improved physicochemical properties and a more robust metabolism profile. These studies in the mdx mouse demonstrate that oral administration of SMT022357 leads to increased utrophin expression in skeletal, respiratory and cardiac muscles. Significantly, utrophin expression is localized along the length of the muscle fibre, not just at the synapse, and is fibre-type independent, suggesting that drug treatment is modulating utrophin transcription in extra-synaptic myonuclei. This results in improved sarcolemmal stability and prevents dystrophic pathology through a significant reduction of regeneration, necrosis and fibrosis. All these improvements combine to protect the mdx muscle from contraction induced damage and enhance physiological function. This detailed evaluation of the SMT C1100 drug series strongly endorses the therapeutic potential of utrophin modulation as a disease modifying therapeutic strategy for all DMD patients irrespective of their dystrophin mutation.
Therapeutic potential of highly functional codon-optimized microutrophin for muscle-specific expression. [2022]High expectations have been set on gene therapy with an AAV-delivered shortened version of dystrophin (µDys) for Duchenne muscular dystrophy (DMD), with several drug candidates currently undergoing clinical trials. Safety concerns with this therapeutic approach include the immune response to introduced dystrophin antigens observed in some DMD patients. Recent reports highlighted microutrophin (µUtrn) as a less immunogenic functional dystrophin substitute for gene therapy. In the current study, we created a human codon-optimized µUtrn which was subjected to side-by-side characterization with previously reported mouse and human µUtrn sequences after rAAV9 intramuscular injections in mdx mice. Long-term studies with systemic delivery of rAAV9-µUtrn demonstrated robust transgene expression in muscles, with localization to the sarcolemma, functional improvement of muscle performance, decreased creatine kinase levels, and lower immunogenicity as compared to µDys. An extensive toxicity study in wild-type rats did not reveal adverse changes associated with high-dose rAAV9 administration and human codon-optimized µUtrn overexpression. Furthermore, we verified that muscle-specific promoters MHCK7 and SPc5-12 drive a sufficient level of rAAV9-µUtrn expression to ameliorate the dystrophic phenotype in mdx mice. Our results provide ground for taking human codon-optimized µUtrn combined with muscle-specific promoters into clinical development as safe and efficient gene therapy for DMD.
Early phase 2 trial of TAS-205 in patients with Duchenne muscular dystrophy. [2021]Label="OBJECTIVE">Duchenne muscular dystrophy (DMD) is a progressive muscular disease characterized by chronic cycles of inflammatory and necrotic processes. Prostaglandin D2 (PGD2 ) is produced by hematopoietic PGD synthase (HPGDS), which is pathologically implicated in muscle necrosis. This randomized, double-blind, placebo-controlled early phase 2 study (NCT02752048) aimed to assess the efficacy and safety of the novel selective HPGDS inhibitor, TAS-205, with exploratory measures in male DMD patients aged ≥5 years.
A prostaglandin D2 metabolite is elevated in the urine of Duchenne muscular dystrophy patients and increases further from 8 years old. [2022]Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by muscle dystrophin deficiency. Downstream of the primary dystrophin deficiency is not well elucidated. Here, the hypothesis that prostaglandin D2 (PGD2)-mediated inflammation is involved in the pathology of DMD was examined by measuring tetranor PGDM, a major PGD2 metabolite, in urine of DMD patients.
A Randomized, Double-Blind, Placebo-Controlled, Global Phase 3 Study of Edasalonexent in Pediatric Patients with Duchenne Muscular Dystrophy: Results of the PolarisDMD Trial. [2021]Edasalonexent (CAT-1004) is an orally-administered novel small molecule drug designed to inhibit NF-κB and potentially reduce inflammation and fibrosis to improve muscle function and thereby slow disease progression and muscle decline in Duchenne muscular dystrophy (DMD).
[Hematopoietic prostaglandin D synthase inhibitors for the treatment of duchenne muscular dystrophy]. [2022]Duchenne muscular dystrophy (DMD) is a severe X-linked muscle disease, characterized by progressive skeletal muscle atrophy and weakness. DMD is caused by mutations in the dystrophin gene, which encodes for the cytoskeletal protein dystrophin. DMD is one of the most common types of muscular dystrophies, affecting approximately 1 in 3,500 boys. There is no complete cure for this disease. Clinical trials for gene transfer therapy as a treatment for DMD have been performed but mainly in animal models. Hematopoietic prostaglandin (PG) D synthase (H-PGDS) was found to be induced in grouped necrotic muscle fibers of DMD patients and animal models, mdx mice, and DMD dogs. We found an orally active H-PGDS inhibitor (HQL-79) and determined the 3D structure of the inhibitor-human H-PGDS complex by X-ray crystallography. Oral administration of HQL-79 markedly suppressed prostaglandin D2 (PGD2) production, reduced necrotic muscle volume, and improved muscle strength in mdx dystrophic mice. Based on the high-resolution 3D structures of the inhibitor-H-PGDS complex, we designed alternative H-PGDS inhibitors, which were 100- to 3000-times more potent than HQL-79, as assessed by in vitro and in vivo analyses. We used these novel inhibitors for the treatment of DMD dogs and confirmed that oral administration of these inhibitors prevented skeletal muscle atrophy and weakness by decreasing PGD2 production. These results indicate that PGD2, synthesized by H-PGDS, is involved in the expansion of muscle necrosis in DMD. Thus, inhibition of H-PGDS by using inhibitors is a novel therapy for DMD.
Highly sensitive screening of antisense sequences for different types of DMD mutations in patients' urine-derived cells. [2021]Exon skipping using short antisense oligonucleotides (AONs) is a promising treatment for Duchenne muscular dystrophy (DMD). Several exon-skipping drugs, including viltolarsen (NS-065/NCNP-01), have been approved worldwide. Immortalized human skeletal muscle cell lines, such as rhabdomyosarcoma cells, are frequently used to screen efficient oligonucleotide sequences. However, rhabdomyosarcoma cells do not recapitulate DMD pathophysiology as they express endogenous dystrophin. To overcome this limitation, we recently established a direct human somatic cell reprogramming technology and successfully developed a cellular skeletal muscle DMD model by using myogenic differentiation 1 (MYOD1)-transduced urine-derived cells (MYOD1-UDCs). Here, we compared in vitro drug screening systems in MYOD1-UDCs and rhabdomyosarcoma cells. We collected UDCs from patients with DMD amenable to exon 51 skipping, and obtained MYOD1-UDCs. We then compared the efficiency of exon 51 skipping induced by various morpholino-based AONs, including eteplirsen in differentiated MYOD1-UDCs (UDC-myotubes) and rhabdomyosarcoma cells. Exon skipping was induced more efficiently in UDC-myotubes than in rhabdomyosarcoma cells even at a low AON concentration (1 μM). Furthermore, exon 51 skipping efficiency was higher in UDC-myotubes with a deletion of exons 49-50 than in those with a deletion of exons 48-50, suggesting that the skipping efficiency may vary depending on the DMD mutation pattern. An essential finding of this study is that the sequence of eteplirsen consistently leads to much lower efficiency than other sequences. These findings underscore the importance of AON sequence optimization by our cellular system, which enables highly sensitive screening of exon skipping drugs that target different types of DMD mutations.