PGN-EDODM1 for Muscular Dystrophy

(FREEDOM2-DM1 Trial)

Recruiting at 7 trial locations

Overseen By PepGen

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: PepGen Inc

Must not be taking: Myotonia medications

Disqualifiers: Congenital DM1, Abnormal labs, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: 12 weeks

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial evaluates whether PGN-EDODM1, a new medicine, is safe and tolerable for individuals with myotonic dystrophy type 1 (DM1), a condition that affects muscles and causes stiffness (myotonia). Participants will receive either the new medicine or a placebo (inactive substance) every four weeks for 12 weeks to assess the effects. The trial seeks individuals diagnosed with DM1 who experience muscle stiffness and can still move their foot muscles against some pressure. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that PGN-EDODM1 is likely to be safe for humans?

Research has shown that PGN-EDODM1 appears safe based on studies conducted so far. Early results suggest that patients tolerated single doses well. These studies focused on safety and found no major concerns.

In earlier research, participants received varying doses, and effects differed with the dose. Some side effects occurred, but they were generally mild and manageable. The progression to a later stage of testing indicates that earlier safety results were positive enough to warrant continuation.

Overall, current data suggests that PGN-EDODM1 is relatively safe, with no significant adverse events reported in earlier trials. However, ongoing monitoring remains important as more people receive the treatment in current studies. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for muscular dystrophy?

PGN-EDODM1 is unique because it introduces a novel approach to treating muscular dystrophy by using ascending doses aimed at enhancing muscle function. Unlike standard treatments, which often focus on symptom management with corticosteroids, PGN-EDODM1 targets the underlying muscle degeneration process. Researchers are excited about this treatment because it has the potential to improve muscle strength and function more effectively, offering hope for a better quality of life for those affected by the condition.

What evidence suggests that PGN-EDODM1 might be an effective treatment for myotonic dystrophy type 1?

Research has shown that PGN-EDODM1, which participants in this trial may receive, might be a promising treatment for myotonic dystrophy type 1 (DM1). In studies, a single dose of PGN-EDODM1 improved the genetic issue common in DM1 patients by 53.7%, helping to correct a genetic error. All patients in that study experienced improvements in their genetic makeup. Early research also found that PGN-EDODM1 reduced harmful RNA spots in cells and corrected gene errors at doses safe for the body. These findings suggest that PGN-EDODM1 could be an effective treatment for DM1. ^{1 2 6 7 8}

Are You a Good Fit for This Trial?

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.

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• PGN-EDODM1

Trial Overview 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.

How Is the Trial Designed?

Group I: PGN-EDODM1 Experimental Treatment 1 Intervention

Participants will be randomized to receive ascending doses of PGN-EDODM1, once every 4 weeks (Q4W) for 12 weeks

Group II: Placebo Placebo Group 1 Intervention

Participants randomized to the placebo arm will receive doses of saline (0.9% NaCl), once every 4 weeks (Q4W) for 12 weeks

Who Is Running the Clinical Trial?

PepGen Inc

Lead Sponsor

Trials

4

Recruited

80+

Published Research Related to This Trial

In a 48-week study involving 57 DMD patients, the 6-minute walk distance (6MWD) was confirmed as a strong predictor of ambulation decline, with a baseline distance of less than 350 meters indicating a higher risk of functional decline.

The study found that only 2.3% of subjects who could stand from a supine position lost their ability to walk, highlighting the importance of baseline functional assessments in predicting outcomes in DMD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The 6-minute walk test and other endpoints in Duchenne muscular dystrophy: longitudinal natural history observations over 48 weeks from a multicenter study. McDonald, CM., Henricson, EK., Abresch, RT., et al.[2022]

A new cellular model using MYOD1-transduced urine-derived cells (MYOD1-UDCs) from DMD patients shows significantly better efficiency for exon skipping compared to traditional rhabdomyosarcoma cells, making it a more relevant system for drug screening.

The study highlights that the effectiveness of exon skipping varies based on the specific DMD mutation, and that the sequence of the antisense oligonucleotide eteplirsen is less effective than other tested sequences, emphasizing the need for optimization in drug design.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Highly sensitive screening of antisense sequences for different types of DMD mutations in patients' urine-derived cells. Takizawa, H., Takeshita, E., Sato, M., et al.[2021]

In a phase 3 study involving 131 children aged 4 to under 8 years with Duchenne muscular dystrophy, edasalonexent was generally well-tolerated and had a manageable safety profile, with most side effects being mild gastrointestinal issues like diarrhea.

While edasalonexent did not show statistically significant improvements in overall muscle function compared to placebo, younger patients (6 years or younger) demonstrated more promising results, suggesting that early treatment may help slow disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized, Double-Blind, Placebo-Controlled, Global Phase 3 Study of Edasalonexent in Pediatric Patients with Duchenne Muscular Dystrophy: Results of the PolarisDMD Trial. Finkel, RS., McDonald, CM., Lee Sweeney, H., et al.[2021]

In a phase 2 study involving 36 male patients with Duchenne muscular dystrophy (DMD), the selective HPGDS inhibitor TAS-205 demonstrated a favorable safety profile, with no specific adverse drug reactions reported.

While TAS-205 did not show significant improvements in the 6-minute walk distance compared to placebo, the changes were less negative in both low-dose and high-dose groups, suggesting potential benefits that warrant further investigation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early phase 2 trial of TAS-205 in patients with Duchenne muscular dystrophy. Komaki, H., Maegaki, Y., Matsumura, T., et al.[2021]

In a phase 3 study involving 79 patients aged 7-16 with Duchenne muscular dystrophy, eteplirsen treatment for 96 weeks resulted in a significant increase in dystrophin production (7-fold) and exon skipping (18.7-fold), indicating its efficacy in addressing the underlying cause of the disease.

The study also demonstrated a favorable safety profile, with most adverse events being mild to moderate and unrelated to the treatment, while showing a notable slowing of disease progression compared to untreated controls.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-Label Evaluation of Eteplirsen in Patients with Duchenne Muscular Dystrophy Amenable to Exon 51 Skipping: PROMOVI Trial. McDonald, CM., Shieh, PB., Abdel-Hamid, HZ., et al.[2022]

A study measuring urinary tetranor PGDM levels in 191 Duchenne muscular dystrophy (DMD) patients and 79 healthy controls found that DMD patients had approximately 2.2 times higher levels of this inflammatory marker, suggesting a link between PGD2-mediated inflammation and DMD pathology.

The concentration of tetranor PGDM in DMD patients increased significantly with age, particularly surging at around 8 years old, indicating that inflammation may worsen as the disease progresses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A prostaglandin D2 metabolite is elevated in the urine of Duchenne muscular dystrophy patients and increases further from 8 years old. Nakagawa, T., Takeuchi, A., Kakiuchi, R., et al.[2022]

In a long-term study of patients with Duchenne muscular dystrophy (DMD) treated with eteplirsen, 100% of patients showed successful skipping of exon 51, confirming the drug's mechanism of action.

Eteplirsen treatment resulted in significant increases in dystrophin production, with an 11.6-fold increase in dystrophin content and a 7.4-fold increase in the percentage of dystrophin-positive fibers compared to untreated controls, indicating its potential efficacy in restoring dystrophin levels in muscle cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eteplirsen treatment for Duchenne muscular dystrophy: Exon skipping and dystrophin production. Charleston, JS., Schnell, FJ., Dworzak, J., et al.[2019]

Daily treatment with SMT022357, a second-generation compound, significantly increases utrophin expression in various muscle types, which helps stabilize muscle fibers and prevent damage associated with Duchenne muscular dystrophy (DMD).

The study in mdx mice shows that SMT022357 not only reduces muscle degeneration but also enhances overall muscle function, indicating its potential as a disease-modifying therapy for all DMD patients, regardless of their specific dystrophin mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Second-generation compound for the modulation of utrophin in the therapy of DMD. Guiraud, S., Squire, SE., Edwards, B., et al.[2022]

The study developed a human codon-optimized version of microutrophin (µUtrn) that showed robust muscle expression and functional improvement in mdx mice, indicating its potential as a safer alternative to traditional dystrophin gene therapy for Duchenne muscular dystrophy (DMD).

Long-term administration of rAAV9-µUtrn resulted in lower immunogenicity and no adverse effects in toxicity studies, supporting its safety for clinical development as a gene therapy for DMD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic potential of highly functional codon-optimized microutrophin for muscle-specific expression. Starikova, AV., Skopenkova, VV., Polikarpova, AV., et al.[2022]

A novel oral inhibitor of hematopoietic prostaglandin D synthase (H-PGDS), called HQL-79, was found to significantly reduce muscle necrosis and improve muscle strength in mdx dystrophic mice, suggesting a potential therapeutic approach for Duchenne muscular dystrophy (DMD).

Further development of more potent H-PGDS inhibitors showed even greater efficacy in preventing muscle atrophy and weakness in DMD dogs, indicating that targeting PGD2 synthesis could be a promising strategy for treating this severe muscle disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Hematopoietic prostaglandin D synthase inhibitors for the treatment of duchenne muscular dystrophy]. Kamauchi, S., Urade, Y.[2022]

Citations

1. investors.pepgen.com investors.pepgen.com/news-releases/news-release-details/pepgen-announces-highest-mean-splicing-correction-reported-dm1

PepGen Announces Highest Mean Splicing Correction ... 53.7% mean splicing correction observed following a single 15 mg/kg dose of PGN-EDODM1, with all patients showing an improvement in splicing ...

2. clinicaltrialsarena.com clinicaltrialsarena.com/news/pepgens-stock-up-120-on-dm1-trial-success/

PepGen's stock up 120% on DM1 trial success PepGen's stock has risen by over 120% after its investigational myotonic DM1 candidate reported the highest mean splicing correction in a ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06204809

Safety, Tolerability, PK, and PD Study of PGN-EDODM1 in ... The primary purpose of the study is to evaluate the safety and tolerability of single intravenous (IV) doses of PGN-EDODM1 administered to participants with ...

4. neurology.org neurology.org/doi/10.1212/WNL.0000000000203804

PGN-EDODM1: Preclinical Data Supporting the ... These preclinical studies demonstrate that PGN-EDODM1 reduced nuclear RNA foci and corrected mis-splicing at clinically relevant, tolerable doses with effects ...

5. firstwordpharma.com firstwordpharma.com/story/5958604

PepGen Reports First Quarter 2025 Financial Results and ... Reported positive DM1 patient data with mean splicing correction of 29.1% following a single dose of PGN-EDODM1 at 10 mg/kg –– FREEDOM-DM1.

6. neurology.org neurology.org/doi/10.1212/WNL.0000000000203993

Design of a Phase 1, Placebo-Controlled Study to Assess ... The primary objective of this single-ascending dose (SAD) study is to evaluate the safety and tolerability of PGN-EDODM1 in adults living with DM1.

7. neurologylive.com neurologylive.com/view/early-phase-1-trial-data-suggests-therapeutic-potential-pgn-edodm1-myotonic-dystrophy-type-1

Early Phase 1 Trial Data Suggests Therapeutic Potential ... Initial data reported from the FREEDOM-DM1 trial suggest PGN-EDODM1 has dose-dependent effects in patients with DM1, with further results from study cohorts ...

8. myotonic.org myotonic.org/sites/default/files/2024-09/PepGen-2024-Mid-Year-Advocacy-Update.pdf

PEPGEN'S 2024 MID-YEAR ADVOCACY UPDATE The placebo-controlled study will study safety and tolerability, as well as levels of dystrophin in skeletal muscle, following monthly intravenous doses of PGN- ...