PGN-EDODM1 for Muscular Dystrophy

(FREEDOM2-DM1 Trial)

Recruiting at 3 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

Trial Summary

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. ^{1 2 3 4 5}

How 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. ^{6 7 8 9 10}

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.

Eligibility 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.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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 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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Eteplirsen treatment for Duchenne muscular dystrophy: Exon skipping and dystrophin production. [2019]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Open-Label Evaluation of Eteplirsen in Patients with Duchenne Muscular Dystrophy Amenable to Exon 51 Skipping: PROMOVI Trial. [2022]

3. United States 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. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Second-generation compound for the modulation of utrophin in the therapy of DMD. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Therapeutic potential of highly functional codon-optimized microutrophin for muscle-specific expression. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Early phase 2 trial of TAS-205 in patients with Duchenne muscular dystrophy. [2021]

7. Netherlands 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. [2022]

8. Netherlands 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. [2021]

9. Japan pubmed.ncbi.nlm.nih.gov

[Hematopoietic prostaglandin D synthase inhibitors for the treatment of duchenne muscular dystrophy]. [2022]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Highly sensitive screening of antisense sequences for different types of DMD mutations in patients' urine-derived cells. [2021]