PGN-EDO51 for Duchenne Muscular Dystrophy

(CONNECT1-EDO51 Trial)

Recruiting at 4 trial locations

Overseen By Director, Patient Advocacy

Age: < 18

Sex: Male

Trial Phase: Phase 2

Sponsor: PepGen Inc

Must not be taking: Gene therapy

Disqualifiers: Systemic infection, Recent surgery, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: 4

7 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have had gene replacement therapy for DMD or recent infections or surgeries.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, it does exclude those who have had recent infections or surgeries, so it's best to discuss your specific medications with the trial team.

What data supports the idea that PGN-EDO51 for Duchenne Muscular Dystrophy is an effective drug?

The available research does not provide specific data on the effectiveness of PGN-EDO51 for Duchenne Muscular Dystrophy. However, it does mention other treatments like eteplirsen, edasalonexent, SMT022357, and ataluren, which have shown some promise in treating the condition. For example, edasalonexent was found to slow disease progression and preserve muscle function in young boys with Duchenne Muscular Dystrophy. Similarly, SMT022357 improved muscle function by increasing utrophin expression, and ataluren has been developed to restore dystrophin expression. These treatments highlight ongoing efforts to find effective therapies for Duchenne Muscular Dystrophy. ^{1 2 3 4 5}

What data supports the effectiveness of the drug PGN-EDO51 for Duchenne Muscular Dystrophy?

While there is no direct data on PGN-EDO51, similar treatments like eteplirsen have shown effectiveness in increasing dystrophin production, a protein missing in Duchenne Muscular Dystrophy. Additionally, drugs like edasalonexent have demonstrated the ability to slow disease progression and improve muscle function by targeting inflammation pathways. ^{1 2 3 4 5}

What safety data exists for PGN-EDO51 for Duchenne Muscular Dystrophy?

The provided research does not contain any safety data for PGN-EDO51 or its evaluation for Duchenne Muscular Dystrophy. The studies listed focus on palonosetron and its use in preventing nausea and vomiting related to chemotherapy and surgery, which is unrelated to PGN-EDO51. ^{6 7 8 9 10}

Is the drug PGN-EDO51 a promising treatment for Duchenne Muscular Dystrophy?

Yes, PGN-EDO51 is a promising drug for Duchenne Muscular Dystrophy because it is similar to eteplirsen, which has been shown to help produce dystrophin, a protein that strengthens muscle fibers. This approach, known as exon skipping, has been effective in treating some patients with this condition. ^{1 11 12 13 14}

How is the drug PGN-EDO51 different from other drugs for Duchenne muscular dystrophy?

The research does not provide specific information about PGN-EDO51, but it suggests that novel nucleic acid modifications and antisense oligonucleotide designs, like those potentially used in PGN-EDO51, are being developed to improve the effectiveness of exon skipping therapies for Duchenne muscular dystrophy. ^{1 11 12 14 15}

What is the purpose of this trial?

The study consists of 3 periods: A Screening Period (up to 45 days), a Multiple Ascending Dose (MAD) Period (16 weeks), and a Long-Term Extension (LTE) Period (108 weeks). The primary purpose of the MAD period is to evaluate the safety and tolerability of multiple ascending intravenous (IV) doses of PGN-EDO51 administered to participants with Duchenne Muscular Dystrophy (DMD). The primary purpose of the LTE period is to evaluate the long-term safety and tolerability of PGN-EDO51 in participants who have completed the MAD period.

Eligibility Criteria

This trial is for males born with Duchenne muscular dystrophy (DMD) who are at least 10 years old, weigh a minimum of 25kg, and have a type that can be treated by skipping Exon 51. They should also be able to perform certain upper limb movements.

Inclusion Criteria

My upper limb function score is 3 or more.

My DMD can potentially be treated by skipping Exon 51.

My body weight is at least 25kg.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

6 weeks

Multiple Ascending Dose (MAD)

Participants receive multiple ascending intravenous doses of PGN-EDO51 to evaluate safety and tolerability

16 weeks

4 visits (in-person)

Long-Term Extension (LTE)

Participants continue to receive PGN-EDO51 to evaluate long-term safety and tolerability

108 weeks

Regular visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• PGN-EDO51

Trial Overview The study tests the safety and effects of multiple IV doses of PGN-EDO51 in DMD patients. It includes up to 45 days of screening followed by a treatment and observation period lasting 16 weeks.

Participant Groups

Group I: PGN-EDO51 at Dose Level 2 every 4 weeks Experimental Treatment 1 Intervention

Group II: PGN-EDO51 at Dose Level 1 every 4 weeks Experimental Treatment 1 Intervention

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 2 study involving boys aged 4 to 8 with Duchenne muscular dystrophy, edasalonexent was found to be well-tolerated, with mild gastrointestinal side effects and no serious adverse events reported.

The treatment with edasalonexent at 100 mg/kg/day showed promising results in slowing disease progression and preserving muscle function, alongside reductions in NF-κB-regulated gene levels and improvements in muscle health biomarkers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disease-modifying effects of edasalonexent, an NF-κB inhibitor, in young boys with Duchenne muscular dystrophy: Results of the MoveDMD phase 2 and open label extension trial. Finkel, RS., Finanger, E., Vandenborne, K., 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]

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]

Ataluren, a read-through compound (RTC), has completed Phase III clinical studies for Duchenne muscular dystrophy (DMD) and represents a promising approach to restoring full-length dystrophin expression, potentially leading to better outcomes for patients.

Previous RTCs like gentamicin faced challenges due to toxicity and limited efficacy, highlighting the significance of ataluren as a new option that may offer clinical benefits for DMD patients as it becomes available in various markets.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical potential of ataluren in the treatment of Duchenne muscular dystrophy. Namgoong, JH., Bertoni, C.[2020]

Palonosetron was compared to other 5-HT3 receptor antagonists (5-HT3RAs) in a systematic review involving 4,145 patients receiving palonosetron and 4,911 receiving other 5-HT3RAs, showing consistent efficacy and safety profiles over time.

The review concluded that no new evidence suggests a need for further randomized controlled trials (RCTs) for palonosetron, indicating that resources should be redirected to explore other less-studied prophylactic treatments for chemotherapy-induced nausea and vomiting (CINV).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Do we still need to study palonosetron for chemotherapy-induced nausea and vomiting? A cumulative meta-analysis. Chow, R., Aapro, M., Navari, RM., et al.[2019]

In a study of 26 Japanese patients receiving highly or moderately emetogenic chemotherapy, repeated doses of palonosetron (0.75 mg) on days 1 and 3 were found to be safe and well tolerated, with a high complete response rate of 96.2% for preventing nausea and vomiting in the acute phase.

The pharmacokinetics showed expected accumulation of the drug, and while the complete response rate in the delayed phase was lower at 76.9%, the results indicate that palonosetron is effective for managing chemotherapy-induced nausea and vomiting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and pharmacokinetic evaluation of repeated intravenous administration of palonosetron 0.75 mg in patients receiving highly or moderately emetogenic chemotherapy. Ikari, Y., Ogata, K., Nakashima, Y., et al.[2021]

In a study of 118 patients undergoing laparoscopic surgery, the combination of palonosetron and dexamethasone did not significantly reduce the incidence of postoperative nausea and vomiting (PONV) compared to palonosetron alone, with both groups showing low rates of vomiting (1.7% for Pal + Dex and 6.8% for Pal).

Despite similar efficacy in preventing PONV, the combination therapy showed a trend toward improved patient satisfaction in the nausea domain of the quality of life assessment, suggesting potential benefits in patient experience even if not in clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized double blind study to evaluate efficacy of palonosetron with dexamethasone versus palonosetron alone for prevention of postoperative and postdischarge nausea and vomiting in subjects undergoing laparoscopic surgeries with high emetogenic risk. Blitz, JD., Haile, M., Kline, R., et al.[2022]

In a Phase 3 study involving pediatric patients aged 6 months to 17 years, aprepitant combined with ondansetron significantly improved the rates of complete response (CR) to chemotherapy-induced nausea and vomiting, especially in older children (ages 12-17) where CR was 51% compared to 10% with the control.

The aprepitant regimen was also effective in younger children (6 months to <2 years) receiving dexamethasone, showing a CR rate of 50% versus 25% in the control group, indicating its safety and efficacy across different age groups and treatment conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in paediatric subjects: An analysis by age group. Kang, HJ., Loftus, S., DiCristina, C., et al.[2019]

In a study of 90 adult patients undergoing middle ear surgery, the combination of palonosetron and dexamethasone did not show superior effectiveness in preventing postoperative nausea and vomiting (PONV) compared to palonosetron alone.

The incidence of nausea and vomiting was similar between the two groups, with complete response rates of 84.4% for palonosetron alone and 91% for the combination, indicating that adding dexamethasone does not significantly enhance PONV prevention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Palonosetron with Combination of Palonosetron and Dexamethasone in the Prevention of Post Operative Nausea and Vomiting in Patients Undergoing Middle Ear Surgery: A Prospective Randomized Trial. Sahni, N., Panda, N., Kumar, A., et al.[2023]

In a phase 1-2a study involving 12 patients with Duchenne's muscular dystrophy, the antisense oligonucleotide PRO051 was administered subcutaneously, showing dose-dependent efficacy in inducing exon-51 skipping and new dystrophin expression in muscle fibers.

After 12 weeks of treatment, patients demonstrated a modest improvement in walking distance, with an average increase of 35.2 meters on the 6-minute walk test, indicating potential clinical benefits alongside observed safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic administration of PRO051 in Duchenne's muscular dystrophy. Goemans, NM., Tulinius, M., van den Akker, JT., et al.[2023]

Eteplirsen significantly increased dystrophin production in boys with Duchenne muscular dystrophy (DMD) after 24 weeks of treatment, with 23% of normal dystrophin levels observed in the 30 mg/kg group, and even higher levels (52% and 43%) at 48 weeks for the 30 and 50 mg/kg groups, respectively.

The treatment also improved walking distance on the 6-minute walk test (6MWT) by an average of 67.3 meters compared to placebo, indicating that longer treatment duration is more important for efficacy than the dosage, and no severe adverse events were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eteplirsen for the treatment of Duchenne muscular dystrophy. Mendell, JR., Rodino-Klapac, LR., Sahenk, Z., et al.[2022]

Antisense oligonucleotides (AOs) for exon skipping are a promising treatment for Duchenne muscular dystrophy (DMD), but some candidates, like eteplirsen, have shown poor efficacy, highlighting the need for better screening methods.

The study introduces a reliable in vitro screening procedure using immortalized muscle cells from DMD patients, which allows for accurate evaluation of AOs based on their ability to skip exons and rescue dystrophin protein, improving the chances of finding effective treatments before clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantitative Evaluation of Exon Skipping in Immortalized Muscle Cells In Vitro. Lim, KRQ., Yokota, T.[2019]

Eteplirsen (Exondys 51) has received accelerated FDA approval as a treatment for Duchenne muscular dystrophy (DMD) by promoting dystrophin production through exon skipping, specifically targeting exon 51, which is relevant for about 14% of DMD patients.

The review highlights the pharmacological, efficacy, safety, and tolerability data from preclinical and clinical trials, while also addressing concerns regarding the drug's efficacy and its role as a potential therapeutic strategy for DMD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eteplirsen in the treatment of Duchenne muscular dystrophy. Lim, KR., Maruyama, R., Yokota, T.[2022]

References

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

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

2. England pubmed.ncbi.nlm.nih.gov

Disease-modifying effects of edasalonexent, an NF-κB inhibitor, in young boys with Duchenne muscular dystrophy: Results of the MoveDMD phase 2 and open label extension trial. [2021]

3. 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]

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

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

5. New Zealand pubmed.ncbi.nlm.nih.gov

Clinical potential of ataluren in the treatment of Duchenne muscular dystrophy. [2020]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Do we still need to study palonosetron for chemotherapy-induced nausea and vomiting? A cumulative meta-analysis. [2019]

7. Germany pubmed.ncbi.nlm.nih.gov

Safety and pharmacokinetic evaluation of repeated intravenous administration of palonosetron 0.75 mg in patients receiving highly or moderately emetogenic chemotherapy. [2021]

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

A randomized double blind study to evaluate efficacy of palonosetron with dexamethasone versus palonosetron alone for prevention of postoperative and postdischarge nausea and vomiting in subjects undergoing laparoscopic surgeries with high emetogenic risk. [2022]

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

Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in paediatric subjects: An analysis by age group. [2019]

10. India pubmed.ncbi.nlm.nih.gov

Comparison of Palonosetron with Combination of Palonosetron and Dexamethasone in the Prevention of Post Operative Nausea and Vomiting in Patients Undergoing Middle Ear Surgery: A Prospective Randomized Trial. [2023]

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

Systemic administration of PRO051 in Duchenne's muscular dystrophy. [2023]

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

Eteplirsen for the treatment of Duchenne muscular dystrophy. [2022]

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

Quantitative Evaluation of Exon Skipping in Immortalized Muscle Cells In Vitro. [2019]

14. New Zealand pubmed.ncbi.nlm.nih.gov

Eteplirsen in the treatment of Duchenne muscular dystrophy. [2022]

15. Switzerland pubmed.ncbi.nlm.nih.gov

Intramuscular Evaluation of Chimeric Locked Nucleic Acid/2'OMethyl-Modified Antisense Oligonucleotides for Targeted Exon 23 Skipping in Mdx Mice. [2021]