PGN-EDO51 for Duchenne Muscular Dystrophy

(CONNECT1-EDO51 Trial)

No longer 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called PGN-EDO51 for Duchenne Muscular Dystrophy (DMD), a condition that causes muscle weakness. The study evaluates the safety and tolerability of the treatment when administered in increasing doses over time. It consists of two parts: one tests different doses for 16 weeks, and the other examines long-term safety for over two years. Suitable participants have DMD that may benefit from exon 51 skipping, weigh at least 18 kg, and have some arm mobility. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that PGN-EDO51 is likely to be safe for humans?

Research has shown that PGN-EDO51 is generally safe. In one study, participants tolerated a dose of 5 mg/kg well and continued with the trial for an extended period. Previous participants demonstrated that PGN-EDO51 is usually well tolerated at effective treatment doses. This suggests the treatment is safe for people, with no major side effects reported at these doses. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Duchenne Muscular Dystrophy?

Unlike the standard treatments for Duchenne Muscular Dystrophy, which often include corticosteroids and gene therapies, PGN-EDO51 is unique because it uses a novel mechanism targeting RNA to promote production of dystrophin, a protein crucial for muscle function. This RNA-targeted approach offers the potential for more precise treatment, potentially addressing the underlying genetic cause of the disease. Researchers are excited about PGN-EDO51 because it promises a more targeted therapy that could lead to improved muscle health and function for patients with this challenging condition.

What evidence suggests that PGN-EDO51 might be an effective treatment for Duchenne Muscular Dystrophy?

Research shows that PGN-EDO51 is a promising treatment for Duchenne muscular dystrophy (DMD). The trial will evaluate PGN-EDO51 at two different dose levels, administered every 4 weeks. This treatment targets exon 51, a part of the gene needed to produce dystrophin, a protein that helps maintain muscle strength. Studies have found that PGN-EDO51 can effectively skip exon 51, a key target for about 13% of DMD patients. Early results from animal studies and initial human trials suggest that PGN-EDO51 is safe and can effectively reach muscle cells. This may improve muscle function in people with DMD. ^{1 2 4 6 7}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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 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]

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 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]

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]

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]

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]

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]

Citations

1. investors.pepgen.com investors.pepgen.com/news-releases/news-release-details/pepgen-announces-positive-data-low-dose-cohort-pgn-edo51-ongoing

PepGen Announces Positive Data from Low-Dose Cohort ... PGN-EDO51 is designed to skip exon 51 of the dystrophin transcript, an established therapeutic target for approximately 13% of DMD patients.

2. mdaconference.org mdaconference.org/abstract-library/connect1-edo51-and-connect2-edo51-phase-2-study-designs-to-evaluate-safety-and-efficacy-for-duchenne-muscular-dystrophy-amenable-to-exon-51-skipping/

CONNECT1-EDO51 and CONNECT2- ... PGN-EDO51 is PepGen's clinical candidate for the treatment of Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping. Nonclinical data from mdx mice and ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06079736

NCT06079736 | A Study Of PGN-EDO51 In Participants ... 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 ...

4. parentprojectmd.org parentprojectmd.org/pepgen-reports-data-from-phase-1-trial-of-pgn-edo51/

PepGen Reports Data from Phase 1 Trial of PGN-EDO51 PGN-EDO51 is an PMO-exon skipping therapy bound to a peptide which improves uptake into muscle cells, and targets those amenable to exon 51 skipping.

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0960896623002055

P44 Phase 1 study of PGN-EDO51 demonstrates ... P44 Phase 1 study of PGN-EDO51 demonstrates tolerability, delivery and high levels of exon skipping for treatment of Duchenne muscular dystrophy (DMD). Author ...

6. mdaconference.org mdaconference.org/abstract-library/positive-results-from-a-first-in-human-study-support-continued-development-of-pgn-edo51-for-the-treatment-of-duchenne-muscular-dystrophy-dmd/

Positive Results from a First-in-Human Study Support ... The Phase 1 study results demonstrate that PGN-EDO51 has a generally tolerable profile at clinically relevant doses.

7. checkrare.com checkrare.com/safety-efficacy-of-pgn-edo51-in-duchenne-muscular-dystrophy-dmd/

Safety & Efficacy of PGN-EDO51 in Duchenne Muscular ... Michelle Mellion, MD, discusses results from study testing the safety and efficacy of PGN-EDO51 in people with DMD.