Engensis (donaperminogene seltoplasmid) / Beijing Northland, Reyon Pharma, Helixmith - LARVOL DELTA

Seltoplasmid Plus Revascularization for Diabetic Infrapopliteal Chronic Limb-Threatening Ischemia (clinicaltrials.gov) - P4 | N=180 | Not yet recruiting | Sponsor: First Affiliated Hospital of Wenzhou Medical University

New P4 trial • Cardiovascular • Diabetes • Metabolic Disorders • Peripheral Arterial Disease

Pharmacological Management of Diabetic Neuropathy: Current Evidence, Clinical Positioning, and Emerging Therapeutic Targets. (PubMed, Curr Neuropharmacol) - "Managing diabetic neuropathy necessitates personalized treatment that equilibrates analgesia with tolerability. Current medications primarily alleviate symptoms; however, ongoing investigations into antioxidant and neuroprotective agents present the potential for therapies that may decelerate or reverse nerve damage."

Journal • Addiction (Opioid and Alcohol) • Anesthesia • Diabetes • Diabetic Neuropathy • Inflammation • Metabolic Disorders • Neuralgia • Pain

Translational Barriers to AAV and CRISPR Gene Therapy in Diabetes. (PubMed, Saudi Med J) - "Only zimislecel achieved Phase III outcomes (83% insulin independence at 12 months, n=12, requiring immunosuppression). VM202 for diabetic neuropathy failed Phase III despite positive extension results...These constraints explain why ex vivo cell therapies advanced to efficacy trials while in vivo gene delivery remains in Phase I despite longer development timelines. Research priorities should emphasize non-viral delivery systems offering scalable manufacturing and universal hypoimmune donor cells to address access barriers."

Journal • Review • Diabetes • Diabetic Neuropathy • Gene Therapies • Immune Modulation • Immunology • Metabolic Disorders • Pain

An open-label single-arm phase 1/2a study to evaluate the safety and exploratory efficacy of a VM202 in patients with Charcot-Marie-Tooth disease 1A. (PubMed, Orphanet J Rare Dis) - No abstract available

Journal • P1/2 data • Gene Therapies • Genetic Disorders

Efficacy and Safety of VM202 in Painful Diabetic Peripheral Neuropathy -The HOPES Trial (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Brigham and Women's Hospital | N=50 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Addiction (Opioid and Alcohol) • Diabetic Neuropathy • Pain • Peripheral Neuropathic Pain

Safety Study of Gene Therapy for Ischemic Heart Disease in Korea (clinicaltrials.gov) - P1/2 | N=9 | Completed | Sponsor: Helixmith Co., Ltd. | Phase classification: P1 ➔ P1/2

Phase classification • Cardiovascular • Coronary Artery Disease • Gene Therapies • Heart Failure

Multicenter Cohort Long-term Follow-up Study of Participants from Phase III Clinical Trials of Donaperminogene Seltoplasmid Injection for Critical Limb Ischemia (ChiCTR) - P=N/A | N=542 | Not yet recruiting | Sponsor: Peking Union Medical College Hospital, Chinese Academy of Medical Sciences; Beijing Northland Biotechnology Co., Ltd

New trial • Cardiovascular • Peripheral Arterial Disease • HGF

Follow-up Study Using Gene Therapy for Critical Limb Ischemia (NL003-CLI-III-L) (clinicaltrials.gov) - P=N/A | N=542 | Enrolling by invitation | Sponsor: Beijing Northland Biotech. Co., Ltd.

New trial • Atherosclerosis • Cardiovascular • Gene Therapies • Peripheral Arterial Disease

REViVALS-1B: A 6-Month Extension Study to Assess the Long-Term Safety of Engensis in Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P2 | N=8 | Completed | Sponsor: Helixmith Co., Ltd. | Phase classification: P2a ➔ P2 | Trial completion date: Dec 2022 ➔ Aug 2024

Phase classification • Trial completion date • Amyotrophic Lateral Sclerosis • CNS Disorders

REViVALS-1A: Safety of Engensis in Participants With Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P2 | N=18 | Completed | Sponsor: Helixmith Co., Ltd. | Phase classification: P2a ➔ P2 | Trial completion date: Aug 2022 ➔ Jul 2024

Phase classification • Trial completion date • Amyotrophic Lateral Sclerosis • CNS Disorders

Seltoplasmid promotes ulcer healing versus placebo for treating patients with chronic limb-threatening ischemia: HOPE CLTI-2 trial. (PubMed, Mol Ther) - "Intramuscular injection of donaperminogene seltoplasmid (recombinant human hepatocyte growth factor plasmids) represents a gene therapy that treat patients with chronic limb-threatening ischemia (CLTI)...Serious adverse events were rare. Our study demonstrated that seltoplasmid significantly improved ulcer healing rates in patients with Rutherford class 5 CLTI compared to placebo."

Journal • Atherosclerosis • Cardiovascular • Gene Therapies • Peripheral Arterial Disease • HGF

Optimal injection sites for therapeutic angiogenesis: HGF-mediated regulation of HIF-1α via MAPK/PI3K pathways in hypoxic endothelial cells. (PubMed, Tissue Cell) - "However, the optimal administration sites for gene therapy agents, such as pCK-HGF-X7, remains undefined...However, in ischemic rat hindlimbs, it markedly promoted angiogenesis and improved tissue perfusion in the gastrocnemius muscle. These findings indicate that therapeutic angiogenesis agents should primarily target hypoxic tissues, extending to the interface between normoxic and hypoxic regions, to optimize treatment efficacy."

Journal • Cardiovascular • Gene Therapies • Peripheral Arterial Disease • HIF1A • MET

Safety and Efficacy Study of Gene Therapy for Acute Myocardial Infarction in Korea (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Helixmith Co., Ltd. | N=108 ➔ 0 | Unknown status ➔ Withdrawn

Enrollment change • Trial withdrawal • Cardiovascular • Coronary Artery Disease • Gene Therapies • Heart Failure • Myocardial Infarction

Safety Study of VM202 to Treat Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P1/2 | N=18 | Completed | Sponsor: Helixmith Co., Ltd. | Trial completion date: Dec 2017 ➔ Mar 2024

Trial completion date • Amyotrophic Lateral Sclerosis • CNS Disorders

Gene Therapy and Diabetes: A Narrative Review of Recent Advances and the Role of Multidisciplinary Healthcare Teams. (PubMed, Genes (Basel)) - "Other studies involving intramuscular injections of VM202 and bicistronic VEGF165/HGF plasmid have reported pain reduction, improved healing of ischemic lesions, and increased angiogenesis...Diabetes is a metabolic syndrome that requires the collaboration of a multidisciplinary team to assist in several aspects of implementing successful gene therapy. Several healthcare providers and policy makers may play a crucial role in patient education, counseling, and the management of gene therapy treatments."

Journal • Review • Diabetes • Diabetic Neuropathy • Gene Therapies • Metabolic Disorders • Pain • Type 1 Diabetes Mellitus • Type 2 Diabetes Mellitus

REGAiN-1A: Study to Assess Safety and Efficacy of Engensis in Painful Diabetic Peripheral Neuropathy (clinicaltrials.gov) - P3 | N=162 | Completed | Sponsor: Helixmith Co., Ltd. | Active, not recruiting ➔ Completed | Trial completion date: Jun 2023 ➔ Jul 2024

Trial completion • Trial completion date • Diabetic Neuropathy • Pain • Peripheral Neuropathic Pain

REGAiN-1B: A 6-Month Extension Study of VMDN-003-2 to Assess Engensis in Participants With Painful Diabetic Peripheral Neuropathy (clinicaltrials.gov) - P3 | N=106 | Completed | Sponsor: Helixmith Co., Ltd. | Recruiting ➔ Completed | N=250 ➔ 106 | Trial completion date: Dec 2023 ➔ Jul 2024

Enrollment change • Trial completion • Trial completion date • Diabetic Neuropathy • Pain • Peripheral Neuropathic Pain

HEPATOCYTE GROWTH FACTOR FOR WALKING PERFORMANCE IN PERIPHERAL ARTERY DISEASE. (PubMed, J Vasc Surg) - "These data do not support gastrocnemius injections of VM202 to improve 6-minute walk in PAD. Secondary outcomes suggested potential benefit of VM202 on skeletal muscle measures and treadmill walking, while post-hoc analyses suggested benefit in PAD participants with diabetes."

Journal • Cardiovascular • Diabetes • Gene Therapies • Metabolic Disorders • Pain • Peripheral Arterial Disease • HGF

Safety and Efficacy Study Using Gene Therapy for Critical Limb Ischemia (NL003-CLI-III-1) (clinicaltrials.gov) - P3 | N=302 | Completed | Sponsor: Beijing Northland Biotech. Co., Ltd. | Recruiting ➔ Completed | Trial completion date: Dec 2023 ➔ Jun 2024 | Trial primary completion date: Oct 2023 ➔ Jun 2024

Gene therapy • Trial completion • Trial completion date • Trial primary completion date • Cardiovascular • Gene Therapies • Peripheral Arterial Disease

Helixmith's Chinese Partner Enzensis' Second CLI Phase 3 Clinical Trial Also Achieves Primary Endpoint [Google translation] (Hankyung) - P3 | N=44 | NCT02563522 | Sponsor: Helixmith Co., Ltd. | "Northland Biotech, Helixmith ’s Chinese partner, has also achieved its primary endpoint in a Phase 3 clinical trial of Enzensis (VM202, Chinese name NL003) for pain reduction in patients with critical limb ischemia (CLI). The results announced this time are the top-line data from the clinical trial with the primary endpoint of resting pain reduction among the two Phase 3 clinical trials. According to Northland, the primary endpoint of resting pain reduction rate was significantly superior to the placebo control group, safety was excellent, and no serious adverse reactions related to the drug were found."

P3 data: top line • CNS Disorders • Pain

Safety and Efficacy Study Using Gene Therapy for Critical Limb Ischemia (NL003-CLI-III-2) (clinicaltrials.gov) - P3 | N=242 | Completed | Sponsor: Beijing Northland Biotech. Co., Ltd. | Recruiting ➔ Completed

Gene therapy • Trial completion • Cardiovascular • Gene Therapies • Peripheral Arterial Disease

Helixmith's gene therapy fails phase 3 trial for diabetic peripheral neuropathy (Korea Biomedical Review) - P3 | N=507 | NCT02427464 | Sponsor: Helixmith Co., Ltd. | "Helixmith said its gene therapy Engensis, also known as VM202-DPN, failed to meet the primary endpoint in a phase 3 clinical trial for treating diabetic peripheral neuropathy (DPN) conducted in the U.S....However, the top-line data analysis did not prove the superiority of the Engensis treatment group over the placebo group. This result differs from the past two double-blind placebo-controlled clinical trials....Over the next minimum of two months, analyses of secondary endpoints, exploratory endpoints, and subgroups will continue, and the differences observed between participants enrolled during the Covid-19 pandemic and those enrolled later will be investigated during the preparation of the Clinical Study Report (CSR)."

P3 data • CNS Disorders • Neuralgia • Pain • Peripheral Neuropathic Pain

Hepatocyte Growth Factor to Improve Functioning in PAD (clinicaltrials.gov) - P2 | N=39 | Completed | Sponsor: Northwestern University | Active, not recruiting ➔ Completed

Trial completion • Cardiovascular • Peripheral Arterial Disease

Gene therapy for diabetic foot ulcers: Interim analysis of a randomised, placebo-controlled phase 3 study of VM202 (ENGENSIS), a plasmid DNA expressing two isoforms of human hepatocyte growth factor. (PubMed, Int Wound J) - "Intramuscular injections of VM202 plasmid DNA to calf muscle may have promise in the treatment of chronic neuroischemic diabetic foot ulcers (DFUs). Given the safety profile and potential healing effects, continuing a larger DFU study is warranted with modifications of the current protocol and expansion of enrolling sites."

Gene therapy • Journal • P3 data • P3 data: top line • Cardiovascular • Gene Therapies • Peripheral Arterial Disease • HGF

Hepatocyte Growth Factor to Improve Functioning in PAD (clinicaltrials.gov) - P2 | N=39 | Active, not recruiting | Sponsor: Northwestern University | Recruiting ➔ Active, not recruiting

Enrollment closed • Cardiovascular • Peripheral Arterial Disease