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

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Safety and Efficacy Study of Gene Therapy for Acute Myocardial Infarction in Korea (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Helixmith Co., Ltd. | N=108 ➔ 0 | Unknown status ➔ Withdrawn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

REViVALS-1B: A 6-Month Extension Study to Assess the Long-Term Safety of Engensis in Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P2a | N=8 | Completed | Sponsor: Helixmith Co., Ltd. | Active, not recruiting ➔ Completed | N=18 ➔ 8

Enrollment change • Trial completion • Amyotrophic Lateral Sclerosis • CNS Disorders

Hepatocyte Growth Factor to Improve Functioning in PAD (clinicaltrials.gov) - P2 | N=39 | Recruiting | Sponsor: Northwestern University | Trial primary completion date: Dec 2022 ➔ Mar 2023

Trial primary completion date • Cardiovascular • Peripheral Arterial Disease

Safety and Efficacy Study of Engensis (VM202) in the Treatment of Chronic Non-Healing Foot Ulcers (clinicaltrials.gov) - P3 | N=44 | Terminated | Sponsor: Helixmith Co., Ltd. | N=300 ➔ 44 | Unknown status ➔ Terminated; Low enrollment

Enrollment change • Trial termination • Cardiovascular • Diabetes • Metabolic Disorders • Peripheral Arterial Disease

Helixmith shares nosedive after CanariaBio M’s acquisition news (Korea Biomedical Review) - "According to Helixmith...the company agreed to transfer management rights to CanariaBio M, the parent company of CanariaBio. CanariaBio M has decided to pay 35 billion won ($27.2 million) for 2,971,137 shares of Helixmith issued through a third-party allotment. When the transaction is completed, CanariaBio M will secure a 7.3 percent stake in Helixmith and become the largest shareholder of the latter. Notably, the company is about three months before announcing the results of the most recent phase 3 trial of Engensis, a diabetic peripheral neuropathy (DPN) treatment, which it had stressed on numerous occasions will be a huge success and a turning point for the company."

M&A • P3 data • CNS Disorders • Diabetic Neuropathy • Neuralgia • Pain • Peripheral Neuropathic Pain

Helixmith wins freeze-drying formulation patent for gene therapy Engensis in US (Korea Biomedical Review) - "Helixmith said Wednesday that it has developed a new freeze-drying formulation for its gene therapy, Engensis (VM202), further improving advantages in its manufacturing process and obtaining a patent in the U.S....The new formulation forms a superior cake quality and increases the stability of Engensis....The U.S. patent registration of the new formulation extends the patent monopoly on Engensis until 2039. Helixmith has continuously upgraded and applied for patents for the formulation and use of Engensis."

Patent • CNS Disorders • Diabetic Neuropathy • Neuralgia • Pain • Peripheral Neuropathic Pain

Helixmith files an arbitration claim for damages to the analysis CRO of ’Engensys DPN’ [Google translation] (PRESS9) - "Two years after Helixmith failed in the US phase 3-1 clinical trial of its gene therapy 'Ngensys (development name: VM202-DPN)', it filed an arbitration claim against an analysis agency for damages....The purpose of the claim is that Charles River caused a blood sample analysis error (PK anomaly) for the DPN and NHU study, which amounts to contractual default."

Corporate lawsuit • CNS Disorders • Diabetic Neuropathy • Neuralgia • Pain

REViVALS-1B: A 6-Month Extension Study to Assess the Long-Term Safety of Engensis in Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P2a | N=18 | Active, not recruiting | Sponsor: Helixmith Co., Ltd. | Recruiting ➔ Active, not recruiting

Enrollment closed • Amyotrophic Lateral Sclerosis • CNS Disorders

Helixmith patents new neuropathic pain therapy in Russia (Korea Biomedical Review) - "Helixmith said...that it has acquired a Russian patent for a next-generation gene therapy candidate, pMUN+VM202, to treat neuropathic pain....In this patent, pMUN and VM202 are simultaneously administered to demonstrate better therapeutic effects in neuropathic pain animal models than VM202 alone. According to a Helixmith representative, it is expected to be developed as a next-generation gene therapy for various types of neuropathic pain in the future."

Patent • CNS Disorders • Neuralgia • Pain • Peripheral Neuropathic Pain

REViVALS-1A: Safety of Engensis in Participants With Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P2a | N=18 | Completed | Sponsor: Helixmith Co., Ltd. | Active, not recruiting ➔ Completed

Trial completion • Amyotrophic Lateral Sclerosis • CNS Disorders

Helixmith Announces Topline Results from Phase 2A Study of Engensis for Treatment of ALS (Amyotrophic Lateral Sclerosis) (PRNewswire) - P2a | N=18 | REViVALS-1A (NCT04632225) | Sponsor: Helixmith Co., Ltd. | “The results of the study demonstrated that Engensis was safe and well tolerated at this dosing regimen. There was no difference in the frequency of TEAEs (83% for each group) between the Engensis and the placebo groups. One TEAE, bronchitis, was reported in the Engensis group but was determined to not be related to the study drug. Injection site reactions were reported by 50% of the Engensis group and by 66.7% of the placebo group. Most of the injection site reactions were Grade 1 or 2 and resolved within a short time, and none of the participants in the study discontinued due to the number of injections. These data suggest that high dose, repeated treatments of Engensis, were safe and well tolerated, providing a great deal of flexibility in designing dosing schemes for future clinical studies.”

P2a data • Amyotrophic Lateral Sclerosis • CNS Disorders