Safety of Engensis in Participants With Amyotrophic Lateral Sclerosis

A Phase 2a, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Assess the Safety of Engensis in Participants With Amyotrophic Lateral Sclerosis

The purpose of this study was to evaluate the safety of intramuscular administration of Engensis in Participants with Amyotrophic Lateral Sclerosis as compared to Placebo. Safety will be assessed by incidences of treatment-emergent adverse events, treatment-emergent serious adverse events, injection site reactions and other adverse events of special interest, and the clinically significant laboratory values after injections of Engensis compared to Placebo. Exploratory endpoints include assessment of muscle function using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale subscores for Fine and Gross Motor Function; muscle strength by quantitative testing using handheld dynamometry and the Accurate Test of Limb Isometric Strength where available; quality of life using the Amyotrophic Lateral Sclerosis Assessment Questionnaire-40; patient global impression of change, clinical global impression of change, and clinical global impression of severity; and evaluation of lung function using Slow Vital Capacity. Muscle biopsies will be performed during the study for future biomarker analyses.

VMALS-002-2 was a controlled study to evaluate the safety of intramuscular administration of Engensis to subjects with Amyotrophic Lateral Sclerosis, as compared to Placebo. Subjects randomly assigned to Engensis were to receive a total dose of 192 mg Engensis divided into 3 treatment cycles of 64 mg Engensis each. A dosing schedule developed from those used in the Phase 1/2 Amyotrophic Lateral Sclerosis study and in three diabetic peripheral neuropathy studies were used in this study. The intramuscular injections to each target muscle group were divided into three Injection Visits (equal halves), two weeks apart on Days 0, and 14, with retreatment at Days 60 and 74, and Days 120 and 134. Engensis was delivered in a solution of 0.5 mg VM202/mL.

Results from this Phase 1/2 study suggest that targeted delivery of hepatic growth factor to motor neurons via intramuscular injections of Engensis was safe and well tolerated, based on data from 18 enrolled subjects who were followed through 90 days after the first injection [Sufit et al., 2017]. Following injections until Day 90, a plateau or a relative slowing in decline of the Amyotrophic Lateral Sclerosis Functional Rating Scale scores and muscle strength was noted, suggesting a slowing of disease progression. After 90 days, the plateau was no longer observed in the Amyotrophic Lateral Sclerosis Functional Rating Scale, with the notable exception of a trend toward better preservation of bulbar and breathing functions as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale subscore, which appeared to persist out to 180 days. The change in Amyotrophic Lateral Sclerosis Functional Rating Scale total score over time or "slope" (>0, indicating clinical stability or improvement) following Engensis treatment was greatest at 2 months in 50% of subjects. At 3 months following Engensis, this improvement was observed in 25% of subjects. Muscle strength was stable for the first 3 months following Engensis administration and then steadily declined in both upper and lower limbs at subsequent months.

Inclusion Criteria:

1. Clinically definite or probable Amyotrophic Lateral Sclerosis or laboratory-supported probable Amyotrophic Lateral Sclerosis as defined in the revised El Escorial/Airlie House diagnostic criteria
2. The site of onset of Amyotrophic Lateral Sclerosis symptoms is a limb and experiencing symptoms of lower motor dysfunction (e.g., weakness, atrophy, cramps, poor circulation, etc.) with upper motor neuron symptoms (e.g., weakness, brisk reflexes, spasticity)
3. Onset of Amyotrophic Lateral Sclerosis symptoms ≤ 4 years
4. Slow Vital Capacity ≥ 50% of predicted value at Screening
5. Not taking riluzole, or on a stable dose (defined as no noted toxicities) for at least 30 days prior to Screening and throughout the study
6. Not taking edaravone or on a maintenance cycle for at least 30 days prior to Screening and throughout the study
7. For females of childbearing potential, a negative urine pregnancy test at Screening and on Day 0
8. Male Participants and their female partners must agree to use double-barrier contraception during the study or provide proof of postmenopausal state (minimum 1 year) or surgical sterility
9. Male Participants must not donate sperm during the study
10. Female Participants must be nonpregnant, nonlactating, and either postmenopausal for at least 1 year, or surgically sterile for at least 3 months, or agree to use double-barrier contraception from 28 days prior to randomization (Day 0) and/or their last confirmed menstrual period prior to study randomization (whichever is longer) until the end of the study
11. Capable of complying and willing to comply with the requirements and restrictions in the informed consent form and this protocol
12. Willing to forgo new experimental Amyotrophic Lateral Sclerosis treatments for at least 6 months following randomization

Exclusion Criteria:

1. Progressive or degenerative neurological disorder such as Alzheimer's disease, Parkinson's disease, vascular dementia, multiple sclerosis, and other neurological or vascular disorders felt by the Investigator to preclude participation
2. Requires tracheotomy ventilation or noninvasive ventilation related to bulbar function
3. Evidence by physical examination, history, or laboratory evaluation of significant concomitant disease with a life expectancy of < 6 months at Screening
4. International Normalized Ratio values >2.0
5. Platelet count <100,000/µL
6. Inflammatory disorder of the blood vessels (inflammatory angiopathy or vasculitis, such as Buerger's disease)
7. Active infection (chronic infection or severe active infection that may compromise the Participant's wellbeing or participation in the study in the Investigator's judgment)
8. Chronic inflammatory disease (e.g., Crohn's disease, rheumatoid arthritis)
9. Positive human immunodeficiency virus or human T-cell lymphotrophic virus I/II test at Screening
10. Active acute or chronic hepatitis B
11. Active hepatitis C
12. Immunosuppression due to underlying disease (e.g., rheumatoid arthritis, systemic lupus erythematosus) or to currently receiving immunosuppressive drugs, (e.g., chemotherapy, corticosteroids) or to radiation therapy
13. Stroke or myocardial infarction within 3 months prior to Screening
14. Active deep vein thrombosis
15. Recent history (< 3 years) or presence of cancer except basal cell carcinoma or squamous cell carcinoma of the skin that was excised and has shown no evidence of recurrence for at least 1 year
16. Major psychiatric disorder diagnosed in the past 6 months that has not been stabilized or in the Investigator's opinion would not allow the patient to participate in the scheduled procedures
17. Use of an investigational drug for the treatment of Amyotrophic Lateral Sclerosis in the past 30 days or 5 half-lives (if available), whichever is longer, or previous participation in a clinical study with Engensis
18. Stem cell administration for investigational treatment of Amyotrophic Lateral Sclerosis or other conditions in the 6 months prior to Screening