Background

This gene therapy involves intramuscular injection of a proprietary DNA plasmid encoding the two natural isoforms of hepatocyte growth factor. HGF is a multifunctional peptide with neurotrophic and angiogenic activity. The goal of this treatment is to prevent or reverse motor neuron loss in ALS by boosting muscle HGF concentration.

Extensive research has shown that HGF acts through its tyrosine kinase receptor c-met to promote neuron survival and axonal outgrowth from sensory and motor neurons (e.g., see Ebens et al., 1996; Wong et al.,1997; Ko et al., 2018). In ALS rodent models, HGF delivered to the central nervous system lessened motor neuron degeneration and prolonged life span (Sun et al., 2002; Ishigaki et al., 2007). These and other studies suggest HGF acts through multiple mechanisms including neurotrophic support for motor neurons, suppression of microgliosis, dampening of excitotoxic injury, facilitation of muscle reinnervation, and inhibition of apoptotic cell death. 

Engensis delivers HGF to muscle, not the central nervous system. Injection of the plasmid into the hind limb muscles of rabbits or mice caused detectable HGF expression for about two weeks, with peak protein production after seven days (Pyun et al., 2010). No preclinical data on this DNA construct in ALS models are published. However, an adenovirus vector version with the same HGF coding sequence was tested in the SOD1-G93A genetic model of ALS. Intermuscular injection of the viral vector led to prolonged protein expression, increased muscle mass, alleviation of disease symptoms, and longer survival (Lee et al., 2019). Helixmith has shown effectiveness of HGF-expressing adenoviruses after injection into the central nervous system in ALS animal models (Lee et al., 2019; Genc et al., 2023).

Findings

A Phase 1, open-label safety study in 18 ALS patients ran from February 2014 to December 2017. Participants received intramuscular injections of 64 mg DNA four times, at baseline, one, two, and three weeks, alternating each week to arms or legs. DNA was split between 72 sites in leg muscles, or 52 sites in arm muscles, for a total of 256 injections in the trial. Volunteers were followed for nine months after the last injections. Seventeen patients completed the study; all tolerated the regimen with no serious adverse events. Twelve reported mild or moderate injection site reactions. Five serious adverse events, including one death, were attributed to ALS progression (Sufit et al., 2017). After injections, DNA was detected in blood, but there was no increase in HGF protein. This safety profile was similar to previous studies in painful diabetic neuropathy and other indications, involving more than 175 patients (e.g., see Kessler et al., 2015; Kibbe et al., 2016).

A placebo-controlled Phase 2a study began in February 2021. In this study, 18 ALS patients received 64 mg engensis or placebo injections three times over four months, for a total dose of 192 mg. Each treatment involved two sessions of 256 injections to arm and leg muscles over two days, spaced two weeks apart. The trial collected muscle biopsies. On September 8, 2022, the company announced top-line results of the placebo-controlled phase of the trial (press release). The treatment was safe, with no excess adverse events in drug versus placebo group. Half of the treatment group, and two-thirds of the placebo group, reported injection site reactions, but no one discontinued due to the number of injections.

This trial offered a six-month extension, which eight people completed in December 2022

Engensis is in Phase 3 for painful diabetic neuropathy. After positive Phase 2 findings, a Phase 3 trial completed in June 2019 was inconclusive (Kessler et al., 2021); a second Phase 3 trial is underway and expected to end in June 2023. A large Phase 3 trial for critical limb ischemia, running in China under the drug name pCK-HGF-X7 or NL003, is slated for completion in December 2023. A Phase 3 program for diabetic foot ulcers was terminated due to low enrollment. Other indications in development are peripheral artery disease, and Charcot-Marie-Tooth neuropathy.

For more details, see clinicaltrials.gov