Helixmith Facing Engensis Challenges After Disappointing First Phase III Data
Executive Summary
Helixmith delays making conclusions on disappointing first top-line data from lead US Phase III study of plasmid DNA therapeutic Engensis, citing unexpected pharmacokinetic results in the placebo and treatment groups. The South Korean biotech vows to improve strategy for upcoming trials, but much may hinge on their success.
Helixmith has found serious flaws in pharmacokinetic data from the first Phase III trial with its lead product Engensis (VM202) and has delayed making conclusions based on what were the first top-line results from a US study.
During a review of the recently completed Phase III study of Engensis versus placebo in 500 patients with painful diabetic peripheral neuropathy (PDPN), the South Korean venture discovered that Engensis DNA was also found in some placebo group subjects. In the Engensis group, there were also some subjects with Engensis DNA concentrations that were overly low compared to others in the Engensis group, explained Helixmith, formerly known as ViroMed Co. Ltd.
Engensis is a plasmid DNA product that encodes human hepatocyte growth factor (HGF), and was administered via intramuscular injection by medical personnel during four study visits during the nine-month clinical trial. Engensis has previously been shown to alleviate neuropathic pain in DPN subjects in Phase I and II trials.
“With the current information, it is difficult to determine the precise reason for these results,” the company said, apologizing for the flaws in data given that clear conclusions from the findings will have to be made after completion of the second Phase III trial. Top-line data from the PDPN program was the firm's major business milestone for this year.
Helixmith plans to share further details of the clinical study report meeting in November and then through a meeting with the FDA.
Uncertain Efficacy Conclusions
In the intent-to-treat (ITT) population, the primary endpoint of change in pain at three months was not statistically meaningful. Although the adjusted ITT group - which removes subjects with unexpected pharmacokinetic results - gave different results, the company said it is impossible at the present time to derive accurate conclusions on the efficacy of Engensis.
In a note on the results, Biomedtracker noted that Engensis DNA was found in patients who received placebo, while in the Engensis arm some patients had surprisingly low concentrations of Engensis DNA. Numerical details were not released, but the company has noted that removal of those suspicious datapoints from the ITT group resulted in different outcomes and further information will be shared with the FDA in December.
“This news will also be disappointing to pain specialists as excitement was being generated for gene therapies and growth factors within the pain space to potentially combat nerve degradation at the early stages and improve the healing of underlying disease conditions,” Biomedtracker analysts commented.
Adverse event rates in the entire ITT population were very low and no serious adverse event was determined to be related to the study medication. Also, injection site reactions were all Grade 1 except for one that was Grade 2. Therefore, the data are consistent with previous results supporting the safety profile of Engensis, Helixmith said.
The top-line Phase III data for Engensis were also highly anticipated within the wider South Korean pharma industry this year, as Helixmith is one of the few drug developers in the country progressing global Phase III trials, particularly in the gene therapy area.
The unexpected results disappointed investors and dragged down the venture's stock price by the daily 30% limit on 24 September on the Kosdaq market.
PK Probe, Smaller Phase III Plans
Helixmith has now set up a team to run a detailed investigation into the pharmacokinetic results, the outcome of which will be disclosed.
In the meantime, the company plans to conduct two or three smaller-scale Phase III studies of about 150-200 subjects each to further evaluate Engensis versus placebo in PDPN. These will start in the next six months and are expected to be completed around early 2022, with the aim of submitting a US Biologics License Application in the latter half of that year.
The company plans to use 180-day pain reduction data as the primary efficacy endpoint for the trials and to exclude patients who have been administered gabapentin/pregabalin to maximize pain reduction effects.
It also aims to conduct long-term clinical trials (roll-over extension study), simultaneously or separately, on the subjects who participated in the Phase III study, to prove the “regeneration effects” of Engensis. It will also come up with various plans to ensure the best quality data and speed up ongoing Engensis trials in other indications in the US.
Helixmith's flagship product, Engensis is being developed for four indications with high unmet medical needs: two cardiovascular disorders, coronary artery disease and peripheral artery disease; and two neurological conditions, amyotrophic lateral sclerosis (ALS) and PDPN.
The company is progressing a US Phase III clinical trial for diabetic foot ulcers as well as PDPN, along with a Phase II study for ALS, which is set to begin in December.
'Highly Uncertain' Future?
Following the failure to demonstrate clinically significant improvements in the first Phase III trial, Biomedtracker lowered Engensis’ likelihood of US approval by eight percentage points to 44%, pending future data from the additional planned smaller Phase III trials.
It noted that key opinion leaders have suggested that efficacy indicators for a gene therapy would include a 50% improvement in pain with 50% of patients responding, as well as reductions in numbness or areas of pain, particularly in diabetic neuropathy patients. Improvements in function, decreases in night time pain, improved ability to walk and quantitative sensory tests would also be important efficacy indicators for potential gene therapies in this space.
“Having missed its primary endpoint of 3-month pain change, however, it seems the future of Helixmith’s gene therapy is highly uncertain unless it can demonstrate positive data in future planned trials,” Biomedtracker concluded.