SEOUL, South Korea, Nov. 13, 2023 /PRNewswire/ -- OliPass Corporation, an RNA therapeutics platform company, disclosed uncanny clinical findings from a multi-center Phase 2a trial with Nav1.7 selective OLP-1002 in osteoarthritis (OA) patients with moderate to severe pain in Australia with Novotech. The Phase 2a trial consists of an open label dose range finding study (stage 1) and a placebo-controlled double blind study (stage 2).
1. Stage 1 Open Label Study
In this dose range finding study, patients were administered with a single subcutaneous injection of 1, 3, 10, 25, 50 or 80 microgram (mcg) OLP-1002, and then subjected to pain assessment for 4 weeks. 1 mcg OLP-1002 turned out to be most effective, showing average pain reductions of 50 ~ 70% by WOMAC Pain and 60 ~ 80% by VAS over the period of 4 weeks. All the five patients on 1 mcg OLP-1002 effectively responded to the medication. Other doses were also effective but with large inter-subject variability. OLP-1002 shows a bell-shape dose-response pattern in cells and higher dose may not be translated into stronger analgesic efficacy.
2. Stage 2 Placebo-controlled Double Blind Study
Patients received a single subcutaneous injection of placebo, 1 mcg or 2 mcg OLP-1002, and then were subjected to pain assessment primarily by WOMAC Pain and VAS for 6 weeks post dose. An interim analysis was conducted for the first 30 patients (10 patients per group) to estimate due statistical power for efficacy. The interim analysis suggested that the study be properly powered for efficacy if evaluated in 60 to 90 patients. The study was extended to evaluate 59 additional patients.
3. Executive Summary of Phase 2a Studies
The stage 2 placebo-controlled double blind study was overrun by excessive placebo effect for the two primary end points of efficacy. Excessive placebo effect would not be unusual in many trials for drug candidates with marginal efficacy. Even in such cases, however, the efficacy of the placebo group is hardly more effective than the treatment group with statistical significance (p < 0.05). In this Phase 2a trial, the placebo group repeatedly showed pain reduction significantly (p < 0.05) stronger than OLP-1002 treatment group.
"It would be hilarious if placebo were widely accepted as the most efficacious pain killer with excellent safety. Otherwise, OLP-1002 must be a pain evoker to best explain the efficacy profile of the placebo group observed in the Phase 2a study as well as the Phase 1b study with OLP-1002.", said Dr. Shin Chung, CEO of OliPass Corporation. "Although OLP-1002 was found inferior to placebo in this Phase 2a trial, there are still hundreds of reasons to believe that OLP-1002 is the most effective pain killer ever developed. In order to develop OLP-1002, we would need an extremely sensitive detection method for OLP-1002 in plasma to block the loophole of bioanalysis while implementing clinical trials. The exposure to OLP-1002 is hardly traceable for now due to the infinitesimal therapeutic dose level. In this regard, we should be serious about a collaboration early on with a big pharma with strong bioanalysis capability. We are certainly destined to serve people with refractory pain.", added Dr. Chung.
Provided below are the observed clinical findings of excessive placebo effect from the Phase 2a studies as well as the Phase 1b study conducted in the middle of the Covid19 pandemic.
4. WOMAC Pain Findings from Interim Analysis
The 2 mcg group showed a pattern of pain reduction gradually increasing to reach 55% in Day 43. In case of the placebo group, pain reduction reached its maximum of 43% in Day 15 and then gradually decreased to 26% in Day 43. The 1 mcg group showed a pain reduction of 18% in Day 43, and was the least effective among the three groups. The difference in Day 43 was slightly short of significance (p < 0.1 by t-test) between the 2 mcg group and the placebo group as well as between the 2 mcg group and the 1 mcg group. It would be interesting to reason why the efficacy of the 1 mcg group in the open label study was not reproduced in the interim analysis.
5. VAS Findings from Interim Analysis
The 2 mcg group showed a pattern of pain reduction gradually increasing to reach 65% on average in week 6. The placebo group showed pain reduction reaching a plateau of 33 ~ 35% on average in weeks 3 ~ 6. In case of the 1 mcg group, pain reduction reached its maximum of 28% in week 4 and diminished to 17% in week 6. The difference in week 6 between the 1 mcg and the 2 mcg group was statistically significant. Based on the efficacy findings by WOMAC Pain and VAS, the 1 mcg group rather looks like placebo. Peculiar to note that acetaminophen consumption was the heaviest in the 1 mcg group.
6. WOMAC Pain Findings from Extension Study
A preliminary in-house statistical analysis is now available for the extension study employing the additional 59 patients. The 2 mcg group showed pain reduction reaching its maximum of 34% in Day 22 and then decreased to 23% in Day 43. In case of the 1 mcg group, pain reduction reached a plateau of 21% in Day 22 and remained stable afterwards. The placebo group showed pain reduction plateauing at 45% in Day 15 and afterwards. The placebo group was significantly better (p < 0.05) than the treatment groups in Day 43, raising concerns about the real nature of the placebo group. Furthermore, the placebo group showed a pain reduction of 41% on average for the whole six weeks, whilst 22% for the 1 mcg group and 25% for the 2 mcg group. The placebo group was significantly better than the 1 mcg group on average for the whole 6 weeks. 4 out of the 20 patients in the placebo group showed a pain reduction of 78% or higher on average for 6 weeks. 10 out of the 20 patients in the placebo manifested a pain reduction of 50% or higher on average for 6 weeks. The efficacy profile of the 2 mcg group was strikingly different from the profile observed in the interim analysis. Judging from the efficacy profiles, the 1 mcg group looks more like placebo.
7. VAS Findings from Extension Study
The 2 mcg group showed pain reduction reaching a plateau of 27% in week 4 and afterwards. In case of the placebo group, pain reduction reached a plateau of 43% in week 4 and afterwards. The 1 mcg group showed a pain reduction of 19% stably maintained from week 1 and afterwards. The placebo group was not significantly different from the treatment groups. Based on the efficacy findings by WOMAC Pain and VAS, however, the 1 mcg group in this extension study looks more like placebo.
8. Excessive Placebo Effect from Phase 1b Study
Overt placebo effect has not been unprecedented with OLP-1002. In a Phase 1b study in OA patients conducted in Australia again with Novotech, patients were subcutaneously administered with placebo, 5 mcg OLP-1002 or 10 mcg OLP-1002 two times per week for two weeks, and then subjected to pain assessment for six weeks post the first dose. At the end of the study, i.e., Day 45, the observed pain reduction by WOMAC Pain was 21% for the 5 mcg group (n = 13), 32% for the 10 mcg group (n = 11), and 55% for the placebo group (n = 10). The placebo group was significantly (p < 0.05) more effective than the 5 mcg group by WOMAC Pain in Days 25, 32 and 45. In the meantime, the observed pain reduction by VAS was 11% for the 5 mcg group, 20% for the 10 mcg group and 47% for the placebo group on average during the period of Day 33 to 45. The placebo group was significantly (p < 0.05) more effective than the 5 mcg group by VAS on average during the period of Day 33 to 45. Judging from the efficacy readouts, however, the 5 mcg group looks rather like placebo.
[Loss-of-function Mutation in SCN9A gene & Safe Pain Killer] People with a null mutation in the SCN9A gene encoding Nav1.7 sodium ion channel subtype were found insensitive to pain but with other sensory functions undisturbed. A selective inhibitor of Nav1.7 has been implicated to safely treat pain. Unfortunately, there are ca 10 sodium channel subtypes structurally indistinguishable with small molecule inhibitors. Inhibition of Nav1.5 subtype, for example, may cause life-threatening heart arrhythmia. Nav1.7 selectivity really matters to safety. Despite a huge number of Nav1.7 selective small molecule inhibitors have been evaluated, none have manifested strong efficacy and good safety in patients. Lack of safe and effective pain killers triggered the outbreak of opioid crisis. Opioid crisis is getting worse and taking lives of more than 100,000 victims each year. The urgency and importance of identifying safe and effective pain killers can never be overemphasized.
[About OLP-1002] OLP-1002 is an SCN9A antisense PNA and selectively inhibits the expression of Nav1.7 sodium channel in neuronal cells. OLP-1002 replicates much of the phenotype of people with a null mutation in the SCN9A gene. OLP-1002 shows an attomolar (10-18M) in vitro potency and broadly distributes to tissues, which would be responsible for its very small therapeutic dose and long therapeutic duration. Unlike small molecule inhibitors of Nav1.7, OLP-1002 possesses disease-modifying activity by down-regulating neuropathic hypersensitization. OLP-1002 would be the first Nav1.7 selective inhibitor manifesting strong efficacy and good safety.
[About OliPass Corporation] OliPass Corporation is a public biotech company listed in KOSDAQ in South Korea (ticker: KQ244460). The company is developing RNA therapeutics based on its proprietary oligonucleotide platform called OPNA (OliPass Peptide Nucleic Acid). OPNA was derived from PNA by rational chemical modifications to show good cell permeability and ultra-strong affinity for RNA. For therapeutic intervention, OPNA potently binds to target pre-mRNA, induces exon skipping, and yields mRNA splice variant. Unlike other types of RNA therapeutics, OPNA does not require formulational aid for in vivo therapeutic activity.