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)..

韩国首尔，2023年11月13日/PRNewswire/-OliPass公司，一家RNA治疗平台公司，披露了Nav1.7选择性OLP-1002多中心2a期临床试验在骨关节炎（OA）中的不可思议的临床发现。澳大利亚Novotech患有中度至重度疼痛的患者。2a期试验包括开放标签剂量范围发现研究（阶段1）和安慰剂对照双盲研究（阶段2）。。

1. Stage 1 Open Label Study

1.第一阶段开放标签研究

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.

在该剂量范围发现研究中，给患者单次皮下注射1,3,10,25,50或80微克（mcg）OLP-1002，然后进行疼痛评估4周。1 mcg OLP-1002证明是最有效的，显示WOMAC疼痛平均疼痛减少50~70%，VAS在4周内平均疼痛减少60~80%。

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..

1 mcg OLP-1002上的所有5名患者均对该药物有效。其他剂量也有效，但受试者间差异很大。OLP-1002在细胞中显示钟形剂量反应模式，较高剂量可能不会转化为更强的镇痛效果。。

2. Stage 2 Placebo-controlled Double Blind Study

2.第2阶段安慰剂对照双盲研究

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.

患者接受单次皮下注射安慰剂，1 mcg或2 mcg OLP-1002，然后在给药后6周主要通过WOMAC疼痛和VAS进行疼痛评估。对前30名患者（每组10名患者）进行中期分析，以估计疗效的适当统计效力。

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..

中期分析表明，如果在60至90名患者中进行评估，该研究可以适当地提高疗效。该研究扩展到评估另外59名患者。。

3. Executive Summary of Phase 2a Studies

3.2a期研究的执行摘要

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).

第2阶段安慰剂对照双盲研究被两个主要疗效终点的过度安慰剂效应所超越。在许多试验中，对于边缘疗效的候选药物，过量的安慰剂效应并不罕见。然而，即使在这种情况下，安慰剂组的疗效几乎不比具有统计学意义的治疗组更有效（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..

在这个2a期试验中，安慰剂组反复显示疼痛减轻显着（p<0.05）强于OLP-1002治疗组。。

'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.

“如果安慰剂被广泛接受为最有效的止痛药，具有极好的安全性，那将是肝门部的。否则，OLP-1002必须是疼痛唤起者，以最好地解释在2a期研究中观察到的安慰剂组的功效特征以及OLP-1002的1b期研究。

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.

OliPass Corporation首席执行官Shin Chung虽然OLP-1002在2a期试验中被发现不如安慰剂，但仍有数百个理由相信OLP-1002是有史以来最有效的止痛药。为了开发OLP-1002，我们需要对血浆中的OLP-1002进行极其灵敏的检测方法，以在实施临床试验时阻断生物分析的漏洞。

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..

由于无限小的治疗剂量水平，OLP-1002的暴露目前几乎不可追踪。在这方面，我们应该认真对待与具有强大生物分析能力的大型制药公司的早期合作。我们当然注定要为那些患有顽固性疼痛的人服务。”，钟博士补充说。。

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.

下面提供了2a期研究以及在Covid19大流行期间进行的1b期研究中观察到的过度安慰剂效应的临床发现。

4. WOMAC Pain Findings from Interim Analysis

4.中期分析的WOMAC疼痛发现

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.

2 mcg组显示疼痛减轻模式逐渐增加，在第43天达到55%。在安慰剂组的情况下，疼痛减轻在第15天达到最大值43%，然后在第43天逐渐降低至26%。1 mcg组在第43天显示疼痛减轻18%，并且在三组中效果最差。

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..

第43天的差异在2mcg组和安慰剂组之间以及2mcg组和1mcg组之间略微不显着（t检验p<0.1）。有趣的是，为什么在中期分析中没有复制1 mcg组在开放标签研究中的疗效。。

5. VAS Findings from Interim Analysis

5.中期分析的VAS结果

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.

2 mcg组显示疼痛减轻模式逐渐增加，在第6周平均达到65%。安慰剂组显示疼痛减轻在第3~6周平均达到33~35%的平台期。对于1 mcg组，疼痛减轻在第4周达到最大值28%，在第6周减少到17%。

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..

1 mcg和2 mcg组之间第6周的差异具有统计学意义。根据WOMAC疼痛和VAS的疗效结果，1 mcg组更像安慰剂。特别值得注意的是，对乙酰氨基酚的消耗量是1 mcg组中最重的。。

6. WOMAC Pain Findings from Extension Study

6.扩展研究中的WOMAC疼痛发现

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.

现在可以进行初步的内部统计分析，以用于另外59名患者的扩展研究。2 mcg组显示疼痛减轻在第22天达到最大值34%，然后在第43天降至23%。在1微克组的情况下，疼痛减轻在第22天达到21%的平台并且之后保持稳定。

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.

安慰剂组在第15天及之后显示疼痛减轻平台在45%。安慰剂组在第43天显着优于治疗组（p<0.05），引起人们对安慰剂组真实性质的担忧。此外，安慰剂组在整个六周内平均疼痛减轻41%，而1mcg组为22%，2mcg组为25%。

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.

在整个6周内，安慰剂组平均明显优于1 mcg组。安慰剂组的20名患者中有4名在6周内平均疼痛减轻78%或更高。安慰剂组20例患者中有10例平均6周疼痛减轻50%或更高。

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..

2 mcg组的疗效特征与中期分析中观察到的特征明显不同。从疗效来看，1 mcg组看起来更像安慰剂。。

7. VAS Findings from Extension Study

7.扩展研究的VAS发现

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.

2 mcg组在第4周及之后疼痛减轻达到27%的平台期。在安慰剂组的情况下，疼痛减轻在第4周及之后达到43%的平台。1 mcg组从第1周及之后显示疼痛减轻19%稳定维持。安慰剂组与治疗组没有显着差异。

Based on the efficacy findings by WOMAC Pain and VAS, however, the 1 mcg group in this extension study looks more like placebo..

然而，根据WOMAC疼痛和VAS的疗效结果，本次扩展研究中的1 mcg组看起来更像安慰剂。。

8. Excessive Placebo Effect from Phase 1b Study

8.1b期研究中的过度安慰剂效应

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.

OLP-1002并没有前所未有的安慰剂效应。在再次使用Novotech在澳大利亚进行的OA患者的1b期研究中，患者每周两次皮下注射安慰剂，5 mcg OLP-1002或10 mcg OLP-1002，持续两周，然后进行疼痛评估。第一剂后的六周。

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.

在研究结束时，即第45天，观察到的WOMAC疼痛减轻5微克组（n=13）为21%，10微克组（n=11）为32%，安慰剂组为55%（n=10）。在第25,32和45天，安慰剂组比5mcg组通过WOMAC疼痛显着（p<0.05）更有效。

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.

与此同时，在第33天至第45天期间，观察到的VAS疼痛减轻5微克组为11%，10微克组为20%，安慰剂组为47%。在第33天至第45天期间，安慰剂组平均比5微克组更有效（p<0.05）。

Judging from the efficacy readouts, however, the 5 mcg group looks rather like placebo..

然而，从疗效读数来看，5 mcg组看起来更像安慰剂。。

[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.

[SCN9A基因功能丧失突变和安全止痛药]发现编码Nav1.7钠离子通道亚型的SCN9A基因无效突变的人对疼痛不敏感，但其他感觉功能不受干扰。Nav1.7的选择性抑制剂与安全治疗疼痛有关。

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.

不幸的是，存在与小分子抑制剂在结构上无法区分的ca 10钠通道亚型。例如，抑制Nav1.5亚型可能导致危及生命的心律失常。Nav1.7选择性对安全性非常重要。尽管已经评估了大量Nav1.7选择性小分子抑制剂，但没有一种在患者中表现出强效和良好的安全性。

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..

缺乏安全有效的止痛药引发了阿片类药物危机的爆发。阿片类药物危机越来越严重，每年夺走10多万受害者的生命。确定安全有效的止痛药的紧迫性和重要性怎么强调都不为过。。

[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.

[关于OLP-1002]OLP-1002是SCN9A反义PNA，选择性抑制神经元细胞中Nav1.7钠通道的表达。OLP-1002复制了SCN9A基因中具有无效突变的人的大部分表型。OLP-1002显示阿托摩尔（10-18M）体外效力并广泛分布于组织，这将导致其非常小的治疗剂量和长的治疗持续时间。

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..

与Nav1.7的小分子抑制剂不同，OLP-1002通过下调神经性超敏反应而具有改善疾病的活性。OLP-1002将成为第一个具有强效和良好安全性的Nav1.7选择性抑制剂。。

[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.

[关于OliPass公司]OliPass公司是在韩国KOSDAQ上市的公共生物技术公司（勾选：KQ244460）。该公司正在基于其专有的称为OPNA（寡肽核酸）的寡核苷酸平台开发RNA治疗剂。OPNA通过合理的化学修饰从PNA衍生而来，以显示良好的细胞渗透性和对RNA的超强亲和力。

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..

对于治疗干预，OPNA有效结合靶前mRNA，诱导外显子跳跃，并产生mRNA剪接变体。与其他类型的RNA治疗剂不同，OPNA不需要用于体内治疗活性的配方辅助。。

SOURCE OliPass Corporation

SOURCE OliPass公司