■ Helios <4593> Development Pipeline

3. HLCM051 (treatment drug for cerebral infarction)

Cerebral infarction refers to a disease where blood vessels in the brain become blocked, preventing nutrients from reaching the cells beyond the blockage, causing dysfunction in brain activity. Symptoms vary depending on the site of the blockage, but once the disease develops, even if life is saved, many cases leave behind sequelae such as paralysis or speech disorders. According to the company’s financial results presentation materials, the annual number of new cases is estimated to be 0.33 million in japan, 0.69 million in the usa, 0.84 million in the european index, and 3.4 million in china, totaling over 5.26 million worldwide.

※ The target patients for HLCM051 are those who are brought to medical facilities within 36 hours of the onset of the condition, and it is estimated that the number of target patients in japan under the same conditions would be around 0.062 million according to the company.

In the acute phase of treating cerebral infarction, treatments generally include "thrombolysis" to dissolve blood clots that have obstructed blood vessels in the brain, and "mechanical thrombectomy," which restores blood flow by directly retrieving clots from the obstructed cerebral arteries. However, the application of "thrombolysis" is limited to within 4.5 hours of onset, and "mechanical thrombectomy" is also restricted to within 8 hours. Therefore, there is a strong desire for the development of new drugs that are effective for treatment even after a certain period has passed since the onset of cerebral infarction.

HLCM051 is administered intravenously within 36 hours after the onset of cerebral infarction, suppressing the activation of inflammatory immune cells in the spleen, which is the site of immune response, thereby reducing inflammation and immune reactions to limit damage to nerve cells. Furthermore, it is expected to enhance the proliferation of anti-inflammatory cells and release nutritional factors, providing a neuroprotective effect.

As for the progress of development, the company conducted Phase 2/3 trials in japan and announced the results in November 2022, while in October 2023, Asasis announced the interim analysis results of the Phase 3 trials in the usa. In japan, 220 patients within 18 to 36 hours of cerebral infarction onset were divided into HLCM051 group and placebo group of 110 each, and the degree of improvement was compared on the 90th and 365th days post-administration. The primary endpoint compared the number of cases with Excellent Outcome, judged as having virtually no restrictions on daily life, while secondary endpoints compared the number of cases in a state of independence in daily life identified as GR (Global Recovery) and those with BI index of basic daily activities scoring at least 95. As a result, there was no statistically significant difference for the primary endpoint at both the 90th and 365th days post-administration compared to the placebo group, but a significant difference was observed for GR (p value = 0.037) and BI index (p value = 0.045) on the 365th day post-administration, and the safety of HLCM051 post-administration was also confirmed.

Regarding future development policies, the company intends to integrate and further analyze clinical trial data collected in japan and the usa, considering clinical trial designs that may allow for a higher likelihood of obtaining manufacturing and marketing approval. The main points hinge on whether GR and BI index on the 365th day post-administration can be established as primary endpoints. On the other hand, since it is certified under the SAKIGAKE system in japan, there is also a possibility of pursuing conditional and time-limited approval applications based on the secondary endpoints that showed significant differences following consultations with the PMDA.

Regarding the development for stroke in the usa, resources will be concentrated on the development of ARDS therapeutics, so for the time being, the priority will be lowered; however, the market scale is expected to be larger than that of ARDS and continue to increase with the progress of an aging society, hence the hope for future development. As for the development costs for conducting clinical trials, the policy is to procure them through royalty investments and third-party allocated capital at the us subsidiary or a newly established subsidiary, similar to the ARDS therapeutics. Furthermore, the direction for regions outside the usa and japan is to license out, and there appear to be inquiries from pharmaceutical companies.

The clinical trial for trauma is currently being carried out in phase II with the budget from the usa Department of Defense.

4. HLCM051 (Trauma Treatment Drug)

HLCM051 is being developed as a treatment drug for trauma in the USA, sponsored by the US Department of Defense and the Memorial Hermann Foundation. The Phase 2 trial, which included 156 patients, was temporarily suspended due to the bankruptcy of Assisis, but resumed in October 2024. The enrollment progress rate appears to be about 20%, and it is expected to conclude by the end of 2025. If good results are obtained, the Department of Defense and others will continue to sponsor the Phase 3 clinical trial. The company will not bear the financial burden, and if successful in development, there is potential for large-scale deployment for the US military, attracting attention to future developments.

In the usa, deaths due to trauma from traffic accidents, workplace accidents, and gunshot wounds are common. According to the company's financial explanation materials, it ranks first among the causes of death for those under 45 years old, third overall, and is the leading cause of decreased quality of life (QOL). The annual death toll is 0.22 million, with general trauma accounting for 55%, and trauma or acute poisoning under the influence of drugs making up 45%. If systemic inflammatory response syndrome due to trauma occurs, it initially serves a protective purpose; however, it can escalate into an uncontrollable cytokine storm, triggering a large-scale inflammatory cascade, leading to organ damage such as renal failure and ultimately death. Currently, there are no effective drugs for patients in such conditions, and only symptomatic treatments are being provided. It is expected that administering HLCM051 will suppress the cytokine storm and positively affect the prognosis for patients.

In the phase II clinical trial, a double-blind placebo-controlled comparison study is being conducted targeting multi-organ failure/systemic inflammatory response syndrome due to trauma, with the primary evaluation item comparing the improvement in kidney function 30 days post-administration with the placebo group. Additionally, mortality rates and other secondary evaluation items will also be assessed. The target patients are those with severe trauma who have undergone initial resuscitation within a few hours of hospitalization. If successful in development, there is potential for large-scale adoption by the us military, and future developments are being closely monitored.

Cancer immunotherapy using eNK cells aims to start clinical trials within 2025.

5. HLCN061 (Next-Generation Cancer Immunotherapy)

Cancer immunotherapy using eNK cells, uniquely developed using gene editing technology derived from iPSC, is being jointly researched with multiple academies, aiming to start clinical trials within 2025.

eNK cells are characterized by enhanced tumor cell-killing ability and tumor site infiltration ability compared to NK cells due to gene editing technology. As a result of internal research, an anti-tumor effect has been confirmed in mouse models for lung cancer orthotopic implantation, subcutaneous transplantation models for liver cancer, peritoneal dissemination models for gastric cancer, and subcutaneous transplantation models for mesothelioma. An anti-tumor effect has also been confirmed in organoids derived from lung cancer patients that possess a similar environment to cancer in vivo.

※ Organoids are tissues or cells with a three-dimensional structure that have characteristics extremely similar to those of tissues and organs in vivo.

In collaborative research projects, eNK cells' anti-tumor effects are being evaluated using PDX (patient-derived tumor xenograft) transplantation mice derived from multiple cancer types held by the National Cancer Center. Additionally, joint research on cancer immunotherapy for liver cancer with Hiroshima University Graduate School and for mesothelioma with Hyogo Medical University is being advanced. Research results are expected to be presented at academic conferences from 2024.

Regarding research and development, it is planned that the subsidiary eNK Therapeutics will take the lead. If development costs are required, such as for clinical trials, funding will be secured through royalty investments or third-party allotments of new shares. The company expects that fundraising will lead to a reduction in the annual development cost burden of approximately 1 billion yen.

(Written by FISCO guest analyst, Jo Sato)