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AI-Driven New Mechanism Discovery: Targeting an undisclosed novel mechanism empowered by PandaOmics, the PCC ISM9528 offers a potential first-in-class, brain-penetrant, non-opioid solution for pain management. Superior Therapeutic Profile: In preclinical studies, ISM9528 demonstrated superior efficacy compared to the standard of care, along with a favorable safety profile as an oral treatment, and promising DMPK properties. Proven Reproducibility and Scale: As Insilico's 31st PCC nominated since 2021, ISM9528 further validates the capabilities of Insilico's proprietary Pharma.AI platform to consistently accelerate and empower drug R&D innovation. CAMBRIDGE, Mass., July 22, 2026 /PRNewswire/ -- Despite the widespread availability of analgesics, pain management remains one of the most significant and pervasive challenges in modern medicine, with more than 20% of the global population suffering from chronic pain, especially chronic neuropathic pain characterized by central sensitization. However, the standard of care currently continues to rely heavily on opioids and NSAIDs, which are limited by inadequate efficacy, gastrointestinal toxicity, and the serious risks of dependence and addiction, calling for novel, effective, non-addictive, brain-penetrant analgesics. Insilico Medicine ("Insilico", HKEX:3696), a clinical-stage, generative AI-driven drug discovery company, is addressing this critical unmet need by using AI to uncover novel biological mechanisms and develop innovative therapies. The company recently announced the nomination of ISM9528 as a Preclinical Candidate Compound (PCC) for pain management. Identified by PandaOmics, ISM9528 is a potential first-in-class, brain-penetrant, orally available inhibitor of Target Z that offers a novel, non-opioid treatment approach by acting on a previously unexplored biological mechanism. Notably, this marks the 31st PCC nominated by Insilico since 2021, further validating the company's AI-driven R&D capabilities. "To see a non-opioid candidate outperform morphine in preclinical models is an unprecedented milestone, perhaps one of the most remarkable and unexpected results in our company's history, a result of frontier AI, human ingenuity and scientific serendipity." says Alex Zhavoronkov, PhD, Founder, CEO, and CBO of Insilico Medicine. "Target discovery for highly complex human mechanisms like chronic pain and migraine historically takes over a decade, but PandaOmics precisely mapped this pathway, driving us to our 31st PCC since 2021. By understanding the biology behind, we are not only addressing pain management, but moving one step closer to our ultimate ambition: decoding the biology of aging through our dual-purpose strategy." To find a new path forward for pain management, the team leveraged PandaOmics, Insilico's AI engine for identification and prioritization of therapeutic targets. By analyzing massive datasets of omics, textual and multimodal data, PandaOmics helped the team uncover a new pain-related pattern, highlighting the potential of Target Z in Insilico's current portfolio, a novel target not systematically linked to pain management before, and driving their attention to a compound they had already developed. Subsequent bioinformatics analyses of human and animal model data showed high expression of Target Z in pain-related cell types, strengthening the team's confidence to advance into wet lab testing. Moving swiftly into in vivo validation, The research utilized specialized mice models to imitate human pain mechanisms, demonstrating robust, dose-dependent pain management efficacy, with potential comparable or surpassing current solutions, including morphine. Following target validation, the team aimed at brain-penetrant properties and a balance between efficacy and safety, deploying Chemistry42, Insilico's generative chemistry platform compassing 40+ selective models integrated into several affiliated applications to re-generate compounds with optimized selectivity and ADMET properties for pain indication. After iterative cycles of AI generation, human feedback and refinement, ISM9528 was selected as the lead compound for the project. "The nomination of ISM9528 as the 31st drug candidate of Insilico validates the reproducibility and precision of our end-to-end AI platform," says Feng Ren, PhD, Co-CEO and CSO of Insilico Medicine, "Featuring both a novel mechanism of action and a highly distinct chemical structure, ISM9528 delivers superior efficacy and a favorable safety profile, with promising brain penetrant traits. Looking ahead, we are confident that our continuous integration of generative AI and automation will set new standards, deliver solid proof of concept, and introduce real-world clinical benefits for patients." In preclinical studies, ISM9528 demonstrated superior efficacy compared to standard of care in validated models of acute postsurgical pain and neuropathic pain, as an oral treatment. Moreover, comprehensive in vitro and in vivo safety screenings across multiple panels and animal models confirmed exceptional safety properties, while rapid systemic absorption and excellent blood-brain barrier permeability support a favorable DMPK profile. In the Spinal Nerve Ligation (SNL) rat model for neuropathic pain, ISM9528 dose-dependently restored mechanical allodynia. The middle dose delivered a significant analgesic effect across all time points up till 6h post dosing, which was comparable to Pregabalin, a standard of care for pain at similar dose level. In the postsurgical acute pain model, in addition to the dose dependent efficacy, ISM9528 demonstrated a rapid-acting efficacy at 0.5-hour post-dosing outperforming the equivalent dose of Pregabalin. "There is a tremendous unmet need for non-opioid pain medications, and the preclinical data for ISM9528 is quite promising," says Carol Satler, MD, PhD, Senior Vice President for Clinical Development, Non-Oncology, Insilico Medicine, "This is what we call a 'Eureka' moment, the kind of discovery that completely changes the landscape of how we treat patients. We are fast-tracking this exciting program toward clinical trials in 2027, driven to deliver a medicine that will genuinely transform patient care." As an AI-native biotechnology company, Insilico is redefining the efficiency of preclinical drug development through its advanced AI and automation platform, setting a new standard for the industry. While traditional early-stage drug discovery typically takes 2.5 to 4 years, Insilico has consistently reached preclinical candidate (PCC) nomination in an average of just 12 to 18 months, with only 60 to 200 molecules synthesized and tested per program. Since 2021, the company has nominated 31 PCCs, 13 of which have received IND approval or clearance. While expanding the practical applications of its technology in drug discovery and life science research, Insilico is also continuously enhancing the performance of its AI platform. Drawing on extensive experience and datasets from its training platform, the company has distilled thousands of benchmarks and integrated them into MMAI Gym. Serving as both a "trainer and benchmark" for scientific AI, MMAI Gym enables organizations to train models for domain-specific reasoning while rigorously evaluating their performance on real-world tasks, advancing the path toward pharma superintelligence. To date, Human Longevity and Liquid AI have collaborated with Insilico, joining as partners of MMAI Gym. About Insilico Medicine Insilico Medicine is a pioneering global biotechnology company dedicated to integrating artificial intelligence and automation technologies to accelerate drug discovery, drive innovation in the life sciences, and extend healthy longevity to people on the planet. The company was listed on the Main Board of the Hong Kong Stock Exchange on December 30, 2025, under the stock code 03696.HK. By integrating AI and automation technologies and deep in-house drug discovery capabilities, Insilico is delivering innovative drug solutions for unmet needs including fibrosis, oncology, immunology, pain, and obesity and metabolic disorders. Additionally, Insilico extends the reach of Pharma. AI across diverse industries, such as advanced materials, agriculture, nutritional products and veterinary medicine. 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PHOENIX, June 22, 2026 (GLOBE NEWSWIRE) -- Creative Medical Technology Holdings, Inc. (NASDAQ: CELZ) ("Creative Medical" or the "Company"), a clinical-stage biotechnology company advancing regenerative medicine solutions, today announced that the U.S. Food and Drug Administration (FDA) has cleared an expansion of the Company’s FDA-cleared ADAPT clinical trial evaluating CELZ-201 (Olastrocel) for chronic lower back pain associated with degenerative disc disease. Under the amended protocol, the Company is enrolling an additional 15 patients receiving less than 90 mg per day in morphine equivalents to further characterize safety and efficacy in patients with ongoing opioid use associated with the treatment of chronic lower back pain. The new cohort is already more than 85% enrolled and leverages the Company’s newly implemented, patient-centric AI pain medication monitoring system to capture rapid, accurate patient-reported outcome measures and analgesic-use patterns in real time. This expansion follows previously reported completion of enrollment in the original ADAPT study population and positive interim 180-day data demonstrating statistically significant, clinically meaningful improvements in functional disability (ODI%) and pain, together with an excellent safety profile. The trial remains supported by a favorable independent Data Safety Monitoring Board (DSMB) review, which reported no significant adverse events and recommended continued advancement of the program. “The FDA’s clearance of this expansion cohort represents another important step in the clinical and strategic maturation of Olastrocel,” said Timothy Warbington, President and CEO of Creative Medical Technology. “With enrollment in our original ADAPT population completed, encouraging safety and efficacy signals, and the new less-than-90 mg morphine-equivalent cohort already largely enrolled, we believe we are rapidly building a robust, real-world data package around chronic lower back pain patients who urgently need non-opioid, disease-modifying options. “We are now actively preparing for Phase 3 discussions with the FDA focused on a broader chronic lower back pain indication,” Mr. Warbington continued. “Our priority is disciplined execution: completing this expansion cohort, fully leveraging our AI-enabled, patient-centric monitoring platform, and positioning Olastrocel as a scalable, allogeneic regenerative solution in a market that still relies heavily on opioids, injections and invasive surgery. We believe this strategy has the potential to create significant value for patients and for our shareholders as we transition from a purely clinical story to a data-driven, late-stage development opportunity.” Clinical and Technology Highlights ADAPT trial momentum: The ADAPT study previously met its interim 180-day endpoints with statistically significant and clinically meaningful reductions in functional disability (ODI%) and pain, alongside an excellent safety profile.Original cohort completed: Enrollment of the original FDA-cleared cohort was completed in December 2025 following a positive DSMB safety review.New under-90 mg morphine-equivalent cohort: The newly cleared cohort of 15 patients focuses on individuals receiving less than 90 mg morphine equivalents per day, providing a controlled view into Olastrocel’s performance in patients with ongoing but moderate opioid use.Rapid enrollment: Enrollment of this expansion cohort is already greater than 85%, and the Company anticipates completing enrollment before the end of summer 2026.AI-enabled monitoring: The expansion cohort incorporates the Company’s new AI-driven pain medication monitoring and patient-reported outcome system, designed to enhance data granularity, improve adherence to electronic diaries, and accelerate high-quality data capture for both pain and functional endpoints. Addressing a Persistent Opioid and Chronic Pain Crisis Chronic lower back pain remains one of the most common and disabling conditions in the United States, with limited durable treatment options for many patients. Current treatment pathways often include physical therapy, oral analgesics, steroid injections, chronic opioid use or invasive spine procedures, yet many patients continue to experience persistent pain and functional impairment. Drug overdose remains one of the nation’s most urgent public health challenges, and opioids continue to account for the majority of overdose deaths in the United States. Creative Medical believes the development of new non-opioid therapeutic approaches for chronic pain remains a critical medical and societal priority. Olastrocel (CELZ-201) is designed as an off-the-shelf, allogeneic regenerative cell therapy intended to deliver a scalable, non-surgical treatment option for patients with chronic lower back pain associated with degenerative disc disease. The therapy is administered via a minimally invasive, ultrasound-guided intramuscular procedure. Financial and Operational Positioning The Company currently expects to complete enrollment of the 15-patient expansion cohort before the end of summer 2026 using existing resources and does not anticipate the need for additional resources to execute this specific trial expansion. The Company plans to use the expanded dataset, together with existing ADAPT safety and efficacy data, to support upcoming regulatory planning and Phase 3 discussions with the FDA. These discussions are expected to focus on the design of a potential pivotal program and the opportunity to evaluate CELZ-201 in a broader chronic lower back pain population. “Every step forward in ADAPT brings us closer to our goal of changing the treatment paradigm for patients who have too few durable options today,” Mr. Warbington added. “Our mission is to advance CELZ-201 with discipline, transparency and urgency, while building a development pathway that can create meaningful value for patients, physicians and shareholders.” The Company intends to continue operating in a capital-disciplined manner as it advances regulatory engagement, potential strategic partnerships, and broader commercialization planning around Olastrocel. Forward-Looking Statements This press release contains forward-looking statements regarding, among other things, the safety and efficacy of CELZ-201 (Olastrocel), the timing and completion of clinical trial enrollment, the design and impact of the AI pain medication monitoring system, the Company’s expectations regarding additional resource needs, its plans and timing for potential Phase 3 discussions and broader indications, and its views of market size and opportunity. These statements are based on current expectations, estimates and projections and involve risks and uncertainties that could cause actual results to differ materially from those expressed or implied. Risks and uncertainties include, but are not limited to, risks related to clinical trial conduct and outcomes, patient enrollment rates, regulatory review and feedback, manufacturing and supply, competition, macroeconomic conditions, capital markets, and the Company’s ability to execute its strategy. Additional information about these and other risk factors is contained in the Company’s filings with the U.S. Securities and Exchange Commission, including its most recent Annual Report on Form 10-K. The Company undertakes no obligation to update any forward-looking statements except as required by law. About CELZ-201 (Olastrocel) CELZ-201 (Olastrocel) is Creative Medical’s proprietary perinatal tissue-derived, allogeneic regenerative cell therapy candidate being evaluated for chronic lower back pain associated with degenerative disc disease. CELZ-201 is designed to be an off-the-shelf therapy administered through a minimally invasive, ultrasound-guided intramuscular procedure. About Creative Medical Technology Holdings, Inc. Creative Medical Technology Holdings, Inc. (NASDAQ: CELZ) is a clinical-stage biotechnology company pioneering regenerative medicine therapies derived from adult and perinatal stem cell technologies. The Company’s pipeline targets large, underserved markets across orthopedics, immunotherapy, endocrinology, urology, and gynecology, with CELZ-201 (Olastrocel) positioned as a lead clinical asset for chronic lower back pain and as the backbone for additional platform programs. For more information, visit www.creativemedicaltechnology.com. ContactCreative Medical Technology Holdings, Inc.Investor Relations: IR@CreativeMedicalTechnology.com Devin Sullivan, Managing Director - The Equity Group Inc.Devin.Sullivan@theequitygroup.com Conor Rodriguez, Associate - The Equity Group Inc.Conor.Rodriguez@theequitygroup.com