The Effects of Multiple Doses of Lomecel‐B, Longeveron’ s Cell‐based Therapy, on Alzheimer’s disease: Study Design and Rationale of this Phase 2a Multi‐ center Clinical trial

Background Lomecel‐B is an allogeneic medicinal signaling cell (MSC) formulation under clinical investigation for Alzheimer’s disease (AD). We have successfully completed a double‐blinded, placebo‐controlled Phase 1 safety trial, in which Lomecel‐B was found to be safe and tolerable in patients with mild AD, and yielded preliminary evidence supporting potential efficacy. Mechanistically, this included evidence of pro‐vascular and anti‐inflammatory activities. Extending upon these promising results, we present the rationale and design of the next‐phase 2a trial in this program. Method The primary objective of this double‐blinded, randomized, and placebo‐controlled Phase 2a trial is to evaluate the safety of multiple doses of Lomecel‐B versus a single dose or placebo. Forty‐eight participants will be equally randomized to four study arms, and will receive intravenous infusions at Weeks 0, 4, 8, and 12, and followed up through Week 39 post‐first infusion. Arm 1 will receive four intravenous infusions of placebo. Arm 2 will receive one infusion of low‐dose Lomecel‐B (2.5×107 cells) followed by three infusions of Placebo. Arm 3 will receive four infusions of low‐dose Lomecel‐B. Arm 4 will receive four infusions of high‐dose Lomecel‐B (108 cells). Enrolled subjects will undergo a multi‐tiered screening process (clinical evaluation, blood‐work, MRI, and PET). Major enrollment criteria are mild AD with confirmatory beta‐amyloid tracer PET, 60‐85 years of age, and a MMSE score of 18‐24. Safety will be monitored by examining vital signs, physical and neurological exams, laboratory tests (hematology, coagulation, blood chemistry, and urinalysis), and neuroimaging. The secondary objectives are to assess the effects of Lomecel‐B on the cognitive function, and pro‐vascular and anti‐inflammatory biomarkers. Exploratory objectives include neurocognitive, neuropsychiatric, quality‐of‐life, activities‐of‐daily‐living, frailty status, and biomarkers assessments. Result This multicenter phase 2a trial has been allowed to proceed by FDA, is IRB approved, and actively enrolling. Conclusion This trial is designed to obtain safety and preliminary efficacy data on the effects of a multiple doses of Lomecel‐B on mild AD, with an emphasis on biomarkers related to proposed mechanisms of action (MOAs). We anticipate this trial will have complete enrollment by early 2023, and preliminary safety findings available soon thereafter

Safety and efficacy of Lomecel‐B in patients with mild Alzheimer’s disease: Results of a double‐blinded, randomized, placebo‐controlled phase 1 clinical trial

Background Lomecel‐B is a formulation of allogeneic medicinal signaling cells (MSCs), which exert pleiotropic mechanisms of action (MOAs) with potential to simultaneously target multiple pathophysiological features of Alzheimer’s disease (AD). Method We conducted a double‐blinded, randomized, placebo‐controlled trial (ClinicalTrials.gov: NCT02600130). Mild AD patients (Table) were infused with Lomecel‐B at 20 (20M, N=15) or 100 million cells (100M, N=10), or placebo (N=8). Eligibility screening included clinical evaluation, MRI to exclude other etiologies, and beta‐amyloid tracer PET to confirm AD. Scheduled follow‐ups were conducted through 1‐year post‐treatment. The primary endpoint was safety. Pre‐specified secondary endpoints evaluated efficacy in neurocognitive/neuropsychological, quality‐of‐life (QOL)/activities of daily living (ADL), and biomarker domains. Result Lomecel‐B was well‐tolerated and did not trigger safety stopping rules, meeting the primary endpoint. Efficacy endpoints were improved in the Lomecel‐B groups. Whereas the Mini Mental State Exam (MMSE) declined in placebo by 2.99±1.12 points at Week 13 (p=0.0337; 95%CI ‐5.84 – ‐0.31), the 20M Lomecel‐B group showed minimal decline (difference from placebo: 2.69±1.39 points; p=0.0182; 95%CI 0.51 – 4.97). This difference persisted over one year (Figure). On the QOL‐AD patient version, the 20M Lomecel‐B group significantly improved versus placebo at Week 26 by 3.85±1.94 points (p=0.0444; 95%CI 0.13 – 9.12). On the ADCS‐ADL, the placebo group significantly declined at Week 26 by 9.27±2.78 points (p=0.0211; 95%CI ‐17.83 – ‐2.10), and was significantly worse versus 20M Lomecel‐B by 6.95±3.46 points (p=0.0118; 95%CI 1.99 – 13.94). In contrast, these assessments did not significantly differ in the 100M Lomecel‐B group versus placebo. Anti‐inflammatory (IL‐10, IL‐12, sIL‐2Rα) and pro‐vascular (VEGF, IL‐4, IL‐6) serum biomarkers were significantly higher in both Lomecel‐B groups versus placebo, with 100M Lomecel‐B generally showing the greatest rises. Left hippocampal volume increased in the 100M Lomecel‐B group versus placebo at Week 13 (p=0.0311). Conclusion These results support the safety and clinical potential of Lomecel‐B for AD. These hypothesis‐generating results also revealed potentially important biomarkers which are consistent with multiple MOAs of Lomecel‐B. Ongoing investigation of Lomecel‐B for AD in larger clinical trials powered for clinical efficacy is warranted. This study was supported through Alzheimer’s Association Part the Cloud Challenge on Neuroinflammation grants #PTC C‐16‐422443 and PTC‐CS‐19‐623225

Clinical evaluation of allogeneic mesenchymal stem cells for Alzheimer's disease

Background Therapeutic interventions that can broadly target the complex multiple pathological features of Alzheimer’s disease (AD) would be highly desirable approaches for treating these disorders. Mesenchymal stem cells (MSCs) have pleiotropic mechanisms of action that make them highly attractive as therapeutic candidates for AD. These include powerful anti‐inflammatory properties, ability to improve vascular functioning, ability to promote intrinsic regenerative mechanisms, and ability to promote beta‐amyloid clearance. Given these highly desirable properties of MSCs, we set out to clinically evaluate their safety and therapeutic potential for AD, using a proprietary formulation called Longeveron Mesenchymal Stem Cells (LMSCs). Method Central to this study is a Phase I clinical trial powered to evaluate the safety of LMSCs for mild AD. Provisional efficacy is also being evaluated. This trial is double‐blinded, randomized, and placebo‐controlled, and registered with ClinicalTrials.gov (NCT02600130). Trial oversight includes FDA, an IRB, and an independent Data Monitoring Safety Board (DSMB). Subjects are enrolled after passing a 3‐step screening process, which sequentially consists of clinical diagnosis of mild AD, a confirmatory MRI, and a confirmatory PET scan using a beta‐amyloid tracer. Enrolled subjects are randomized to receive a single intravenous infusion of a low‐dose of LMSCs (20 million cells), a high‐dose of LMSCs (100 million cells), or placebo. Evaluated for safety and effect are performed over the 1‐year follow‐up. Result This multi‐site trial has proceeded ahead of schedule, and was fully enrolled as of September 2019. The trial was designed to enroll 30 patients; ultimately, 33 patients were enrolled. Results support the high safety profile LMSCs for AD: the DSMB has found no safety concerns, and the primary objective of no treatment‐related serious adverse events (SAEs) within 1 month post‐treatment was met. Preliminary data suggest the feasibility of biomarker analyses for evaluating effect changes, and the final lock and unblinding is anticipated in late 2020. Conclusion The results support the conclusion that LMSCs are safe in AD patients, and that advancing to higher phase clinical studies is warranted. We thank the Alzheimer’s Association for supporting this research through the Part the Cloud Challenge on Neuroinflammation grant awards #PTC C‐16‐422443 and PTC‐CS‐19‐623225

Results and insights from a phase I clinical trial of Lomecel-B for Alzheimer's disease

HypothesisWe hypothesized that Lomecel-B, an allogeneic medicinal signaling cell (MSC) therapeutic candidate for Alzheimer's disease (AD), is safe and potentially disease-modifying via pleiotropic mechanisms of action.Key predictionsWe prospectively tested the predictions that Lomecel-B administration to mild AD patients is safe (primary endpoint) and would provide multiple exploratory indications of potential efficacy in clinical and biomarker domains (prespecified secondary/exploratory endpoints).Strategy and key resultsMild AD patient received a single infusion of low- or high-dose Lomecel-B, or placebo, in a double-blind, randomized, phase I trial. The primary safety endpoint was met. Fluid-based and imaging biomarkers indicated significant improvement in the Lomecel-B arms versus placebo. The low-dose Lomecel-B arm showed significant improvements versus placebo on neurocognitive and other assessments.InterpretationOur results support the safety of Lomecel-B for AD, suggest clinical potential, and provide mechanistic insights. This early-stage study provides important exploratory information for larger efficacy-powered clinical trials

Results and insights from a phase I clinical trial of Lomecel-B for Alzheimer's disease

Hypothesis We hypothesized that Lomecel-B, an allogeneic medicinal signaling cell (MSC) therapeutic candidate for Alzheimer's disease (AD), is safe and potentially disease-modifying via pleiotropic mechanisms of action. Key Predictions We prospectively tested the predictions that Lomecel-B administration to mild AD patients is safe (primary endpoint) and would provide multiple exploratory indications of potential efficacy in clinical and biomarker domains (prespecified secondary/exploratory endpoints). Strategy and Key Results Mild AD patient received a single infusion of low- or high-dose Lomecel-B, or placebo, in a double-blind, randomized, phase I trial. The primary safety endpoint was met. Fluid-based and imaging biomarkers indicated significant improvement in the Lomecel-B arms versus placebo. The low-dose Lomecel-B arm showed significant improvements versus placebo on neurocognitive and other assessments. Interpretation Our results support the safety of Lomecel-B for AD, suggest clinical potential, and provide mechanistic insights. This early-stage study provides important exploratory information for larger efficacy-powered clinical trials

Results and insights from a phase I clinical trial of Lomecel‐B for Alzheimer's disease

HypothesisWe hypothesized that Lomecel-B, an allogeneic medicinal signaling cell (MSC) therapeutic candidate for Alzheimer's disease (AD), is safe and potentially disease-modifying via pleiotropic mechanisms of action.Key predictionsWe prospectively tested the predictions that Lomecel-B administration to mild AD patients is safe (primary endpoint) and would provide multiple exploratory indications of potential efficacy in clinical and biomarker domains (prespecified secondary/exploratory endpoints).Strategy and key resultsMild AD patient received a single infusion of low- or high-dose Lomecel-B, or placebo, in a double-blind, randomized, phase I trial. The primary safety endpoint was met. Fluid-based and imaging biomarkers indicated significant improvement in the Lomecel-B arms versus placebo. The low-dose Lomecel-B arm showed significant improvements versus placebo on neurocognitive and other assessments.InterpretationOur results support the safety of Lomecel-B for AD, suggest clinical potential, and provide mechanistic insights. This early-stage study provides important exploratory information for larger efficacy-powered clinical trials