ceralifimod (ONO 4641) / Ono Pharma - LARVOL DELTA

Sphingosine 1-Phosphate Receptor Modulators for Multiple Sclerosis. (PubMed, CNS Drugs) - "In March 2019, a breakthrough in MS treatment was achieved with the FDA approval for the second S1PR modulator, siponimod (Mayzent), for both active secondary progressive MS and relapsing-remitting MS...Furthermore, ozanimod received FDA approval in March 2020 for treatment of relapsing forms of MS, followed by subsequent approvals from Health Canada and the European Commission. Other second-generation selective S1PR modulators that have been tested for MS, with statistically significant data from phase II and phase III clinical studies, include ponesimod (ACT-128800), ceralifimod (ONO-4641), and amiselimod (MT-1303). This review covers the available data about the mechanisms of action, pharmacodynamics and kinetics, efficacy, safety, and tolerability of the various S1PR modulators for patients with relapsing-remitting, secondary progressive, and, for fingolimod, primary progressive MS."

Journal • Review • Cardiovascular • CNS Disorders • Immunology • Multiple Sclerosis • Rare Diseases

Preventive and Therapeutic Efficacy of ONO-4641, a Selective Agonist for Sphingosine 1-Phosphate Receptor 1 and 5, in Preclinical Models of Type 1 Diabetes Mellitus. (PubMed, Biol Pharm Bull) - "Histopathological analysis demonstrated that insulin-positive areas in the islets of mice administered 0.03 and 0.1 mg/kg ONO-4641 showed a tendency of high values although they were not significantly different from the Control group, which was treated with vehicle. These observations suggest ONO-4641 may delay the onset and progression of type 1 diabetes mellitus."

Journal • Preclinical • CNS Disorders • Diabetes • Immune Modulation • Immunology • Inflammation • Metabolic Disorders • Multiple Sclerosis • Obesity • Type 1 Diabetes Mellitus

Sphingosine 1-phosphate Receptor Modulator ONO-4641 Regulates Trafficking of T Lymphocytes and Hematopoietic Stem Cells and Alleviates Immune-Mediated Aplastic Anemia in a Mouse Model. (PubMed, J Pharmacol Exp Ther) - "Significance Statement ONO-4641 is a second-generation sphingosine 1-phosphate (S1P) receptor modulator selective for S1P receptors 1 and 5. In this study, we demonstrated that ONO-4641 regulates the trafficking of T lymphocytes along with hematopoietic stem and progenitor cells leading to alleviation of pancytopenia and destruction of bone marrow in a bone marrow failure-induced mouse model mimicking human aplastic anemia."

Journal • Anemia • Aplastic Anemia • CNS Disorders • Hematological Disorders • Immune Modulation • Inflammation • Multiple Sclerosis

Q4 & FY '11 Results (Merck Serono) - ONO-4641 / Merck Serono; Anticipated data readout for DreaMS P2 trial in MS in H1 2012

Anticipated data read out • Multiple Sclerosis

Merck KGaA’s Oschmann sees U.S. as new emerging market (Bloomberg.com) - "The company will decide by year end whether to pursue a late-stage trial for ONO-4641 and is talking to regulatory authorities."

Anticipated pipeline update • Immunology • Multiple Sclerosis

Q2 2012 Results (Merck Serono) - Anticipated decision on initiation of P3 trial for MS in 2013

Anticipated new P3 trial • Anticipated phase shift • Immunology • Multiple Sclerosis

Magnetic resonance imaging measures of efficacy in patients with multiple sclerosis receiving ONO-4641, a sphingosine-1-phosphate receptor-1 and -5 agonist: Interim results from an extension of the DreaMS study (ECTRIMS 2013) - Presentation time: Thursday, October 03, 2013, 15:45 - 17:00; Abstract #P 547; P2, N=343; Sponsor: EMD Serono; NCT01226745; “There were notable reductions in the numbers of Gd+ lesions in patients switching from placebo to active treatment in the extension study, while efficacy was sustained for patients on continuous active treatment.”

P2 data • Multiple Sclerosis

An exploratory analysis of magnetic resonance imaging outcomes in the DreaMS Trial: A double-blind, placebo-controlled, phase 2, 26-week trial of a selective sphingosine 1-phosphate receptor agonist ONO-4641 in patients with relapsing–remitting... (AAN 2013) - Presentation time: Wednesday, March 20, 2013 4:52 PM; P2, N=376; DreaMS trial (NCT01226745); "The cumulative number of new/enlarging T2 lesions was also significantly reduced (p<0.0001) with all three doses of ONO-4641 versus placebo..."

P2 data • Immunology • Multiple Sclerosis

ONO-4641 met primary endpoint of phase II study in multiple sclerosis patients (Ono Pharmaceuticals) - P2, N=407; Patients taking 0.05, 0.10, or 0.15mg of ONO-4641 had 82%, 92% & 77% fewer Gd-enhancing brain lesions (all p<0.0001), respectively, compared to placebo; Adverse events appeared to be generally dose related; Slower heartbeat & atrioventricular blocks associated with the initiation of treatment was noted, which were asymptomatic, transient & did not require ONO-4641 discontinuation; Anticipated data presentation at the AAN's 64th Annual Meeting in New Orleans April 21 to April 28, 2012

P2 data • Immunology • Multiple Sclerosis

MRI endpoints and relapse rates in the double-blind, placebo-controlled, phase 2, 26-week DreaMS trial of a selective S1P receptor agonist ONO 4641 in patients with relapsing-remitting multiple sclerosis (ENS 2012) - presentation time: Sunday, June 10, 2012, 16:00 - 16:15; P2, N=407; DreaMS; Cumulative number of Gd-enhancing lesions from Week 10 to 26 was significantly reduced in all three active groups vs. PBO, with a relative reduction in mean cumulative lesions of 82%, 92%, and 77% at 0.05, 0.10, and 0.15 mg, respectively (mean±SD: 1.5±3.8, 0.7±1.5, 1.9±8.5 vs. 8.3±11.5 in PBO, p<0.0001 for all groups); Cumulative number of new or enlarged T2 lesions was significantly reduced with ONO-4641 versus placebo, with reductions of 73%, 82%, 71% with 0.05, 0.10, and 0.15 mg doses, respectively (p<0.001 for all groups)

P2 data • Immunology • Multiple Sclerosis

Effect of ceralifimod (ONO-4641), a sphingosine-1-phosphate receptor-1 and -5 agonist, on magnetic resonance imaging outcomes in patients with multiple sclerosis: Interim results from the extension of the DREAMS study (AAN 2014) - Presentation time: Tuesday, April 29, 2014 3:00 PM; Abstract #;P3.161; P2, N=343; Sponsor: Ono Pharma; NCT01081782; "The proportions of patients free of new/enlarging T2 lesions increased from extension study baseline to Week 52 in patients switched to active treatment: placebo/0.05 mg, 52% to 62%; placebo/0.10 mg, 56% to 87%; placebo/0.15 mg, 21% to 71%. Consistent effects were seen on the mean number of Gd+ lesions and patients free of Gd+ lesions."

P2 data • Multiple Sclerosis