Kymab Ltd.

Amgen released data from two pivotal trials on Tuesday that showed its experimental drug rocatinlimab succeeded in a Phase 3 test in atopic dermatitis, while its approved drug Uplizna also yielded positive results in myasthenia gravis. The data are a boost to Amgen’s immunology hopes, and the success with rocatinlimab — an anti-OX40 monoclonal antibody — will solidify its advantage over Sanofi’s asset amlitelimab, which goes after a related target. The rocatinlimab results are the first of eight different Phase 3 trials Amgen is running for the drug. In Tuesday’s trial, called ROCKET-Horizon, rocatinlimab met its primary endpoint and all secondary endpoints by a statistically significant margin, Amgen said. The drug induced at least a 75% reduction in the Eczema Area and Severity Index (EASI-75) in 32.8% of patients, compared with 13.7% on placebo after 24 weeks. Amgen said that the study’s other co-primary endpoints, also measuring skin clearance, were successful as well. Sanofi has positioned amlitelimab, which binds to OX40-Ligand, as one of its key growth drivers in its pivot to immunology. But its first Phase 3 readout won’t take place until the end of 2026. In the meantime, Amgen has at least four other Phase 3 trials for rocatinlimab expected to report data before next July, including studies looking at different doses, the drug’s use as a combination or maintenance therapy, and a trial in adolescents. Amgen will likely have a significant market advantage by filing for rocatinlimab approval much earlier, although on a conference call Tuesday, CSO Jay Bradner didn’t say when it might file with the FDA. Amgen licensed rocatinlimab from Kyowa Kirin in 2021, a few months after it reported Phase 2 results, paying $400 million upfront and promising another $850 million in milestones. Sanofi acquired amlitelimab in its $1.1 billion buyout of Kymab in 2021. Sanofi is still hoping for big things from amlitelimab. Earlier this year, an early look at Phase 2b data prompted the company to amend its Phase 3 trial protocol to allow for increased time off-drug. Amgen also said Tuesday that its rare disease drug Uplizna hit its primary endpoint in a Phase 3 trial for the autoimmune disease myasthenia gravis. In a measurement scale called the Myasthenia Gravis Activities of Daily Living, or MG-ADL, two doses of Uplizna produced an improvement of -4.2 points after 26 weeks, compared with -1.9 points on placebo (p<0.0001). Four of the study’s five secondary endpoints were also statistically significant, Bradner said. The win comes a few months after Uplizna recorded a successful Phase 3 study in IgG4-related disease back in June. Uplizna was first approved in 2020 for an autoimmune disease that affects the eyes called neuromyelitis optica spectrum disorder, or NMOSD.

Sanofi released new Phase 3 data for its BTK inhibitor tolebrutinib in non-relapsing secondary progressive multiple sclerosis (nrSPMS), showing a 31% improvement in delaying onset of disease progression compared to placebo. But safety issues that have dogged the drug class could complicate the readout. Tolebrutinib is a BTK inhibitor, and it and other related drugs have faced issues with elevated liver enzymes. In the Phase 3 readout, those signals showed up again — 4.1% of patients on tolebrutinib had their liver enzymes jump to three times the normal limit, compared with 1.6% in the placebo group. A smaller group in the trial, called HERCULES, showed even sharper liver enzyme increases: 0.5% of patients saw their liver enzymes spike to 20 times the normal limit, and one of those patients died after needing a liver transplant and suffered post-surgery complications. Every other case resolved without medical intervention, but Sanofi had to implement more rigorous monitoring of patients. Robert Fox, a clinician at the Cleveland Clinic and chair of the HERCULES global steering committee, said that if tolebrutinib is approved, he wouldn’t be surprised if it came with a boxed warning. “Would I be surprised if it’s in a black box? No,” Fox said. “But predicting whether it is or not, that’s not something I can do.” More intensive safety monitoring has lessened the amount of patients whose liver enzymes exceed the 20-fold threshold, but hasn’t eliminated cases entirely, a Sanofi spokesperson told Endpoints News . The spokesperson also said the company is still working through unblinding its safety data and can’t give an exact number of cases after the new protocols were instituted (the patient who died after a liver transplant received the drug beforehand). Sanofi presented the data at the 2024 ECTRIMS conference in Copenhagen. It plans to file with the FDA by the end of 2024. Despite the safety concerns, Fox said the data represented an impressive milestone in MS treatment — the efficacy results were statistically significant, with a p-value of p=0.0026. Fox noted that there isn’t anything on the market to slow secondary progressive MS’ disease progression, and that approved drugs only reduce the frequency of relapse episodes. Tolebrutinib “actually does something where none of the other therapies do anything. So that’s where we are, and so that is the decision that a clinician will have to consider,” Fox said. “If this were to be available for clinical use, how much anti-inflammation does my patient need, and how much slowing [of] that insidious progression does my patient need?” Sanofi acquired tolebrutinib as part of its $3.7 billion acquisition of Principia Biopharma in 2020 and has made it a central part of its new pipeline focus around immunology in addition to amlitelimab (bought from Kymab), lunsekimig (developed from Ablynx’s platform) and rilzabrutinib (also from Principia), among others. But the FDA placed a partial clinical hold on the drug in June 2022 in both MS and myasthenia gravis, an autoimmune disease, after reports of liver injury. While the partial hold remains in effect for other Phase 3 MS studies (it was “modified” to account for the new monitoring protocols, the spokesperson said), Sanofi discontinued development in myasthenia gravis in early 2023. Sanofi released data from two other Phase 3 relapsing MS trials earlier this month comparing tolebrutinib to standard of care, which showed mixed efficacy results. While neither study hit their primary endpoints, a pooled analysis showed they successfully delayed the time to disability. Safety data also presented at ECTRIMS across these two trials were more numerically balanced between the active and standard-of-care arms, but there were still cases of liver enzymes rising 20 times above the normal limit and patient deaths, though the latter were deemed unrelated to treatment. Another Phase 3 in patients with primary progressive MS is expected to read out in 2025. Editor’s note: This story has been updated to correct the p-value from 0.026 to 0.0026, that previously released mixed data came in RMS studies, not nrSPMS, and that patient deaths in these studies were not linked to treatment.

Navigator is planning to launch additional clinical studies with NAV-240 in the coming months. Navigator Medicines has equipped itself with $100 million in series A funds as the young biotech charts a course for its newly acquired autoimmune drugs.The company, which was founded earlier this year as a subsidiary of Sera Medicines, has bought itself a pipeline of OX40L-targeted mono- and bispecific antibodies from Korea’s IMBiologics. According to reporting shared on IMBiologics’ website, Navigator secured the licenses for the drugs outside of Asia—but including Japan—for $20 million upfront and with $924.7 million in potential milestone payments.Headlining the group is IMB101, now rebranded as NAV-240, a bispecific antibody against OX40L and TNFα in a phase 1 study in healthy subjects. OX40L and TNFα have already been established as critical in the pathogenesis of several inflammatory diseases, pointed out Navigator, which added that targeting both signaling pathways “may improve upon the efficacy of either monotherapy alone as a potential treatment option for complex, heterogeneous diseases with unmet medical needs.”IMBiologics previously touted NAV-240 as offering a fresh way to address unmet needs for a range of autoimmune diseases, including patients with rheumatoid arthritis who are non-responsive or resistant to anti-TNF agents. Navigator will be able to push ahead with these assets courtesy of $100 million from a series A funding round co-led by well-known VC names RA Capital Management and Forbion. As part of the financing, Wouter Joustra, a general partner at Forbion, and Andrew Levin, M.D., Ph.D., a partner and managing director at RA Capital Management, are joining Navigator’s board.“NAV-240 has the potential to make an impact on patients living with autoimmune diseases, and our series A funding will be pivotal in accelerating its development alongside other exciting programs within our pipeline,” said Navigator’s chief medical officer Dana McClintock, whose appointment was also announced in the same release.“We look forward to initiating additional clinical studies with NAV-240 in the coming months and delivering on our commitment to innovation that enhances patient care,” McClintock added.Last year, Sanofi pointed to positive phase 2 results for an anti-OX40-ligand monoclonal antibody called amlitelimab that it acquired as part of its Kymab buyout as proof that targeting OX40-ligand offers a therapeutic option for inflammatory diseases.