1. In this combined phase 1-2a study, mogamulizumab used for treatment of human T-lymphotropic virus type 1 (HTLV-1) associated myelopathy was safe and associated with improvement in biomarkers of disease, as well as improvements in spasticity and motor disability.
2. The most common side effect was rash, and lymphopenia or leukopenia were seen in one third of patients.
Evidence Rating Level: 4 (Below Average)
Study Rundown: HTLV-1 is the causal agent in development of adult T-cell leukemia-lymphoma (ATLL) and HTLV-1-associated myelopathy (HAM). Spinal cord inflammation in HAM causes weakness, spasticity, and incontinence. HAM is typically symptomatically treated with glucocorticoids and interferon-a, but these treatments do not target specific cell populations, such as CCR4+ T cells, that are responsible for disease propagation. This phase 1-2a trial investigated mogamulizumab, a monoclonal antibody targeting CCR4 and previously approved in Japan for treatment of ATLL, for its safety, pharmacokinetics, and efficacy in patients with HAM. Rash was the most common side effect, but there were no dose-limiting side effects seen at the maximum dose. Reductions were seen in the frequency of CCR4+ cells and the HTLV-1 proviral load, as well as CSF inflammatory markers. Participants improved in multiple indices of disability.
Assessments of efficacy are limited in this study given the lack of a placebo group, small sample size, and focus on biomarker related outcomes. The long-term adverse effects of this treatment regimen also remain unclear; a long-term safety trial is underway.
In-Depth [case series]: This was an uncontrolled phase 1-2a Japanese trial conducted from 2013 to 2015 that recruited 21 patients with HAM to investigate the safety and efficacy of mogamulizumab. Eligible patients met World Health Organization diagnostic criteria for HAM and must have been trialed on prednisolone with no benefit. Major exclusion criteria included severe infection or autoimmune disease. Phase 1 of the trial involved dose-escalation of the trial drug, and phase 2a tested repeated infusions over 24 weeks. The primary endpoints assessed were safety and pharmacokinetics. Drug efficacy was a secondary endpoint and was primarily assessed through proviral load. Finally, a multitude of biochemical and clinical investigations were undertaken as exploratory endpoints.
The most common drug reaction was rash, which occurred in 48% of participants. Lymphopenia and leukopenia were each seen in 33% of participants. No deaths or adverse events at or above grade 4 were noted, though 4 (19%) patients experiences grade 3 adverse events. At day 15, the proviral load was found to have decreased by 64.9% (95%CI, 51.7 to 78.1). CSF inflammatory markers were also decreased at day 29. Both of these responses were dose-dependent. The degree of participant’s clinical disability also decreased, with improvement in indices of motor and global function; two participants regained the ability to run. Clinical improvements were maintained during throughout the trial. Reduction in HTLV-1 associated T-cells (CADM1+ CD4) was 67.3% through 24 weeks of treatment.
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