Vice Chair and Associate Professor, Weill Cornell Medical College
Dr. Safdieh reports no financial relationships relevant to this field of study.
SYNOPSIS: Mogamulizumab reduces central nervous system inflammation and improves spasticity in patients with HTLV-1-associated myelopathy.
SOURCE: Sato T, Coler-Reilly ALG, Yagishita N, et al. Mogamulizumab (anti-CCR4) in HTLV-1-associated myelopathy. N Engl J Med 2018;378:529-538.
Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that causes a disabling myelopathy. It is also causes adult T-cell leukemia-lymphoma (ATLL). HTLV-1 affects millions worldwide, and is quite prevalent in Caribbean countries. Hence, the associated myelopathy also is known as HTLV-1-associated myelopathy-tropical spastic paraparesis (HAM-TSP). HAM-TSP manifests as a subacute progressive myelopathy with the development of spastic weakness, urinary urgency, and sensory ataxia. Less than 2% of patients with HTLV-1 infection develop HAM-TSP. Currently, there are no established effective therapies for HAM-TSP, and patients eventually become severely disabled.
HTLV-1 is believed to cause myelopathy by producing spinal cord inflammation. HTLV-1 infects CCR4+ T-lymphocytes, converting them into abnormal cells that drive inflammation in the spinal cord. In Japan, the anti-CCR-4-binding monoclonal antibody mogamulizumab is approved for the treatment of ATLL. In this study, Sato et al hypothesized that lower doses of mogamulizumab administered on a regular basis to patients with HAM-TSP could help reduce spinal cord inflammation and improve neurologic symptoms.
Sato et al performed a Phase I and IIa study. Initially, they recruited 21 patients who received a single dose of mogamulizumab and were observed for 85 days. Of those 21 patients, 19 were advanced into the Phase IIa trial, where they were treated with repeat doses every eight weeks for 24 weeks. The primary endpoints were safety and pharmacokinetics. The secondary endpoint was measurement of proviral load in peripheral blood mononuclear cells. Other measures investigated included markers of cerebrospinal fluid (CSF) inflammation (CXCL10 and neopterin) as well as clinical measurements of activities of daily living, spasticity, dysuria, sensory dysfunction, and mobility.
The results of the study demonstrated that the drug did not cause side effects that limited treatment dose. Most common side effects were rash and leukopenia. There were no deaths during the study. Proviral load in peripheral blood mononuclear cells was reduced by 65%. Levels of the two studied inflammatory CSF markers both were reduced significantly with treatment. Very notably, spasticity, as measured by the Ashworth Scale Score, was reduced by almost 80% and motor disability improved by 32%.
Clearly, this is an important study. There is a serious need for a therapy that can treat patients with HAM-TSP, as current agents are off-label and do not provide significant relief or sustained improvement. Further studies are needed, including a randomized trial of mogamulizumab in patients with HAM-TSP. Suppression of CCR-4 T-cells may lead to serious infections, which is why the study authors used a lower dose of mogamulizumab than used to treat ATLL, a very aggressive form of cancer. However, even at lower doses, longer-term follow-up will be needed to assess safety. It is unclear how long patients would need to be treated and it is possible that treatment would need to be indefinite, further supporting the need for follow-up studies.
Monoclonal antibodies have revolutionized the treatment of many medical disorders, including common and disabling neurologic disorders. We already have seen the approval of monoclonal antibodies for multiple sclerosis (natalizumab, ocrelizumab, alemtuzumab), myasthenia gravis (eculizumab), and giant cell arteritis (tocilizumab). There is also a great deal of anticipation for the calcitonin gene-related peptide monoclonal antibodies in the treatment of migraine. There have been failed trials of monoclonal antibodies, most notably bapineuzumab and solenezumab (see this ALERT, page 61) for Alzheimer’s disease. If mogamulizumab succeeds in larger and longer studies, the treatment for yet another previously devastating neurologic disorder will be possible.