Safety and Efficacy of Mogalizumab in HTLV-1-Associated Myelopathy

By Hai H. Hoang, MD

Assistant Professor of Clinical Neurology, Weill Cornell Medical College

SYNOPSIS: Human T-cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis develops in a small number of carriers of this retrovirus as the result of infection and suppression of CD4+ T-cells. Therapy with steroids has been the mainstay but is not safe or effective for the long term. Mogalizumab shows promise as long-term therapy of this debilitating disease.

SOURCE: Sato T, Yamauchi J, Yagishita N, et al. Long-term safety and efficacy of mogamulizumab (anti-CCR4) for treating virus-associated myelopathy. Brain 2023;146:3181-3191.

Human T-cell leukemia virus type 1 (HTLV-1) affects CD4+ T cells, leading to lifelong infections. A rare complication includes HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This disorder leads to chronic inflammation of the spinal cord, which can manifest as spastic paraparesis, bladder and bowel dysfunction, sensory disturbances, and difficulty ambulating. The current mainstay management of inflammation is steroids, but efficacy is insufficient, with many long-term side effects.

Mogalizumab is an antibody against C-C motif chemokine receptor 4 (CCR4). It has been used to treat peripheral and cutaneous T-cell lymphoma. A large amount of HTLV-1-infected CCR4 cells are found in patients with HAM/TSP. Therefore, the expectation is that the administration of mogalizumab in patients with HAM/TSP would reduce the number of infected cells and subsequent inflammatory markers in the cerebrospinal fluid (CSF). The authors of this study already have established that patients with HAM/TSP treated with mogalizumab had improved clinical symptoms. However, the long-term efficacy and safety record for this drug is unknown.

This study was Phase I-IIa trial to investigate the safety and efficacy of mogalizumab in patients with HAM/TSP over four years. All patients were diagnosed with HAM/TSP and had no improvement with oral prednisolone for at least three months. Mogalizumab treatment was dosed at five levels: 0.003 mg/kg, 0.01 mg/kg, 0.03 mg/kg, 0.1 mg/kg, and 0.3 mg/kg. Repeated doses every two to three months were followed by dosing every 48 months. Dose increase was permitted if the HTLV viral load did not fall below 40% of baseline values. All participants received oral prednisolone 10 mg/day simultaneously and the steroid dose was allowed to change only after the 56th week. Other therapies, including methylprednisolone pulse therapy, IFN-α, or immunosuppressive drugs, were not allowed.

The primary endpoint was safety (presence of adverse events), with the secondary endpoint being drug efficacy measured by HTLV-1 viral load. Functional outcome was measured using the 10-meter walking time test. Nineteen of 21 participants enrolled in the initial Phase I study also participated in the current study. By the end of the study, 15 of 21 participants completed 48 months of treatment and evaluation. No serious adverse events or deaths were reported. The most frequent drug-related adverse event was lymphopenia (62%), but incidence of skin-related events was high and occurred in 81% of participants. Other notable events included one participant each with microscopic polyangiitis, elevated aspartate aminotransferase, and neutropenia.

After the initial dose of mogalizumab, the mean HTLV-1 viral load in the blood decreased by less than 50% and then increased. It decreased again after the initial dose in the Phase IIa arm. There also was reduction in CSF concentrations of inflammatory markers neopterin and CXCL10 by 37% and 31%, respectively.

The mean percentage change from baseline in 10-meter walking time, timed up-and-go time, and two- and six-minute walk distances improved by approximately 10% within the first month after initial administration in Phase I and remained at the same level until the 12th month, after the functional measures gradually worsened.

Subgroup analysis identified that most improvement on the disability scale after four years was observed in participants with a disease duration of less than five years. This group also had a significant change in viral load when compared to the group that did not improve on the disability scale.

COMMENTARY

Overall, this study concluded that the long-term administration of mogalizumab generally was well tolerated, with clinical improvement in spasticity and voiding dysfunction. There also was a notable inhibitory effect on progression of motor disability. Regarding inflammatory biomarkers, there was a notable decrease in CSF concentration of neopterin and CXCL10. Unfortunately, the study was not able to conclude that mogalizumab had strong beneficial effects on all patients with HAM/TSP. Limitations of the study were that there was no placebo-control group, and the study was limited to a Japanese-only population, which limits the generalizability of the study.

Taken altogether, in a disorder where clinical trials are rarely performed, I commend the authors of this study for conducting research on a rare but debilitating neurologic condition. As the field of neuroinfectious disease continues to repurpose treatments from other fields in which chronic inflammation is the underlying pathology, practicing clinicians soon will be able to provide better guidance and answer difficult questions with evidence-based studies so that patients and providers can choose the best plan of care through a shared medical decision-making model.