New Med Beats Old in First Head-to-Head Neuromyelitis Optica Trial

Nancy A. Melville

October 15, 2019

ST. LOUIS — Tocilizumab (Actemra, Genentech) is more effective than a more commonly prescribed drug for the treatment of neuromyelitis optica spectrum disorder (NMOSD), new research suggests.

In the first head-to-head study of the two immunosuppressive drugs, tocilizumab was significantly more effective than azathioprine (Azasan, Bausch Health).

In addition, significantly reducing relapse risk, there was also a lower probability of disability progression in the tocilizumab group vs the azathioprine group.

"This is the first comparison, large, multicenter NMOSD trial ever conducted," said senior investigator Fu-Dong Shi, MD, PhD, Integral Center for Neuroinflammation, Tianjin General Hospital, Beijing Tiantan Hospital, China.

"The study provides important evidence useful for choosing medications in terms of newer over the older medications for patients with NMOSD," Shi told Medscape Medical News.

The findings were presented here at ANA 2019: 144th Annual Meeting of the American Neurological Association.

Few Treatment Options

In NMOSD, a rare autoimmune disease involving demyelinating of the central nervous system, patients experience common relapses without complete recovery, especially inflammation of the optic nerve and spinal cord. Consequently, this increases progression and disability.

More than half of patients with NMOSD can become blind in one or both eyes or need help walking; mortality relating to cervical spinal relapses is reported in as many as 20% of patients.

There are few studies comparing the effects of newer disease-modifying therapies with the commonly used older drugs for NMOSD, so the investigators conducted the Tocilizumab versus Azathioprine in Highly Relapsing Neuromyelitis Optica Spectrum Disorders (TANGO) trial.

The study included 118 patients with NMOSD who had experienced at least two attacks in the prior year or three attacks in the prior 2 years. Participants were enrolled at six centers in China between October 2017 and August 2018.

Half of the participants were assigned to receive 8 mg/kg intravenous tocilizumab monthly, while the other half received 2 to 3 mg/kg oral azathioprine daily.

Tocilizumab or azathioprine was administered with the gradual discontinuation of previous external treatments and then as monotherapy for 12 months.

The patients (97% women; mean age, 47 years) had an average of a 6-year history of NMOSD.


The primary endpoint was time to first relapse. For this outcome, 86% of the tocilizumab group were relapse-free after a mean period of 48 weeks vs 48.1% of the azathioprine group (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.107 - 0.518; P < .001).

Patients treated with tocilizumab were also more likely to have a sustained reduction in disability compared with those treated with azathioprine, with 8.9% vs 29.5% showing progression, respectively (HR, 0.28; 95% CI, 0.10 - 0.79; P = .01).

Serum levels of anti-AQP4-ab titers were also significantly reduced in the tocilizumab group compared with almost no change in the azathioprine group (P = .03).

In terms of safety, 61% of the tocilizumab group experienced treatment-related adverse events (AEs), including fatigue, skin rash, leukopenia, or elevated liver enzyme compared with 83% of the azathioprine group.

Three patients in the azathioprine group withdrew from the study because of severe AEs. About half of each treatment group had AQP4-IgG positivity.

A key limitation of the study was that it was not blinded, Shi noted.

However, "blinding does not make sense in this type of trial because we kind of know the side effects of azathioprine and its efficacy," he said.

Impressive, Robust Efficacy

Commenting on the findings for Medscape Medical News, Brian G. Weinshenker, MD, consultant in the Department of Neurology and professor of neurology at the Mayo Clinic, Rochester, Minnesota, said that tocilizumab's efficacy was notable.

"The effects in prolonging the time to the first attack appear to be robust," said Weinshenker, who was not involved with the research.

"There was also a significant reduction in disability worsening [with tocilizumab], which likely reflects the decrease in attacks, as most incremental disability in NMOSD is related to attack events," he added.

Weinshenker noted that the differences between tocilizumab and azathioprine in terms of side effects are difficult to interpret.

"My own impression from extensive use of azathioprine is that it is usually well tolerated, although it is quite believable that 3 of 59 who received azathioprine withdrew because of adverse effects," he said.

Key questions that remain include whether the effects on patients who are AQP4-IgG seropositive are different, and what kind of effects are observed on MRI, Weinshenker noted.

"Obviously, there is no information on long-term benefits/durability of response, which will be an important consideration in the future," he added.

Shi responded that the study samples were too small to compare those who were AQP4-IgG positive and negative, and that results from MRI imaging, optical coherence tomography, and visual evoked potentials are forthcoming.

One of the World's Most Expensive Drugs

As reported by Medscape Medical News, eculizumab (Soliris, Alexion Pharmaceuticals), was approved in June by the US Food and Drug Administration (FDA) as the first maintenance drug for the prevention of attacks in NMOSD in AQP4-seropositive patients.

However, eculizumab is considered among the most expensive drugs in the world, with a cost of more than $500,000 per year. Comparatively, tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, has an estimated US price for a patient weighing 70 kg (154 lb) of about $40,000. The estimated price per year for azathioprine is $9000, Shi said.

Disease-modifying drugs in addition to eculizumab are also in development for the treatment of NMOSD. However, the safety and efficacy of those drugs in comparison with commonly prescribed medications — including azathioprine — have not been established, Shi noted.

As part of its FDA approval, eculizumab, a C5 complement protein inhibitor, has a boxed warning alerting that "life-threatening and fatal meningococcal infections have occurred in patients" treated with the drug.

The study was supported in part by Tianjin Medical University, the Advanced Innovation Center for Human Brain Protection, and Capital Medical University, China. Shi has disclosed no relevant financial relationships. Weinshenker consults with Chugai, Roche, and Genentech, which all have interests in sartalizumab, a drug similar to tocilizumab.

ANA 2019: 144th Annual Meeting of the American Neurological Association: Abstract S101. Presented October 13, 2019.

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