Sunday, September 15, 2019

Inebilizumab and eculizumab for treatment of neuromyelitis optica

A new drug for the treatment of neuromyelitis optica (NMO) — an aggressive inflammatory, immune-mediated disorder of the central nervous system often confused with a severe form of multiple sclerosis, reduced clinical relapses by 73% in a phase 3 study that was stopped early for benefit.

In the N-MOmentum study, the anti-CD19 monoclonal antibody inebilizumab (Viela Bio), which works by depleting B cells, was also associated with a 63% reduction in worsening of clinical disability, and a 44% reduction in active MRI lesions.

The trial was presented this week at the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2019. It was also published online September 5 in The Lancet.

"Inebilizumab is one of three new agents — all with different mechanisms of action — for the treatment of NMO, all of which show very high efficacy in the condition," Bruce Cree, MD, lead N-MOmentum investigator and clinical research director at the University of California San Francisco Multiple Sclerosis Center, told Medscape Medical News. 

"All these new agents have striking degrees of efficacy, with disease activity being reduced by more than 70% — a stunning feature for any drug in medicine," he added.

"We are going to go in just a year or so from having no approved therapies for NMO to potentially having three approved therapies, each with a different mechanism of action. This is an extremely exciting time for NMO patients and those caring for them," Cree said.

The greatest issue with these new drugs likely will be their cost.

The first of the three new agents, eculizumab (Soliris, Alexion), which recently became available in the US and Europe, has been priced at around $500,000 per year, making it one of the world's most expensive pharmaceutical products.

Commenting for Medscape Medical News, ECTRIMS president Bernhard Hemmer, MD, Technical University of Munich, Germany, said: "The new NMO drugs are certainly very exciting. We will soon have three approved therapies for this condition, which is a great step forward. But we already have a drug — rituximab [Rituxan, Genentech] — which, although not specifically indicated for NMO, is widely used and appears to be effective.

"The big question is whether these new drugs, which are all likely to be very expensive, will be any better than rituximab," Hemmer said. 

"We may have patients that are stable and happy on rituximab but as it is not formally approved for NMO, we may be forced to stop a $5000-a-year drug and switch to one that costs maybe 80 or 100 times more," he added. "But we don't know if these more expensive drugs are actually any more effective."

How NMO Differs From MS

Cree explained that NMO can appear similar to multiple sclerosis in that both can cause optic neuritis and spinal cord inflammation.

"The two disorders have been confused for many years because of the clinical overlap. But the discovery of the AQP4 antibody only in patients with NMO now allows us to distinguish the two conditions," he said. "This antibody is pathogenic and NMO is thought of as an antibody-specific autoimmune disease whereas a specific pathogenic antigen for MS has not been identified."

The AQP4 antibodies target astroglial cells and this distinguishes NMO from being a classic demyelinating disorder, Cree noted. "Demyelination does occur in NMO, but this appears to be secondary to astroglial injury and complement fixation that occurs."

NMO is a rare disorder occurring in 0.5-4.4 per 100,000 people. In the US, roughly 15,000 to 16,000 individuals are estimated to be living with NMO.

"Patients are often initially diagnosed with MS, but generally don't do well on MS therapies, and progress quickly. Most can now be easily identified with the AQP4 antibody test," Cree said. 

While NMO is a severe disease, the prognosis has evolved in recent years. "Before we knew what to do with these patients, their 5-year survival was only about 68%," Cree noted. "Lesions in the cervical spinal cord interrupted the ability to breathe and patients died from respiratory failure."

More recently, off-label use of immunosuppressive drugs have had a major impact on the disease.

"The anti-CD20 antibody rituximab is now widely used for NMO, and many patients have now been spared from having such a severe disease course. Patients still die from the disease, and attacks are still associated with irreversible neurological damage, but the face of the disease has been changed by off-label use of rituximab firstly, and then later mycophenolate and azathioprine," Cree reported.  

The new crop of drugs now being reported on have been developed specifically for NMO.

N-MOmentum study

Inebilizumab, an anti-CD19 antibody, targets a wider range of B cells — thought to be the key cells in the pathogenesis of NMO — than anti-CD20 drugs, Cree said.

The N-MOmentum study enrolled 230 NMO patients (94% positive for AQP4 antibody) with an Expanded Disability Status Scale score of 8.0 or less, 174 of whom were randomly assigned to inebilizumab (two doses of 300 mg given by IV infusion on days 1 and 15) and 56 to placebo. Further doses every 6 months were planned to maintain B-cell depletion. 

The study was stopped before complete enrollment because of a clear demonstration of efficacy, and all patients were then switched to open-label active treatment. 

Results showed that 12% of those on inebilizumab had an attack vs 39% of the placebo group (hazard ratio 0.27; P < .0001). The number needed to treat was 3.73.

Worsening of disability on the EDSS score occurred in 16% of inebilizumab patients vs 34% of placebo (odds ratio 0.37; P = .0049). Inebilizumab was also associated with reductions in active MRI lesions (rate ratio], 0.56; P = .0034) and hospitalizations (RR, 0.28; P = .01).

Adverse events occurred in 72% of inebilizumab patients and 73% of placebo patients, whereas serious adverse events occurred in only 5% of the inebilizumab group and 9% of the placebo group.

Two deaths occurred in the treatment group, which the investigators believe were not related to the drug.

In The Lancet article, the investigators report that although treatment with inebilizumab reduced the risk of optic neuritis attacks (6% vs 18% with placebo), this did not result in a benefit to low-contrast binocular vision (the key secondary endpoint related to vision).

"This observation suggests that inebilizumab treatment might not reduce optic neuritis attack severity or facilitate recovery," the authors say.
Also, because the study included few AQP4 seronegative participants, the efficacy of inebilizumab in this subgroup could not be determined, they report.

"Although longer-term efficacy and safety data are needed, the positive results seen with inebilizumab and the emergence of other developmental therapies have the potential to provide a useful range of treatment options and to establish a new therapeutic landscape for NMO," the researchers conclude.

In an accompanying commentary , Elizabeth Silbermann, MD, and Dennis Bourdette, MD, Oregon Health & Science University, Portland, point out some limitations of the N-MOmentum study.

The editorialists say the follow-up safety period of 12 months is too short to adequately assess for long-term risks of opportunistic infections, secondary malignancies, or prolonged hypogammaglobinemia. "Long-term monitoring is crucial, especially in light of the two deaths reported in the study," they write.

Silbermann and Bourdette also point out that clinicians will question whether inebilizumab offers therapeutic benefit over rituximab, which is a mainstay therapy for NMO and available at a much cheaper price. But they suggest that by targeting CD19, inebilizumab might provide a more targeted attack on pathological autoantibodies while preserving overall humoral immunity.

Inebilizumab is just one of several new drugs for NMO. The others are eculizumab, a complement inhibitor; and two IL-6 antibodies — satralizumab and tocilizumab. New data on all these agents, showing high levels of efficacy against NMO, were also presented here at the ECTRIMS meeting.

"So far, eculizumab seems to have perhaps slightly better efficacy, with 90% suppression in attacks, but we have to be very cautious about cross-trial comparisons," Cree commented.

Eculizumab has recently been approved for use in NMO in both the US and Europe. Inebilizumab and satralizumab are nearing the market, and tocilizumab is already commercially available for other indications but is not licensed for NMO.

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