A new indirect comparison of the three new FDA-approved treatment options for adults with aquaporin4+ (AQP4+) neuromyelitis optica spectrum disorder (NMOSD), has suggested that eculizumab is far more effective than the other two agents in preventing time to first relapse.
The Alexion-sponsored study was presented at the recent virtual 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2021 by Dean Wingerchuk, MD, of the Mayo Clinic in Scottsdale, Arizona.
Other experts in the field have highlighted limitations to the analysis and pointed out that all three agents are very effective in treating AQP4+ NMOSD, and many other considerations need to be taken into account as well as time to first relapse when selecting a therapy, leaving the door open for all three agents.
Wingerchuk explained that NMOSD is a rare severely disabling complement-mediated autoimmune neuroinflammatory disease of the central nervous system, characterized by devastating and unpredictable attacks (relapses) that can cause immediate and irreversible damage.
There are three recently approved monoclonal antibody treatment options in the US for adults with AQP4+ NMOSD: eculizumab (Soliris, Alexion), inebilizumab (Uplizna, Horizon), and satralizumab (Enspryng, Genentech). A comparison of the relative treatment effects of these drugs would facilitate the treatment selection process, Wingerchuk said.
The objective of this study was to perform an indirect treatment comparison on the efficacy of these three FDA-approved treatment options for adults with AQP4+ NMOSD, in the absence of any head-to-head studies.
Using published data from randomized controlled trials, which were identified by a systematic literature review in September 2020, the researchers performed a Bayesian network meta-analysis to estimate the relative effects between eculizumab, inebilizumab, and satralizumab.
Network meta-analyses were performed for clinically relevant subpopulations based on three treatment networks: (1) patients who received monotherapy with one of the monoclonal antibodies or in combination with an immunosuppressant therapy; (2) patients who received monotherapy with the monoclonal antibody alone; and (3) patients who received a combination of both the monoclonal antibody and immunosuppressant therapy.
Time to first relapse was the primary efficacy outcome assessed. Relative treatment effects were expressed as hazard ratios and the probability that a treatment was the best at delaying time to first relapse was also evaluated.
In the systematic literature review, 29 publications from four unique clinical trials were identified and include in the network meta-analysis. These included publications from congress proceedings and peer-reviewed journals.
The four clinical trials were the N-MOmentum trial of inebilizumab vs placebo; the PREVENT trial of eculizumab with or without immunosuppressant therapy vs placebo with or without immunosuppressant therapy; the SAkuraSky trial of satralizumab plus immunosuppressant therapy vs placebo plus immunosuppressant therapy; and the SAkuraStar trial of satralizumab vs placebo.
Results showed that for the first analysis of mono or combination therapy, patients treated with eculizumab with or without immunosuppressant therapy were 76% less likely to experience a first relapse when compared with patients treated with satralizumab with or without immunosuppressant therapy.
In the monotherapy network, patients on eculizumab were 90% less likely to experience a first relapse when compared with patients treated with satralizumab, and patients on eculizumab were 89% less likely to experience a first relapse when compared with patients treated with inebilizumab.
In the third network analysis — a comparison of eculizumab plus immunosuppressant therapy with inebilizumab plus immunosuppressant therapy, the point estimate appeared to favor eculizumab but the confidence intervals were wide and not significant.
|Table 1. Hazard Ratios for Time to First Relapse|
|Network||Treatment Comparison||Hazard Ratio (95% CI)|
|Mono or Combination Therapy||Eculizumab ± IST (n = 96) vs Satralizumab ± IST (n = 104)||0.24 (0.06 – 0.98)|
|Monotherapy||Eculizumab (n = 21) vs Satralizumab (n = 63)||0.10 (0.01 – 0.65)|
|Eculizumab (n = 21) vs Inebilizumab (n = 161)||0.11 (0.02 – 0.68)|
|Combination therapy||Eculizumab + IST (n = 75) vs Satralizumab + IST (n = 41)||0.41 (0.07 – 2.34)|
|Abbreviation: IST, immunosuppressant therapy.|
A subsequent analysis looked at the rank order of the best treatment option, with eculizumab coming out first in all three networks.
|Table 2. Likelihood of Being the Best Treatment for Delaying Time to First Relapse|
|Treatment||Mono or Combination Therapy||Monotherapy||Combination Therapy|
Wingerchuk acknowledged that there were many limitations to this study, including that analyses for annualized relapse rate, disability, and quality of life were not included because of a lack of consistent outcome reporting by AQP4+ status in the randomized trials.
Safety outcomes were also excluded because of a lack of standardized baseline risks and inconsistent reporting by AQP4+ status across trials.
Because this study focused on drugs approved in the United States in a rare disease area, there were a limited number of studies with intervention effects.
There were also differences in follow-up durations across the different trials, with N-MOmentum having a follow-up of 197 days compared with 144 weeks for other trials.
“In the absence of head-to-head trials, this network meta-analysis provides important evidence on the relative efficacy of eculizumab versus satralizumab or inebilizumab for the treatment of patients with AQP4+ NMOSD, with significant differences in two out of the three treatment comparison scenarios observed,” Wingerchuk concluded.
“Based on current evidence, monotherapy and mono-combination therapy with eculizumab appear to more efficacious at preventing relapses than satralizumab or inebilizumab for the treatment of adults with AQP4+ NMOSD. These findings appear to suggest that C5 complement inhibition with treatments such as eculizumab appear to prevent relapses more effectively than other mechanisms involving IL-6 receptor or CD19 inhibition among adults with AQP4+ NMOSD,” he added.
Commenting on the study for Medscape Medical News, several experts in the field provided some balancing views.
Bruce Cree, MD, University of California San Francisco, who was the chief investigator of the N-MOmentum study with inebilizumab, said he was skeptical about this new indirect comparison. “The results of this study seem too good to be true; a 90% difference between agents has to be an overestimate,” he commented.
“We know from independent studies that all three drugs are very effective. If we take each trial separately, eculizumab reduced attack risk by 90% versus placebo; and the other two drugs by 77% to 78% versus placebo. For eculizumab to be 90% better than inebilizumab or satralizumab its basically like saying these drugs perform like placebo, but we know that is not the case,” Cree argued.
He pointed out that when comparing results across studies there are many factors that have to be considered, including the different patient populations include in the different studies, with the characteristic of each population in each trial being unique to that dataset.
In addition, Cree suggested that all the studies included in the comparison were relatively small for this type of analysis. “Normally this type of analysis is done with much larger studies, so the resulting database is closer to a representation of the disease state itself,” he said.
Cree also questioned the role of the sponsor in this meta-analysis. “The analysis was sponsored by Alexion and several co-authors were employees of Alexion. There was not much description available of how the statistics were done. I am concerned that the company was involved in the analysis, which could introduce bias. I look forward to seeing details of the statistical methodology,” he commented.
“This is definitely a provocative study. The have thrown down the gauntlet. If they are so confident in the results they should now do a head-to-head study to back this result up. If they don’t do that, then I think physicians should ignore it as there are just too many problems with this analysis,” Cree stated.
Cree acknowledges that when looking at the four trials separately, eculizumab does look a little better than the other two agents in delaying time to first relapse. “But there are some caveats. Despite a larger reduction in relapse rate there was no reduction in disability in the eculizumab trial. Whereas the inebilizumab trial did show a reduction in disability. And while the PREVENT trial with eculizumab was a good study, during the course of the trial the definition of clinical relapse was changed, and as a consequence that increased the product’s performance — that’s a little bit curious,” he added.
How to Choose?
On how to choose between the three agents, Cree says they are all “extraordinarily effective” at reducing relapse activity. “They are all ‘home run’ products, but they have differences in safety,” he says.
“Inebilizumab is linked to hypogammaglobulinemia over time — we haven’t seen an increase in infection risk linked to this, but with enough time, I would expect that there probably will be. But inebilizumab is a B cell depleting agent like the agents used in MS, and we now have a lot of experiences with this type of product, which gives us more confidence on the safety profile,” Cree notes.
“Eculizumab was linked to a risk of meningococcal meningitis and other bacterial infections, and satralizumab seems to [be] overall well tolerated with no obvious safety concerns to date, but the studies have been quite small,” he added.
On routes of administration and frequency of dosing, Cree points out that while all three drugs have an intensive loading schedule, for maintenance, eculizumab needs to be given as an IV infusion every 2 weeks. Inebilizumab needs just two infusions a year for maintenance, while satralizumab is given by subcutaneous injection once a month.
“It may be that eculizumab could be used at the time of an acute attack but then treatment could be switched to one of the other two for long-term maintenance,” he suggests.
But Cree points out that the biggest challenge for all three agents is access. “The costs are astronomically high ($200,000-$770,000). They are prohibitively expensive and very few insurance companies are covering them.”
Also commenting for Medscape Medical News, Brian Weinshenker, MD, from the Mayo Clinic in Rochester, Minnesota, who was a member of the attack adjudication committee for both PREVENT and N-MOmentum studies, pointed out that as well as differences in the populations enrolled, and study designs, the studies with the three different drugs also had differences in attack adjudication criteria.
“These factors make it very difficult to compare across studies, which is what was done in this analysis, so I would be reluctant to reach many conclusions about differences.”
Weinshenker added: “All three treatments provided strong benefit. We are still learning about long-term benefits, but emerging data have suggested that all three seem to provide persistent benefits for the length of the open-label extension study. We don’t have much evidence about the severity of the attacks that did occur, although some limited data suggest that both eculizumab and inebilizumab reduce attack severity.”
Dennis Bourdette, MD, professor emeritus, Department of Neurology, Oregon Health & Science University, who was not involved in any of the studies, said he thought the new analysis was “a worthwhile effort to determine the relative effectiveness of the three different drugs in treating AQP4+ NMOSD.”
“Given the rarity of APQ4+ NMOSD, it will be difficult to perform randomized head-to-head clinical trials of the agents, so this type of comparison is the best we can do at this time,” he said.
While Bourdette feels this study supports the notion that eculizumab is more effective at delaying time to first relapse than inebilizumab and satralizumab, he does not believe the results should have a major impact on decisions about which agent to use in clinical practice.
“A difference in delaying time to first relapse tells us little about the relative effectiveness of the long-term benefit of these [agents], particularly with regards to permanent disability or frequency of relapses. However, it is possible that the difference reflects the efficacy kinetics of the agents with eculizumab working faster than the other two agents, which would be useful in making a decision about a patient with very active NMOSD where one wants to get the disease under control as quickly as possible,” Bourdette noted.
But he added that neurologists should also consider safety profile, convenience, and contraindications. “Eculizumab is clearly less convenient in terms of dosing schedule than the other two agents, and patient convenience is important for long-term compliance.”
Bourdette pointed out that another consideration is prior treatment. “Many patients with NMOSD will receive the anti-CD20 monoclonal antibody, rituximab — which depletes B cells — off-label. Inebilizumab also depletes B cells, so a patient who has had continued NMOSD disease activity on rituximab probably should not be treated with inebilizumab, making eculizumab or satralizumab preferable,” he suggests.
Finally, Bourdette also highlighted the sponsorship of the current study by the manufacturer of eculizumab, Alexion, and that all of the authors have some financial relationship with Alexion as described in their disclosures. “Whether this resulted in any biases about the design, conduct, or interpretation of the study is uncertain but is always a concern,” he said.
The companies selling inebilizumab and satralizumab also sent statements on the new analysis and repeated many of the above points.
Genentech also noted that new longer-term data presented at ECTRIMS show that satralizumab is effective in significantly reducing relapses over 4 years of treatment in people with AQP4+ NMOSD, with a favorable safety profile both as a monotherapy and in conjunction with immunosuppressive therapy. More than 70% of people treated with satralizumab remained relapse-free after 4 years in the SAkuraStar (73%) and SAkuraSky (71%) open-label extension studies, and 90% and 91%, respectively, were free from severe relapse, the company reported.
Horizon said: “We are confident in the efficacy and safety of Uplizna (inebilizumab) — a convenient, twice-annual monotherapy — that was studied in the largest randomized, placebo-controlled, global trial of a monotherapy in NMOSD. The endpoints in this trial were prospectively defined and assessed by an adjudication committee as published in The Lancet, with long-term follow-up data now published in the Multiple Sclerosis Journal that further support the efficacy and safety.”
The current study was funded by Alexion–AstraZeneca Rare Disease. Wingerchuk has participated on data safety monitoring or advisory boards for Roche, Viela Bio, Genentech, Biogen, Reistone, TG Therapeutics, Celgene, Novartis, and Alexion–AstraZeneca Rare Disease. He has also received grants for clinical trials through Alexion–AstraZeneca Rare Disease and TerumoBCT, and has been paid consulting fees by Mitsubishi Tanabe. Several co-authors of this study are employees of Alexion Pharmaceutics. Cree was principle investigator on the N-MOmentum study with inebilizumab. He also has a grant from Genentech for MS research, and has consulted for Alexion in the past. Weinshenker has served as a member of the attack adjudication committee for both PREVENT and N-MOmentum studies and has financial relationships with the manufacturers of all three drugs. Bourdette has disclosed no relevant financial relationships.
37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2021: Abstract 118. Presented October 14, 2021.