Experts respond
Commenting on the study, 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 said.
“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,” Dr. 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 included in the different studies, with the characteristic of each population in each trial being unique to that dataset.
In addition, Dr. 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.
Dr. Cree also questioned the role of the sponsor in this meta-analysis. “The analysis was sponsored by Alexion and several coauthors 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 said.
“This is definitely a provocative study. They 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,” Dr. Cree stated.
Dr. Cree acknowledged 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, Dr. Cree said they are all “extraordinarily effective” at reducing relapse activity. “They are all ‘home run’ products, but they have differences in safety,” he said.
“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,” Dr. Cree noted.
“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, Dr. Cree pointed 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 per year for maintenance, while satralizumab is given by subcutaneous injection once per 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 suggested.
But Dr. Cree pointed 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, Brian Weinshenker, MD, from the Mayo Clinic in Rochester, Minn., 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.”
Dr. 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, Portland, 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 Dr. 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,” Dr. 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.”
Dr. 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 suggested.
Finally, Dr. Bourdette 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.
Company statements
The companies selling inebilizumab and satralizumab sent statements on the new analysis and repeated many of the above points.
Genentech 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. Dr. 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 received grants for clinical trials through Alexion–AstraZeneca Rare Disease and Terumo BCT, and has been paid consulting fees by Mitsubishi Tanabe. Several coauthors of this study are employees of Alexion Pharmaceutics. Dr. Cree was principal investigator on the N-MOmentum study with inebilizumab. He has a grant from Genentech for MS research, and has consulted for Alexion in the past. Dr. 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. Dr. Bourdette has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.