26 Feb 2021
While its NDA languishes at the US Food and Drug Administration, the EMA’s CHMP has said yes to dostarlimab’s marketing...
FDA advisory committee's concerns about a mortality imbalance in Plivensia clinical trials would appear to reduce the odds that the interleukin-6 inhibitor will reach the US market in the near term.
A US FDA advisory committee found Janssen Biotech Inc.'s Plivensia (sirukumab) for rheumatoid arthritis stands out from competitors by concerns over a mortality signal, but not by any apparent efficacy advantages versus treatments already available.
The concerns about the mortality imbalance seen in clinical trials for the interleukin-6 inhibitor certainly make approval seem unlikely. However, even if FDA were to clear sirukumab, such as for a narrower indication that drew more support from the panel, commercial prospects seem limited by lingering safety questions and an efficacy profile that advisory committee members said does not appear to stand out from other IL-6-targeting products or other biologic therapies used to treat rheumatoid arthritis (RA).
Janssen is seeking approval of sirukumab for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or are intolerant to one or more disease-modifying anti-rheumatic drugs (DMARDs).
FDA's Arthritis Advisory Committee met Aug. 2 to discuss the biologics license application (BLA), but the review did little to boost sirukumab's chances of licensure by its Sept. 22 user fee goal date. The panel recommended against approval in a 12-1 vote. Although the committee unanimously endorsed sirukumab's efficacy, it voted 11-2 that the safety profile was inadequate to support approval. (See sidebar for Pink Sheet coverage).
Advisory committee members said they could not know for certain whether a mortality imbalance in the placebo-controlled trials was an artifact of the studies' design or a true safety signal. However, they seemed unwilling to take the chance that it might be the latter given the availability of numerous other biologic RA treatments that have not shown a mortality imbalance.
They also questioned the need for another IL-6-targeting agent in the absence of head-to-head data suggesting sirukumab might be better than the two IL-6 inhibitors currently on the market, Roche's Actemra (tocilizumab) and Sanofi and Regeneron Pharmaceuticals Inc.'s Kevzara (sarilumab).
"We've got two other drugs that are [Il-6] inhibitors … but the [mortality] signals didn't appear there, and we have no suggestion of efficacy differences between this drug and those other two," said Steven Meisel, system director of patient safety at Fairview Health Services in Minneapolis. "If I was on a formulary committee, which I know this is not, this would be a no brainer. You wouldn't add it."
"If I was on a formulary committee, which I know this is not, this would be a no brainer. You wouldn't add it." – Fairview Health Services' Meisel
Some analysts seemed to agree that sirukumab's commercial prospects, which were handicapped to begin with, were further dampened by the advisory committee review.
"We had assumed relatively modest revenues for the product given its profile and its entry into a highly competitive market," Credit Suisse analysts said in an Aug. 2 note following the advisory committee meeting. "We decrease our probability of success for the product to 30%, lowering our global probability adjusted peak sales to less than $300m in 2026."
Sirukumab is a monoclonal antibody that targets the IL-6 cytokine. Janssen said that while this mechanism of action overlaps with that of tocilizumab and sarilumab, which target the IL-6 receptor, sirukumab has the potential benefit of more selective inhibition of IL-6.
The mechanism of actions differs from that of Janssen's two currently marketed biologic RA treatments, Remicade (infliximab) and Simponi (golimumab), which are TNF inhibitors. Janssen has been successful thus far in protecting Remicade sales from biosimilar competition, but this may become more difficult as additional biosimilar versions of TNF inhibitors enter the market. (Also see "Exclusive Remicade Contracts Are Slowing Biosimilar Uptake" - Scrip, 1 Aug, 2017.)
The proposed sirukumab dose is 50 mg given subcutaneously every four weeks. This dosing schedule would give Janssen's agent a competitive advantage relative to tocilizumab (dosed subcutaneously every week or every other week), and sarilumab (given subcutaneously once every two weeks).
Janssen is preparing to commercialize sirukumab on its own following partner GlaxoSmithKline PLC's decision, announced one week before the advisory committee, to return rights to the biologic to the Johnson & Johnson division. (Also see "J&J Prepares For US Sirukumab Launch After Regaining Rights From GSK" - Scrip, 26 Jul, 2017.)
The primary efficacy evidence in the BLA is from two double-blind, placebo-controlled trials in the SIRROUND clinical development program.
Study ARA3002 was a 52-week, placebo-controlled trial in which patients were required to have had an inadequate response to DMARD therapy. The trial included escape points at weeks 18 and 40, at which time patients in the placebo arm who had less than 20% improvement from baseline in both swollen and tender joint counts could be re-randomized to one of the two sirukumab arms – 50 mg every four weeks (q4w) or 100 mg every two weeks (q2w).
Study ARA3003 employed a 24-week placebo control, and subjects were required to have had an inadequate response to one or more anti-TNF agents or intolerance to two or more TNF inhibitors.
FDA did not raise any efficacy concerns about sirukumab. In both placebo-controlled trials, sirukumab was associated with a statistically significantly higher proportion of ACR20 responders at both doses relative to placebo. The estimated absolute increases in ACR20 response for the 50 mg q4w dose compared to placebo were 28% and 16% in the two studies.
In Study ARA3002, sirukumab also demonstrated a statistically significant effect on the primary radiographic endpoint of change from baseline in van der Heijde-modified Sharp score at Week 52.
In a third study, ARA3005, sirukumab was compared to AbbVie Inc.'s Humira (adalimumab). Although the trial did not show superiority for sirukumab compared to the TNF inhibitor, the relatively similar improvements observed between the two drugs provide additional support for sirukumab's efficacy, FDA said in its advisory committee briefing document.
Despite the generally positive clinical efficacy results, analysts had previously raised concerns that the data did not sufficiently differentiate sirukumab from that of other agents in the IL-6 class or from the more widely used TNF inhibitors. (Also see "ACR 2016 Roundup: Remicade Copy Not So Similar; Mixed Sirukumab Results; Corbus’s Resunab Surge" - Scrip, 16 Nov, 2016.)
The advisory committee members found themselves weighing what one panelist described as "marginal efficacy" against a potentially concerning mortality signal – an imbalance that FDA said was not seen in the registrational studies for tocilizumab or sarilumab.
There were a total of 35 deaths reported in the RA clinical development program as of Feb. 2, 2016, 34 of which occurred in sirukumab-treated patients. Most of the deaths occurred in ARA3002.
While there was no mortality difference in the placebo-controlled period of the two sirukumab pivotal trials through 18 weeks of exposure, the imbalance appeared in the pooled data through 52 weeks of exposure, with incidence rates of 0.2, 0.5 and 0.8 per 100 patient years of exposure for subjects in the placebo, 50 mg and 100 mg arms, respectively. In addition, the incidence rate of death was higher for the sirukumab groups that included patients who were originally randomized to placebo and crossed over to sirukumab (0.9 combined 50 mg, and 1.1 combined 100 mg) compared to those randomized to sirukumab from the start.
Janssen asserted the mortality imbalance was an artifact of the trial design, because placebo patients who escaped and crossed over to treatment had more severe disease, confounding the 52-week mortality findings.
Janssen asserted the imbalance was an artifact of the trial design, because placebo patients who escaped and crossed over to treatment had more severe disease, confounding the 52-week mortality findings.
The sirukumab mortality rates were consistent with the rates observed in clinical studies of other drugs developed for RA and were within the range of those previously reported in the general RA population from epidemiology studies, Janssen said.
There also was an imbalance in major adverse cardiovascular events in the sirukumab 50 mg group compared to the placebo group, but no imbalance was seen for the 100 mg group. In addition, there were higher rates of malignancy with the two sirukumab doses compared to the placebo group.
While committee members said the mortality imbalance in the placebo-controlled trials may well have resulted from the trials' design, as Janssen asserted, they could not be certain. Panelists questioned whether sirukumab might fill a void for patients who do not respond to the other IL-6 blockers.
Rheumatologist Michael Weisman from the University of California, Los Angeles asked whether Janssen had identified any biomarkers for better patient response relative to the two currently marketed IL-6 agents or other biologics.
"This company was very determined to try to find markers of response," said George Vratsanos, vice president of translational medicine at Janssen. "We did a very exhaustive search with a dedicated team for many months looking at genomics, looking at transcriptome, looking at protein markers. Unfortunately, like other companies, we could not identify a reliable marker or markers of response or even certain safety events."
David Felson, director of the clinical epidemiology research and training unit at Boston University, questioned whether given the large number of biologics and second-line drugs approved for RA, sirukumab is "worth a potential safety signal that may be different from other second-line agents we have."
"I think the question ultimately is … is this worth that safety concern," Felson said. "This does not provide dramatic results or responses to people who have failed these other treatments."
Maria Suarez-Almazor, a rheumatologist at University of Texas MD Anderson Cancer Center, said she would have been more enthusiastic about sirukumab had it been a completely novel mechanism of action.
"With the imbalance in all-cause death data that's been presented here, it would be really hard for me to use this as the next line therapy if someone failed a DMARD." – University of Missouri's Becker
"Part of what I'm struggling with is the benefit of the drug given that this is a drug that's in the same class [of] mechanism of these two other approved drugs," Suarez-Almazor said. "If this was a new agent that was targeting a different cytokine that hasn't been targeted before, I would probably be a little bit more enthusiastic, because I could see that it could fill a niche of patients that have failed everything else. But here, I'm not sure."
Mara Becker, a pediatric rheumatologist at University of Missouri-Kansas City, said she could not envision prescribing sirukumab for the proposed indication, given what is currently known about the agent's efficacy and safety.
"With the imbalance in all-cause death data that's been presented here, it would be really hard for me to use this as the next line therapy if someone failed a DMARD, which is the indication that the sponsor's asking," Becker said. "It would be pretty unlikely for me to choose this agent with that risk profile, and that to me says it all. That to me makes me worry that the safety of this is still in question too much for me to take that risk."
Becker was one of several panelists who raised concerns about the breadth of Janssen's proposed indication, which is the same as that for tocilizumab and sarilumab.
"What was in front of me was a very broad indication," Weisman said in explaining his negative vote on safety. "If the indication was biologic non-responders or inadequate responders I would have voted yes. That's the fence and that's the cut-point that disturbed me."
While such comments leave open the possibility that a narrower indication could increase the agent's chances for approval, Janssen also faces the unhappy commercial prospect of labeling that reflects a mortality imbalance pending further characterization of the drug's safety profile.
In finding that sirukumab's safety profile was not adequate to support approval, several panelists said they would like to see a head-to-head safety comparison against an active comparator that assesses long-term outcomes.
Some analysts believe the negative panel vote, coupled with GSK's decision to hand back rights for the biologic, have put sirukumab's future development in question.
Janssen has a Phase II trial underway in major depressive disorder (MDD), and GSK is conducting a Phase III study in giant cell arteritis. When asked what would happen to the giant cell arteritis study now that GSK is handing back sirukumab rights, a Janssen spokesman said there has been no decision made on the future of that trial.
Nevertheless, in an Aug. 2 note, BTIG Analyst Dane Leone said that when it comes to giant cell arteritis, "the company will likely run into the same issues as RA given the recent approval of Actemra … within the same indication."
Furthermore, "the mechanism of action for sirukumab in MDD is interesting, but we do not think that the toxicity profile will be acceptable within the indication," Leone said.
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