Rheumatoid arthritis safety spotlight widens

Gaining market share in rheumatoid arthritis has been looking ever more difficult because of new entries and looming biosimilar competition, and now a spotlight on safety has only added to the uncertainty.

The US FDA has cited specific cardiovascular safety issues with two of the current wave of rheumatoid arthritis agents, Lilly’s Olumiant and Johnson & Johnson’s Plivensia, the former of which might need to conduct a new clinical trial to rule out risk. The eligible population for these agents numbers in the millions and has several existing choices, so regulators seem to be taking a more assertive approach on the safety profile of follow-on products.

Imbalance

Briefing documents released yesterday before an FDA advisory committee meeting on Plivensia, whose active ingredient is sirukumab, revealed that the staff wants its expert consultants to consider an imbalance in deaths, major cardiovascular events like heart attacks and strokes, and cancer in its clinical programme. This comes a week after Lilly revealed that Olumiant had been knocked back because the FDA wants to analyse an imbalance in thromboembolic events in its trials more closely.

In Plivensia’s trials investigators said 34 of 35 deaths were in patients receiving the injection, and 13 of the 34 were from major adverse cardiovascular events. Like other IL-6 inhibitors, the project raises low-density lipoproteins. Overall, there was an imbalance in overall cardiovascular events in the Plivensia 50mg group, for which J&J is seeking approval, versus placebo, the FDA concluded.

Last week, Lilly reported that the FDA had cited five cases of deep-vein thrombosis or pulmonary embolism in its complete response letter denying approval of Olumiant.

In both cases, the regulator’s caution might have been motivated by experiences with products in the same classes already on the market. The FDA’s adverse events monitoring has identified 18 primary cases of pulmonary embolism with Olumiant’s Jak inhibitor predecessor Xeljanz, according to FAERS data compiled by Advera Health. Actemra, which is an IL-6-inhibiting antibody like Plivensia, has reported 21 (Olumiant clot signal echoes Xeljanz experience, July 26. 2017). 

As Lilly did last week with Olumiant, J&J says it is confident that the benefit of Plivensia outweighs the risk.

The end of unmet needs

The allure of the $25bn rheumatoid arthritis space is strong, but as biosimilars of established products prepare to enter it is becoming harder to argue that there is an unmet medical need in the disease and in associated autoimmune disorders.

The RA population numbers nearly two million in the US, and if all the indications for which the market leader, Humira, is prescribed excluding psoriasis are considered, the eligible population rises to more than four million. Thus the FDA might be growing more cautious about approving agents that could result in a significant number of complications and deaths.

Moreover, biosimilars are on their way – so far, the US FDA has approved copycats of Abbvie’s Humira and Amgen’s Enbrel, and Pfizer has launched the Remicade biosimilar Inflectra. Their entry means that the US market for rheumatoid arthritis agents is not expected to expand measurably in sales terms from $14bn this year, and new entrants will not want to test a fiercely competitive market at a safety disadvantage.

Rheumatoid arthritis outlook by class and category
US sales (RA only; $m)
Product Company 2016 2018 2020 2022
TNF inhibitors
Humira Abbvie 3,548 4,564 4,652 4,028
Enbrel Amgen 3,851 3,345 3,081 2,827
Simponi J&J 692 917 1,094 1,084
Cimzia UCB 511 570 561 519
Remicade J&J 1,199 795 350 139
IL-6 inhibitors
Actemra Roche 657 806 928 930
Kevzara Sanofi - 124 249 358
Plivensia* J&J - 164 383 638
Jak inhibitors
Xeljanz Pfizer 805 1,053 1,089 1,121
Olumiant* Lilly - - 99 280
Biosimilars**
Inflectra (Remicade) Pfizer 4 117 179 261
Amjevita (Humira) Amgen  - 40 173 331
*Filed; Olumiant consensus predates CRL; **No forecast for Enbrel biosimilar Erelzi. Source: EvaluatePharma.

Forecasts for Olumiant have shrunk to less than $1bn in 2022 since Lilly received the bad news from the FDA, and Plivensia US sales forecasts remain modest at $638m in 2022; Actemra will top out at about $1bn in 2021. Taken together the IL-6s are dwarfed in autoimmune disease by the anti-TNF class of Humira, Enbrel and Remicade.

In a saturated market it looks tough for Plivensia to meet these forecasts even with a clean label. A cardiovascular warning, should the FDA require one, will make it even more difficult.

To contact the writer of this story email Jonathan Gardner in Virginia at [email protected] or follow @ByJonGardner on Twitter

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