Stelara Clears FDA; Different Class, But REMS Looks Similar To TNF Blockers

Centocor Ortho Biotech's Stelara (ustekinumab) brings a novel mechanism and superior efficacy to the plaque psoriasis marketplace, but in terms of risk management, the anti-inflammatory biologic differs little from the tumor necrosis factor inhibitor class.

As an inhibitor of interleukin-12 and 23, Stelara differs from the TNF blocker's mode of action. FDA's Sept. 25 approval of the first-in-class agent for treatment of plaque psoriasis carries with it a requirement for a Risk Evaluation and Mitigation Strategy that mirrors that for the anti-TNF class.

FDA's announcement states the main reason for the Stelara REMS is the risk of serious infections - including those caused by viruses, fungi and bacteria - some of which have led to hospitalization, as well as a possible increased risk of developing cancer.

Last September, FDA announced it was requiring a class-wide REMS for the TNF blockers to address the risk of serious fungal infections (¹ (Also see "TNF Blocker Fungal Infection: FDA Uses REMS For Relabeling, Education" - Pink Sheet, 8 Sep, 2008.)). The biologic agents also carry risk of other serious infections and a potential increased risk of cancer in juvenile patients.

Two members of the five agent class - UCB's Cimzia and Centocor's Simponi (golimumab) - have approved REMS, both of which include Medication Guides and communication plans. The MedGuides have been updated for all of the agents, FDA recently confirmed that the communication plans are still in development for the remaining, earlier anti-TNF drugs: Amgen's Enbrel , Centocor's Remicade and Abbott's Humira (² Pharmaceutical Approvals Monthly September 2009).

The Stelara REMS consists primarily of a MedGuide that addresses both the infection and malignancy concerns, according to Centocor. There will also be a communication plan, consisting of "Dear Health Care Provider" letters for both doctors and pharmacists, an adverse event reporting awareness campaign and other outreach efforts. Centocor will target dermatologists as well as a range of other specialists, including immunologists and rheumatologists.

The implicit message for sponsors of other novel therapeutics set to compete with an existing class is that the new agents will be expected to carry warnings relevant to the existing drugs until they prove otherwise in extensive use.

With two entrants already in the TNF class, Centocor is playing up the unique mechanism for Stelara, emphasizing that it is designed to act on the development of psoriasis. The releases from both the company and FDA note that the biologic blocks two proteins that contribute to the overproduction of skin cells and inflammation.

Centocor's two anti-TNF agents, the elder statesmen Remicade and the newer entrant Simponi are differentiated by the form of administration and therefore have different reimbursement opportunities. Remicade is indicated for plaque psoriasis, but Simponi is not. Stelara's main competition in the psoriasis market will be from the TNF class: Enbrel and Humira.

[Editor's note: This story updated Sept. 29 to correct Remicade indications.]

The unique mechanism and the improved efficacy will be the central focus of Centocor's promotional push. The Phase III trial program for Stelara included a head-to-head comparison versus etanercept, where ustekinumab came out the clear winner (³ (Also see "J&J’s Stelara Beats Enbrel In Psoriasis" - Pink Sheet, 19 Sep, 2008.)).

Stelara also brings another key advantage in dosing. Whereas Humira and Enbrel are dosed every other week or twice-weekly, respectively, Stelara is injected every 12 weeks (after two starter doses at weeks 0 and 4). Stelara will be priced comparably to other biologics in the field, Centocor said.

The drug has drawn a lot of attention within the dermatology community during development. At the FDA advisory committee review in June 2008, the panel discussed the likely fast uptake for the drug once approved because of the signs from clinical trials that the drug would be more efficacious than existing drugs. The panel voted unanimously in favor of approval. The expectations of wide use may have contributed to the lag from the advisory committee to final approval (over 15 months). The panel called for caution - particularly because the subunit that Stelara blocks on IL-12 and IL-23 could lead to increased malignancy (⁴ (Also see "FDA Panel Unanimously Recommends Centocor’s Ustekinumab" - Pink Sheet, 17 Jun, 2008.)).

That eventually took the form of a request for a REMS, in a "complete response" letter sent in December 2008 (⁵ (Also see "FDA To Centocor: Show Me The REMS" - Pink Sheet, 22 Dec, 2008.)). Centocor responded in January. Work on the REMS was not the only delaying factor - manufacturing issues also came up, in June of 2009.

- Mary Jo Laffler ( ⁶ [email protected] )