FDA's first-cycle approval of Centocor's TNF inhibitor Simponi (golimumab) encapsulates the double-edged position of late entrants into crowded drug classes: while differentiating a new product may pose a commercial challenge, FDA's experience with early members of the class can smooth the way to approval for late-comers.

"This is the fifth anti-TNF [alpha] antibody product submitted for licensure, and a great deal is already known about this class of biologic products after over a decade of use in patients with arthritis," Division of Anesthesia, Analgesia and Rheumatology Product Director Bob Rappaport wrote in a summary review.

The anti-tumor necrosis factor MAb class has proven both lucrative and complex. FDA has repeatedly expanded safety labeling and has been applying its authority to require REMS for both newly approved and marketed products (see ¹ sidebar ).

FDA's experience with the series of TNF inhibitor crises gives a depth of safety experience to similar investigational products. "While this group of drugs can have serious and life-threatening safety issues that should not be minimized, golimumab did not appear to have an additional risk to those already identified for other agents," Office of Drug Evaluation II Director Curtis Rosebraugh wrote in an April 24, 2009 approval memo.

Simponi appears to have cleared the approval bar easily despite the high degree of difficulty inherent in the anti-TNF class. Simponi is the first TNF blocker to seek a rheumatology grand slam - concurrent claims for rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis - and was approved on the user fee goal date after a textbook 10-month review.

The sponsor's experience in the class also contributed to the efficient review process. Centocor has been working with TNF inhibitors from the start: the then-independent company's Remicade (infliximab) was the first TNF blocker approved by FDA, in 1998 for Crohn's disease. The TNF expertise was critical to Centocor's subsequent acquisition by its Remicade partner Johnson & Johnson in 1999.

In end-of-Phase II meetings in 2005, FDA determined that Simponi would qualify for a streamlined series of trials in rheumatology indications. The company originally proposed two studies for each of the three indications, but at an EOP2 meeting April 19, 2005, FDA concluded that "only one trial in AS is required and only one trial in PsA is required to support the AS and PsA indications because in principle, golimumab would be the fourth TNF inhibitor in the United States."

"In closely related diseases, the data from one disease (typically RA) that has demonstrated efficacy in at least two adequate trials can be used to support single adequate trials conducted in the other indications," Rosebraugh explained. "This approach has been historically accepted by the rheumatology group."

"If an unexpected safety signal arises, then additional data may be required," FDA warned Centocor.

Three Indications In One BLA

Initial labeling for Simponi covers treatment of the three rheumatology indications as well as information about improved physical functioning in RA and PsA patients - an outcome that the drug's competitors had gone through several review cycles to achieve.

Amgen/Wyeth's Enbrel (etanercept), approved for RA in 1998, had all three indications by 2005. Remicade added RA in 1999, AS in 2004, and PsA in 2005. Abbott's Humira (adalimumab) joined the RA market with a New Year's Eve approval in 2002, followed by PsA in 2005 and AS in 2006. A month after Simponi's approval, UCB's Cimzia (certolizumab) joined the anti-TNF roster for RA after an initial 2008 approval for Crohn's disease (² Also see "Just-Approved Cimzia Set To Enter Tough RA Market" - Pink Sheet, 14 May, 2009.).

The earlier TNF inhibitors also had higher hurdles for incorporating physical function claims.

Shallow Recruitment Pool

FDA's determination that only one trial would be required for PsA and AS claims helped Centocor avoid some of the complications of conducting the two additional trials (one in each claim) that would otherwise be required. Among the many difficulties Centocor thus avoided is another drawback of being a late entrant in a crowded field: difficulty recruiting patients for blinded, randomized, placebo-controlled trials when similar effective medications are already available.

Institutional review boards expressed concerns that patients in the Simponi trials could be insufficiently treated, review documents indicate. During the 2004 planning meeting, FDA said that blinded six-month data would be needed for approval of each of the three indications. However, "given the difficulty with IRB committees regarding undertreating subjects and that the efficacy for this class of drugs is well-studied, we would accept additional data from a double-blind, randomized withdrawal study of responsive PsA and [2 study] RA subjects following 24 weeks" to support long-term efficacy in the two diseases, the minutes report.

FDA warned that its understanding was "the IRB would not approve another study over three months."

FDA Urges Physical Function Language In Label

FDA's attitude toward the amount of data needed to show improved physical function also had evolved by the time Simponi's BLA was reviewed, with the agency willing to base a claim on six-month rather than two-year data.

Centocor did not request an indication for improvement of physical function for Simponi, but ended up describing improved physical function in golimumab-treated RA and PsA patients in the Clinical Studies section of labeling.

"The clinical team is also recommending the inclusion of the physical function data in the product label, to allow a claim for this outcome," Rappaport reported.

Based on rheumatoid arthritis guidance dating to 1999, FDA historically had sought at least two years of Health Assessment Questionnaire Disability Index (HAQ-DI) data to support a claim of improved physical function in the condition.

Such was the case for golimumab during the 2004 planning conference when FDA said it would accept Healh Assessment Questionnaire (HAQ) results sustained at 24 months in an open-label extension.

FDA acknowledged the difficulty of collecting two-year data and suggested that "if Centocor can provide robust data for one year and then maintain it through the second year, the data would be sufficient. It is recommended to have one-year blinded data and then demonstrate this data out to two years."

The rationale "was that effective treatments would have to prevent the joint damage associated with uncontrolled disease for an extended period of time in order to demonstrate a reduction in physical dysfunction that results from this damage," medical reviewer Eric Brodsky explained.

"Experience with other TNF inhibitors has since demonstrated that improvement in physical functioning occurs rapidly, and that much of physical dysfunction in RA is actually the result of uncontrolled inflammation," Brodsky reported. "Therefore, an extended period of time, such as two years, is no longer considered necessary to demonstrate efficacy for this claim," he concluded.

Cross-Discipline Team Leader Sarah Okada agreed that "it is reasonable to consider granting the claim based on physical function endpoint results (HAQ-DI, in this case) at similar time points as the signs and symptoms endpoints, i.e., 12 or 24 weeks." Instead of two years of data showing HAQ improvement with Simponi, analyses of improvement from baseline to week 24 "form the basis of the data in this submission that could support this claim," Okada noted.

FDA determined that less data was also necessary to support improved physical function in PsA patients. Brodsky noted that "the division now considers shorter duration controlled data to be adequate to grant this claim in PsA."

The company's and FDA's statistical analyses, although using different methods, found similar results: golimumab groups in the PsA trial, "compared to the placebo group, had greater proportions of HAQ responders at week 24."

Physical Function Results Mixed For AS

Short-term physical function and mobility results were mixed for golimumab in AS patients, so labeling includes no information about success in this area. No other AS agents have function or mobility claims, Okada pointed out.

This appears to be related to the presence of more physical damage.

The mobility data are not inconsistent with primary efficacy findings, Brodsky suggested, since "reduction in hip and spine mobility in AS occurs as a result of long durations of disease and treatment effects may not have been possible to demonstrate in the timeframe of this clinical trial."

Studies with other TNF inhibiters indicate that their mechanism of action "appears to have salutary effects on function and MRI evidence of spinal inflammation," Okada explained.

"It is not clear whether the lack of evidence of effect is due to the long duration over which these structural effects occur (and that therefore changes may not be captured in the timeframe of typical clinical trials), or whether this is due to pathophysiologic processes in play that may not be particularly susceptible to TNF inhibition," Okada said.

- Cathy Dombrowski ( ³ c.dombrowski@elsevier.com )

FDA's Decade Of TNF Blocker Experience Eased Path For Simponi Approval

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