Centocor should conduct additional studies of ustekinumab to evaluate potential interim doses, according to FDA's Dermatologic and Ophthalmic Drugs Advisory Committee.

The panel unanimously recommended the first-in-class immunosuppressant for treatment of moderate to severe psoriasis during a June 17 meeting.

The firm is proposing two doses, calibrated for patient weight, based on findings from two Phase III clinical trials. The studies that show efficacy at 45 mg and 90 mg suggest patients weighing equal to or more than 100 kg should receive the higher dose. However, the committee raised concerns regarding the range of body masses that qualify individuals for the 45 mg dose.

In its briefing materials, FDA observes that there appears to be a relationship between efficacy outcomes and weight, with higher success rates seen in heavier subjects dosed with 90 mg.

In addition, some panelists raised concerns about possible overdose among lower-weight patients.

"If you have a 100 percent response to any of these drugs, you're treating a person who is 110 pounds with the same amount of dose as someone who is 190 pounds," said temporary voting member Robert Katz, Dermatology Clinic. "Maybe 50 kilos would get half a dose."

FDA Seeks Middle Ground With Dosing Suggestion

The sponsor's finding that efficacy was significantly demonstrated for both doses was unanimously accepted by the advisory panel. FDA agreed with that conclusion, but suggested an interim 67.5 mg dose. The proposal was rejected by Centocor, which noted that other doses have not been studied.

"We don't see the benefit of exposing that mid-way group of patients to additional drugs," Centocor execs said.

"To me going from two to three [doses] is not complex," said temporary voting member Robert Stern, Beth Israel Deaconess Medical Center. "The idea there is a relationship between weight and needed dose ... I don't see how you could argue that there should be a cut point."

In any case, Centocor argued that it would "take a long time" to obtain stability data to manufacture a 67.5 mg vial. The firm plans to distribute the medicine in 45 mg or 90 mg single-dose vials.

Centocor's proposed dosing regimen includes an initial subcutaneous injection and one four weeks later with additional dosing every 12 weeks.

Panelists recommended enabling physicians to determine the best dose for patients, possibly by indicating a stop-line for lower doses on the 90 mg vial.

The committee also agreed more data is needed to determine an appropriate stopping point for treatment due to the potential for patients to build up resistance over time.

Animal Studies Suggest Possible Malignancy Risk

Though dosing remains an immediate concern, a looming safety issue has yet to be studied in the long-term - ustekinumab's theoretical link to increased malignancy.

Panelists evaluated the risk profile of the fully human injectable monoclonal antibody, specifically the theoretical link to malignancy in agents directed against the p40 subunit of the interleukin 12 and interleukin 23 cytokines .

As a class, there seems to be a dearth of malignancy data for biological psoriasis treatments. Carcinogenicity studies have not been performed in animals for Genentech's Raptiva (efalizumab), Astellas' Amevive (alefacept), Johnson & Johnson's Remicade (infliximab), Abbott's Humira (adalimumab) or Amgen's Enbrel (etanercept), according to FDA. However, mice treated with anti-IL-12/IL-23p40, the mechanism of action in ustekinumab, showed decreased neoplasia defense.

Temporary voting member Lynn Drake, Massachusetts General Hospital, asserted that more studies would be needed to assess carcinogenic risk.

"Yes, there's a risk for malignancy. ... It's going to take years to determine if it's a real risk or a hypothetical risk," she said.

"The animal studies are very worrisome for malignancy compared with other biologics I've heard about," temporary voting member Eileen Ringel, a Maine-based Dermatologist, told the committee. "The risk for malignancy is considerable and the risk for infection is considerable, and I think we're too cavalier for biologics in general."

FDA concluded that though there is no apparent pattern to types of malignancies through 18 months of follow-up, the available data may not account for the long latency period of tumor development.

Although no studies with ustekinumab, in animals or humans, have shown an increased risk of malignancies, FDA is considering including a statement about the carcinogenic potential of the biologic in the label, based on a positive signal noted in the literature about malignancy risk with antagonism of IL-12/IL-23p40 in mice.

Committee Calls For Patient Registry

The committee requested additional long-term safety studies with more patient enrollment to monitor adverse events, such as cardiovascular events and serious infection, in addition to malignancies.

Several members also favored a mandatory patient registry.

"Without registering patients and restricting distribution you'll never get a concrete answer," said Drug Safety and Risk Management Advisory Committee member Susan Heckbert, University of Washington.

The panel supported the suggestion by Centocor to extend its pivotal trials, but was critical of the sponsor's proposed PSOLAR registry. Panelists felt that the initiative to track an additional 4,000 patients for at least eight years requires higher enrollment and more follow-up to answer long-term safety questions.

"Ultimately the number of patients enrolled in these trials is not going to be sufficient to answer the questions about malignancies," committee chair Michael Bigby, Beth Israel Deaconess Medical Center, said. "I don't think PSOLAR is the solution to this issue."

The firm submitted a last-minute update to its Risk Management Plan, following the example of Cephalon during its Fentora (fentanyl buccal tablets) review (¹ Also see "The Role Of RiskMAPs: Fentora Shows Shift From Post-Market To Pre-Market" - Pink Sheet, 12 May, 2008.. p. 3).

The revised plan, the details of which FDA had not seen prior to the advisory committee meeting, includes a more comprehensive use of patient and health care registries for post-market surveillance, as well as use of specialty pharmacies for self-administered dosing.

In addition to patient registries, panelists agreed Centocor's five-year extensions of its current pivotal trials would be useful.

In comparison, FDA requested an additional 5,000-patient, 10-year post-market study for J&J's psoriasis treatment Remicade, which had eight years of marketing history when approved for psoriasis.

Centocor's pivotal studies - Phoenix I (T08) and Phoenix II (T09) - compared ustekinumab to placebo over 12 weeks with follow-up at 52 weeks for T08 and at 28 weeks for T09.

The panel also requested further studies to evaluate the drug's effects on asthma, pneumonia and non-melanoma skin cancer - risk factors tied to immunosuppressant use.

Is Self-Administration Foolproof?

Centocor is requesting that the ustekinumab approval allow for self-administration by patients; FDA and the advisory panel remained concerned that the clinical setting of the pivotal trials does not reflect real-world use.

The committee raised concerns regarding whether patients would be able to inspect the product for potential problems.

Furthermore, self-administration could reduce follow-up, and potentially the identification of emergent malignancies or other adverse outcomes.

The firm proposes to monitor malignancy, cardiovascular events and serious hypersensitivity in psoriasis patients as part of its risk management plan.

- Carlene Olsen (c.olsen@elsevier.com)

FDA Panel Recommends Centocor’s Ustekinumab Approval; Questions Dosing

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