The approval of Biogen Idec/Elan's multiple sclerosis treatment Tysabri (natalizumab) for Crohn's disease will expand the use of the product's multi-layered risk management program.

The new indication is an endorsement of the product and the TOUCH program that allowed it to return to the market in 2005 after a year's hiatus prompted by concerns about progressive multifocal luekoencephalopathy. But the new indication also brings new challenges for the sponsors, who must educate a market about a risky product, rather than navigate the return of a desperately requested one.

"With the addition of Tysabri to the treatment options for sufferers of Crohn's disease, we make an important step in the armentarium for treatment, but one that carries serious risks," Joyce Korvick, FDA Deputy Director for the Division of Gastroenterology Products, said during a Jan. 14 conference call announcing the approval.

A Limited Indication

The promotional hurdles for Biogen and Elan are illustrated in the scope of the indications for the two diseases. Whereas in MS, Tysabri is "generally recommended" for patients who have failed other treatments, in Crohn's the product is truly second-line, approved for "inducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn's disease with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional Crohn's disease therapies and inhibitors of TNF-alpha."

Also, in Crohn's disease, Tysabri is contraindicated "with immunosuppressants or inhibitors of TNF-alpha."

The sponsors took the unusual step of limiting the Crohn's indication during presentation to the advisory committee in order to boost their chances of endorsement, which they received by a vote of 12-3 from a joint meeting of the Gastrointestinal Drugs and the Drug Safety and Risk Management Advisory Committees (¹ Also see "Firms Tighten Tysabri Indication To Gain Panel Endorsement For Crohn’s" - Pink Sheet, 6 August, 2007., p. 13).

In Europe, however, the Committee for Human Medicinal Products recommended against Tysabri's approval for Chron's disease, citing insufficient evidence to show efficacy given the drug's risks.

Several trials supported FDA's approval, including ENCORE, ENACT-1 and ENACT-2. Tysabri induced response and remission among patients with moderately to severely active Crohn's disease and reduced objective evidence of inflammation (as measured by elevated C-reactive protein), according to results from ENCORE.

After 12 weeks of therapy, 60 percent of patients on Tysabri attained response, compared to 44 percent of placebo-treated patients, and 48 percent of patients had sustained response at weeks eight and 12, compared to 32 percent of placebo-treated patients. Among the patients who had inadequate response to prior treatment with inhibitors of TNF-alpha, 38 percent achieved sustained response at weeks eight and 12.

Biogen Idec estimates Tysabri will be available by the end of February for patients with Crohn's disease.

A Risk Management Plan That Touches Everyone

MS-TOUCH and CD-TOUCH are risk reduction prescribing programs designed to limit the use of the biologic. Tysabri is available only through this restricted distribution program, and can be administered only to patients enrolled in it (² Also see "Strict Tysabri Risk Management Plan Drives Panel Support For Crohn’s" - Pink Sheet, 6 August, 2007., p. 15).

Under the program, only prescribers, infusion centers and pharmacies associated with infusion centers and registered with the program are able to prescribe, distribute or infuse the biologic.

There is a prescriber/patient acknowledgement form, whereby physicians sign that they are aware of the risks, that they've discussed the risks and benefits with the patient, and that the patient is indeed an appropriate patient for Tysabri. The patients sign that they have read the medication guide, discussed the risks and benefits with their physician, and will report any new or worsening symptoms to their physician promptly. The form must be signed and sent to Biogen Idec before the start of therapy.

Furthermore, prescribers also must complete a patient reauthorization questionnaire on every patient every six months and submit it to Biogen Idec. The questionnaire includes information about whether the patient has experienced PML or other opportunistic infections, and whether the patient has received any concurrent immunomodulatory or immunosuppressant therapies. Prescribers then must explicitly reauthorize the dosing of Tysabri for the next six months.

Infusion centers have stringent requirements as well. Only registered infusion centers trained in the requirements of the program and that have attested that they will follow the requirements can administer Tysabri. Centers are allowed to dose only patients enrolled in the program, and they must verify the patients' enrollment status before every dose. Centers are required to give a medication guide to patients prior to every dose and ask the patient to read it.

Centers also are required to complete a patient pre-infusion checklist (a series of questions that screens the patient for any new or worsening symptoms) for each patient dose. If there are any changes of symptoms listed, the nurses are not to administer Tysabri, and instead should contact the patient's prescribing physician. Centers must then submit pre-infusion checklists to Biogen Idec within one business day of completion

"It's a very complicated, close-looped system, with multiple layers of control, both at the prescriber level, the patient level, the infusion center level, and the distribution level," said Bozic at DIA's recent Conference for Contemporary Pharmacovigilence and Risk Management Strategies.

"We know every patient enrolled in the program, we know where they're receiving Tysabri, and we know how many doses they've received, and which days they've received it," she said. "So we get a very accurate denominator of exposure."

Risk Management Compliance Is At 99%

Such rigorous reporting allows the company to better track PML and other adverse events. According to Biogen Idec, 99.9 percent of Tysabri infusions are to patients enrolled in the program, and almost 98 percent of patients receive Tysabri without any concurrent immunomodulatory or immunosuppressant therapy. Further, 99.9 percent of the drug shipments are to authorized infusion sites, and 99 percent of the expected pre-infusion checklists are received.

Overall, the awareness of PML is "extremely high" according to Biogen Idec. Almost 98 percent of prescribers understand the risks of PML, and 100 percent of the nurses know that Tysabri should be administered only to patients enrolled in the program.

"That tells us that the system is reinforcing the importance of clinical vigilance in the early detection of PML," Bozic said.

Biogen Idec recently released positive safety data on the ongoing use of Tysabri in MS patients, showing that as of late December, more than 21,000 patients were being treated with the drug globally, with no new cases of PML reported.

- Lauren Smith (Lauren.Smith@elsevier.com)

Tysabri For Crohn’s: Risk Management Is Same, But Could Be Higher Hurdle

More from Archive

More from Pink Sheet