The FDA ( U.S. Food and Drug Administration ) has approved the reintroduction of Tysabri ( Natalizumab ) as a monotherapy treatment for relapsing forms of multiple sclerosis to slow the progression of disability and reduce the frequency of clinical relapses.

TYSABRI will be available upon the completion of key activities related to the risk management plan ( TOUCH Prescribing Program ), including FDA review of educational and training materials, internal validation of systems based on final FDA requirements and training of internal personnel.

TOUCH Prescribing Program has been designed to inform physicians and patients of the benefits and risks of Tysabri treatment and minimize potential risk of progressive multifocal leukoencephalopathy.

Biogen Idec and Elan voluntarily suspended Tysabri from the U.S. market and all ongoing clinical trials in February 2005 based on reports of progressive multifocal leukoencephalopathy, an opportunistic viral infection of the brain that usually leads to death or severe disability.


TOUCH Prescribing Program

TOUCH ( TYSABRI Outreach: Unified Commitment to Health ) Prescribing Program was developed in conjunction with the FDA to facilitate the appropriate use of Tysabri and to assess, on an ongoing basis, the incidence and risk factors for progressive multifocal leukoencephalopathy, and other serious opportunistic infections associated with Tysabri treatment.

Elements of the TOUCH Prescribing Program include:

- Revised labeling with a prominent boxed warning of the risk of progressive multifocal leukoencephalopathy, and warnings against concurrent use of Tysabri with chronic immunosuppressant or immunomodulatory therapies, and patients who are immunocompromised due to HIV, hematological malignancies, organ transplants or immunosuppressive therapies

- Mandatory enrollment for all prescribers, central pharmacies, infusion centers and patients who wish to prescribe, distribute, infuse, or receive, respectively, Tysabri

- Controlled, centralized distribution only to authorized infusion centers

- Mandatory FDA-reviewed educational tools for patients and physicians, including a patient medication guide, TOUCH enrollment form and a monthly pre-infusion checklist

- Ongoing assessment of progressive multifocal leukoencephalopathy, risk and overall safety. A 5,000 patient cohort observational study over five years, the Tysabri Global Observation Program in Safety ( TYGRIS )



Two-year data from the AFFIRM monotherapy trial showed that treatment with Tysabri reduced the risk of disability progression by 42% ( p<0.001 ), the primary endpoint of the study, and led to a 67% reduction ( p<0.001 ) in the annualized relapse rate compared to placebo.
Tysabri treatment also resulted in sustained and statistically significant reductions in brain lesion activity as measured by MRI.
The two-year data from the SENTINEL add-on trial also demonstrated that treatment with Tysabri in addition to Avonex ( Interferon beta-1a ) had a significant effect on disability progression, relapse rate and brain MRI disease activity compared to Avonex alone.

Tysabri can increase the risk of progressive multifocal leukoencephalopathy, an opportunistic viral infection of the brain that usually leads to death or severe disability.
Three cases of PML occurred in clinical trial patients who were concomitantly exposed to immunomodulators ( Interferon beta in the patients with multiple sclerosis ) or were immunocompromised due to recent treatment with immunosuppressants ( e.g., Azathioprine in the patient with Crohn's disease ).
Two of the cases were observed in 1,869 patients with multiple sclerosis treated for a median of 120 weeks. A third case of PML occurred among 1,043 patients with Crohn's disease after the patient received eight doses.
The number of cases is too few and the number of patients treated too small to reliably conclude that the risk of progressive multifocal leukoencephalopathy, is lower in patients treated with Tysabri alone than in patients who are receiving other drugs that decrease immune function or who are otherwise immunocompromised.

Tysabri is contraindicated in patients who have or have had progressive multifocal leukoencephalopathy, or with known hypersensitivity to Tysabri or any of its components.
In Phase III placebo-controlled trials of Tysabri in multipel sclerosis, the overall incidence and rate of other infections were balanced between Tysabri-treated patients and controls.
Herpes infections were slightly more common in patients treated with Tysabri.
Commonly reported infections with Tysabri included urinary tract infections, lower respiratory tract infections, gastroenteritis and vaginitis.
Serious opportunistic and other atypical infections have been observed in Tysabri-treated patients, some of these patients were receiving concurrent immunosuppressants.

The incidence and rate of other serious and common adverse events in clinical trials were similarly balanced between treatment groups. Serious events that occurred in Tysabri-treated patients included hypersensitivity reactions ( e.g., anaphylaxis ), depression and gallstones.
Appendicitis was more common in patients receiving Tysabri with Avonex.
Common adverse events reported in Tysabri-treated patients include infusion reactions, headache, fatigue, joint and limb pain, abdominal discomfort, diarrhea and rash.

Source: Biogen, 2006


XagenaMedicine2006