22 Nov Multiple Sclerosis: Interim Report on the Safety and Efficacy of Long-Term Daclizumab Treatment for Up to Five Years

MedicalResearch.com Interview with
Ralph Kern, M.D.
Senior vice president, Worldwide Medical
Biogen

MedicalResearch.com: What is the background for this study?

Response: Previously reported clinical trials of daclizumab demonstrated significant efficacy across clinical and MRI measures, compared to placebo and interferon beta-1a 30 mcg intramuscular (IM) injection, and established the therapy’s safety profile for up to two to three years. These trials were the basis for approval by health authorities in the United States, European Union and Australia. Daclizumab is a once-monthly, self-administered, subcutaneous therapy for relapsing forms of MS (RMS).

At ECTRIMS we presented the first interim results from EXTEND, a long-term extension study. EXTEND is an ongoing multicenter, open-label study to evaluate the safety and efficacy of daclizumab treatment in more than 1,500 patients with RMS.

This interim ECTRIMS analysis includes up to five years of data from patients who were previously enrolled in DECIDE. DECIDE was a Phase 3 study evaluating the effects of daclizumab relative to interferon beta-1a IM. In the new analysis, patients who were treated with interferon beta-1a IM for two to three years in DECIDE switched to daclizumab when they enrolled in EXTEND, and were compared to daclizumab patients treated continuously in both DECIDE and EXTEND.

MedicalResearch.com: What are the main findings?

The interim results show that treatment with daclizumab led to sustained efficacy in the proportion of patients who remained relapse-free, as well as those who did not experience 24-week confirmed disability progression. Annualized relapse rate (ARR) decreased for patients who switched to daclizumab in the EXTEND study (from 0.317 to 0.152), and remained stable for patients who took daclizumab continuously in the DECIDE and EXTEND studies (0.195 vs. 0.156, respectively).

Compared with patients who were switched to daclizumab in EXTEND, patients treated continuously with daclizumab from DECIDE baseline up to week 192 experienced a 21 percent relative risk reduction in 24-week confirmed disability progression (hazard ratio: 0.79; 95% confidence interval: 0.62–1.00; p=0.047). Improvements in MRI data, from baseline to week 48 in EXTEND, were observed in both groups (based on new T2 hyperintense lesions, new T1 hypointense lesions and the number of gadolinium-enhancing lesions).

In this new analysis, the safety profile of ZINBRYTA was similar to that observed in DECIDE. The overall incidence of serious adverse events (AEs), excluding MS relapses, remained stable over time. For patients who received interferon beta-1a IM in the DECIDE study and switched to daclizumab in EXTEND, the incidence of serious AEs (excluding MS relapse) over the first two years of treatment was similar to daclizumab-treated patients in DECIDE. In addition, most AEs of special interest (including liver AEs, skin-related AEs, infections and lymphadenopathy, or abnormal enlargement of lymph nodes) were mild to moderate in severity.

MedicalResearch.com: What should readers take away from your report?

The interim EXTEND results build on existing clinical data by providing longer-term safety and efficacy data on daclizumab. These data support the safety profile of daclizumab for up to five years and reinforce the treatment’s efficacy across clinical and MRI measures.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

The EXTEND study is ongoing and will continue to follow RMS patients, who will receive subcutaneous daclizumab every four weeks for up to five years. Together with our partners at AbbVie, we look forward to sharing additional results from EXTEND in the future.

MedicalResearch.com: Is there anything else you would like to add?

MS is a heterogeneous, chronic disease that affects each person differently, so it is important that healthcare providers have additional therapeutic options to address their patients’ needs throughout the course of the disease. At Biogen, we are committed to advancing MS research and understanding the impact the disease has on the community.

INDICATION

ZINBRYTA (daclizumab) is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis (MS). Because of its safety profile, the use of ZINBRYTA should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.

IMPORTANT SAFETY INFORMATION

WARNING: HEPATIC INJURY INCLUDING AUTOIMMUNE HEPATITIS and OTHER IMMUNE-MEDIATED DISORDERS

Hepatic Injury Including Autoimmune Hepatitis

• ZINBRYTA can cause severe liver injury including life-threatening events, liver failure, and autoimmune hepatitis. Obtain transaminase and bilirubin levels before initiation of ZINBRYTA. Monitor and evaluate transaminase and bilirubin levels monthly and for 6 months after the last dose
• ZINBRYTA is contraindicated in patients with pre-existing hepatic disease or hepatic impairment

Other Immune-Mediated Disorders

• Immune-mediated disorders including skin reactions, lymphadenopathy, non-infectious colitis, and other immune-mediated disorders can occur with ZINBRYTA

These conditions may require treatment with systemic corticosteroids or immunosuppressive medication

ZINBRYTA is available only through a restricted distribution program called the ZINBRYTA REMS Program

Contraindications

ZINBRYTA is contraindicated in patients with pre-existing hepatic disease or hepatic impairment, including alanine aminotransferase (ALT) or aspartate aminotransferase (AST) at least 2 times the upper limit of normal (ULN); a history of autoimmune hepatitis or other autoimmune condition involving the liver; or a history of hypersensitivity to daclizumab or any other components of the formulation.

Hepatic Injury

ZINBRYTA can cause life-threatening severe liver injury, including liver failure and autoimmune hepatitis. In controlled studies, serious drug-related hepatic injury occurred in 0.7% of ZINBRYTA-treated patients compared with 0.4% of AVONEX-treated patients (Study 1) and in 1.0% of ZINBRYTA-treated patients compared with no injury in placebo patients (Study 2). A fatal case of autoimmune hepatitis occurred in a patient re-initiating ZINBRYTA after a planned 6 month treatment interruption period. The incidence of increases in hepatic transaminases was greater in patients taking ZINBRYTA than in those taking AVONEX or placebo. Prior to starting treatment with ZINBRYTA, obtain serum transaminases (ALT and AST) and total bilirubin levels. Test transaminase levels and total bilirubin monthly and assess before the next dose of ZINBRYTA. Follow transaminase levels and total bilirubin monthly for 6 months after the last dose of ZINBRYTA. If a patient develops clinical signs or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine), promptly measure serum transaminases and total bilirubin and interrupt or discontinue treatment with ZINBRYTA, as appropriate. Discontinue ZINBRYTA if autoimmune hepatitis is suspected. Caution should be used when using hepatotoxic drugs, including nonprescription drugs, herbal products, and dietary supplements, concomitantly with ZINBRYTA.

Immune-Mediated Disorders

Treatment with ZINBRYTA increases the risk of immune-mediated disorders, including autoimmune disorders such as autoimmune hepatitis. Across all clinical studies (controlled and open-label), immune-mediated disorders occurred in 28% of patients on ZINBRYTA, the most common of which were skin reactions and lymphadenopathy. In the active-control study (Study 1), immune-mediated disorders were observed in 32% of ZINBRYTA-treated patients compared with 12% for AVONEX-treated patients. Some patients required invasive procedures for diagnosis (e.g., colonoscopy, liver biopsy, kidney biopsy, lung biopsy), hospitalization for fluid replacement or blood transfusion, or prolonged treatment with systemic corticosteroids or immunosuppressant drugs. Some of these events did not resolve after stopping ZINBRYTA during study followup. Prescribers should be vigilant regarding emergent immune-mediated disorders. For suspected immune-mediated disorders, ensure adequate evaluation to confirm etiology or to exclude other causes. If a patient develops a serious immune disorder, consider stopping ZINBRYTA and refer the patient to an appropriate specialist for further evaluation and treatment.

• ZINBRYTA causes skin reactions. In clinical trials, skin reactions occurred in 37% of ZINBRYTA-treated patients compared with 19% of AVONEX-treated patients (Study 1) and in 18% of ZINBRYTA-treated patients compared with 13% of patients on placebo (Study 2). Skin reactions occurred at any time during treatment with ZINBRYTA. If a patient develops a serious diffuse or inflammatory rash, it is recommended that a dermatologist evaluate the patient before the next dose of ZINBRYTA. Discontinuation of ZINBRYTA may be appropriate.
• ZINBRYTA increases the incidence of lymphadenopathy. In controlled studies, lymphadenopathy or lymphadenitis occurred in 6% of ZINBRYTA-treated patients compared with 1% of AVONEX-treated patients (Study 1) and in 2% of ZINBRYTA-treated patients compared with 1% of placebo-treated patients (Study 2).
• An increased incidence of serious colitis (less than 1%) was reported in patients treated with ZINBRYTA compared with none for patients treated with AVONEX or placebo in clinical trials.
• A wide variety of other immune-mediated disorders, some serious, have occurred infrequently with the use of ZINBRYTA. If a patient develops a serious immune disorder, consider stopping ZINBRYTA.

ZINBRYTA REMS Program

ZINBRYTA is available only through a restricted program called the ZINBRYTA REMS Program, because of the risks of hepatic injury including autoimmune hepatitis, and other immune-mediated disorders. Only certified prescribers and pharmacies and patients enrolled in the REMS program can prescribe, dispense or receive ZINBRYTA.

Acute Hypersensitivity

ZINBRYTA can cause anaphylaxis, angioedema, and urticaria after the first dose or at any time during treatment. Discontinue and do not re-start ZINBRYTA if anaphylaxis or other allergic reactions occur.

Infections

ZINBRYTA increases the risk for infections. The most common types of infections observed were upper respiratory tract infections, urinary tract infections and viral infections. Avoid initiating ZINBRYTA in patients with severe active infection until the infection is fully controlled. If serious infection develops, consider withholding treatment with ZINBRYTA until the infection resolves.

• Vaccination with live vaccines is not recommended during treatment and up to 4 months after discontinuation of ZINBRYTA

Depression and Suicide

In controlled trials, depression-related events occurred in 10% of ZINBRYTA-treated patients compared with 8% of AVONEX-treated patients (Study 1) and in 7% of ZINBRYTA-treated patients compared with 2% of patients taking placebo (Study 2). Administer ZINBRYTA with caution to patients with previous or current depressive disorders. Advise patients and/or caregivers to immediately report any symptoms of new or worsening depression and/or suicidal ideation. If a patient develops severe depression and/or suicidal ideation, consider discontinuation of ZINBRYTA.

Adverse Reactions

The most common adverse reactions (incidence at least 5% and at least 2% higher incidence than comparator) that occurred in ZINBRYTA-treated patients were nasopharyngitis, upper respiratory tract infection, rash, influenza, dermatitis, oropharyngeal pain, bronchitis, eczema, and lymphadenopathy compared with AVONEX; and upper respiratory tract infection, depression, rash, pharyngitis, and increased ALT compared with placebo.

Please see Full Prescribing Information including Boxed Warning and Medication Guide for additional Important Safety Information

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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Last Updated on November 22, 2016 by Marie Benz MD FAAD