Introduction to Daclizumab

Daclizumab (brand name Zinbryta) is a humanized monoclonal antibody against the alpha subunit (CD25) of the high-affinity interleukin-2 (IL-2) receptor. It was initially approved by the FDA in 1997 for the prevention of acute organ rejection in patients receiving renal transplants. A new formulation, Daclizumab High-Yield Process (DAC HYP), was later developed and approved in 2016 for the treatment of relapsing forms of multiple sclerosis (MS). However, it's crucial to note that Daclizumab was voluntarily withdrawn from the global market in March 2018 due to safety concerns.

Mechanism of Action

Daclizumab works by binding to CD25, the alpha subunit of the high-affinity IL-2 receptor, which is expressed on activated T cells. This binding inhibits IL-2-mediated cell activation, thereby modulating immune responses.

Key points:

• Binds to CD25 on T cells, preventing the formation of the high-affinity IL-2 receptor
• Inhibits IL-2-dependent T cell activation and proliferation
• Leads to expansion of CD56bright natural killer (NK) cells, which have regulatory functions in MS
• Reduces the number of pro-inflammatory T cells crossing the blood-brain barrier
• May promote the differentiation of regulatory T cells, further modulating immune responses

Indications

Before its withdrawal, Daclizumab was FDA-approved for:

1. Treatment of adult patients with relapsing forms of multiple sclerosis (2016-2018)
2. Prevention of acute organ rejection in patients receiving renal transplants (1997-2009, different formulation)

Off-label uses included:

• Treatment of uveitis
• Graft-versus-host disease prophylaxis
• Treatment of T-cell lymphoma

Dosage and Administration

When it was available, Daclizumab was administered as follows:

• For multiple sclerosis: 150 mg subcutaneous injection once monthly
• For renal transplant patients (older formulation): 1 mg/kg intravenous infusion every 14 days for a total of 5 doses

Important administration notes:

• Patients were advised to inject in areas such as the thigh, abdomen, or back of the upper arm
• The injection site was to be rotated with each dose to reduce the risk of injection site reactions
• Daclizumab was to be stored in a refrigerator (2°C to 8°C) and protected from light
• The drug could be kept at room temperature (up to 30°C) for up to 30 days, but not returned to the refrigerator

Efficacy

Multiple Sclerosis:

• Reduced annualized relapse rate by 45% compared to interferon beta-1a in the DECIDE trial
• Decreased the number of new or enlarging T2-hyperintense lesions by 54% over 96 weeks
• Reduced the number of gadolinium-enhancing lesions by 65% at week 96
• Slowed the progression of disability by 16% over 144 weeks (not statistically significant)

Renal Transplantation (older formulation):

• Reduced the incidence of acute rejection episodes in the first 6 months post-transplant
• Improved graft survival rates at 1 and 3 years post-transplant
• Allowed for reduction in concomitant immunosuppressive therapy

Side Effects

Common side effects (≥5% incidence and at least 2% greater than interferon beta-1a) included:

• Nasopharyngitis (25%)
• Upper respiratory tract infection (17%)
• Rash (11%)
• Influenza (9%)
• Dermatitis (9%)
• Oropharyngeal pain (8%)
• Bronchitis (7%)
• Eczema (5%)
• Lymphadenopathy (5%)

Serious side effects that led to its withdrawal:

• Severe liver injury, including autoimmune hepatitis and liver failure requiring transplant
• Immune-mediated disorders such as skin reactions, lymphadenopathy, and non-infectious colitis
• Encephalitis and meningoencephalitis (including anti-NMDA receptor encephalitis)

Precautions and Monitoring

When Daclizumab was in use, the following precautions were recommended:

• Monthly monitoring of liver function tests
• Screening for hepatitis B and C before initiation of therapy
• Monitoring for signs and symptoms of hepatic injury during treatment
• Evaluation of patients with prolonged fever or lymphadenopathy for potential serious infections or immune-mediated conditions
• Monitoring for skin reactions and prompt referral to a dermatologist if severe rashes occur
• Vigilance for symptoms of depression and suicidal ideation
• Caution in patients with pre-existing hepatic disease or hepatic impairment
• Avoid live vaccines during treatment and for 4 months after the last dose
• Pregnancy Category C: Use only if the potential benefit justifies the potential risk to the fetus

Market Withdrawal

Daclizumab was voluntarily withdrawn from the global market by its manufacturers (Biogen and AbbVie) on March 2, 2018, due to safety concerns. Key points about the withdrawal include:

• The decision was based on the nature and complexity of adverse events reported
• Reports of serious inflammatory brain disorders, including encephalitis and meningoencephalitis, were a primary concern
• The European Medicines Agency (EMA) had started a review of Daclizumab following reports of autoimmune hepatitis
• The manufacturers concluded that the benefit-risk profile of Daclizumab was no longer favorable
• Patients were advised to immediately discontinue use and contact their healthcare providers
• Healthcare providers were instructed not to start new patients on Daclizumab and to transition existing patients to alternative therapies

This withdrawal highlights the importance of post-marketing surveillance and the ongoing evaluation of drug safety profiles, even after FDA approval.