NewsSpeak: FDA approves daclizumab

Another milestone for daclizumab in the treatment of relapsing forms of MS. #MSBlog #MSResearch #NewsSpeak

"The FDA has approved daclizumab (Zinbryta) for the treatment of relapsing forms of MS. However, the FDA have recommended it be used second or third line, presumably because of its safety profile and need for monitoring. The US label is very different to the recommendation of the CHMP (Committee for Human use of Medicinal Products, see below), which has recommend daclizumab for relapsing forms of MS, a label not too dissimilar to that of alemtuzumab (Lemtrada) in Europe. It is interesting that the EMA's and FDA's approach to labelling of MS DMTs has flipped. In the past the FDA simply licensed DMTs for relapsing forms of MS and then allowed people with MS, neurologists and payers to sort out how the drug was used in clinical practice. In contrast, the CHMP used to license treatments with a narrow indication, for example natalizumab is licensed for rapidly evolving severe MS and fingolimod for highly-active MS in people with MS who have failed another therapy. The labelling of alemtuzumab, and now daclizumab, shows a change of heart; the FDA have become more conservative and the EMA less conservative, or dare we say liberal? Is this an interesting observation?"

"I am very upbeat about daclizumab because it has an interesting mode of action. Daclizumab is not immunosuppressive, but immunomodulatory. It binds to the so called high affinity IL2 receptor that is mainly expressed on proliferating T cells and T-reg cells; by doing this it diverts IL2 away from these cells to the intermediate IL2 receptor that is expressed on a population of cells called CD56-bright NK or natural killer cells. The expansion of the NK cells is most likely how this drug works. NK-cells are able to regulate T-cells, by killing them, and NK-cells are antiviral. Importantly, daclizumab appears to leave CD4+, CD8+ and B cell function relatively intact. For example, antibody responses to the flu vaccine in daclizumab treated MSers is fine. These latter observations are important as we need both our T and B cells to fight infection. The one downside of blunting the T-cell proliferative responses is that it takes longer to mount an adequate immunological response to common infections. This is probably why we see more infections, and more severe infections, in the daclizumab treated groups of study subjects. Please note these are common infections and not opportunistic infections. If you choose to go onto daclizumab you will need to take infections seriously and get them treated promptly."

"Where will daclizumab will be placed in the current treatment paradigm? As always I say it has a role in DMT-naive MSers, typically those with more active disease, as an alternative to natalizumab or alemtuzumab. It is also a good escalation option instead of DMF, fingolimod, natalizumab or alemtuzumab. The fact that it is not overtly immunosuppressive may make it appealing to some people. The latter is particularly important that we are now seeing an opportunistic infection signal emerging with drugs that are immunosuppressive, i.e. DMF (lymphopaenics) and fingolimod. Finally, it will likely be the switch drug of choice when transitioning MSers onto who are JCV+ on natalizumab and at risk if PML onto another DMT. The fact that daclizumab is not immunosuppressive and the NK-cells may have antiviral effects make it appealing with regard to the potential carry-over risk of PML. I am aware that a safety switch study is being proposed to support this strategy."

"The downside of daclizumab is the possibility of secondary immune mediated adverse events in particular skin hypersensitivity, hepatitis and inflammatory bowel disease, hence the requirement for daclizumab treated patients to have regular monthly blood monitoring. The secondary immune-mediated events on daclizumab may be related to its impact on T-reg cell function; depriving these cells of IL2 reduced their numbers. Despite the latter hypothesis there is no definitive link between T-reg numbers, and function, and the occurrence of adverse events."

"Please note that daclizumab is another repurposed drug. At one stage in its life-cycle it was used as an add-on drug to manage solid organ transplant rejection. Hats off the the groups at the NIH, Biogen and Abbvie for developing this drug. Based on its mode of action I think daclizumab should be tested in progressive MS; let's hope Biogen and Abbvie do a progressive trial. I have always used the mode of action of daclizumab to support my viral hypothesis. If we ever get to use the drug in the UK I have several add-on studies I would like to do to test the antiviral hypothesis; i.e. another Charcot Project study."

"For the immunologists reading this post; daclizumab also reduces the numbers of lymphoid tissue inducer cells (LTIs). LTIs play a role in the development of organized lymphoid structures and hence may affect antibody responses within the central nervous system (CNS). It will be interesting to see if the treatment effect of daclizumab may relate to its effects on this population of cells and its effect of lymphoid-like structures in the central nervous system of MSers. We need more data on the latter; at this point this is only an hypothesis."

Excerpts from the FDA press release:

“Zinbryta provides an additional choice to patients who may require a new option for treatment,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research.

The effectiveness of Zinbryta was shown in two clinical trials. One trial compared Zinbryta and Avonex in 1,841 participants who were studied for 144 weeks. Patients on Zinbryta had fewer clinical relapses than patients taking Avonex. The second trial compared Zinbryta with placebo and included 412 participants who were treated for 52 weeks. In that study, those receiving Zinbryta had fewer relapses compared to those receiving placebo.

Zinbryta should generally be used only in patients who have had an inadequate response to two or more MS drugs because Zinbryta has serious safety risks, including liver injury and immune conditions. Because of the risks, Zinbryta has a boxed warning and is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy.

The boxed warning tells prescribers that the drug can cause severe liver injury, including life-threatening and fatal events. Health care professionals should perform blood tests to monitor the patient’s liver function prior to starting Zinbryta, monthly before each dose, and for up to six months after the last dose.

The boxed warning also highlights other important risks of Zinbryta treatment including immune conditions, such as inflammation of the colon (non-infectious colitis), skin reactions, and enlargement of lymph nodes (lymphadenopathy).

Additional highlighted warnings include hypersensitivity reactions (anaphylaxis or angioedema), increased risk of infections, and symptoms of depression and/or suicidal ideation.

The most common adverse reactions reported by patients receiving Zinbryta in the clinical trial that compared it to Avonex include cold symptoms (nasopharyngitis), upper respiratory tract infection, rash, influenza, dermatitis, throat (oropharyngeal) pain, eczema, and enlargement of lymph nodes. The most common adverse reactions reported by patients receiving Zinbryta when compared to placebo are depression, rash, and increased alanine aminotransferase.

The CHMP (EMA) Summary of Opinion:

CoI: multiple

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