Another DMT for MSers to get their heads around #MSResearch #MSBlog #ResearchSpeak
“Finally the phase 3 results of daclizumab have been published. This studied shows that daclizumab is superior to interferon-beta (Avonex) in terms of its impact on relapse reduction and disability progression. Daclizumab had a significant impact on disability progression confirmed at 6-months, but not at 3-months. This is not surprising given the wobbliness of the EDSS at 3-months. The EMA have put out a guidance to only use 6-month confirmed EDSS progression in clinical trials going forward. Daclizumab is only given once a month by subcutaneous injection and is well tolerated locally. Based on these results I would place daclizumab in the high-efficacy category alongside fingolimod, but probably below natalizumab and alemtuzumab. Please remember that for DMTs it horses for courses; there will be responders and non-responders to daclizumab and in my experience in the trials the responders to very well.”
“The most interesting thing about daclizumab is its mode of action. It 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 IL-2 away from these cells to the intermediate IL-2 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 they are antiviral. Importantly, daclizumab leaves CD4+, CD8+ and B cell function relatively intact. At ECTRIMS there was a poster showing antibody responses to the flu vaccine in daclizumab treated MSers were 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 why we see slightly more infections, and more severe infections, in the daclizumab treated group compared to interferon treated MSers. 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.”
“I am often asked were 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 almost certainly be my switch drug of choice to transition MSers onto who are JCV+ on natalizumab and at risk if PML. The fact that daclizumab is not immunosuppressive and the NK-cells may have antiviral effects make it appealing to handle the risk of carry-over PML. I sincerely hope Biogen and Abbvie do a safety study in this switch group to provide us with the necessary evidence to support this statement.”
“The downside of daclizumab is the possibility of secondary immune mediated adverse events in particular autoimmune, or hypersensitivity, hepatitis and skin reactions. There has also been a few cases of inflammatory bowel disease and glomerulonephritis. Therefore daclizumab will almost certainly require regular monthly blood monitoring. The secondary autoimmunity on daclizumab may be related to its impact on T-reg cell function; depriving these cells of IL-2 reduced their numbers. Despite the latter hypothesis we have not been able to show a 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. Let’s hope the regulators give it a broad label that will allow us to offer to MSers with active disease. 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 can 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 simply an hypothesis.”
Kappos et al. Daclizumab HYP versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 2015 Oct 8;373(15):1418-28. doi: 10.1056/NEJMoa1501481
BACKGROUND: Daclizumab high-yield process (HYP) is a humanized monoclonal antibody that binds to CD25 (alpha subunit of the interleukin-2 receptor) and modulates interleukin-2 signaling. Abnormalities in interleukin-2 signaling have been implicated in the pathogenesis of multiple sclerosisand other autoimmune disorders.
METHODS: We conducted a randomized, double-blind, active-controlled, phase 3 study involving 1841 patients with relapsing-remitting multiple sclerosis to compare daclizumab HYP, administered subcutaneously at a dose of 150 mg every 4 weeks, with interferon beta-1a, administered intramuscularly at a dose of 30 μg once weekly, for up to 144 weeks. The primary end point was the annualized relapse rate.
RESULTS: The annualized relapse rate was lower with daclizumab HYP than with interferon beta-1a (0.22 vs. 0.39; 45% lower rate with daclizumab HYP; P<0.001). The number of new or newly enlarged hyperintense lesions on T2-weighted magnetic resonance imaging (MRI) over a period of 96 weeks was lower with daclizumab HYP than with interferon beta-1a (4.3 vs. 9.4; 54% lower number of lesions with daclizumab HYP; P<0.001). At week 144, the estimated incidence of disability progression confirmed at 12 weeks was 16% with daclizumab HYP and 20% with interferon beta-1a (P=0.16). Serious adverse events, excluding relapse of multiple sclerosis, were reported in 15% of the patients in the daclizumab HYP group and in 10% of those in the interferon beta-1a group. Infections were more common in the daclizumab HYP group than in the interferon beta-1a group (in 65% vs. 57% of the patients, including serious infection in 4% vs. 2%), as were cutaneous events such as rash or eczema (in 37% vs. 19%, including serious events in 2% vs. <1%) and elevations in liver aminotransferase levels that were more than 5 times the upper limit of the normal range (in 6% vs. 3%).
CONCLUSIONS: Among patients with relapsing-remitting multiple sclerosis, daclizumab HYP showed efficacy superior to that of interferon beta-1a with regard to the annualized relapse rate and lesions, as assessed by means of MRI, but was not associated with a significantly lower risk of disability progression confirmed at 12 weeks. The rates of infection, rash, and abnormalities on liver-function testing were higher with daclizumab HYP than with interferon beta-1a.