MS has traditionally been considered the ‘classical’ prototype of a T cell-mediated autoimmune disease [
19]. Even if this view is considered no longer correct and involvement of nearly all cell types of the immune system was shown [
20,
21], T cells still play a central role in the MS pathophysiology [
22]. This view is based not only on data from extensive studies in animal models, but also accumulation of considerable numbers of T cells in inflammatory MS lesions [
23] and data from different genome-wide susceptibility studies [
24]. Many of the currently approved DMTs for MS target T lymphocytes, either by immune modulation (e.g., interferons), by depleting immune cell populations involving T cells (e.g., alemtuzumab), or by selective inhibition of distinct molecular pathways in order to sequester leucocytes (e.g., natalizumab) [
22].
Daclizumab
In CHOICE (NCT00109161), add-on subcutaneous high-dose daclizumab (2 mg/kg every 2 weeks,
n = 75) could significantly reduce the number of new/enlarged gadolinium-enhanced lesions (GELs) (= pSE) in MS patients (92% relapsing–remitting MS (RRMS), 8% SPMS) with active disease despite treatment with interferon beta (IFNβ) compared to IFNβ alone (
n = 77) and add-on low dose daclizumab (1 mg/kg every 4 weeks;
n = 78) [
31]. After this study, the chemical structure of daclizumab was modified to reduce the antibody-dependent cellular cytotoxicity (ADCC) and complement fixation [
36] and called daclizumab high-yield process (DAC HYP).
In SELECT (NCT00390221), both DAC-HYP 150 mg (
n = 208) and 300 mg (
n = 209) significantly reduced the annualized relapse rate (ARR) (= pSE), the mean number of new GELs and T2 lesions, and the 12-week confirmed disability progression (CDP) compared to placebo (
n = 204) [
30]. 91% patients who completed SELECT enrolled into the 1-year extension trial SELECTION (NCT00870740) where those patients who received placebo in SELECT (
n = 170) were randomized 1:1 to DAC-HYP 150 mg or 300 mg and those originally treated with DAC-HYP were randomized (1:1) either to continue prior treatment (
n = 173) or to undergo a washout period of 20 weeks followed by reinitiation of their original dose (
n = 174) [
33]. The pSE was the safety and immunogenicity of DAC-HYP. Overall, frequencies of AEs and SAEs were similar between the treatment initiation and continuous treatment groups [
33]. 90% (410/455) participants who completed SELECT and SELECTION received DAC-HYP 150 mg s.c. every 4 weeks for up to 6 years in the open-label extension study SELECTED (NCT01051349) (69% for > 3 years, 39% for > 4 years, and 9% for > 5 years) [
34]. The efficacy of DAC-HYP on clinical and radiological disease activity was maintained throughout the study for up to ~ 8 years [
34].
In DECIDE (NCT01064401), 1841 patients with active RRMS were randomized (1:1) to either 150 mg DAC-HYP or intramuscular IFNβ-1a for 96–144 weeks [
32]. DAC-HYP significantly reduced the ARR (= pSE), the number of new GELs and T2 lesions, the brain atrophy, and the risk of increased 48-week CDP [
32].
In EXTEND (NCT01797965), all participants who received either DAC-HYP (
n = 606) or IFNβ-1a (
n = 597) in DECIDE received DAC-HYP 150 mg for up to 5 years, followed by 24 weeks of post-dosing follow-up [
35]. In the continuous DAC-HYP group, more participants were relapse free and fewer had experienced 24-week CDP than those who switched from IFNβ-1a in DECIDE to DAC-HYP in EXTEND [
35].
The incidence of SAEs that were reported with DAC-HYP in the clinical trials was higher compared to placebo and IFNβ-1a [
30,
32‐
35]. Potentially serious infections, cutaneous reactions, and liver abnormalities were already described in the pivotal studies SELECT and DECIDE under treatment with 150 mg DAC-HYP. The extension studies additionally revealed serious inflammatory syndromes and lymphadenopathy that were previously not apparent.
Serious infections were more common in the 150 mg DAC-HYP groups (3% in SELECT and SELECTION, 4% in DECIDE, 6% in SELECTED, and 5% in EXTEND) compared to placebo (0%) and IFNβ-1a (2%) [
30,
32‐
35]. In general, infections were managed in a conventional manner and for the most part did not require the suspension of DAC-HYP.
A variety of cutaneous AEs, mainly rash and eczema, occurred in up to one-third of patients, were mostly mild to moderate in intensity and resolved either spontaneously or after standard interventions [
38]. Serious cutaneous events (e.g., exfoliative rash or dermatitis, toxic skin eruption, drug reaction with eosinophilia, and systemic symptoms (DRESS) syndrome) developed in < 1 to 2% under 150 mg DAC-HYP in the pivotal studies and up to 4% in the extension studies [
30,
34,
35].
Elevations > 5 times the upper limit of normal (ULN) were more frequent under 150 mg DAC-HYP (4% in SELECT, 1% in SELECTION, 6% in DECIDE, 9% in SELECTED, and 8% in EXTEND) compared to placebo (< 1%) and IFNβ-1a (3%) [
30,
32‐
35]. These increases were evenly distributed over time during treatment with DAC-HYP, self-limited, or could be successfully managed by treatment discontinuation and/or treatment with cortisone, and tended not to recur with continued treatment [
27,
32,
38].
After one case of fatal liver failure due to hepatitis (in the washout and 300 mg DAC-HYP reinitiation group) in the SELECTION trial [
33] as well as four cases of serious liver injury (confounded by concomitant drugs associated with liver toxicity) in EXTEND [
35], a benefit-risk reassessment procedure was initiated in the European Union. This resulted in transitional safety regulations for treatment with daclizumab and licensing restriction to those adult patients who have had an inadequate response to at least two previous DMTs and for whom treatment with any other DMT was contraindicated or otherwise unsuitable (EMA/707022/2017).
Across all clinical studies, immune-mediated disorders occurred in 28% of patients on DAC-HYP, including lymphadenopathy and skin reactions [
27,
39]. Immune-mediated SAEs developed in three patients in the SELECT trial under 300 mg daclizumab (thyroiditis, Crohn’s disease, hypersensitivity) [
30], in five patients in the SELECTION trial (hepatitis, Graves’ disease, glomerulonephritis, and two cases of ulcerative colitis) [
33], and in eight patients in SELECTED (two cases of hepatitis and uveitis, one case of vitiligo, morphoea, rheumatoid arthritis, and Sjögren’s syndrome) [
34]. Surprisingly, no immune-mediated condition secondary to daclizumab treatment was reported in the DECIDE trial [
32]. In EXTEND, 15 patients developed immune-mediated SAEs, of which three were encephalitis [
35].
Following another case of fatal liver failure [
40] and 12 reports of serious inflammatory brain disorders, including encephalitis and meningoencephalitis, three of them with fatal outcome [
41‐
43], daclizumab was withdrawn from the market by the manufacturer in March 2018. The EMA recommended the immediate suspension and recall of daclizumab. Follow-up for at least 6 months after treatment with DAC-HYP was mandatory.
All cases of encephalitis were spontaneous reports, except for the three cases which came from the EXTEND trial [
35], and showed significant heterogeneity. At least five of these patients had clinical symptoms compatible with DRESS syndrome with CNS involvement [
41,
44], while others demonstrated evidence of CNS vasculitis or were associated with anti-N-methyl-d-aspartate (anti-NMDA) or anti-glial fbrillary acidic protein (anti-GFAP) antibodies [
37,
43,
45]. One encephalitis have also been reported months after stopping treatment, suggesting that vigilance for secondary autoimmunity may need to be extended for many months after drug cessation [
46].
The example of daclizumab illustrates quite well that there is no guarantee that a therapy which has been proven to be effective and safe for use in one condition, will work with the same safety profile in another condition. Daclizumab was initially developed as an intravenous therapy (Zenapax®) to prevent acute organ rejection in patients with de novo allogeneic renal transplantation. While Zenapax® has shown excellent tolerability and long-term safety in kidney transplant patients [
47‐
49], this was not the case for Zinbryta™ in MS patients. One reason could be the fact that Zenapax® was only used in combination with cyclosporine and corticosteroids, thereby preventing the development of serious autoimmune and inflammatory events. Another likely reason could be differences in the immunogenetic background of both diseases [
50‐
54]. This would mean that blocking the same IL-2R-HA α-chain likely triggers different immunogenetically predisposed cytokine-signalling pathways.
Even if the precise mechanisms of these serious inflammatory syndromes under Zinbryta™ still need to be clarified, various theories have been postulated.
Both CD56bright NK and CD4
+CD25
+Foxp3
+ Tregs cells play a major role in controlling T cell responses and thereby maintaining homeostasis [
55‐
57]. While daclizumab leads to an expansion and stimulation of CD56bright NK cells, it reduces the number of circulating CD4
+CD25
+Foxp3
+ Tregs cells without affecting their function [
58,
59].
On the one hand, diminished cell-surface expression of the activating receptor DNAM-1 (DNAX Accessory Molecule-1), which has been recently identified as a crucial player in NK- and Treg-cell mediated control of T cell activity, on NK [
60] and Treg [
61] was suggested to result in impaired immune regulatory function [
40]. On the other hand, it was speculated that a predicted daclizumab-induced decline of CD4
+CD25
+Foxp3
+ Treg cells without an expected concomitant expansion of immunoregulatory CD56bright NK cells (probably genetically determined) leave Zinbryta™-treated patients vulnerable to severe inflammatory syndromes [
28,
38,
62].
Moreover, the story of daclizumab demonstrates the difficulty of detecting rare SAEs in clinical trials and highlights the importance of phase IV studies (post-marketing surveillance trials) of newly approved treatments [
4,
46,
63,
64]. Thus, clinical trials can only provide limited exposure of an investigated drug to a highly selected and controlled cohort. Identification of rare AEs may, however, require a more heterogeneous patient group, with more potential for drug-drug and drug-other condition interactions, treated for longer periods of time before such events can be recognized [
42].
Although SAEs were also observed with other DMTs, daclizumab is the first licensed MS biological agent that was permanently withdrawn after regular approval from the world-wide market [
46]. Natalizumab, for example, was withdrawn in 2005 after the first three cases of PML, however reintroduced under strict monitoring requirements 1 year later. While two decades ago there was a substantial unmet need for new DMTs because treatment options for MS patients were limited, a wide range of therapies is now available. Natalizumab might not be licensed if it was introduced today, and the safety profile of daclizumab might have been evaluated differently if it had been the first highly effective MS treatment introduced to the market.