BOSTON — Full results of the phase 3 DECIDE trial show that daclizumab HYP (Zinbryta, Biogen Idec/AbbVie Biotherapeutics) has the potential to be a new once-monthly treatment option for patients with relapsing-remitting multiple sclerosis (RRMS), according to the trial's lead investigator.
Ludwig Kappos, MD, University Hospital, Basel, Switzerland, noted that daclizumab HYP showed "consistently superior" efficacy vs interferon β in relapse rate and MRI lesion activity and reduced 6-month disability progression.
He presented the data here at MS Boston 2014, the 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS) meeting. Topline results from DECIDE were announced in June by Biogen Idec and AbbVie, the companies jointly developing the drug.
All Eyes on Safety
Because of safety issues observed previously — including 1 death due to autoimmune hepatitis — all eyes were on the adverse event data in DECIDE.
Dr. Kappos reported that the risk with daclizumab was characterized by a "slight increase in rash, infections and elevated ALT [alanine aminotransferase] liver enzymes" and was "manageable with standard monitoring."
Asked if any of these reactions could be signs of secondary autoimmunity, Dr. Kappos said, "We didn't see any hints of secondary autoimmunity. You may consider cutaneous reactions as an autoimmune phenomenon, but their pathogenesis may be mixed. Every intervention with an immunomodulatory substance has such a risk but we didn't observe any additional cases that would indicate this in the DECIDE trial."
On the cutaneous reactions, Dr. Kappos noted that these were mostly erythemas that developed slowly and, if recognized early and treated with steroids, can be reversible without the need for discontinuing medication. "It is always reversible if therapy is discontinued," he added.
Session co-chair Tanuja Chitnis, MD, Brigham and Women's Hospital, Boston, told Medscape Medical News: "There have been some concerns about 1 or 2 more serious infections and this needs to be examined, but this study is fairly positive in terms of adverse events. The main side effect differences vs placebo were cutaneous events on daclizumab, but these seem to be short lived when treated with steroids."
Where Will Daclizumab Fit?
Commenting for Medscape Medical News on where daclizumab may fit into current treatment, Jeff Cohen, MD, Cleveland Clinic, Ohio, said, "The safety is a concern and needs to be sorted out but it could be a useful addition. I like to have choices. I wouldn't think it would be used as initial therapy in most patients, however."
Jerry Wolinsky, MD, University of Texas Health Science Center at Houston, added: "If the drugs available in the US are listed in terms of effectiveness the list would probably be something like: natalizumab, fingolimod, DMF [dimethyl fumarate], β-interferon/Copaxone. l think daclizumab would fit in somewhere in the fuzzy zone between fingolimod and DMF," he said.
"I don't like the skin reactions but they seem to turn up early and go away in time so maybe they are no worse than the GI [gastrointestinal] problems with DMF," he added.
Dr. Chitnis said she thought the efficacy of daclizumab looked good. "It seems to be a potent anti-inflammatory agent — a 45% relapse rate reduction vs β-interferon is very impressive, although we do have to be careful about comparing between clinical trials of course. I think it will be reasonable to use it early on in RRMS."
Lily Jung Henson, MD, medical director of Swedish Neuroscience Neurology, Seattle, Washington, agreed. "Its efficacy data looks great across the board," she told Medscape Medical News. "I think we are learning from the other DMTs [disease-modifying therapies] that side effects are a necessary evil that we have to learn to monitor and deal with, which is a small price to pay for having more choices and great efficacy."
Once-Monthly Dosing "A Major Advantage"
Presenting more data from the DECIDE study in a poster, Krzysztof Selmaj, MD, PhD, Medical University of Lodz, Poland, highlighted the dosing regimen — once-a-month subcutaneous injection — which he said would be a "major advantage for daclizumab."
The DECIDE trial is the second large phase 3 trial of daclizumab, the first one, SELECT, having shown efficacy vs placebo. Data from these studies will be used to support applications for approval, and a submission to the US Food and Drug Administration is expected in the first half of 2015.
The study randomly assigned 1841 patients to 150 mg of subcutaneous daclizumab HYP every 4 weeks or interferon β-1a, 30 μg given by intramuscular injection once weekly. Patients had an average disease duration of 4 years and a mean Expanded Disability Status Scale (EDSS) score of 2.5.
The primary endpoint — annualized relapse rate — showed a highly significant reduction of 45% in the daclizumab group.
Table 1. Primary Endpoint: Annualized Relapse Rate
| Endpoint | Interferon β-1a | Daclizumab | Risk Reduction (%) | P Value |
| Annualized relapse rate | 0.393 | 0.216 | 45 | <.0001 |
MRI lesions were also significantly reduced, and the effect was evident from 24 weeks, Dr. Kappos reported.
Table 2. MRI Lesions at Week 96
| Endpoint | Interferon β-1a | Daclizumab | Risk Reduction (%) | P Value |
| New/enlarging T2 lesions | 9.4 | 4.3 | 54 | <.0001 |
| New gadolinium-enhancing lesion | 1.0 | 0.4 | 65 | <.0001 |
| New T1 hypointensive lesions | 4.4 | 2.1 | 52 | <.0001 |
In terms of disability, 3-month sustained disability progression was nonsignificantly reduced by 16%, but 6-month sustained disability progression was significantly reduced by 27% (P = .0332).
Table 3. Disability Progression Results
| Time Point | 3-Month Disability Progression: Interferon β-1a | 3-Month Disability Progression: Daclizumab | 6-Month Disability Progression: Interferon β-1a | 6-Month Disability Progression: Daclizumab |
| Week 48 (%) | 8 | 6 | 7 | 4 |
| Week 96 (%) | 14 | 12 | 12 | 9 |
| Week 144 (%) | 20 | 16 | 18 | 13 |
The reduction in disability was also reflected in the Multiple Sclerosis Functional Composite (MSFC) score.
Table 4. Change in MSFC Score at 96 Weeks
| Endpoint | Interferon β-1a | Daclizumab | P Value |
| Median MSFC z-score | 0.055 | 0.091 | .0007 |
Daclizumab was associated with reduced rates of brain volume loss and clinically meaningful worsening of MS.
Table 5. Annualized Whole Brain Volume Change by Treatment
| Range (wk) | Interferon β-1a | Daclizumab | P Value |
| 0-24 | 0.74 | 0.67 | .0325 |
| 24-96 | 0.56 | 0.52 | <.0001 |
Table 6. Clinically Meaningful Worsening in Physical Impact of MS by Treatment
| Endpoint | Interferon β-1a | Daclizumab | Risk Reduction (%) | P Value |
| ≥7.5-point decline on Multiple Sclerosis Impact Scale (%) | 23 | 19 | 24 | .0176 |
In terms of safety, overall mild and moderate adverse events were similar in both treatment groups. Severe adverse events were increased in the daclizumab group, with treatment discontinuation because of adverse events occurring in 14% of daclizumab recipients vs 9% of those receiving interferon &beta-1a.
Dr. Kappos reported "adverse events of special interest" — those relating to cutaneous reactions, infections, or liver enzyme elevations — as below:
Table 7. Adverse Effects of Special Interest
| Effect | Interferon β-1a | Daclizumab |
| Infections, n (%) | ||
| Any | 523 (57) | 595 (65) |
| Severe | 15 (2) | 40 (4) |
| Cutaneous events, n (%) | ||
| Any | 177 (19) | 342 (37) |
| Severe | 1 (<1) | 14 (2) |
| Hepatic abnormalities, n (%) | ||
| ALT or AST >5 times ULN | 31 (3) | 59 (6) |
| ALT >3 times ULN and total bilirubin >2 times ULN | 1 (<1) | 7 (<1) |
| Hy's law cases (n) | 1 | 1 |
| AST = aspartate aminotransferase; ULN = upper limit of normal. |
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The study was funded by Biogen Idec and AbbVie Biotherapeutics. Dr. Kappos' Institution (University Hospital Basel) received the following in the last 3 years and used exclusively for research support: steering committee, advisory board, and consultancy fees from Actelion, Addex, Bayer Health Care, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, and Xenoport; speaker fees from Bayer Health Care, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva; support of educational activities from Bayer Health Care, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, and Teva; royalties from Neurostatus Systems GmbH; grants from Bayer Health Care, Biogen, Merck, Novartis, Roche, Swiss MS Society, the Swiss National Research Foundation, the European Union, and Roche Research Foundations. Dr. Selmaj reports receiving compensation for consulting services from Genzyme, Novartis, Ono, Roche, Synthon, and Teva; and compensation for speaking from Biogen Idec.
MS Boston 2014: 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS). Abstract FC1.1. Presented September 12, 2014.
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Cite this: Sue Hughes. Daclizumab in MS: More Detail on Phase 3 Results - Medscape - Sep 15, 2014.
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