The authors of this study evaluated whether daclizumab high-yield process (HYP) would be effective when given as monotherapy for a 1 year treatment period in patients with relapsing-remitting multiple sclerosis (RRMS). Interleukin-2 signalling is involved in the activation and regulation of the human immune system and increased expression of the CD25 subunit of the interleukin-2 receptor increases the risk of MS. Daclizumab is a humanised monoclonal antibody specific for CD25. The authors note that daclizumab high-yield process (HYP) has the same aminoacid sequence as previous versions of daclizumab, but differs in its glycosylation profile, which results in decreased antibody-dependent cellular cytotoxicity activity.
In this study, 204 patients were assigned to receive placebo, 208 to daclizumab HYP 150 mg, and 209 to daclizumab HYP 300 mg, of whom 188 (92%), 192 (92%), and 197 (94%), respectively, completed follow-up to week 52. The annualised relapse rate (primary outcome) was lower for patients given daclizumab HYP 150 mg (0.21, 95% CI 0.16-0.29; 54% reduction, 95% CI 33-68%; p<0.0001) or 300 mg (0.23, 0.17-0.31, 50% reduction, 28-65%; p=0.00015) than for those given placebo (0.46, 0.37-0.57).
The study suggests that subcutaneous daclizumab HYP monotherapy given every 4 weeks for 1 year to mainly treatment-naive patients with RRMS may be have a beneficial effect on disease activity as measured by MRI-defined lesions, clinical relapses, and disability progression. However, the results should be interpreted with caution as there are some limitations to this research, in particular:
§ The study design – this is a phase 2 dose ranging study and the findings need confirmation through larger phase 3 trials.
§ RRMS is a progressive, chronic condition. The study duration was 1 year; hence the long term efficacy and safety of daclizumab in this setting need to be determined. The authors also acknowledge that the short duration is a limitation to their research.
§ It is not currently known how daclizumab compares to other immunomodulating drugs used in the treatment of MS and what its place in therapy would be.
The author of a related Comment article describes the results as “encouraging” and in particular notes the following points:
· Despite the short trial duration, the risk of 3-month sustained disability progression at week 52 was significantly reduced by 57% in the daclizumab-HYP 150 mg group (HR 0.43, 95% CI 0.21–0.88), and 43% in the 300 mg group (0.57, 0.30–1.09). He suggests that this finding represents “one of the most noteworthy findings of the study because longer trial durations and larger sample sizes are often needed to detect effects on disability.” However, these results require confirmation through larger studies.
· Although daclizumab was generally well tolerated, it is noted that two melanomas were reported in the daclizumab-HYP 300 mg group, which he states is of particular concern because high dose interleukin-2 is used as an immunotherapy in patients with metastatic melanoma. Cutaneous events were noted in 38 (18%) patients in the daclizumab-HYP 150 mg, 45 (22%) of those in the daclizumab-HYP 300 mg, and 27 (13%) of those in the placebo group.
He concludes, “Although the long-term risk-benefit profile of daclizumab-HYP is unknown, the results of this phase 2 study are encouraging, and extend previous findings suggesting that daclizumab-HYP could have a role in the growing arsenal of disease-modifying treatments for multiple sclerosis, and therefore warrants further study.”
In England, disease modifying agents for the treatment of MS are commissioned nationally through NHS England (formerly the NHS Commissioning Board) in line with national policy. The policy covers commissioning of beta interferon, glatiramer acetate, natalizumab and fingolimod and includes starting and stopping criteria. In addition, NICE has issued the following sets of technology appraisal guidance in this area (also referred to in the national policy):