Promising Results for Daclizumab High-Yield in MS

Susan Jeffrey

October 27, 2011

October 27, 2011 (Amsterdam, the Netherlands) — Full results of the SELECT trial comparing 2 doses of daclizumab high-yield process (Biogen Iden/Abbott) with placebo confirm that both doses reduced annualized relapse rates by around 50% and had a somewhat surprisingly positive effect in reducing disability in patients with relapsing-remitting multiple sclerosis (MS).

"Monthly subcutaneous injections of daclizumab demonstrated robust clinically meaningful effects on [MS]," principal investigator Gavin Giovannoni, MBBCh, PhD, chair of neurology at the Institute of Cell and Molecular Science at Barts and the London School of Medicine and Dentistry in the United Kingdom, concluded in his presentation here at 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

The effect of the drug on disability, he noted, "was interesting, given the duration of this trial." During only 52 weeks of follow-up, the drug reduced disability vs placebo by 57% in the 150-mg daclizumab group and by 43% with the 300-mg dose.

Safety results showed that adverse events were comparable between groups, but there was an increase in liver enzymes seen with treatment, and 1 death occurred in the treated group, possibly related to infection.

"The results of this trial have informed the ongoing program, and monitoring and treatment algorithms have been implemented to mitigate the safety concerns," Dr. Giovannoni added. "And clearly the results of this study suggest that daclizumab needs to be further investigated in ongoing trials."

Top-line results were released August 9 and reported by Medscape Medical News at that time.

SELECT Trial

Daclizumab high-yield process is an investigational once-monthly treatment given by subcutaneous injection; the term high-yield process refers to the manufacturing of the product, Dr. Giovannoni noted. It is a humanized monoclonal antibody that binds to CD25, a receptor subunit of the interleukin 2 (IL-2) receptor that is expressed at high levels on activated T cells.

Daclizumab binds to the high-affinity receptor, preventing IL-2 uptake and increasing the amount of IL-2 available to bind to the intermediate-affinity receptor, Dr. Giovannoni explained. This increases the number of other types of cells, particularly CD56bright natural killer cells that have an immunoregulatory role in controlling autoimmune cells.

SELECT was a randomized, double-blind, controlled trial of monotherapy with daclizumab in patients with relapsing-remitting MS. Investigators randomly assigned 600 patients with clinically definite MS to receive either 150 mg or 300 mg of daclizumab or placebo given by subcutaneous injection every 4 weeks for 52 weeks. Eligible patients had at least 1 relapse in the 12 months before randomization or 1 new gadolinium-enhancing lesion in the prior 6 weeks.

The primary endpoint was annualized relapse rate. A nested magnetic resonance imaging substudy included 309 of the overall patients.

"Compared to placebo, daclizumab at both doses reduced the annualized relapse rate by 50% to 54%," Dr. Giovannoni told attendees.

Table 1. SELECT: Primary Endpoint for Daclizumab vs Placebo

Endpoint Placebo Daclizumab 150 mg P Daclizumab 300 mg P
Annualized relapse rate 0.46 0.21 <.001 0.23 .0002

More than 80% of daclizumab-treated patients were relapse-free at 52 weeks compared with 64% of patients receiving placebo.

Quality of life, as measured by the Multiple Sclerosis Impact Scale physical score, improved in both groups, but "was much more pronounced," he noted, in the 150-mg group, with a 4.1-point relative improvement (P = .0007) vs the nonsignificant 1.6-point relative improvement over placebo seen in the 300-mg group.

"A surprising result, considering it's only a 52-week study, was the impact of daclizumab on disability progression, which was defined as confirmed at 3 months," he said. There was a 57% reduction in the 150-mg group (P = .021); the 43% reduction with 300 mg did not reach statistical significance (P = .09).

Results of the magnetic resonance imaging substudy in 309 patients showed that compared with placebo, there was a 69% to 78% reduction in new or enlarging gadolinium-enhancing lesions between weeks 8 and 24.

"So when does daclizumab have its action? You can see there is a significant drop in the number of gadolinium-enhancing lesions between weeks 4 and 8," he said. "We think the difference between the 2 doses here has to do with an imbalance between the groups at baseline in the number of gadolinium-enhancing lesions, but by week 52 there's no difference between the 2 doses."

Looking at this outcome in the overall population of 600 patients, there was a 79% to 86% reduction in new gadolinium-enhancing lesions at week 52 vs placebo, he said. "Similarly, there was a robust impact on new or enlarging T2 lesions, with a reduction of 70% to 79% in the whole cohort at week 52."

Table 2. SELECT: Reduction in New or Enlarging T2 Lesions for Daclizumab vs Placebo at Week 52

Endpoint Placebo Daclizumab 150 mg P Daclizumab 300 mg P
New or newly enlarging T2 lesions 8.1 2.4 <.0001 1.7 <.0001

Safety Results

Adverse events and serious adverse events were similar in all 3 groups, Dr. Giovannoni noted. There was 1 death in the trial in a patient with a psoas abscess that was not diagnosed before death. "We think daclizumab may be related to this complication, in terms of the infection," he said.

Table 3. SELECT: Adverse Events

Event Placebo Daclizumab 150 mg Daclizumab 300 mg
Any adverse event (%) 78 72 76
Any serious adverse event (%) 27 16 18
Any serious adverse event excluding MS relapse (%) 6 7 9
Death (n) 0 1 0

The most common adverse events were nasopharyngitis, upper respiratory infection, and headache. Serious infections occurred in 1% and 3% of the daclizumab groups. "These infections were not opportunistic infections," Dr. Giovannoni noted. "They were infections you see in the normal population, and there was no particular pattern to these infections." There were 4 malignancies: 1 in each of the placebo and 150-mg groups, and 2 in the 300-mg group.

"An adverse event that emerged during the study was a transaminitis," he noted, with liver enzyme levels greater than 5 times the upper limit of normal seen in 4% of daclizumab-treated patients. The increases generally occurred late in treatment, with a median of 308 days, and in all patients, except 1 who had hepatitis B, the increases resolved spontaneously. "I must point out that in almost half, 7 out of 16 patients, the transaminitis resolved despite ongoing treatment," he noted.

Daclizumab is now being studied in a phase 3 registrational clinical trial called DECIDE, which is currently enrolling patients. DECIDE is evaluating the efficacy and safety of once-monthly subcutaneous administration as a monotherapy compared with interferon beta 1-a.

Excellent Data

Ralf Gold, MD, professor and chair, Department of Neurology, St. Josef-Hospital, Ruhr-University, Bochum, Germany, gave a talk on the last day of the conference on the clinical highlights presented here, and listed these results from the SELECT trial among them, although he too is listed as a coauthor on the data. Dr. Gold was also principal investigator of the DEFINE trial, presented earlier at this meeting, of BG-12 or oral fumarate, which is also an investigational drug for MS.

He started by pointing out that daclizumab has been withdrawn as a treatment option to prevent rejection after transplantation. A previous phase 2 study, called CHOICE, of daclizumab in MS used it as add-on therapy to interferon beta, he pointed out, whereas the current trial uses the drug as monotherapy.

The reduction in lesions with daclizumab was comparable to that seen with BG-12, he noted, being on the order of 50%, but the reduction in disability was somewhat greater, with a 40% reduction in the risk for disability progression.

"I think these are encouraging data," he said. There were few adverse effects, except for 1 patient with bacteremia resulting from a skin infection.

More has been made of the BG-12 findings, he noted, "maybe because every one of us expects antibodies to be very effective, and something like fumarate, which is in our body since we were born, they don't expect it to be that active." But these are excellent data, he concluded, and said "[W]e will see, when this is published."

Asked for comment, Lily Jung-Henson, MD, medical director of the Swedish Neuroscience Institute Eastside Neurology, chief of staff at Swedish Issaquah Hospital, Seattle, Washington, and a member of the American Academy of Neurology, said that in her view, the daclizumab efficacy data "look great."

"Even though it is an injectable, its once a month administration makes it attractive," Dr. Jung-Henson noted. "However, we are going to need more safety data."

This study was supported by Biogen Idec and Abbott Biotherapeutics Corp. Dr. Giovannoni reports he has received research grant support from Bayer Schering Healthcare, Biogen Idec, GW Pharma, Merck Serono, Merz, Novartis, Teva, and sanofi-aventis, and personal compensation for participating on advisory boards in relation to clinical trial design, trial steering committees, and data and safety monitoring committees from Bayer Schering Healthcare, Biogen Idec, Eisai, Elan, Five Prime Therapeutics, Genzyme, Genentech, GSK, Ironwood Pharma, Merck Serono, Novartis, Pfizer, Roche, sanofi-aventis, Synthon BV, Teva, UCB Pharma, and Vertex Pharmaceuticals. Dr. Gold reports he has received speakers' honoraria and research grant support from Bayer Schering Healthcare, Biogen Idec, Merck Serono, Merz, Novartis, Teva, and sanofi-aventis, as well as compensation for advisory board activities from Biogen Idec, Merck Serono, Novartis, and Teva. Disclosures for coauthors are found in the abstract. Dr. Jung-Henson reports no ties with this study; she is a speaker for Biogen Idec, Serono, Teva, Novartis, and sanofi-aventis.

5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS): Abstract 149. Presented October 22, 2011.

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