AT THE AAN 2015 ANNUAL MEETING
WASHINGTON (FRONTLINE MEDICAL NEWS) – Beneficial effects of peginterferon beta-1a administered every 2 weeks were evident as early as 12 weeks after starting treatment, in the pivotal phase III study comparing peginterferon beta-1a to placebo in patients with relapsing remitting multiple sclerosis, Dr. Scott Newsome, said at the annual meeting of the American Academy of Neurology.
At 12 weeks, treatment with peginterferon beta 1-a was associated with a 37% reduction in the adjusted annualized relapse rate (ARR) compared with placebo, in the ADVANCE study, said Dr. Newsome of the department of neurology at Johns Hopkins University, Baltimore.
ADVANCE compared 125 mcg of peginterferon beta-1a administered every 2 or 4 weeks to placebo in patients with relapsing remitting MS. The efficacy of peginterferon beta-1a was maintained over 2 years. Greater efficacy was seen with administration every 2 weeks ( Lancet Neurol. 2014;13:657-65 ). In August 2014, the Food and Drug Administration approved peginterferon beta-1a, at a dose of 125 mcg administered subcutaneously every 14 days, for relapsing forms of multiple sclerosis; it is marketed as Plegridy by Biogen Idec.
Interim results of the follow-up study of patients enrolled in ADVANCE – the ATTAIN trial – have shown that over 3 years of treatment, no new safety issues or concerns have emerged, and the clinical effects of treatment are maintained, according to Dr. Marcelo Kremenchutzky of Western University, London, Ont., who presented those results at the meeting.
Dr. Newsome presented the 12-week data among 512 patients randomized to treatment every 2 weeks and 500 randomized to placebo in the ADVANCE study; their mean age was 36-37 years, almost two-thirds were female, and 81%-82% were white. They were enrolled for a mean of 6-7 years from their first MS symptoms and had had a mean of 2.6 relapses within the previous 3 years. Their mean Expanded Disability Status Scale (EDSS) scores were 2.44-2.47.
At 12 weeks, the ARR, the primary endpoint, among those on peginterferon beta-1a was 0.259 vs. 0.414 among those on placebo, a 37.4% reduction over placebo (P = .045), Dr. Newsome said. The ARR was adjusted for baseline EDSS, relapse rate, and age. (At 48 weeks, the ARR among those on peginterferon beta-1a every 2 weeks was 0.26, compared with 0.40 among those on placebo, a significantly reduced risk of 36%, with a P value of .0007.)
The proportion of patients who relapsed at 12 weeks – 6% of those on peginterferon beta-1a vs. 9.5% of those on placebo – was reduced by 36.8% (P = .041), with a “clear separation” between the treatment and control arms at 12 weeks, he noted.
In addition, the estimated proportion of patients with an onset of 24-week confirmed disability progression (CDP) was 0 among those on peginterferon beta-1a versus 1.0% among those on placebo (P = .026). This result was not as robust as the relapse results, but there was a clear separation between the arms with statistical significance, said Dr. Newsome, director of outpatient neurology services at Johns Hopkins.
In the ADVANCE study, PEG administered every 2 or 4 weeks was well tolerated with a favorable safety profile in the first year, and a similar safety profile between the two dosing regimens, he added.
Dr. Kremenchutzky , director of the Multiple Sclerosis Clinic in London, Ont., presented the 1-year data in the ongoing extension study that is evaluating long-term MS outcomes, safety, and tolerability of peginterferon beta-1a among patients enrolled in ADVANCE, including those treated with peginterferon beta-1a every 2 weeks (376) or every 4 weeks (354).
Also included are 344 patients who were on placebo but were rerandomized to peginterferon beta-1a every 2 or 4 weeks (the delayed treatment group) after 1 year in the ADVANCE study; they were included in the analyses after they had been on treatment for 2 years.
After 1 year in the ATTAIN study, injection-site reactions and flu-like symptoms remained the most frequent adverse events associated with peginterferon beta-1a, and most were mild to moderate. Treatment has also been associated with “low levels” of laboratory abnormalities and immunogenicity, and clinical efficacy has been maintained for 3 years, Dr. Kremenchutzky said at the meeting.
Adverse events were “very similar” in the 4-week and 2-week treatment groups. Over 3 years, 96% of patients in both groups had experienced an adverse event, and the rates of treatment-related adverse events (91%), and severe adverse events (24%) were the same in both groups. The rates of treatment discontinuations due to an adverse event (7%-8%) and withdrawal from the study due to an adverse event (8%-9%) were similar.
The rates of flu-like symptoms over 3 years were also similar (62%-64%) in the two groups, and influenza-like illness was reported in 55% of those dosed every 2 weeks and in 45% of those dosed every 4 weeks. In addition to influenza-like illness, pyrexia was the most common flu-like symptom reported over 3 years (43%-45%).
About 65%-69% of those in the two groups reported injection-site reactions, with erythema the most common (62%-64%), followed by pain (17%-18%) and pruritus (12%-16%).
Lab abnormalities were comparable with both dosing schedules: Over 3 years, white blood cell counts were reduced in 6% of those on the 2-week schedule, compared with 8% among those on the 4-week schedule. Lymphocyte counts were reduced in 12% and 9% of those on the 2-week and 4-week schedules, respectively. In addition, 8% of those on the 2-week dose and 6% of those on the 4-week dose had low hemoglobin (100 g/L or less) over the 3 years.
Rates of anti-IFN and anti-PEG antibodies associated with both schedules were low, Dr. Kremenchutzkysaid. Over 3 years, 7%-9% tested positive for IFN binding antibody at least once, and 4%-6% of the total were “persistent positive.” Another 9% of those on the 4-week schedule and 6% of those on the 2-week schedule were anti-PEG antibody positive at least once, and 3%-5% of the patients in total had persistent levels. Titers were high in less than 1% of the total.
In ATTAIN, efficacy endpoints were secondary, and included ARR, which was reduced by 25.1% over 3 years among those receiving the dose every 2 weeks, compared with every 4 weeks (P = .0199). By 144 weeks, 30.5% of those on the 2-week schedule and 41.1% of those on the 4-week schedule had experienced a relapse, a significant difference (P = .0070), Dr. Kremenchutzky said.
The proportion of those with CDP by 144 weeks was 15.5% among those on the 4-week schedule, vs. 9.2% among those on the 2-week schedule (P = .0098), he added.
The studies were funded by Biogen Idec. Dr. Newsome and Dr. Kremenchutzky both disclosed having been compensated for activities with Biogen Idec and other companies that market MS drugs.