Two-year data from a phase 3 study of peginterferon beta-1a in patients with relapsing-remitting multiple sclerosis show that more frequent dosing yields greater improvements, and that treatment with the drug was associated with a reduction in relapse rates, slower disease progression, and fewer T2 lesions compared to placebo, regardless of dosing schedule. In the study, the side effect profile of peginterferon beta-1a was comparable to other forms of interferon therapy.
Peter Calabresi, MD, director of the Division of Neuroimmunology and Neuro-infectious Diseases at Johns Hopkins School of Medicine, reported two-year results from the ADVANCE clinical trial on April 29, 2014, at the 2014 American Academy of Neurology annual meeting in Philadelphia, PA.
Calabresi clarified that a full two years of study data were reported, rather than the interim analysis suggested by the original title of the talk. For the first year of the study, 1,516 study participants were randomized by approximate thirds to receive peginterferon beta-1a 125 mcg (injected subcutaneously) every two weeks or every four weeks, or to receive placebo. After one year when unblinding occurred, placebo patients were then randomized approximately equally to the two treatment arms.
Participants were matched evenly in terms of demographics and disease state across the treatment arms. Retention rates were approximately 80 percent over two years.
Pegylation is the process of attaching polyethylene glycol (PEG) polymers to a pharmaceutical agent. The need for less frequent dosing and decreased immunogenicity are clinically important effects of the pegylation of interferons.
In the ADVANCE peginterferon beta-1a study, primary and secondary efficacy and safety endpoints were met, according to the study authors. Using a post-hoc intention to treat analysis, researchers examined the primary endpoint of relapses, expressed as annualized relapse rate. This rate was .351 with placebo, .291 for the four-week interferon group, and .221 for the biweekly group; these figures represent a 17 percent improvement in relapse rate for monthly peginterferon beta-1a versus placebo, and a 35 percent improvement over placebo for those receiving biweekly treatment. Subjects completing their second year in the treatment arms showed a maintained annual relapse rate when dosed every four weeks with peginterferon beta-1a, and a year-over-year reduction in relapses for biweekly dosing.
Time to disability, a secondary endpoint, was measured as progression on the Expanded Disability Status Scale (EDSS). Both of the treatment arms of the study at the end of year two showed less progression to disability compared to the previous placebo arm, with the every two-week treatment group showing a larger effect (HR 0.89 [0.58, 1.35], p=0.57).
Neuroimaging showed fewer new or enlarging lesions on T2-weighted magnetic resonance imaging, and fewer gadolinium (Gd)-enhancing lesions in both treatment arms compared to previous placebo patients, with the more frequent dosing again showing benefit (T2 lesion mean ratio: 0.36 [027, 0.49], p<0.0001; Gd-enhancing lesion odds ratio 0.34 [0.19, 0.61], p=0.0004).
Immunogenicity of the pegylated interferon beta-1a remained low at the end of year two, with less than 1% of subjects exhibiting antibodies to interferon.
Calabresi commented that the side effect profile of peginterferon beta-1a is similar to other interferons, with over half of patients in both treatment arms reporting injection site erythema (59 percent for biweekly and 64 percent for monthly dosing). Influenza-like symptoms were experienced by approximately 50 percent and 80 percent the two groups, respectively. Thirty-one percent and 50 percent of study subjects experienced abnormalities in liver enzymes; however, only about 2 percent of subjects had elevations of liver enzymes more than five times the upper limit of normal. Enzymes normalized after cessation of treatment. Hematologic abnormalities were relatively rare, occurring in 3 percent and 10 percent of patients, with leukopenias most commonly seen.
In summary, Calabresi emphasized that the new findings at the end of year two of the ADVANCE study show ongoing improvements in relapse rate, slower progression in disability, and fewer abnormalities on neuroimaging for both peginterferon beta-1a treatment arms, with numeric superiority across all measures for more frequent dosing.