New Data from Plegridy (pegylated interferon beta-1a) Phase 3 Trial Shows Improved Recovery from Relapses

Improvements in MS treatments make for exciting news.  The currently available injectable drugs are given as often as daily to once weekly.  A new formulation of interferon beta-1a is under review which would require only one shot every two weeks.  PLEGRIDY™ (peginterferon beta-1a or PEG-IFN) is an investigational subcutaneous injectable drug for relapsing forms of multiple sclerosis in which interferon beta-1a has been pegylated, a process which extends a molecule’s half-life, prolongs its exposure in the body, and enables less frequent dosing (i.e. fewer shots).

At the recent 66th annual American Academy of Neurology (AAN) annual meeting in Philadelphia, researchers presented new data regarding the safety and efficacy of pegylated interferon beta-1a (Plegridy) from the two-year Phase 3 ADVANCE clinical trial in 1,512 patients with relapsing-remitting multiple sclerosis (RRMS) [2].

The ADVANCE study investigated two dosing regimens of Plegridy, 125 mcg administered subcutaneously every two weeks (n=512) or every four weeks (n=500), as compared to placebo (n=500).  The analysis for all primary and secondary efficacy endpoints occurred at the end of year one. After the first year, patients on placebo were re-randomized to one of the two treatment groups.  Upon completion of the 2-year ADVANCE study, participants had the option of enrolling in the ATTAIN open-label extension study and will be followed for up to four years.

Clinical and MRI data from the ADVANCE study demonstrated that Plegridy dosed once every two weeks (bi-weekly) resulted in reduced relapse rates, disability progression, and the number of MS lesions when compared to placebo.  Treatment effects were greater in the bi-weekly dosing schedule of Plegridy versus every four weeks [3].  Annualized relapse rate and number of new or newly-enlarging T2 lesions were further reduced in year two of the trial for the bi-weekly dose.  The most common adverse reactions (incidence ≥10% and at least 2% more frequent on Plegridy than on placebo) were injection site reactions (redness, pain, itching), flu-like symptoms (fever, headache, chills), muscle pain, joint pain, and weakness.  These side-effects were consistent with other interferon-based MS therapies.

Other medications in the interferon class of drugs used to combat multiple sclerosis include Avonex (interferon beta-1a, once a week intramuscular (IM) injection; Biogen Idec), Rebif (interferon beta-1a, 3 sub-Q injections each week; EMD Serono), Betaseron (interferon beta-1b, every other day sub-Q injection; Bayer Healthcare), and Extavia (interferon beta-1b, every other day sub-Q injection; Novartis).

Results from a systematic literature and network meta-analysis [6] presented at the AAN meeting confirm that pegylated interferon beta-1a (bi-weekly dose) significantly reduced both annualized relapse rate (AAR) and 3 month-confirmed disability progression (CDP3M) compared to placebo which is consistent with the ADVANCE study findings.  However, the meta-analysis showed no statistically significant difference in ARR or CDP3M for Plegridy compared to the other treatments assessed (Avonex, Rebif, Betaseron, Copaxone, and Abagio).  Patients on Plegridy did have a lower probability of serious adverse events compared to other therapies.

Additional post-hoc analyses from year one of the ADVANCE study show an association with improved recovery from relapses and high rates of freedom from measured disease activity in patients with relapsing MS who used Plegridy every two weeks.  Freedom from measured disease activity (FMDA) was defined as no relapses, no disability progression, no Gd+ (gadolinium-enhancing) lesions, and no new or newly-enlarging T2-hyperintense lesions compared to baseline.  The proportions of overall FMDA were significantly higher in the two Plegridy groups (125 mcg every 2 or 4 weeks) versus placebo, 33.9% and 21.5%, 15.1%, respectively.  Proportions of MRI measures of FMDA were 40.9%, 24.9%, 19.1%, respectively, and clinical measures (relapses and disability progression) were 79.3%, 76.2%, 68.4%, respectively [1].

Improved recovery from relapse was seen in patients who used Plegridy in the ADVANCE study.  Following a recent relapse, a lower proportion of patients receiving Plegridy every two weeks (13.6%) or every four weeks (15.2%) had sustained disability progression versus placebo (19.6%); indicating relative reductions in risk of progression following any relapse of 30% and 22%, respectively.  Sustained disability progression was defined as ≥1.0- or ≥1.5-point increase in Expanded Disability Status Scale score lasting 3 months.  However, not all cases of disability progression were associated with relapses.  Approximately half of the cases of confirmed disability progression were seen in patients who had not experienced a relapse (n=57) as compared to patients who had relapsed (n=55) [5].

Plegridy (either dose) significantly reduced the risk of 12-week confirmed disability progression by 38% versus placebo and annualized relapse rate by 36% (bi-weekly dose) and 28% (every 4 weeks), respectively.  “The combination of the overall reduction in risk of relapses plus higher chance of avoiding disease progression from experiencing any relapse resulted in an overall reduction in risk of experiencing disability progression caused by a relapse in the range of 56% in favor of treatment with pegylated interferon given twice monthly compared to placebo,” Dr. Keiseier, lead author, told Medscape [4].

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View References
  1. Arnold D, Kieseier B, et al. [S4.007] Peginterferon Beta-1a Significantly Increases the Proportion of Patients with Freedom from Measured Disease Activity in Relapsing-Remitting Multiple Sclerosis: Findings from the ADVANCE Study [Abstract].  Platform session presented at 66th annual meeting of the American Academy of Neurology; 2014 April 26-May 3; Philadelphia, PA. Retrieved from http://www.abstracts2view.com/aan/view.php?nu=AAN14L1_S4.007
  2. Biogen Idec to Present New Two-Year Data from the PLEGRIDY™ (Peginterferon Beta-1a) Phase 3 ADVANCE Study at AAN Annual Meeting [Press release]. Published April 29, 2014. Retrieved from http://www.biogenidec.com/press_release_details.aspx?ID=14712&Action=1&NewsId=2319&M=NewsV2&PID=61997
  3. Deykin A, Arnold D, et al. [S4.005] Interim Analysis of 2-year Clinical Efficacy and Safety of Peginterferon Beta-1a in Patients with Relapsing-Remitting Multiple Sclerosis: Data from the Pivotal Phase 3 ADVANCE Study [Abstract]. Platform session presented at 66th annual meeting of the American Academy of Neurology; 2014 April 26-May 3; Philadelphia, PA. Retrieved from http://www.abstracts2view.com/aan/view.php?nu=AAN14L1_S4.005
  4. Keller DM. Peg-Interferon Beta-1a Reduces MS Relapses and Progression. Medscape. Published May 05, 2014. Retrieved from http://www.medscape.com/viewarticle/824632
  5. Kieseier B, Scott T, et al. [S4.003] Peginterferon Beta-1a May Improve Recovery Following Relapses: Data from the Pivotal Phase 3 ADVANCE Study in Patients with Relapsing-Remitting Multiple Sclerosis [Abstract]. Platform session presented at 66th annual meeting of the American Academy of Neurology; 2014 April 26-May 3; Philadelphia, PA. Retrieved from http:// www.abstracts2view.com/aan/view.php?nu=AAN14L1_S4.003
  6. Tolley K, Hutchinson M, et al. [P7.234] Systematic Literature Review and Network Meta-Analysis of Pegylated Interferon Beta-1a and Disease Modifying Therapies for Relapsing‑Remitting Multiple Sclerosis [Abstract]. Poster session presented at 66th annual meeting of the American Academy of Neurology; 2014 April 26-May 3; Philadelphia, PA. Retrieved from http://www.abstracts2view.com/aan/view.phpnu=AAN14L1_P7.234

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