Clinical profile

ADVANCE pivotal trial design1-3

Efficacy and safety of subcutaneous PLEGRIDY were assessed during the first year (48 weeks) of the 2-year, randomized, double-blind, multicenter ADVANCE clinical study (Study 1) in patients with relapsing multiple sclerosis (MS).

Abbreviations: ARR, annualized relapse rate; PPR, proportion of patients relapsing; MRI, magnetic resonance imaging; Gd+, gadolinium-enhancing; EDSS, Expanded Disability Status Scale; SC, subcutaneous.

Randomization

PLEGRIDY
(peginterferon beta-1a)

n=512
125 mcg
By SC injection
Every 2 weeks

Placebo

n=500
By SC injection
Every 2 weeks

Clinical

  • ARR (primary endpoint)
  • Proportion of patients with confirmed disability progressiona (secondary endpoint)
  • PPR (secondary endpoint)

MRI

  • Number of new or newly enlarging T2 hyperintense lesions (secondary endpoint)
  • Number of Gd+ lesions (tertiary endpoint)

aConfirmed disability progression was defined as a sustained 12-week increase of 1 point from a baseline EDSS score greater than 0 or a sustained 12-week increase of 1.5 points from a baseline EDSS score of 0.

  • Baseline EDSS score ≤5.0

AND

  • ≥2 relapses within 3 years prior to the study and at least 1 within the 12 months prior to randomization
  • Progressive forms of MS
  • Mean age, 37
  • % women, 71
  • Mean disease duration, 3.6 years
  • Mean EDSS score, 2.5
  • Mean number of Gd+ lesions, 1.5
  • Mean number of T2 lesions, 50.2
  • Neurologic examination at baseline, every 12 weeks, and at suspected relapse
  • Brain MRI at baseline, week 24, and week 48

Proven efficacy1,2

PLEGRIDY significantly reduced 3 key measures of disease activity at 48 weeks

ARR at 48 weeks1,2

  • PLEGRIDY demonstrated a 36% relative risk reduction in ARR compared with placebo (0.26 vs 0.40; P=0.0007)

PPR at 48 weeks1,2

  • PLEGRIDY demonstrated a 39% relative risk reduction in PPR compared with placebo (0.19 vs 0.29; P=0.0003)
  • 19% of patients taking PLEGRIDY experienced a relapse compared with 29% of people taking placebo, resulting in a 39% relative risk reduction

Time to progression of disability at 48 weeks1,2,a

  • PLEGRIDY demonstrated a 38% relative risk reduction in the proportion of patients who had 12 weeks of confirmed disability progression compared with placebo (0.07 vs 0.11; P=0.0383)

aConfirmed disability progression was defined as a sustained 12-week increase of 1 point from a baseline EDSS score greater than 0 or a sustained 12-week increase of 1.5 points from a baseline EDSS score of 0.

Number of new or newly enlarging T2 hyperintense lesions at 48 weeks1,2

  • PLEGRIDY demonstrated a 67% relative reduction in the mean number of new or newly enlarging T2 hyperintense lesions compared with placebo (3.6 vs 10.9; P<0.0001)

Number of Gd+ lesions at 48 weeks1,2

  • PLEGRIDY demonstrated an 86% relative reduction in the mean number of Gd+ lesions compared with placebo (0.2 vs 1.4; P<0.0001)

Well-established safety1

Safety of PLEGRIDY versus placebo was assessed in year 1 of ADVANCE (Study 1). Safety experience in year 2 of ADVANCE and its 2-year safety extension (Study 2) were consistent with the experience in year 1 of ADVANCE. Cumulatively, 1468 patients received PLEGRIDY in the 2 studies over 4 years.

The following serious adverse reactions have been associated with PLEGRIDY treatment.

Contraindications

PLEGRIDY is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta or peginterferon, or any other component of the formulation.

Warnings and precautions

Hepatic injury

Severe hepatic injury, including hepatitis, autoimmune hepatitis, and rare cases of severe hepatic failure, have been reported with interferon beta. Asymptomatic elevation of hepatic transaminases has also been reported, and in some patients has recurred upon rechallenge with interferon beta.

Clinical study experience

  • Elevations in hepatic enzymes and hepatic injury have been observed with the use of PLEGRIDY in clinical studies. The incidence of increases in hepatic transaminases was greater in patients taking PLEGRIDY than in those taking placebo
  • The incidence of elevations of alanine aminotransferase above 5 times the upper limit of normal was 1% in placebo-treated patients and 2% in PLEGRIDY-treated patients
  • The incidence of elevations of aspartate aminotransferase above 5 times the upper limit of normal was less than 1% in placebo-treated patients and less than 1% in PLEGRIDY-treated patients
  • Elevations of serum hepatic transaminases combined with elevated bilirubin occurred in 2 patients. Both cases resolved following discontinuation of PLEGRIDY

Guidance

Monitor patients for signs and symptoms of hepatic injury.

Depression and suicide

Depression, suicidal ideation, and suicide occur more frequently in patients receiving interferon beta than in patients receiving placebo.

Clinical study experience

  • Overall incidence of adverse events related to depression and suicidal ideation in multiple sclerosis patients was 8% in both the PLEGRIDY and placebo groups
  • The incidence of serious events related to depression and suicidal ideation was similar and less than 1% in both groups

Guidance

Advise patients to report immediately any symptom of depression or suicidal ideation to their healthcare provider. If a patient develops depression or other severe psychiatric symptoms, consider stopping treatment with PLEGRIDY.

Anaphylaxis and other allergic reactions

Serious allergic reactions are rare complications of treatment with interferon beta; anaphylaxis has been reported with use of PLEGRIDY in the postmarketing setting.

Clinical study experience

Less than 1% of PLEGRIDY-treated patients experienced a serious allergic reaction such as angioedema or urticaria. The rubber tip cap of the PLEGRIDY prefilled syringe for intramuscular administration contains natural rubber latex, which may cause allergic reactions and should not be handled by latex-sensitive individuals.

Guidance

Discontinue PLEGRIDY if a serious allergic reaction occurs.

Injection site reactions

Injection site reactions, including injection site necrosis, can occur with the use of interferon beta.

Clinical study experience

  • In clinical studies of subcutaneous PLEGRIDY, the incidence of injection site reactions (eg, injection site erythema, pain, pruritus, or edema) was 66% in the PLEGRIDY group and 11% in the placebo group
    • Incidence of severe injection site reactions was 3% in the PLEGRIDY group and 0% in the placebo group
    • 1 patient out of 1468 patients who received PLEGRIDY experienced injection site necrosis. The injury resolved with standard medical treatment
  • In a single clinical study of healthy volunteers comparing single doses of intramuscular and subcutaneous PLEGRIDY, the incidence of injection site reactions (e.g., injection site erythema, pain, pruritus, or edema) was 14% in the intramuscular PLEGRIDY group and 32% in the subcutaneous PLEGRIDY group

Guidance

Decisions to discontinue therapy following necrosis at a single injection site should be based on the extent of the necrosis. For patients who continue therapy with PLEGRIDY after injection site necrosis has occurred, avoid administration of PLEGRIDY near the affected area until it is fully healed. If multiple lesions occur, discontinue PLEGRIDY until healing occurs.

Congestive heart failure

Congestive heart failure, cardiomyopathy, and cardiomyopathy with congestive heart failure occur in patients receiving interferon beta.

Clinical study experience

  • Incidence of cardiovascular events was 7% in both PLEGRIDY and placebo treatment groups
  • No serious cardiovascular events were reported in the PLEGRIDY group

Guidance

Monitor patients with significant cardiac disease for worsening of their cardiac condition during initiation and continuation of treatment with PLEGRIDY.

Decreased peripheral blood counts

Interferon beta can cause decreased peripheral blood counts in all cell lines, including rare instances of pancytopenia and severe thrombocytopenia.

Clinical study experience

  • Decreases in white blood cell counts below 3.0 x 109/L occurred in 7% of patients receiving PLEGRIDY and in 1% receiving placebo. There is no apparent association between decreases in white blood cell counts and an increased risk of infections or serious infections
  • The incidence of clinically significant decreases in lymphocyte counts (below 0.5 x 109/L), neutrophil counts (below 1.0 x 109/L), and platelet counts (below 100 x 109/L) were all less than 1% and similar in both placebo and PLEGRIDY groups
    • 2 serious cases were reported in patients treated with PLEGRIDY: one patient (less than 1%) experienced severe thrombocytopenia (defined as a platelet count less than or equal to 10 x 109/L), and another patient (less than 1%) experienced severe neutropenia (defined as a neutrophil count less than or equal to 0.5 x 109/L). In both patients, cell counts recovered after discontinuation of PLEGRIDY
  • Compared to placebo, there were no significant differences in red blood cell counts in patients treated with PLEGRIDY

Guidance

Monitor patients for infections, bleeding, and symptoms of anemia. Monitor complete blood cell counts, differential white blood cell counts, and platelet counts during treatment with PLEGRIDY. Patients with myelosuppression may require more intensive monitoring of blood cell counts.

Thrombotic microangiopathy

Cases of thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, some fatal, have been reported with interferon beta products. Cases have been reported several weeks to years after starting interferon beta products.

Guidance

Discontinue PLEGRIDY if clinical symptoms and laboratory findings consistent with TMA occur, and manage as clinically indicated.

Autoimmune disorders

Autoimmune disorders of multiple target organs including idiopathic thrombocytopenia, hyper- and hypothyroidism, and autoimmune hepatitis have been reported with interferon beta.

Clinical study experience

In clinical studies, the incidence of autoimmune disorders was less than 1% in both PLEGRIDY and placebo treatment groups.

Guidance

If patients develop a new autoimmune disorder, consider stopping PLEGRIDY.

Seizures

Seizures are associated with the use of interferon beta.

Clinical study experience

The incidence of seizures in multiple sclerosis clinical studies was less than 1% in patients receiving PLEGRIDY and placebo.

Guidance

Exercise caution when administering PLEGRIDY to patients with a seizure disorder.

Setting patient expectations about common side effects and equipping patients with strategies to manage these side effects can help prepare them for treatment.

The most common adverse reactions reported in year 1 of ADVANCE, in which patients with relapsing MS received PLEGRIDY or placebo by subcutaneous (SC) injection, were injection site reactions (ISRs) and flu-like symptoms (FLS).1

Incidence and severity of most common adverse reactions in ADVANCE year 11

Most common adverse reactions with an incidence >10% on PLEGRIDY SC and ≥2% more than placebo in ADVANCE (year 1)1

Other adverse reactions that occurred in the 48-week placebo-controlled phase of Study 1 with PLEGRIDY SC-treated patients (n=512) at an incidence of at least 2% more than that observed in the placebo-treated patients (n=500) included1:

  • Nausea: 9% PLEGRIDY-treated versus 6% placebo-treated patients
  • Vomiting: 5% PLEGRIDY-treated versus 2% placebo-treated patients
  • Hyperthermia: 4% PLEGRIDY-treated versus 1% placebo-treated patients
  • Pain: 5% PLEGRIDY-treated versus 3% placebo-treated patients
  • Injection site edema: 3% PLEGRIDY-treated versus 0% placebo-treated patients
  • Injection site warmth: 3% PLEGRIDY-treated versus 0% placebo-treated patients
  • Injection site hematoma: 3% PLEGRIDY-treated versus 1% placebo-treated patients
  • Injection site rash: 2% PLEGRIDY-treated versus 0% placebo-treated patients
  • Body temperature increased: 6% PLEGRIDY-treated versus 3% placebo-treated patients
  • Alanine aminotransferase increased: 6% PLEGRIDY-treated versus 3% placebo-treated patients
  • Aspartate aminotransferase increased: 4% PLEGRIDY-treated versus 2% placebo-treated patients
  • Gamma-glutamyl-transferase increased: 3% PLEGRIDY-treated versus 1% placebo-treated patients
  • Pruritus: 4% PLEGRIDY-treated versus 1% placebo-treated patients

Incidence and tolerability of FLS

  • In ADVANCE, the incidence of FLS was 47% in the PLEGRIDY group and 13% in the placebo group
  • Fewer than 1% of patients discontinued PLEGRIDY due to FLS

Most common adverse reactions with PLEGRIDY SC and PLEGRIDY IM in bioequivalence study1

Comparison between SC and IM administration

An open-label, crossover study analyzed findings from 130 healthy volunteers to assess the bioequivalence of single doses of 125 mcg of PLEGRIDY administered as an SC and intramuscular (IM) injection.

The pharmacokinetics of 125 mcg single dose of PLEGRIDY administered subcutaneously and intramuscularly were similar.

Safety results below, from the bioequivalence study, showed a lower frequency of ISRs with PLEGRIDY IM versus PLEGRIDY SC.

55% relative reduction in ISRs

  • Overall, ISRs (e.g., injection site erythema, pain, pruritus, or edema) were reported with a lower frequency in intramuscular (14%) compared to subcutaneous (32%) administration.

Counsel patients on methods to help manage common side effects

Nurse Educators, available 24/7 through Biogen Support Services, can provide patients with supplemental injection training and guidance on some common side effects. Patients can reach them at 1-800-456-2255.

Nurse Educators are registered nurses working on behalf of Biogen, and many are MS-certified.