Efficacy

  • BECOME Study
  • PreCISE Study
  • REGARD Study
  • BEYOND Trial

STUDY 1: Cadavid et al. (2009)1
Randomized clinical trial
 Patients  Treatment arms/study duration

 n=75

(Treatment-naive patients with relapsing
remitting MS (RRMS) or clinically isolated
syndromes (CIS) suggestive of MS)
  • GA 20 mg daily; n=39
  • IFNβ-1b; n=36
  • 2 years

Primary endpoint: Number of combined active lesions (CAL) per scan in the first year, with the patient as the unit of analysis.

graph

Figure: MRI activity in patients with multiple sclerosis randomised to treatment with Glatirmer Acetate or interferon beta-1b (IFNβ-1b)

Results
  • Similar median (75th percentile) CAL per patient per scan for months 1–12, 0.63 (2.76) for IFNβ-1b, and 0.58 (2.45) for GA (p=0.58).
  • There were no differences in new lesion or clinical relapses for 2 years.

Patients with relapsing multiple sclerosis randomized to interferon beta 1b or Glatiramer Acetate showed similar MRI and clinical activity.1

STUDY 2: Comi et al. (2009)2
Randomized double-blind trial was conducted across 80 sites in 16 countries
 Patients  Treatment arms/study duration

 n=481

Clinically isolated syndrome with unifocal manifestation, >T2-weighted brain lesions measuring >6 mm or more
  • GA 20 mg daily, SC;n=243
  • Placebo; n=238
  • 36 months

Primary endpoint: Time to conversion to clinically definite multiple sclerosis (MS).

graph

Figure: Time to conversion to clinically definite multiple sclerosis (CDMS) in the placebo-controlled phase.

Results
  • Conversion was significantly delayed in the GA group vs. the placebo group, from 336 days to 722 days.
  • Analysis of the number of new T2 lesions at last observed value of the placebo-controlled phase showed a significant reduction of 58% (0.7 vs. 1.8 in the placebo group; RR 0.42, 95% confidence interval).

Time to development of a second exacerbation was significantly delayed in patients treated with Glatiramer Acetate injection compared to placebo (hazard ratio=0.55; 95% confidence interval, 0.40 to 0.77.)2
RR; Rate ratio; GA: Glatiramer acetate.

STUDY 3: Mikol et al. (2008)3
Multicenter, randomized, comparative, parallel-group, open-label study
 Patients  Treatment arms/study duration

 n=764

(Intention-to-treat population; Treatment-naive patients with RRMS, aged between 18 and 60 years)
  • GA, 20 mg once per day; n=378
  • IFNβ-1a, 0.044 mg three times per week; n=386
  • 96 weeks

Primary endpoint: Time to first relapse over 96 weeks, analyzed on the on the intention-to-treat population, with the Cox proportional hazards model with effects for treatment and center.

Results
  • There was no significant difference in the primary outcome measure between the treatment groups (interferon beta-1a vs Glatiramer Acetate, HR 0·94, 95% CI 0.74–1·21; p=0.64).
  • Further, no changes were observed in primary outcome when only qualifying relapses were taken into consideration for the intention-to-treat group.

Qualifying relapse was defined as new or worsening neurological symptoms, without fever, that lasted for 48 h or more and was accompanied by a change in KFS score.
KFS: Kurtzke functional scale.

There was no significant difference in the time to first relapse, between interferon beta-1a and Glatiramer Acetate.3

STUDY 4: O’Connor et al. (2009)4
Randomized, parallel-group, multicenter, phase 3 study
 Patients  Treatment arms/study duration

 n=2244

(RRMS)
  • GA, 20 mg daily; n=448
  • IFNβ-1b, 0.25 or 0.5 mg every other day; n=897
  • Clinical outcomes were assessed quarterly for 2.0-3.5 years

Primary endpoint: Relapse risk, defined as new or recurrent neurological symptoms separated by at least 30 days from the preceding event and that lasted at least 24 h. It was assessed by the Andersen–Gill model for time to recurring events, which includes correction for the interdependency of multiple event.

Results
  • There were no differences between interferon beta-1b and Glatiramer Acetate with respect to relapse risk
Table: Outcome variables and relapse risk
500 µg IFNB-1b vs 250 µg IFNB-1b vs
Glatiramer Acetate Glatiramer Acetate
HR (95%CI) p* HR (95%CI) p*
Primary analysis (unadjusted) 0.98 (0.82-1.18) 0.43 1.06 (0.89-1.26) 0.73
With covariate adjustment† 1.00 (0.83-1.19) 0.48 1.06 (0.89-1.27) 0.74
Per-protocol analysis A‡ 1.00 (0.83-1.20) 0.50 1.06 (0.89-1.27) 0.74
Per-protocol analysis B§ 0.91 (0.74-1.11) 0.18 0.95 (0.78-1.15) 0.80

IFNB-1b=interferon beta-1b. EDSS=expanded disability status sales. *One-sided p value. †Pre-planned, excluding observation time after a major protocol violation or a 3-months interval in which less than 50% of study drug was taken. ‡Baseline covariates: sex, age, disease duration, EDSS, number of relapses in previous year, numbers of gadolinium-enhancing lesion, and T2 lesion volume. §Post-hoc, excluding observation time after a major protocol violation or a 3-month interval in which less than 100% of drug dose was taken.

Both doses had similar clinical effects to Glatiramer Acetate. Although a difference in the adverse event profiles of interferon beta-1b and Glatiramer Acetate was observed, the overall tolerability to both drugs was similar.4

INDICATION

GLATIRAMER ACETATE INJECTION is indicated for the treatment of patients with relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

IMPORTANT SAFETY INFORMATION

GLATIRAMER ACETATE INJECTION is contraindicated in patients with known hypersensitivity to glatiramer acetate or mannitol.

Approximately 16% of patients exposed to GLATIRAMER ACETATE INJECTION 20 mg per mL compared to 4% of those on placebo, and approximately 2% of patients exposed to GLATIRAMER ACETATE INJECTION 40 mg per mL compared to none on placebo experienced a constellation of symptoms that may occur within seconds to minutes after injection and included at least 2 of the following: flushing, chest pain, palpitations, tachycardia, anxiety, dyspnea, throat constriction, and urticaria. In general, these symptoms have their onset several months after the initiation of treatment, although they may occur earlier, and a given patient may experience 1 or several episodes of these symptoms. Typically, the symptoms were transient and self-limited and did not require treatment; however, there have been reports of patients with similar symptoms who received emergency medical care.

Transient chest pain was experienced by 13% of GLATIRAMER ACETATE INJECTION 20 mg per mL patients compared to 6% of placebo patients, and approximately 2% of GLATIRAMER ACETATE INJECTION 40 mg per mL patients compared to 1% on placebo.

While some episodes of chest pain occurred in the context of the immediate post-injection reactions that are described, many did not. The temporal relationship of this chest pain to an injection was not always known. The pain was usually transient, often unassociated with other symptoms, and appeared to have no clinical sequelae. Some patients experienced more than one such episode, and episodes usually began at least one month after the initiation of treatment.

At injection sites, localized lipoatrophy and, rarely, injection site skin necrosis may occur. Lipoatrophy may occur at various times after treatment onset (sometimes after several months) and is thought to be permanent. There is no known therapy for lipoatrophy.

Because GLATIRAMER ACETATE INJECTION can modify immune response, it may interfere with immune functions. For example, treatment with GLATIRAMER ACETATE INJECTION may interfere with recognition of foreign antigens in a way that would undermine the body’s tumor surveillance and its defenses against infection. There is no evidence that GLATIRAMER ACETATE INJECTION does this, but there has not been a systematic evaluation of this risk.

Cases of hepatic injury, some severe, including liver failure and hepatitis with jaundice, have been reported with GLATIRAMER ACETATE INJECTION. Hepatic injury has occurred from days to years after initiating treatment with GLATIRAMER ACETATE INJECTION. If signs or symptoms of liver dysfunction occur, consider discontinuation of GLATIRAMER ACETATE INJECTION.

The most common adverse reactions observed in controlled studies of GLATIRAMER ACETATE INJECTION 20 mg per mL and 40 mg per mL, were injection site reactions (ISRs), vasodilatation, rash, dyspnea and chest pain; ISRs were one of the most common adverse reactions leading to discontinuation of GLATIRAMER ACETATE INJECTION. ISRs, such as erythema, pain, pruritus, mass, edema, hypersensitivity, fibrosis, and atrophy, occurred at a higher rate with GLATIRAMER ACETATE INJECTION than placebo.