Long-term efficacy and safety of three times weekly dosing regimen of glatiramer acetate in relapsing multiple sclerosis patients: Seven-year results of the Glatiramer Acetate Low-frequency Administration (GALA) open-label extension study

Objective Describe the long-term outcomes of early-start (ES) and delayed-start (DS) glatiramer acetate 40 mg/mL treatment three times weekly (GA40) for up to seven years in the Glatiramer Acetate Low-frequency Administration (GALA) study in patients with relapsing multiple sclerosis (RMS). Methods Patients were evaluated every three to six months. The primary efficacy endpoint was annualized relapse rate (ARR); additional endpoints were exploratory or post hoc. For efficacy, data from the entire exposure period were used for the ES and DS cohorts. For safety, exposure only under GA40 was considered. Results Of the patients who continued into the open-label extension (OLE), 580/834 (70%) ES and 261/419 (62%) DS completed the OLE. For the entire placebo-controlled and OLE study period, ARR was 0.26 for ES and 0.31 for DS patients (risk ratio = 0.83; 95% confidence interval [CI]: 0.70–0.99). ES prolonged median time to first relapse versus DS (4.9 versus 4.3 years; hazard ratio = 0.82; 95% CI: 0.6–0.96). OLE-only results showed DS patients experienced similar efficacy for relapse and disability outcomes as ES patients. Adverse events were consistent with the well-established GA safety profile. Conclusions GA40 treatment conferred clinical benefit up to seven years, resulting in sustained efficacy and was generally well tolerated in RMS patients.

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United States open-label glatiramer acetate extension trial for relapsing multiple sclerosis: MRI and clinical correlates

Multiple Sclerosis Journal ◽

10.1177/135245850100700107 ◽

2001 ◽

Vol 7 (1) ◽

pp. 33-41 ◽

Cited By ~ 66

Author(s):

Jerry S Wolinsky ◽

Ponnada A Narayana ◽

Kenneth P Johnson ◽

Keyword(s):

Glatiramer Acetate ◽

Term Treatment ◽

Open Label ◽

Clinical Correlates ◽

Long Term Treatment ◽

Open Label Extension ◽

Long Term Follow Up ◽

Relapsing Multiple Sclerosis

After the placebo-controlled extension of the pivotal US trial of glatiramer acetate for the treatment of relapsing multiple sclerosis ended, 208 participants entered an open-label, long-term treatment protocol. Magnetic resonance imaging (MRI) was added to the planned evaluations of these subjects to determine the consequences of long-term treatment on MRI-defined pathology and evaluate its clinical correlates. Of the 147 subjects that remained on long-term follow-up, adequate images were obtained on 135 for quantitative MRI analysis. The initial imaging sessions were performed between June 1998 and January 1999 at 2447+61 days (mean+standard deviation) after the subject's original randomization. Clinical data from a preplanned clinical visit were matched to MRI within 3+51 days. At imaging, 66 patients originally randomized to placebo (oPBO) in the pivotal trial had received glatiramer acetate for 1476+63 days, and 69 randomized to active treatment with glatiramer acetate (oGA) were on drug for 2433+59 days. The number of documented relapses in the 2 years prior to entering the open-label extension was higher in the group originally randomized to placebo (oPBO=1.86+1.78, oGA=1.03+1.28; P=0.002). The annualized relapse rate observed during the open-label study was similar for both groups (oPBO=0.27, +0.45 oGA=0.28+0.40), but the reduction in rate from the placebo-controlled phase was greater for those beginning therapy with GA (oPBO reduced by 0.66+0.71, oGA reduced by 0.23+0.58; P=0.0002). One or more gadolinium enhancing lesions were found in 27.4% of all patients (number of distinct enhancements=1.16+2.52, total enhanced tissue volume=97+26 ml). The risk of having an enhancement was higher in those with relapses during the open-label extension (odds ratio 4.65, 95% confidence interval (CI) 2.0 to 10.7; P=0.001). The odds for finding an enhancement was 2.5 times higher for those patients originally randomized to placebo (CI 1.1 to 5.4; P=0.02) compared to those always on glatiramer acetate. MRI-metrics indicative of chronic pathology, particularly measures of global cerebral tissue loss (atrophy), were uniformly worse for those originally on placebo. These observations enrich our long-term follow up of the clinical consequences of treatment with glatiramer acetate to include its apparent effects on MRI-defined pathology. They show that the effect of glatiramer acetate on enhancements is definite, but modest, consistent with the drug's described mechanisms of action, and that a delay in initiating treatment results in progression of MRI-measured pathology that can be prevented.

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Effect of ofatumumab versus placebo in relapsing multiple sclerosis patients from Japan and Russia: Phase 2 APOLITOS study

Multiple Sclerosis Journal ◽

10.1177/13524585211055934 ◽

2021 ◽

pp. 135245852110559

Author(s):

Jun-ichi Kira ◽

Jin Nakahara ◽

Denis V Sazonov ◽

Takayoshi Kurosawa ◽

Isao Tsumiyama ◽

...

Keyword(s):

Multiple Sclerosis ◽

Opportunistic Infections ◽

Open Label ◽

Double Blind ◽

Rate Versus ◽

Open Label Extension ◽

Clinical Benefits ◽

Anti Cd20 ◽

Multiple Sclerosis Patients ◽

Relapsing Multiple Sclerosis

Background: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, has been developed as a treatment for relapsing multiple sclerosis (RMS) which can be self-administered at home. Objective: To investigate the efficacy and safety of ofatumumab in RMS patients from Japan and Russia. Methods: APOLITOS included a 24-week, double-blind, placebo-controlled core-part followed by an open-label extension-part. Patients were randomized (2:1) to subcutaneous ofatumumab 20 mg or placebo. Primary outcome was the number of gadolinium-enhancing (Gd+) T1 lesions per scan over 24 weeks. Results: Sixty-four patients were randomized (ofatumumab, n = 43; placebo, n = 21). Primary endpoint was met; ofatumumab reduced Gd + T1 lesions versus placebo by 93.6% ( p < 0.001) and the results were consistent across regions (Japan/Russia). Ofatumumab reduced annualized T2 lesion and relapse rate versus placebo by week 24. Both groups showed benefit from ofatumumab in the extension-part. Incidence of adverse events was lower with ofatumumab versus placebo (69.8% vs 81.0%); injection-related reactions were most common. No deaths, opportunistic infections, or malignancies were reported. Conclusion: Ofatumumab demonstrated superior efficacy versus placebo, with sustained effect through 48 weeks in RMS patients from Japan/Russia. Switching to ofatumumab after 24 weeks led to rapid radiological and clinical benefits. Safety findings were consistent with pivotal trials.

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Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis: results from the 15-year analysis of the US prospective open-label study of glatiramer acetate

Multiple Sclerosis Journal ◽

10.1177/1352458509358088 ◽

2010 ◽

Vol 16 (3) ◽

pp. 342-350 ◽

Cited By ~ 131

Author(s):

C. Ford ◽

AD Goodman ◽

K. Johnson ◽

N. Kachuck ◽

JW Lindsey ◽

...

Keyword(s):

Multiple Sclerosis ◽

Glatiramer Acetate ◽

Progressive Multiple Sclerosis ◽

Immunomodulatory Therapy ◽

Open Label ◽

Safety Issues ◽

Disease Modifying Therapy ◽

Multiple Sclerosis Patients ◽

Relapse Rates

The ongoing US Glatiramer Acetate (GA) Trial is the longest evaluation of continuous immunomodulatory therapy in relapsing—remitting multiple sclerosis (RRMS). The objective of this study was to evaluate up to 15 years of GA as a sole disease-modifying therapy. Two hundred and thirty-two patients received at least one GA dose since study initiation in 1991 (mITT cohort), and 100 (43%, Ongoing cohort) continued as of February 2008. Patients were evaluated every 6 months using the Expanded Disability Status Scale (EDSS). Mean GA exposures were 8.6 ± 5.2, 4.81 ± 3.69, and 13.6 ± 1.3 years and mean disease durations were 17, 13, and 22 years for mITT, Withdrawn and Ongoing cohorts, respectively. For Ongoing patients, annual relapse rates (ARRs) maintained a decline from 1.12 ± 0.82 at baseline to 0.25 ± 0.34 per year; 57% had stable/improved EDSS scores (change ≤ 0.5 points); 65% had not transitioned to secondary progressive multiple sclerosis (SPMS); 38%, 18%, and 3% reached EDSS 4, 6, and 8. For all patients on GA therapy (the mITT cohort), ARRs declined from 1.18 ± 0.82 to 0.43 ± 0.58 per year; 54% had stable/improved EDSS scores; 75% had not transitioned to SPMS; 39%, 23%, and 5% reached EDSS 4, 6, and 8. In conclusion, multiple sclerosis patients with mean disease duration of 22 years administering GA for up to 15 years had reduced relapse rates, and decreased disability progression and transition to SPMS. There were no long-term safety issues.

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Efficacy and safety of a three-times-weekly dosing regimen of glatiramer acetate in relapsing–remitting multiple sclerosis patients: 3-year results of the Glatiramer Acetate Low-Frequency Administration open-label extension study

Multiple Sclerosis Journal ◽

10.1177/1352458516664033 ◽

2016 ◽

Vol 23 (6) ◽

pp. 818-829 ◽

Cited By ~ 20

Author(s):

Omar Khan ◽

Peter Rieckmann ◽

Alexey Boyko ◽

Krzysztof Selmaj ◽

Natalia Ashtamker ◽

...

Keyword(s):

Multiple Sclerosis ◽

Glatiramer Acetate ◽

Gray Matter Volume ◽

Low Frequency ◽

Open Label ◽

Treatment Benefit ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

Multiple Sclerosis Patients ◽

Relapsing Remitting Multiple Sclerosis

Background: The 1-year placebo-controlled (PC) phase of the Glatiramer Acetate Low-Frequency Administration (GALA) study showed that glatiramer acetate 40 mg/mL three times weekly (GA40) significantly reduced annualized relapse rate (ARR) and magnetic resonance imaging (MRI) activity in patients with relapsing–remitting multiple sclerosis. Patients completing the PC phase were invited to an open-label (OL) extension. Objective: To evaluate the effects of early start (ES) and delayed start (DS) of GA40 over 3 years. Methods: A total of 97.2% of patients completing the PC phase received GA40 in the OL extension. ES ( n = 943) patients received GA40 throughout; DS ( n = 461) patients received placebo during the PC phase and GA40 during the OL phase. Relapse, MRI, disease progression, and safety were evaluated. Results: A total of 1041 patients completed 3 years of follow-up. During the OL phase, ES and DS patients showed comparable ARRs (0.20–0.22) and similar numbers of gadolinium-enhancing T1 ( p = 0.49) and new or enlarging T2 lesions ( p = 0.51) at Year 3. ES patients showed significantly smaller changes in gray matter volume than DS patients from Months 12 to 36 (mean difference, 0.371%; p = 0.015), with similar trend in whole-brain volume ( p = 0.080). Adverse events were mild, consistent with the well-established glatiramer acetate (GA) safety profile. Conclusion: GA40 conferred treatment benefit over 3 years: sustained low ARR and lesion activity and favorable safety.

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Brain Atrophy Rates for Stable Multiple Sclerosis Patients on Long-Term Fingolimod versus Glatiramer Acetate

Frontiers in Neurology ◽

10.3389/fneur.2020.01045 ◽

2020 ◽

Vol 11 ◽

Author(s):

Justin M. Honce ◽

Kavita V. Nair ◽

Brian D. Hoyt ◽

Rebecca A. Seale ◽

Stefan Sillau ◽

...

Keyword(s):

Multiple Sclerosis ◽

Glatiramer Acetate ◽

Brain Atrophy ◽

Multiple Sclerosis Patients

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Comparative effectiveness of early intensive or escalation treatment strategies on long term disability trajectories in relapsing multiple sclerosis patients

Journal of the Neurological Sciences ◽

10.1016/j.jns.2021.117749 ◽

2021 ◽

Vol 429 ◽

pp. 117749

Author(s):

Pietro Iaffaldano ◽

Giuseppe Lucisano ◽

Francesca Caputo ◽

Damiano Paolicelli ◽

Francesco Patti ◽

...

Keyword(s):

Multiple Sclerosis ◽

Comparative Effectiveness ◽

Treatment Strategies ◽

Multiple Sclerosis Patients ◽

Relapsing Multiple Sclerosis

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Patients transitioning from non-pegylated to pegylated interferon beta-1a have a low risk of new flu-like symptoms: ALLOW phase 3b trial results

Multiple Sclerosis Journal - Experimental Translational and Clinical ◽

10.1177/2055217318822148 ◽

2019 ◽

Vol 5 (1) ◽

pp. 205521731882214 ◽

Cited By ~ 1

Author(s):

Robert T Naismith ◽

Barry Hendin ◽

Sibyl Wray ◽

DeRen Huang ◽

Fiorenza Gaudenzi ◽

...

Keyword(s):

Multiple Sclerosis ◽

Interferon Beta ◽

Pegylated Interferon ◽

Symptom Duration ◽

Open Label ◽

Open Label Study ◽

Management Guidance ◽

Cumulative Duration ◽

Multiple Sclerosis Patients ◽

Relapsing Multiple Sclerosis

Background Flu-like symptoms are common adverse events associated with interferon beta relapsing multiple sclerosis therapies. Objectives To evaluate the incidence and severity of flu-like symptoms after transitioning from non-pegylated interferons to peginterferon beta-1a and assess flu-like symptom mitigation using naproxen. Methods ALLOW was a phase 3b open-label study in relapsing multiple sclerosis patients. Patients had received non-pegylated interferon for 4 or more months immediately before beginning a 4-week screening period. At baseline, patients switched to peginterferon beta-1a and were randomly assigned (1:1) to continue their current flu-like symptoms management regimen or start twice-daily naproxen 500 mg for 8 weeks. Patients then switched to their preferred regimen and were followed for 48 weeks in total. Results Of 201 patients, 89.6% did not experience new/worsening flu-like symptoms during their first 8 weeks on peginterferon beta-1a. Flu-like symptom severity remained low in current-regimen and naproxen patients, with no significant between-group differences. Median flu-like symptom duration per injection was 3.2 hours longer with peginterferon beta-1a versus prior interferon, but the 4-week cumulative duration was reduced 49–78%. No new safety signals were identified. Conclusion Most patients who switched from non-pegylated interferon to peginterferon beta-1a did not experience new/worsening flu-like symptoms. Flu-like symptom duration per injection increased, but the cumulative duration significantly decreased. These data may inform flu-like symptom management guidance.

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Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years

Multiple Sclerosis Journal ◽

10.1177/135245850000600407 ◽

2000 ◽

Vol 6 (4) ◽

pp. 255-266 ◽

Cited By ~ 150

Author(s):

K P Johnson ◽

B R Brooks ◽

C C Ford ◽

A Goodman ◽

J Guarnaccia ◽

...

Keyword(s):

Multiple Sclerosis ◽

Glatiramer Acetate ◽

Relapse Rate ◽

Open Label ◽

Double Blind ◽

Open Label Study ◽

Label Study ◽

Open Label Phase ◽

Multiple Sclerosis Patients ◽

To Receive

In a randomized, placebo-controlled, double-blind study, glatiramer acetate (Copaxone®) reduced the relapse rate and slowed accumulation of disability for patients with relapsing-remitting multiple sclerosis. Of the original 251 patients randomized to receive glatiramer acetate or placebo, 208 chose to continue in an open-label study with all patients receiving active drug. The majority of the original double-blind cohort continues to receive glatiramer acetate by daily subcutaneous injection and are evaluated at 6-month intervals and during suspected relapse. The data reported here are from approximately 6 years of organized evaluation, including the double-blind phase of up to 35 months and the open-label phase of over 36 months. Daily subcutaneous injections of 20 mg glatiramer acetate were well tolerated. The mean annual relapse rate of the patients who received glatiramer acetate since randomization and continued into the open-label study was 0.42 (95% confidence interval (CI), CI=0.34-0.51). The rate per year has continued to drop and for the sixth year is 0.23. Of the group who have received glatiramer acetate without interruption for 5 or more years, 69.3% were neurologically unchanged or have improved from baseline by at least one step on the Expanded Disability Status Scale (EDSS). Patients who left the open-label phase were surveyed by questionnaire. The majority responded, providing information about their current status and reasons for dropping out. This study demonstrates the sustained efficacy of glatiramer acetate in reducing the relapse rate and in slowing the accumulation of disability in patients with relapsing forms of multiple sclerosis.

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