Author Topic: Plegridy (PEGylated interferon beta-1a) (BIIB017)  (Read 729 times)

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Offline agate

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Plegridy (PEGylated interferon beta-1a) (BIIB017)
« on: February 26, 2014, 01:45:00 pm »
Another interferon, PLEGRIDY, will probably be coming along soon.

From the MSAA 2014 MS Research Update:

Quote
Plegridy® PEGylated interferon beta-1a, also known as BIIB017)

Company: Biogen Idec

Administered by subcutaneous injection once every two weeks at a dose of 125 mcg (micrograms)

Plegridy is being studied for relapsing forms of MS


PEGylation is a chemical modification that has been performed on the interferon beta-1a molecule that allows it to be given subcutaneously (under the skin) every two or four weeks, in contrast to the more frequent injections utilized by the currently approved forms of interferon. The goal is to reduce the number of injections, while maintaining the positive effect of the drug.

Studies have tested this experimental therapy for safety and effectiveness. If approved by the FDA, this would give patients the option of using a single-dose auto-injector with a prefilled syringe less frequently.

The Phase III clinical trial (ADVANCE) enrolled patients with relapsing-remitting MS (RRMS) to determine the safety and efficacy of Plegridy as compared to placebo. Results were presented in 201331 from the first year of this Phase III study, where 1,512 patients were randomized to one of three groups: one group receiving placebo; a second group receiving Plegridy given by subcutaneous injection once every two weeks; and a third group receiving Plegridy by subcutaneous injection once every four weeks.

Plegridy dosed every two weeks significantly reduced MS disease activity versus placebo. Relapses were reduced by 36 percent, and new brain lesions by 67 percent, compared to placebo at one year. Disability outcomes were also positive in this one-year trial. In total, the proportion of disease activity-free patients over one year was significantly higher in the two treatment groups compared to placebo.

The overall incidence of serious adverse events (SAE) and adverse events (AE) was similar among the Plegridy and placebo groups. The most common serious adverse event was infection, which was balanced across all treatment groups (less than or equal to 1 percent per group). The most commonly reported adverse events with Plegridy treatment were redness at the injection site and influenza-like illness. Flu-like illness was reported in 47 percent of both treatment groups compared to 13 percent in the placebo group. These safety data are consistent with the established safety profile of interferon beta-1a therapies for MS.

After the first year, study participants who were taking the placebo were re-randomized to one of the two treatment groups (taking the active drug either once every two weeks or once every four weeks), and will continue on their new treatment for the remainder of the second year in the study. Once the study is completed, participants will be given the option to enroll in the ATTAIN open-label (no longer blinded) extensions study. Participants will be followed for up to four years in this second study.

In a subgroup of ADVANCE participants, up to 120 were enrolled in a sub-study that involves optical coherence tomography (OCT). This is a rapid, noninvasive, office-based imaging technique that allows objective evaluation of the thickness of the retinal axon (the nerve behind the eye) and nerve layers that atrophy (shrinking due to nerve cell death) in MS. Preliminary evidence supports the use of OCT as an objective tool to monitor the effectiveness of a therapy, and it is hoped that OCT may be used as an outcome measure in future studies.

In May 2013, Biogen Idec submitted a new treatment application for multiple sclerosis to the United States FDA for approval, and the application was accepted for review. A decision regarding the approval of Plegridy is expected in 2014.
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Offline agate

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A Biogen-sponsored study, presented at the annual AAN conference in Philadelphia, April 29, 2014:

Quote
[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

Bernd Kieseier,1Thomas Scott,2Scott Newsome,3Sarah Sheikh,4Serena Hung,4Xiaojun You,5Bjorn Sperling5

1Düsseldorf, Germany, 2Pittsburgh, PA, USA, 3Baltimore, MD, USA, 4Cambridge, MA, USA, 5Weston, MA, USA

OBJECTIVE:

To determine whether peginterferon beta-1a improved recovery following relapses in patients with relapsing-remitting multiple sclerosis (RRMS).
BACKGROUND: In Year 1 of the ADVANCE study, subcutaneous peginterferon beta-1a (125 µg) every 2 (Q2W) or 4 (Q4W) weeks significantly reduced, versus placebo, the risk of 12-week confirmed disability progression (by 38% in both dosing arms), and annualized relapse rate (ARR; by 36% and 28%, respectively).

In RRMS populations treated with placebo, approximately 20-30% of all relapses have been reported to lead to confirmed disability progression. However, approximately half of patients experiencing disability progression do so without associated relapses. Thus, a reduction in ARR alone may not explain the reduced risk of disability progression with peginterferon beta-1a in the ADVANCE study.

DESIGN/METHODS:

Post-hoc analyses were conducted using data from 1512 patients who were randomized and dosed in ADVANCE. Disability progression due to incomplete recovery following relapse was defined as onset of 3-month sustained disability progression (≥1.0- or ≥1.5-point increase in Expanded Disability Status Scale score, from a baseline score of ≥1.0 or 0.0, respectively, confirmed after 12 weeks) within 180 days of a relapse.

RESULTS:

Overall, n=55 experienced disability progression associated with relapses; n=57 experienced disability progression not associated with relapses (numerically fewer patients on peginterferon beta-1a versus placebo). Relapse severities were not different between groups. Peginterferon beta-1a Q2W and Q4W reduced the proportion of patients experiencing sustained disability progression due to incomplete recovery following a relapse versus placebo by 56% (p=0.012) and 41% (p=ns), respectively. Following a recent relapse, a lower proportion receiving peginterferon beta-1a Q2W (13.6%) and Q4W (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.

CONCLUSIONS:

The significant reduction in risk of disability progression at Year 1 in ADVANCE observed in patients treated with peginterferon beta-1a versus placebo may be partially due to greater recovery from relapses.

Study Sponsored by: Biogen Idec Inc.

Category - MS and CNS Inflammatory Disease: Clinical Science



S4: Platform Session: MS and CNS Inflammatory Disease: Clinical Trials
 
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Offline agate

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From PubMed, May 6, 2014:

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Lancet Neurol. 2014 Apr 30. pii: S1474-4422(14)70068-7.

Pegylated interferon beta-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study

Calabresi PA1, Kieseier BC2, Arnold DL3, Balcer LJ4, Boyko A5, Pelletier J6, Liu S7, Zhu Y7, Seddighzadeh A7, Hung S7, Deykin A7; for the ADVANCE Study Investigators.

Author information


1Department of Neurology, Johns Hopkins University, Baltimore, MD, USA. Electronic address: pcalabr1@jhmi.edu.
2Department of Neurology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
3Montreal Neurological Institute, McGill University, Montreal, QC, Canada; NeuroRx Research, Montreal, QC, Canada.
4Department of Neurology, New York University, Langone Medical Center, New York, NY, USA.
5Moscow MS Center at 11 City Hospital and Department of Neurology & Neurosurgery of the RSMRU named by Pirogov, Moscow, Russia.
6Departments of Neurology and Research (CRMBM), CHU Timone, Marseille, France.
7Biogen Idec, Cambridge, MA, USA.


BACKGROUND:


Subcutaneous pegylated interferon (peginterferon) beta-1a is being developed for treatment of relapsing multiple sclerosis, with less frequent dosing than currently available first-line injectable treatments. We assessed the safety and efficacy of peginterferon beta-1a after 48 weeks of treatment in the placebo-controlled phase of the ADVANCE trial, a study of patients with relapsing-remitting multiple sclerosis.

METHODS:

We did this 2-year, double-blind, parallel group, phase 3 study, with a placebo-controlled design for the first 48 weeks, at 183 sites in 26 countries. Patients with relapsing-remitting multiple sclerosis (age 18-65 years, with Expanded Disability Status Scale score ≤5) were randomly assigned (1:1:1) via an interactive voice response or web system, and stratified by site, to placebo or subcutaneous peginterferon beta-1a 125 μg once every 2 weeks or every 4 weeks. The primary endpoint was annualised relapse rate at 48 weeks. This trial is registered with ClinicalTrials.gov, number NCT00906399.

FINDINGS:

We screened 1936 patients and enrolled 1516, of whom 1512 were randomly assigned (500 to placebo, 512 to peginterferon every 2 weeks, 500 to peginterferon every 4 weeks); 1332 (88%) patients completed 48 weeks of treatment. Adjusted annualised relapse rates were 0·397 (95% CI 0·328-0·481) in the placebo group versus 0·256 (0·206-0·318) in the every 2 weeks group and 0·288 (0·234-0·355) in the every 4 weeks group (rate ratio for every 2 weeks group 0·644, 95% CI 0·500-0·831, p=0·0007; rate ratio for the every 4 weeks group 0·725, 95% CI 0·565-0·930, p=0·0114). 417 (83%) patients taking placebo, 481 (94%) patients taking peginterferon every 2 weeks, and 472 (94%) patients taking peginterferon every 4 weeks reported adverse events including relapses.

The most common adverse events associated with peginterferon beta-1a were injection site reactions, influenza-like symptoms, pyrexia, and headache. 76 (15%) patients taking placebo, 55 (11%) patients taking study drug every 2 weeks, and 71 (14%) patients taking study drug every 4 weeks reported serious adverse events; relapse, pneumonia, and urinary tract infection were the most common.

INTERPRETATION:

After 48 weeks, peginterferon beta-1a significantly reduced relapse rate compared with placebo. The drug might be an effective treatment for relapsing-remitting multiple sclerosis with less frequent administration than available treatments.

FUNDING:

Biogen Idec.

PMID: 24794721

The abstract can be seen here.
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Offline agate

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A better interferon?
« Reply #3 on: July 09, 2014, 08:43:01 am »
From the MS Discovery Forum "New Findings" (July 2, 2014);

Quote
A Better Interferon?

Subcutaneous injections of pegylated interferon β-1a once every 2 weeks may improve recovery from relapses and increase the likelihood of freedom from measurable disease activity

LISA J. BAIN


Pegylated interferon β-1a (PEG-IFN) continues to show benefits similar to other currently available treatments for multiple sclerosis (MS), according to data presented at the 2014 American Academy of Neurology (AAN) meeting in Philadelphia. Pegylation involves the covalent attachment of a polyethylene glycol (PEG) molecule to a compound as a means of reducing its immunogenicity and increasing its stability, solubility, half-life, and efficacy.
 
In July 2013, MSDF reported preliminary data from the first year of the phase 3 ADVANCE trial of PEG-IFN (Reuss, 2013). These results showed that intravenous administration of 125 µg of PEG-IFN either once every 2 weeks (Q2W) or once every 4 weeks (Q4W) reduced disability progression by 38% in both dosing arms as measured by the Expanded Disability Status Scale. It also reduced annualized relapse rate by 36% (Q2W) and 28% (Q4W).
 
In Philadelphia, Peter Calabresi, M.D., of Johns Hopkins University presented 2-year clinical efficacy and safety data from ADVANCE. These results support maintained benefits of PEG-IFN Q2W or Q4W beyond 1 year, with the Q2W dosing regimen showing greater efficacy across all endpoints. In addition, immunogenicity appears to be extremely low, Calabresi said.
 
Two other post hoc analyses of ADVANCE data explored other, less commonly used outcome measures that may better represent efficacy in MS drug trials. For example, Bernd Kieseier, M.D., of Heinrich Heine University in Düsseldorf, Germany, presented an analysis that asked whether PEG-IFN improves recovery following relapses. According to Kieseier, reduction in annualized relapse rate alone may not explain the reduced risk of disability, since about half of patients experience disability progression without associated relapses. By comparing those with disability progression who did or did not have relapses, this analysis showed that, in comparison to placebo, significantly fewer patients taking PEG-IFN had disability resulting from incomplete recovery from relapse; and that following a relapse, fewer patients receiving PEG-IFN had sustained disability progression—30% reduced risk of progression in those taking the drug every 2 weeks, and 22% in those taking the drug every 4 weeks.   
 
In the other post hoc analysis, Douglas Arnold, M.D., of the Montreal Neurological Institute at McGill University assessed a relatively new measure of therapeutic response: freedom from measured disease activity, or FMDA (also called no evidence of disease activity, or NEDA) (Havrdova et al., 2010). “In the current environment of drug development, it’s becoming less and less acceptable to accept partially effective therapies,” Arnold said during his platform presentation.
 
Arnold tested three subtypes of FMDA: clinical FMDA, in which patients experience no relapses and no sustained accumulation of disability at 12 weeks; MRI FMDA, in which MR studies show an absence of gadolinium-enhancing lesions and no new or enlarging T2 lesions; and the composite of these two, called overall FMDA. Only patients with complete data were included in these FMDA analyses. Compared to placebo, significantly higher proportions of patients receiving PEG-IFN both every 2 weeks and every 4 weeks had overall, clinical, and MRI FMDA. At week 48, 33.9% of patients in the Q2W treatment group achieved overall FMDA, compared to 21.5% in the Q4W group and 15.1% of those receiving placebo.
 
“I think FMDA is a very attractive endpoint,” Arnold concluded. “Why should we settle for incomplete control of a focal inflammatory disease when we know the lesions are associated with axonal transection and irreversible brain damage, which accumulates even if the disease is asymptomatic?”
 


Disclosures and sources of funding

These studies were sponsored by Biogen Idec Inc. Dr. Calabresi has received personal compensation for activities with Biogen Idec, Teva Neuroscience, Genzyme Corporation, Vaccinex, Vertex, and Novartis; and research support from the National Institutes of Health, the National Multiple Sclerosis Society, Nancy Davis Foundation, Biogen Idec, Vertex, Genentech Inc., Abbott, and Bayer.Dr. Arnold has received personal compensation for activities with Acorda Therapeutics, Bayer Pharmaceuticals Corporation, Biogen Idec, Coronado Biosciences, EMD Serono, Genentech Inc., Genzyme Corporation, GlaxoSmithKline Inc., MedImmune, and NeuroRx Research. Dr. Arnold has received research support from Bayer Pharmaceuticals Corporation.
Dr. Kieseier has received personal compensation for activities with Bayer Pharmaceuticals Corp., Schering AG, Biogen Idec, Merck Serono, Novartis, Roche Diagnostics Corp., Sanofi-Aventis Pharmaceuticals Inc., and Teva Neuroscience. Dr. Kieseier has received research support from Bayer Schering, Biogen Idec, Merck Serono, and Teva Neuroscience. Co-authors Drs. Sheikh, Deykin, Zhu, Sperling, Hung, and You have received personal compensation for activities with Biogen Idec as an employee. Co-author Dr. Scott has received personal compensation for activities with Novartis, Biogen Idec, Teva Neuroscience, and Genzyme Corp., and research support from the Pittsburgh Foundation. Dr. Newsome has received personal compensation for activities with Biogen Idec and Genzyme Corp.
 


 

The article, along with references and comments, can be seen here.
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Offline agate

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Plegridy approved by US FDA
« Reply #4 on: August 18, 2014, 05:47:29 am »
Plegridy has been given the US FDA's approval. An MSAA article about it appeared today.
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Offline agate

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Presented at the ACTRIMS/ECTRIMS conference in Boston, September 10-13, 2014:

Quote
Clinical efficacy of peginterferon beta-1a in relapsing-remitting multiple sclerosis: 2-year data from the phase 3 ADVANCE study   
    
PA Calabresi1, BC Kieseier2, DL Arnold3,4, L Balcer5, A Boyko6, J Pelletier7, S Liu8, Y Zhu8, SI Sheikh8, A Seddighzadeh8, A Deykin8, S Hung8

1Johns Hopkins University, Department of Neurology, Baltimore, MD, United States, 2Heinrich-Heine University, Department of Neurology, Düsseldorf, Germany, 3Montreal Neurological Institute, McGill University, Montreal, QC, Canada, 4NeuroRx Research, Montreal, QC, Canada, 5New York University School of Medicine, Departments of Neurology and Population Health, New York, NY, United States, 6Moscow MS Center at RSMU, Moscow, Russian Federation, 7CHU Timone, Departments of Neurology and Research (CRMBM), Marseille, France, 8Biogen Idec Inc., Cambridge, MA, United States
 
Background:

At Year 1 of ADVANCE, subcutaneous peginterferon beta-1a (125 µg every 2 [Q2W] or 4 [Q4W] weeks) significantly reduced annualized relapse rate [ARR; primary endpoint], risk of relapse, and risk of 12-week confirmed disability progression versus placebo. Safety profiles were similar for Q2W and Q4W treatment arms, and consistent with established interferon beta-1a therapies.

Objectives:

To evaluate the efficacy of peginterferon beta-1a over 2 years on relapse and disability endpoints in patients with relapsing-remitting multiple sclerosis (RRMS) in the Phase 3 ADVANCE study.

Methods:

After Year 1, patients randomized to placebo were re-randomized to 125 µg peginterferon beta-1a administered Q2W or Q4W for Year 2. Patients randomized to peginterferon beta-1a in Year 1 remained on the same dosing regimen in Year 2. All efficacy analyses were performed on data from the intent-to-treat population (all randomized patients who received at least one dose of active study treatment over 2 years). Statistical analysis of proportion of patients with disability progression (patients in the original placebo arm in Year 1 versus patients on peginterferon beta-1a dosing regimens over both years) was pre-specified whereas all remaining statistical analyses were post-hoc.

Results:

In Year 2, ARR was further reduced in patients receiving Q2W (Year 1: 0.230 [95% CI 0.183-0.291], Year 2: 0.178 [0.136-0.233]) and was maintained for patients treated with Q4W (Year 1: 0.286 [0.231-0.355], Year 2: 0.291 [0.231-0.368]). Compared to patients originally randomized to placebo in Year 1, reductions were seen for patients on peginterferon beta-1a during both Years 1 and 2 in ARR (Q2W 37% [p< 0.0001], Q4W 17% [p=0.0906]), risk of relapse (Q2W 39% [p< 0.0001], Q4W 19% [p=0.0465]) and risk of disability progression (12-week confirmed: Q2W 33% [p=0.0257], Q4W 25% [p=0.0960]; 24-week confirmed: Q2W 41% [p=0.0137], Q4W 9% [p=0.6243]).

Over 2 years, relative to Q4W dosing, greater reductions were observed with Q2W dosing in ARR (24%, p=0.0209), risk of relapse (24%, p=0.0212), and risk of disability progression (12-week confirmed: 11%, p=0.5665 and 24-week confirmed: 36%, p=0.0459).

Conclusions:

2-year results support the maintained benefits of peginterferon beta-1a beyond 1 year in RRMS, with significantly greater efficacy seen for Q2W versus Q4W across relapse endpoints.

MS Speaks--online for 12 years

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