Tuesday, 16 June 2015

In silico head-2-head studies: pegylated interferon-beta vs. the others

Which interferon-beta preparation is best? In silico head-2-head studies. #MSBlog #MSResearch

"In silico (computer) head-2-head studies are the future. What you do is use a computer model to compare the efficacy of two or more drugs across trials by controlling for baseline covariates (factors that may affect response to treatment). Biogen have done this with their new long-acting pegylated interferon-beta-1a (Plegridy) or PEG-IFNb. Pegylation is the process of attaching a polyethylene glycol molecule onto proteins to extend its life in the body. As  you aware PEG-IFNb has recently been licensed and will soon be available to MSers in the UK. It is given as a subcutaneous injection every 2 weeks. The study below shows that PEG-IFNb is as good, if not better, than other interferons when compared using a network meta-analysis (NMA). These results will be reassuring to MSers who are on an interferon and doing well and would like to switch to PEG-IFNb to reduce their number of injections."

"I am often asked if there is a future for interferon therapy in MS. I say yes, firstly the interferons have a good safety record and when used early in MS they seem to work better with a greater number of MSers being responders (NEDA-3). If only we could identify the responders before they start interferon-beta we would still be using interferons in a large number of MSers. Secondly, in price sensitive markets the appearance of biosimilars should extend the life of interferons. I suspect many payers may still require MSers to fail an injectable before accessing more high-cost drugs. The latter may become irrelevant once fingolimod is off-patent and cheap generic fingolimod formulations flood the market. I suspect it will be cheaper to produce generic fingolimod than a biosimilar interferon-beta."

"The authors make the claim that PEG-IFNb has the potential to improve adherence, which is an issue with all the injectables and tablets. I agree, but I don't think we have had much of a problem with adherence with the once weekly interferon-beta-1a preparation. In addition, new systems have been put in place to improve adherence of all the IFNb formulations. The one disadvantage of PEG-IFNb is that it is given subcutaneously; there are some advantages to IM route; the latter is associated with fewer injection site reactions. I still have no ideas why Biogen squandered this advantage by developing their PEG-IFNb as a subcutaneous formulation."

"This is not the first study to employ an in silico head-2-head method to compare drugs. I was involved with a similar study that compared the efficacy of the oral therapies, which showed fingolimod was superior to DMF and Teriflunomide and that there was little difference between the latter two when looking at the chances of being rendered NEDA (no evident disease activity) on the orals."

"Please note that these in silico head-2-head studies are often done at the request of the payers. They need some comparative analyses to compare the cost-effectiveness of  treatments. Therefore these studies have the potential to be more influential than we in academia realise."

Tolley et al. A Network Meta-Analysis of Efficacy and Evaluation of Safety of Subcutaneous Pegylated Interferon Beta-1a versus Other Injectable Therapies for the Treatment of Relapsing-Remitting Multiple Sclerosis. PLoS One. 2015 Jun 3;10(6):e0127960.

Background: Subcutaneous pegylated interferon beta-1a (peginterferon beta-1a [PEG-IFN]) 125 μg every two or four weeks has been studied in RRMSer in the pivotal Phase 3 ADVANCE trial. 

Objective: In the absence of direct comparative evidence, a network meta-analysis (NMA) was conducted to provide an indirect assessment of the relative efficacy, safety, and tolerability of PEG-IFN versus other injectable RRMS therapies. 

Methods: Systematic searches were conducted in MEDLINE, Embase, and the Cochrane Library, and conference proceedings from relevant annual symposia were hand-searched. Included studies were randomized controlled trials evaluating ≥1 first-line treatments including interferon beta-1a 30, 44, and 22 μg, interferon beta-1b, and glatiramer acetate in patients with RRMS. Studies were included based on a pre-specified protocol and extracted by a team of independent reviewers and information scientists, utilizing criteria from NICE and IQWiG. 

Results: In line with ADVANCE findings, NMA results support that PEG-IFN every 2 weeks significantly reduced annualized relapse rate, and 3- and 6-month confirmed disability progression (CDP) versus placebo. There was numerical trend favoring PEG-IFN every 2 weeks versus other IFNs assessed for annualized relapse rate, and versus all other injectables for 3- and 6-month CDP (6-month CDP was significantly reduced versus IFN beta-1a 30 μg). The safety and tolerability profile of PEG-IFN beta-1a 125 μg every 2 weeks was consistent with that of other evaluated treatments. Study limitations for the NMA include variant definitions of relapse and other systematic differences across trials, assumptions that populations were sufficiently similar, and inability to perform NMA of adverse events. 

Conclusions: With similar efficacy compared to other RRMS treatments in terms of annualized relapse rate and 3- and 6-month CDP, a promising safety profile, and up to 93% reduction in number of injections (which may improve adherence), PEG-IFN every 2 weeks offers a valuable alternative treatment option for patients with RRMS.

CoI: multiple


  1. In a newly dx patient, why would anyone start Rebif over Plegridy? And if the efficacy of Plegridy equals or betters that of Rebif, why would anyone not change to Plegridy?

  2. It would be interesting to think of a way of Glatiramer Acetate Pegylated ... I would love o//


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