Pharmacogenomics of interferon responses

P
Kulakova et al. Allelic combinations of immune-response genes as possible composite markers of IFN-β efficacy in multiple sclerosis patients. Pharmacogenomics. 2012 Nov;13(15):1689-700. doi: 10.2217/pgs.12.161.

Background: IFN-β is widely used as the first-line disease-modifying treatment for multiple sclerosis. However, 30-50% of multiple sclerosis patients do not respond to this therapy. Identification of genetic variants and their combinations that predict responsiveness to IFN-β could be useful for treatment prognosis.

Materials & methods: The combinations of alleles of nine polymorphic loci in immune-response genes were analyzed in 253 Russian multiple sclerosis patients as possible determinants of clinically optimal IFN-β treatment response using APSampler software.

Results: Carriage of TGFB1*-509C (cytokine= a protein that inhibits certain immune function) and CCR5*d (chemokine=chemotactic cytokine= a protein that attracts certain cell type=perfume for cells) was associated with favorable IFN-β response by itself. CCR5*d, IFNAR1*16725G (Interferon alpha receptor) , IFNG*874T (interferon gamma = anti-viral cytokine that activates macrophages) and IFNB1*153T/T (interferon beta = anti-viral cytokine) were the components of the combinations, associated with clinically optimal response to IFN-β. Carriage of composite markers (CCR5*d + IFNAR1*G + IFNB1*T/T) or (CCR5*d + IFNAR1*G + IFNG*T) is beneficial for IFN-β treatment efficacy.

Discussion: The data obtained provides evidence of the cumulative effect of immune-response genes on IFN-β treatment efficacy. This joint contribution may reflect the additive effect of independent allelic variants (genetic varinats) and epistatic (variants that are produced after the genetic variants are produced) interactions between some of them.



Beta Interferons have showed limited efficacy in a significant number of MSers, but historically there was no incentive to pharma to work out which person would respond and those who would not. This is because pharma wanted everyone on and paying for the drug. 

Many Msers develop neutralising antibodies to beta interferons and this stops them working. Again pharma did not appear to be interested. However with the advent of more active drugs, pharma have begun to come around and take an interest. If you remove the MSers who neutralise the beta interferon then they appear to work much more and to a level of the second generation of DMT, so there is an interest in neutralizing antibodies now.
The ability to respond to any drug is determined by the genetic make-up. Analysing the genes to see how genetic variants will impinge on drug action is called Pharmacogenomics. This study identify some related to beta interferon. Pharma have no doubt done a lot more and there are other studies on this. We need to Pharmacogenomics on Lemtrada to work out which people get antibody-induced autoimmunities.

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  • Thank you for your daily information which is always very interesting. I would like to add a comment on one of your sentence: “but historically there was no incentive to pharma to work out which person would respond and those who would not. This is because pharma wanted everyone on and paying for the drug”
    Of course Pharma wants as many as possible people paying for the drug but for interferons another point has totally block the research for responders: unfair competition introduced by health authorities.
    After launch of these products, everybody said they were equal (-30% on relapse rates). The first one trying to find responders and non responders would obviously decrease its own market leaving it to others. So they preferred competing to demonstrate their product was best (Evidence trial, Incomin) or showing that dose and frequency were important (owims) or not (30 vs 60). People selling the two IFN given 3 times (or 3.5) a week knew that the third one main trial was biased and to be somewhat cynic could have given a lot of information on responders and not responders: patients followed for one year only benefited from the placebo -30% increase of relapse rate in the IFN group!- and patients followed up for two years benefited from the IFN, even if only their first year on study is considered. So comparing these two groups would have possibility help to define good and very bad responders!
    Any research on dose or frequency would thus have been at risk of giving advantage to the competitor administered more or less frequently.
    If only IFN given more than once a week had been approved, it would have been easier to build researches on responders according to dose or frequency as the conclusion would have applied equally to both products.
    Pharma is an industry, so they want to make money. If you provide pharma with fair competition rules, may be will you get better researches.

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