Cheap as chips: Azathioprine at least as good as Beta Interferon - Now what?

Massacesi L, Tramacere I, Amoroso S, Battaglia MA, Benedetti MD, Filippini G, La Mantia L, Repice A, Solari A, Tedeschi G, Milanese C. Azathioprine versus Beta Interferons for Relapsing-Remitting Multiple Sclerosis: A Multicentre Randomized Non-Inferiority Trial.PLoS One. 2014 Nov 17;9(11):e113371. doi: 10.1371/journal.pone.0113371. eCollection 2014.

For almost three decades in many countries azathioprine has been used to treat relapsing-remitting multiple sclerosis. However its efficacy was usually considered marginal and following approval of β interferons for this indication it was no longer recommended as first line treatment, even if presently no conclusive direct β interferon-azathioprine comparison exists. To compare azathioprine efficacy versus the currently available β interferons in relapsing-remitting multiple sclerosis, a multicenter, randomized, controlled, single-blinded, non-inferiority trial was conducted in 30 Italian multiple sclerosis centers. Eligible patients (relapsing-remitting course; ≥2 relapses in the last 2 years) were randomly assigned to azathioprine or β interferons. The primary outcome was annualized relapse rate ratio (RR) over 2 years. Key secondary outcome was number of new brain MRI lesions. Patients (n = 150) were randomized in 2 groups (77 azathioprine, 73 β interferons). At 2 years, clinical evaluation was completed in 127 patients (62 azathioprine, 65 β interferons). Annualized relapse rate was 0.26 (95% Confidence Interval, CI, 0.19-0.37) in the azathioprine and 0.39 (95% CI 0.30-0.51) in the interferon group. Non-inferiority analysis showed that azathioprine was at least as effective as β interferons (relapse RRAZA/IFN 0.67, one-sided 95% CI 0.96; p<0.01). MRI outcomes were analyzed in 97 patients (50 azathioprine and 47 β interferons). Annualized new T2 lesion rate was 0.76 (95% CI 0.61-0.95) in the azathioprine and 0.69 (95% CI 0.54-0.88) in the interferon group. Treatment discontinuations due to adverse events were higher (20.3% vs. 7.8%, p = 0.03) in the azathioprine than in the interferon group, and concentrated within the first months of treatment, whereas in the interferon group discontinuations occurred mainly during the second year. The results of this study indicate that efficacy of azathioprine is not inferior to that of β interferons for patients with relapsing-remitting multiple sclerosis. Considering also the convenience of the oral administration, and the low cost for health service providers, azathioprine may represent an alternative to interferon treatment, while the different side effect profiles of both medications have to be taken into account.



Azathioprine (AZA) is an immunosuppressive drug used in organ transplantation and autoimmune diseases and belongs to the chemical class of purine analogues. Synthesized originally as a cancer drug and a prodrug for mercaptopurine in 1957, it has been widely used as an immunosuppressant for more than 50 years.

Azathioprine acts as a prodrug for mercaptopurine, inhibiting an enzyme required for the synthesis of DNA. Thus, it most strongly affects proliferating cells, such as the T cells and B cells of the immune system.


I saw an analyst reporting there were no disruptive influences in the MS pipeline. Well, may be here is one?

The MS neurology community needs to decide what to do.  The FDA will no doubt say it was not double-blinded (only assessor-blinded).  However, this study provides an insight into how "true" drug repurposing could work.

The head-to-head trial by Luca Massacesi and colleagues suggests AZA is at least as effective as beta interferon, a licensed disease modifying drug for relapsing MS.

The question is now: What next?

Prescribe this cheap pill off-label and run the risk of not being protected should anything go wrong?

Apply for a license with legal protection for prescribing physicians, and there will be no room for shouting the playing field is not level?

But who will pay to apply and hold a license (basic application fee at the EMA: €278,500.  Annual fee to maintain a license: €99,900)? http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000327.jsp

Surely it would be in the interests of the NHS that this is investigated.  The cost of AZA in the UK (British National Formulary) is: 28 tablets x 25mg = £6.02; 56 tablets x 50mg = £5.04. 

AZA has been discussed before on this blog and is one of the drugs to consider for poor healtcare environments...
http://multiple-sclerosis-research.blogspot.com/2012/08/beta-interferon-and-azathioprine.html 
http://multiple-sclerosis-research.blogspot.com/2014/10/off-label-azathioprine-for-relapsing.html

I suppose we could do even better than Azathioprine?

CoI: Multiple

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