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New drug approaches to FM: sometimes the patient comes second

research-transEvery now and again, economic decisions can outweigh patient benefits. Whilst 3 drugs are approved for the treatment of FM in the USA, none are approved in the UK. There are 2 main reasons behind the refusal of approval of Lyrica (pregabalin), Cymbalta (duloxetine) and Savella (milnacipran) for the treatment of FM in the UK – the first is the perceived marginal benefit to patients, and the second (not often reported ) is the cost of providing that medication.

Phase II clinical trial results for the drug esreboxetine in FM have just been reported in the journal Clinical Therapeutics, confirming its safety and efficacy in the treatment of FM. The results are interesting and warrant some discussion.

Esreboxetine is made by Pfizer, who are also responsible for Lyrica (pregabalin). However, esreboxetine acts by a different pharmacological mechanism. Its mode of action is to block the reuptake of the neurotransmitter norepinephrine, a molecule involved in pain and mood. Here it shares some commonality with duloxetine and milnacipran, which block the reuptake of both serotonin and norepinephrine in the brain. Therefore esreboxetine would be seen to be distinguishable from these SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors).

Over 260 FM patients were randomised to esreboxetine or placebo over the 8 week safety and efficacy Phase II clinical trial. Primary outcome measures of the trial were threefold – change in pain score (an eleven point scale, from 0 [no pain] to 10 [worst possible pain]), change in the FIQ (Fibromyalgia Impact Questionnaire) total score and the PGIC (Patient Global Impression of Change). The FIQ and PGIC are commonly used in FM clinical trials. The so called secondary outcome measures consisted of an assessment of the change in fatigue, patient function and health-related quality of life, in each case using other established questionnaires.

The results showed that the esreboxetine treated group showed significant lowering of the weekly average pain score, with over 37% of patients showing a greater than 30% reduction in that pain score. Similarly, significant improvements were seen in the FIQ score and in the PGIC, with numbers reporting that their condition was “much improved” or “very much improved” after treatment. Four secondary outcome measures also showed significant benefit in the esreboxetine group – the multidimensional assessment of fatigue, the mental and physical health components of the SF-36 (36 item Short Form health survey) and the Sheehan Disability Scale total score.

There is no doubt from these results that esreboxetine established positive outcomes in a clinical trial for FM: the drug was safe and showed benefit beyond the treatment of the chronic pain aspect of FM.

When a pharmaceutical company needs to demonstrate the final proof of effect of their new drug, they initiate Phase III clinical trials. These comprise a large patient population with a longer treatment time for the new medicine and a massive financial investment for the company. In the case of the positive Phase II results for esreboxetine in FM, the choice for Pfizer were twofold: to choose to invest in a drug that may add to a potential FM “franchise” (Lyrica being the flagship product), or to let Lyrica stand alone. That then became a decision based on what the pharmaceutical companies call “portfolio management”. In this case, the choice was made not to pursue the development of esreboxetine for FM, based on a perceived lack of differentiation of esreboxetine from existing treatments and the financial burden associated with proving that it does offer a viable alternative.

Every company is faced with choices based on the economic climate. In this case Pfizer made one choice. That is not to say that esreboxetine may not be requested for licence by another company. Here’s hoping.

by Colin Dell

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