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An unexpected turn

Clinical trials can prove efficacious for alternative indications and breathe new life into drugs

PlaneDrug development is a long and expensive process, with the cost of bringing a drug to market estimated at $500m to $2bn, and no guarantee that a drug will prove efficacious or well tolerated in clinical trials.

Even when clinical trials are successful, approval will be granted for use of the drug in a small number of indications, limiting the ability of a company to recoup losses incurred during the development process. This is also hindered by the relatively short period of time (7-12 years) in which a new drug is under patent protection following launch; unless a new drug is a veritable cash cow such as sildenafil (Viagra; Pfizer). After patent expiry, the best way to make a substantial profit from the sale of a drug is to find new uses for it.

This is not a new phenomenon. While clinical trials showed that Viagra was not particularly effective for its intended use as a treatment for angina, it was noticed that the drug could induce erections. Following approval as an erectile dysfunction treatment by the US FDA in 1998, annual sales of Viagra exceeded $1 bn annually between 1999 and 2001.

Although doctors are able to prescribe drugs 'off-label' for any intended purpose, it is illegal for a pharmaceutical company to promote them for a non-approved use. Though it is possible to get around this through various methods such as sponsoring research and continued education for doctors, it is far more effective to get a drug approved for a new indication and avoid the risk of fines imposed by regulatory agencies.

Quetiapine (Seroquel; AstraZeneca) is an atypical antipsychotic with antagonist activity at dopamine D2, serotonin 2A and ?2 adrenergic receptors, as well as serotonin 1A receptor agonism and norepinephrine reuptake inhibitor activity. Quetiapine was launched for the treatment of schizophrenia and bipolar disorders, and is currently in preregistration for the treatment of depression and generalised anxiety disorder (GAD) in the US, with supplemental New Drug Applications submitted to the US FDA in February and May 2008, respectively.

Clinical studies of a controlled release formulation of quetiapine as a monotherapy for depression and GAD were presented at the 161st Annual Meeting of the American Psychiatric Association in May 2008. Maintenance therapy with quetiapine was shown to significantly decrease the hazard ratio of depressive and anxiety events, and was associated with significantly less deterioration of symptoms compared with placebo. In another trial, patients with GAD receiving quetiapine monotherapy showed significantly higher response rates and greater improvements in Hamilton Anxiety Rating Scale scores, compared with the placebo group.


Lubiprostone Amitiza (Takeda Pharmaceuticals) Irritable Bowel Syndrome US

Mycophenolate mofetil (Cellcept; Roche) is an immunosupressant commonly used for treating and preventing transplant rejection. It is currently being investigated as a treatment for various auto-immune disorders and multiple sclerosis. In June 2007, the US FDA granted fast-track status for Mycophenolate mofetil (MMF) in the treatment of lupus nephritis. Preliminary results released in June 2007 indicate a lack of efficacy, but the trial is still ongoing. Clinical trials of MMF in multiple sclerosis are also in progress, and results from the first 180 days of a study assessing MMF alone, as well as in combination with interferon ?-1b, were presented at the 161st Annual Meeting of the American Psychiatric Association.

Cladribine (Leustatin), a purine analogue approved for the treatment of various leukaemias and lymphomas, is also currently in development for the treatment of multiple sclerosis. Results presented at the 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis, the 12th Annual Conference on Rehabilitation in MS and the 161st Annual Meeting of the American Psychiatric Association indicate that cladribine is effective, with significant reductions in relapse rates and the severity of relapses. Cladribine also appears to be reasonably well tolerated.

Merck Serono and EMD Serono are conducting the ONWARD study (oral cladribine added ON to Rebif new formulation in patients With Active Relapsing Disease) to assess the tolerability and efficacy of two doses of oral cladribine in combination with interferon b-1b (Rebif; Merck Serono) in a population of 260 patients with active multiple sclerosis. The trial is scheduled for completion in February 2010.

Celecoxib (Celebrex; Pfizer) is a selective cyclo-oxygenase 2 inhibitor initially developed as a non-steroidal anti-inflammatory drug (NSAID) with an improved gastrointestinal tolerability profile compared with non-selective NSAIDS. Celecoxib is being investigated for efficacy in the treatment and prevention of a variety of cancers, particularly colorectal cancer. Results of a trial assessing the efficacy and tolerability of celecoxib in patients at high-risk for the development of colorectal cancer showed significant reductions in the incidence of advanced adenomas at five years.

Ongoing phase III trials are assessing the efficacy of celecoxib for the prevention of Barrett's oesophagus, a premalignant condition caused by gastroesophageal reflux, and the treatment of bladder cancer. Celecoxib may also be effective for the treatment and prevention of breast cancer, as epidemiological data suggests an inverse association between regular NSAID treatment and the occurrence of breast cancer.

As no drug treatment - or our knowledge of human physiology - is perfect, there is always the opportunity for a drug's intended target, or unintended side effect, to be a significant earner for a drug company and a lifesaver for the patient.

Indeed, the wonder drugs of the 21st century may be aspirin and statins. Initially used as an analgesic, aspirin was found to significantly reduce cardiovascular events, and is now being investigated for uses as diverse as cancer prevention and the effect of aspirin on the outcome of in vitro fertilisation. Similarly, from their humble beginnings as antihyperlipidaemics, statins are being assessed for their effects in Alzheimer's disease and prostate cancer, among others.

By no means are these examples the only uses for established drugs; drugs such as rivastigmine (Exelon; Novartis) and galantamine (Razadyne; Ortho-McNeil), used in the treatment of dementia, are being assessed to see if they benefit cognition in patients with schizophrenia, and duloxetine (Cymbalta; Eli Lilly), an antidepressant, approved for the treatment of painful diabetic neuropathy, is being investigated for efficacy in the treatment of back pain and fibromyalgia.

With the number of diseases lacking effective treatments, it would appear that the best compliment to serendipity is human ingenuity.

The Author
Pipeline was written by Bernard Kerr of Adis International, using data derived from Adis Clinical Trials Insight and R&D Insight. For further information on Adis services, please contact Camille Scot-Smith on 020 7981 0733

21st July 2008


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