Dupuytren’s disease, or Dupuytren’s contracture, is a deformity of one or more fingers caused by shortening, thickening and fibrosis of the connective tissue that lies under the skin in the palm of the hand. This leads ultimately to collagen cords that permanently contract the fingers, impeding the ability to grasp or manipulate objects. The disease is more common in men than in women, and the incidence rises progressively with increasing age.
Although Dupuytren’s disease is named for an eminent nineteenth century French surgeon, Baron Guillaume Dupuytren, who delivered a lecture describing an operation to treat the condition in 1831, the disease was well known long before this. The cause of the disease is not known, but it is often said to have originated with the Vikings who spread it as they invaded and settled new regions.
Surgical management has most commonly been used to release the contracture, although the disease can recur or even worsen following surgery, and there is a significant risk of nerve and/or arterial damage. A promising new treatment that has completed phase III clinical studies is the injection of collagenase which weakens the cords of connective tissue. Pfizer and Auxilium have recently announced a strategic alliance to develop XIAFLEX™ (injectable clostridial collagenase) for the treatment of Dupuytren’s contracture. It is expected that XIAFLEX™ will be filed for approval in the US in 2009 and in the European Union in 2010.
There are no medicines that can prevent Alzheimer’s disease and current drugs ease symptoms but do little to stop progression of the disease. There is consequently much current interest in whether lifestyle choices or herbal remedies can prevent or alter the course of Alzheimer’s disease. Two recent reports describe the effect of marijuana-like compounds in elderly rats and extracts of Gingko Biloba in elderly humans.
Previous work has suggested that people who regularly smoked marijuana in the 1960s and 1970s are less likely to develop Alzheimer’s disease in later life. Now scientists at Ohio State University have described details of how constituents of marijuana can combat inflammation and possibly stimulate neurogenesis. The team had found that treatment with WIN-55212-2, a compound with similar pharmacological properties to tetrahydrocannabinol (THC), made a small improvement to the ability of elderly rats to perform memory tests. They then went on to look at how the drug was working, and showed that it lowered inflammation in the hippocampus by acting on the TRPV1 receptor. The team also showed that the action of WIN-55212-2 on CB1 and CB2 receptors led to the generation of new brain cells. The group are continuing to investigate which receptors are most important for reducing inflammation and stimulating neurogenesis. This knowledge could lead to the discovery of new drugs to reduce inflammation and increase the production of new neurons before memory loss becomes apparent.
WIN55212-2 is a full agonist at the CB1 receptor and is not approved as a drug since it elicits cannabis-like effects in humans.
A second report discusses the results of the first randomized, double-blind trial to assess the effectiveness of Ginkgo biloba in reducing the incidence of dementia. Ginkgo is an antioxidant that helps to protect cells in vitro from oxidative damage. Some studies have suggested that ginkgo may also protect against the toxic effects of β-amyloid. Although previous clinical trials of ginkgo leaf extracts have had mixed results, many older people continue to use the herb in the hope of warding off the onset of Alzheimer’s disease. The new study, however, has shown that ginkgo gave no benefit in reducing all-cause dementia or Alzheimer’s dementia. The study involved more than 3000 men and women aged 75 or older who were randomised to placebo or treatment groups. The treated group received 120mg ginkgo twice a day for an average of 6 years. At the end of the study, dementia developed in 246 people taking ginkgo compared with 277 people in the placebo group. The authors note that an effect may have been seen had the study carried on for longer since it is known that there is a significant time lag between initial brain changes and the manifestation of clinical dementia.
In total, around 200million people are thought to be infected hepatitis C virus (HCV). The current standard of care treatment for (HCV) infection is a combination of pegylated interferon, an immune modulator, and ribavirin, an antiviral drug. Interferon/ribavirin therapy is effective in only around 50% of patients with the most difficult-to-treat HCV, type 1. A number of new small molecule antiviral drugs are being developed, and Roche, Pharmasset and InterMune have recently announced the first clinical trial of an interferon-free combination of an HCV NS3/4A protease inhibitor, R7227, and an HCV NS5B polymerase inhibitor prodrug, R7128. Both the protease and polymerase are essential for viral replication and the new study, which will be carried out in Australia and New Zealand, will look at safety and combined antiviral activity of the two compounds in combination.
R7227, which is being developed in collaboration with InterMune, and R7128, which is being developed in collaboration with Pharmasset, have both already successfully completed studies in combination with pegylated interferon and ribavirin.
Rheumatoid Arthritis (RA) is a painful, chronic, progressive and disabling auto-immune disease. Newly released data has shown that a novel biologic, Actemra™ (tocilizumab), is superior to current standard of care in RA patients. Actemra™ is a humanised monoclonal antibody to the interleukin-6 receptor that blocks the activity of interleukin-6, a protein that plays a major role in the RA inflammatory process. Actemra™ is awaiting approval in the United States and Europe. In Japan, Actemra™ was approved for the treatment of RA in April 2008.
Other biologics are already used to treat RA and act at different points in the inflammatory process.
Orencia® (abatacept) works by reducing the activation of T-cells, which reduces the activation of other cells in the RA inflammatory process. Humera®(adalimumab), Enbrel®( etanercept) and Remicade® (infliximab) block the action of TNF-alpha, an inflammatory cytokine that leads to tissue damage. Mabthera® (rituximab) targets B cells, one of the key players in the pathogenesis of RA. Kineret® (anakinra) blocks the actions of the cytokine, IL-1.
The biologic medicines are usually prescribed together with the disease-modifying anti-rheumatic drug, methotrexate.
Quark Pharmaceuticals has recently announced that its partner Pfizer has begun a phase II clinical trial of a chemically modified small interfering RNA (siRNA) molecule in patients with diabetic macular oedema. PF-4523655 inhibits abnormal blood vessel growth and leakage independently of the VEGF pathway, reduces inflammation and suppresses apoptosis. Results from a Phase I/II trial completed by Quark on Pfizer’s behalf showed that PF-4523655 was safe and well tolerated in patients with wet age-related macular degeneration who failed to respond to currently approved therapies. The new trial will test the safety and efficacy of PF-4523655 compared with laser surgery.
siRNA molecules interfere with the expression of specific genes and there is currently much interest in using the technology to treat a wide range of diseases, although there are several challenges that must be overcome if exogenous siRNA is to become widely used.
Despite the challenges, several siRNA molecules have entered clinical trials including TD101 for pachyonychia congenita (PC Project / TransDerm), Sirna-027/AGN-745 for age-related macular degeneration (Allergan), metastatic melanoma (Duke University), CALAA-01 for solid tumours (Calando Pharmaceuticals), Cand5 for diabetic macular oedema (Opko Health) and I5NP for acute kidney injury following cardiac bypass surgery (Quark Pharmaceuticals).
Prostate cancer is the most common cancer among men, and it has been estimated that up to 10,000 men in the UK are diagnosed each year with the most aggressive form of the disease. A small scale clinical trial has now shown that abiraterone is able to shrink prostate cancer tumours in patients who have not responded to alternative medical or surgical treatments. Abiraterone works by inhibiting production of male hormones, which can stimulate the growth of prostate cancer cells, throughout the body and not just in the testes.
Many of men on the trial reported significant improvements in their quality of life and some were able to stop taking morphine for control of pain caused by the cancer spreading into their bones.
A study published in the July 18th issue of The Lancet shows that a drug once used in Russia to treat hayfever has the potential to improve symptoms in dementia patients. The study of 183 patients, tested dimebon (dimebolin) vs placebo in patients with untreated mild-to-moderate dementia. Patients taking dimebon improved over a six month period whilst those taking placebo got worse.
A smaller group of patients who continued taking dimebon for a further six months showed continuing improvement over this period. This ongoing improvement is seen as particularly important since none of the approved drugs for Alzheimer’s Disease has shown increasing improvement over twelve months. Although this was a relatively small study, the initial results are very encouraging and warrant further investigation.
In a separate study, also reported in The Lancet, immunisation against the amyloid-beta peptide was shown to clear amyloid plaques from the brain, but not to prevent the progressive neurodegeneration associated with Alzheimer’s disease.
Although many companies do not publicise trials, the available evidence shows that biologics are still lagging behind traditional small molecules in the drug development stakes. An analysis published by DrugResearcher of drugs entering clinical trials in 2007 showed that more than twice as many small molecules as biologics made it to first time in man. Although biologics are likely to make up an increasing proportion of new products, there will still be areas where small molecules can achieve better results. Biologics work primarily on disease targets outside the cell, whereas small molecules can also work inside cells. In any therapeutic area, ignoring the intracellular targets may prove costly.