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Looking into the pharmaceutical future

Which compounds now in development will become useful future treatments?

Which compounds now in development will become useful future treatments?

The pharmaceutical industry is facing a challenge as patent expiries, generic competition and increasing regulatory pressures reduce income, and research and development departments develop too few new drugs to make up for the shortfall.

Challenging times

In recent years, there has been a steady decline in the industry’s ability to develop innovative, safe and effective drugs, despite a rise in R&D expenditure. Critics have accused companies of focusing for too long on the search for blockbuster drugs and “me-too” compounds and, as a result, have failed to be sufficiently innovative to develop the new classes of medicines needed to generate a return on their investments.

Analyses by WoodMackenzie, a consultancy company specialising in life sciences, suggest that half of the top 10 pharmaceutical companies in the world will face significant challenges in the next five years. Although the industry is aware of the problem and has begun to adopt strategies to cope, changes to the way R&D is carried out take time.

“The discovery and development of new medicines can take up to 12 years and is an extremely complex scientific process,” a spokesman for Pfizer Global Research and Development explained. “While new technologies can help accelerate certain elements of the process, it is unrealistic to expect the fundamentals of drug discovery and development to change in as short a period as five years.” Companies have begun to review their drug discovery processes, nevertheless.

Implementing changes

AstraZeneca has started a major review of every facet of its business in order to boost its returns on investment. Its chief executive, Tom McKillop, has been reported as saying that the company’s long-term goal is to rival Roche and Genentech’s oncology partnership. While GlaxoSmithKline and sanofi aventis each have about a dozen oncology candidates in clinical trials, Roche, in partnership with Genentech, has almost 20. At present, AstraZeneca has 13 candidates in pre-clinical and phase I and II trials, but none in phase III trials.

The company will have to work hard to catch up, however, because a number of Roche’s drugs in development are already in phase II and III trials, including bevacizumab (Avastin) and erlotinib (Tarceva), which are likely to be particularly important in the next few years.

Other companies have developed a variety of other strategies to help improve their return on investment. For example, GSK has entered into talks to license out some up-coming drugs and is keeping compounds in phase II longer, limiting the progression of less-promising candidates to expensive phase III trials.

Pfizer is taking another tack, investing more than $500m over six years to expand its internal compound library to three million screenable compounds, with the aim of generating candidates with an improved chance of surviving early development. In the past, about one in 20 candidate compounds survived from pre-clinical development to approved product. Pfizer aims to increase this to one in 10. The company has also increased its collaborations with other organisations: approximately 25 per cent of its discovery and development activities now involve external partnerships.

Such strategies have had some success. At the end of 2004, AstraZeneca had 60 per cent more drugs in phase II trials than it did at the same time the year before. And since June 2003, Pfizer’s pipeline of novel compounds has grown by more than 20 per cent.

Some interesting developments

Even if changes to research and development strategy take time to come through, the pharmaceutical industry continues to develop interesting and life saving drugs in many treatment areas.

For instance, AstraZeneca, GSK and Amgen all have peroxisome proliferator-activated receptor (PPAR) agonists in development as lipid balance treatments. And antihyperglycaemic agents for the treatment of type II diabetes — dipeptidyl peptidase IV inhibitors — are being developed by Merck Sharp and Dohme, GSK and Novartis.

AstraZeneca had hoped that its PPAR agonist Galida would be one of the big releases of 2006. But its launch has now been put back by a year, in response to the US Food and Drug Administration ruling that all PPAR agonist studies of six months or longer must be delayed until two-year rodent carcinogenicity trials have been completed and reviewed. The delay will also affect Amgen and GSK’s PPAR agonists, both in phase II trials.

Dipeptidyl peptidase IV inhibitors raise levels of glucagon-like peptide (GLP)-1 and gastric inhibitory polypeptide (GIP) in the gut. GLP-1 and GIP are secreted from the intestine in response to food and stimulate insulin production by the beta cells of the pancreas. GLP-1 also reduces the secretion of glucagon.

By reducing glucagon secretion and stimulating insulin production in response to food, DPP-IV inhibitors help to balance insulin supply and demand and, by doing so only when blood sugar is high, they reduce the risk of hypoglycaemia. Novartis hopes to file for approval of its DPP-IV inhibitor in 2007 and GSK and MSD have DPP-IV inhibitors in phase II and III trials, respectively.

Further developments

Innovative anti-infectives are also being developed. For instance, Pfizer and GSK are both studying CCR5 inhibitors as potential HIV treatments. CCR5 inhibitors bind to a chemokine receptor on the membrane of T-cells, stopping HIV from successfully binding and so preventing the virus from infecting healthy cells.

The possibility that inhibiting CCR5 could represent a successful HIV treatment strategy was raised by studies of people with a genetic mutation protecting them against infection by HIV. Pfizer’s drug is further into development than GSK’s and has now entered phase III trials. GSK also has four other HIV treatments in phase I and II clinical trials.

Researchers have also been continuing to investigate potential treatments for
methicillin-susceptible and methicillin-resistant strains of Staphylococcus aureus (MSSA and MRSA). In December 2004 Wyeth filed for worldwide approval of the first-in-class injectable antibiotic Tygacil (tigecycline) as a single agent therapy to treat patients with complicated intra-abdominal and skin and skin structure infections caused by gram- negative and gram-positive pathogens, anaerobes, and both MSSA and MRSA.

The Panel (p45) provides a summary of some of the other cardiology and oncology drugs currently being developed.

Looking ahead

In the long-term, the key to keeping the pipeline of new drugs flowing will be to embrace the opportunities offered by genetic analysis.In the future, researchers hope to be able to use genetic information to focus treatments solely on groups in which they are likely to be effective.

Such strategies have already begun to have an impact on cancer treatments. Roche’s Herceptin (trastuzumab), now well established, is indicated for metastatic breast cancer in patients with tumours overexpressing the human epidermal growth factor receptor 2. Joanne Andrew, oncology horizon scanning pharmacist at Glasgow Royal Infirmary, says that, while traditional cytotoxic chemotherapy will still have a key role in oncology treatments targeted therapies will become increasingly important in the future.

Genetics is also likely to play an important role in diagnostics, a fact that researchers have been quick to recognise. For instance, the Pain Clinical Research Hub, a collaboration between Pfizer, King’s College Hospital and King’s College London, is to focus on developing biomarkers, clinically validated biological measures which, it is hoped, will aid the diagnosis and monitoring of disease progression and responses to treatment, reducing the time it takes to develop compounds.

The real jackpot, in terms of innovative new treatments, will come, however, when analyses of the human genome allows researchers to characterise large numbers of receptors and then specifically design effective drugs to fit them. That is a challenge that researchers have yet to overcome.

Other new treatments currently in development

The next decade is likely to see a number of new approaches to cardiology and oncology and there are a number of trials of interesting treatments currently under way.

In a recent publication, the Association of the British Pharmaceutical Industry highlighted the heart failure and arrythmia treatments that it thought were most likely to have an impact on practice in the next decade.

These included three heart failure treatments now in phase II trials:

· CVT-124 (Biogen Idec), an adenosine-A1 receptor blocker
· SR121463 (sanofi aventis), a selective non-peptide vasopressin receptor antagonist
· Conivaptan (Yamanouchi), a vasopressin receptor blocker
· Daglutril (Solvay Healthcare), an inhibitor of both endothelium converting enzyme and neutral endopeptidase

New arrythmia treatments in development include:

· Tedisamil (Solvay Healthcare), a potassium channel blocker that also acts as an anti-ischaemic and is now in phase III trials
· Azimilide (Procter and Gamble), a potassium channel blocker which is specific for just one of two sites on the potassium channel
· AVE-0118 (sanofi aventis), a potassium channel blocker
· Piboserod (GSK), a 5HT4 receptor antagonist
· Dronedarone and SR-149744 (sanofi aventis), both Class III antiarrythmics

Although Roche and AstraZeneca undoubtedly have the upper hand in oncology in terms of the number of drugs currently in development, Pfizer, Novartis, MSD, Wyeth, GSK and Amgen each have a handful of compounds scheduled for release in the next few years.

Novartis hopes to launch at least four cancer treatments over the next three years. MSD has a similar number in clinical trials, including its human papillomavirus vaccine, which is now entering phase III trials, and Pfizer is carrying out phase II trials of a compound that inhibits the blood supply to tumours.

Wyeth has three compounds in late-stage clinical trials:

· Temsirolimus, which inhibits cell proliferation
· MAC-321, a novel investigational taxane anticancer agent
· Mylotarg, a targeted antibody therapy

Amgen has two oncology treatments in development:

· AMG386, an angiopoietin antagonist which inhibits tumour growth and reduces viable tumour fraction
· Panitumumab, a monoclonal antibody directed against the epidermal growth factor receptor

GSK currently has several drugs in trials which it hopes to license by the end of 2006, including:

· Lapatinib, a kinase inhibitor
· Navelbine, a vinca alkaloid
· Hycamtin, a topoisomerase I inhibitor
· Nelarabine, a guanine arabinoside prodrug

Citation: The Pharmaceutical Journal URI: 10018181

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