Drugs review of the year

The regulatory authorities are increasingly reluctant to approve products that offer few real benefits over therapies already on the market. Sarah Houlton reviews the new drugs reaching the market in the last 12 months

We are used to seeing a steady stream of new therapeutic agents being approved, as pharmaceutical companies strive to find the big blockbuster drug that will guarantee their profits for the next few years. And while a wide variety of novel actives were approved in the past year, ranging from cancer therapies to anti-infectives, it is noticeable that the steady decline in the number of new chemical entities (nce) gaining approval over the past year or two has continued. Regulatory authorities are more cagey about giving their approval, and pharma companies are finding their requirements ever more stringent.

'Me too' drugs with little therapeutic benefit over existing treatments, for example, are now much less likely to get the go-ahead. Add to this the number of high profile withdrawals of approved drugs recently, and the market for new drugs is getting ever more uncertain. But the potential returns for a blockbusting drug are still enormous, and therefore the steady stream of innovative molecules being developed continues.

anticancer treatments

Several very different anticancer agents have gained approval in the past year. Imatinib (Glivec) from Novartis is an important new oncolytic agent. It has been licensed to treat chronic myeloid leukaemia, a condition that can be cured only by an allogeneic stem cell transplant. The difficulty in finding a suitable donor means that finding an effective chemical treatment can often be the only option. Imatinib mesilate is a signal transduction inhibitor that acts on tyrosine kinase at the Philadelphia chromosome, which is abnormal in most patients with chronic myeloid leukaemia. It could also be used in any other tumour that is caused by or dependent on tyrosine kinases.

Also licensed for the treatment of a form of leukaemia, Schering Health Care's alemtuzumab (MabCampath) is a humanised monoclonal antibody for use in patients with B-cell chronic lymphocytic leukaemia, who have not responded to treatment with alkylating agents and fludarabine. It binds to CD52+, an antigen present on the surface of some leukaemic lymphocytes, and the bound drug induces antibody-dependent lysis. This process leads to the removal of the malignant lymphocytes from the blood, bone marrow and other affected organs.

Another novel anticancer agent, capecitabine (Xeloda) from Roche, is related to the established antitumour drug 5-fluorouracil (5-FU), but has fewer of its side-effects. Capecitabine is a fluorinated pyrimidine that is a prodrug for 5-FU. It is converted into 5-FU in the body in a metabolic process involving three enzymes, the third of which, thymidine phosphorylase, is present in particularly high levels in neoplastic tissues, which could well explain its increased potency as an anticancer agent. It has been licensed for the treatment of metastatic colorectal cancer, and could well be of therapeutic use in other forms of solid tumour.

unknown mechanism

A new drug for treating cutaneous T-cell lymphoma is bexarotene (Targretin, Ligand Pharmaceuticals). Licensed for the treatment of cutaneous manifestations of the disease in patients who have failed to respond adequately to at least one other systemic therapy, bexarotene is a member of a subclass of retinoids that selectively activate retinoid X receptors. Once activated, these receptors act as transcription factors that regulate the expression of genes that control cellular differentiation and proliferation. Although its precise mechanism is unknown, it has been shown to induce tumour regression in vivo in some animal models, and inhibits the growth in vitro of some tumour cell lines of haematopoietic and squamous cell origin.

light therapy

Scotia Pharmaceuticals' temoporfin (Foscan) finally got marketing approval in Europe last June, much to the company's relief as its initial knock-back led to the company being placed in administration.

It is indicated for the palliative treatment of advanced head and neck squamous cell carcinoma that is unsuitable for radiotherapy, surgery or systemic chemotherapy, and has failed to respond to other treatment options. Temoporfin is a photosensitiser, which is given systemically a couple of days in advance of light therapy to allow the drug to accumulate within the tumour. The tumour is then illuminated with red light at 630nm, which causes damage to the sensitised tumour as cytotoxic oxygen species are generated. Temoporfin is more rapidly taken up by the tumour cells than older drugs of this type, such as Photofrin, and is believed to be more selective for tumour cells than normal tissue. It also has a longer half-life in the triplet state, so is able to generate more cytotoxic oxygen species.

renal treatments

The drastic nature of many cancer therapies can often result in serious side-effects. Hyperuricaemia can develop during rapid and massive cell destruction, such as that induced by chemotherapy for acute forms of leukaemia. It is characterised by a sudden, substantial increase in the level of uric acid in the blood, and can lead to acute renal failure as a result of crystals of uric acid being deposited in the kidneys. This potentially fatal condition usually means renal dialysis is needed. Rasburicase (Fasturtec, Sanofi-Synthelabo) is a genetically engineered enzyme, urate oxidase, that converts the insoluble, nephrotoxic uric acid, into soluble allantoin, which is then excreted in the urine, thus preventing its build-up in the kidneys.

The introduction of antirejection medicines has meant that many forms of organ transplantation are now considered to be routine. Immunosuppressant drugs, such as cyclosporin, lower the body's immune response, making it much less likely that the new organ will be rejected, and treatment with these drugs must be continued for life to prevent rejection. A new immunosuppressant drug, sirolimus (Rapamune) is now available from Wyeth, and is an effective alternative for cyclosporin for long-term immunosuppression in kidney transplant patients. It also appears to have fewer of the unpleasant side-effects that are seen with cyclosporin in long-term therapy. Trials have shown that cyclosporin can be eliminated from the immunosuppressant regime between two and four months after transplant, and replaced with the less nephrotoxic sirolimus.

The elevated pressure caused within the eye by glaucoma can, if left untreated, lead to optic nerve damage, threatening the eyesight. As many as three million people are affected in the US alone, with glaucoma accounting for 12% of all new cases of blindness there each year. Two treatments for glaucoma were approved last year. Travoprost (Travotran, Alcon Laboratories) and bimatoprost (Lumigan, Allergan Pharmaceuticals) are both indicated for the treatment of elevated intraocular pressure in patients with ocular hypertension or open angle glaucoma. Both compounds are synthetic prostaglandin analogues that target the prostanoid receptor, and are believed to lower intraocular pressure by increasing the drainage of aqueous humour from the eye.

reducing relapse rates

Teva's glatiramer (Copaxone) was approved for the treatment of multiple sclerosis. It is an immunomodulator that appears to block myelin-specific autoimmune responses. It is indicated for the treatment of relapsing-remitting form of the disease, and has been available in the US for some time. Several clinical trials have shown it is able to reduce the mean two-year relapse rate in this extremely difficult to treat condition by as much as 88%. It works in a completely different manner from the interferons, and so may prove useful in patients who have tried other options with no obvious benefit.

The sooner a patient receives medical attention after a heart attack, the better their chances of survival. A new drug from Boehringer Ingelheim, atenecteplase (Metalyse), is the first thrombolytic that can be given within seconds in a single bolus dose. The drug is a plasminogen activator, and the active plasmin it generates attacks the fibrin that holds blood clots together, turning it into soluble degradation products. The main side effects – intracranial haemorrhage and stroke – are similar to those seen with other thrombolytics, but the drug has a number of advantages. It has a longer half-life and greater resistance to the body's plasmin activator inhibitor PA-1, so the single bolus administration is cleared more slowly. Furthermore, it has a higher fibrin specificity, which could reduce bleeding, and it has a higher activity than the body's own fibrinolytic, t-PA, meaning a lower dose can be used while retaining a similar clinical efficacy.

Another new 'emergency' medicine is Elan's afenoldopam (Corolpam), which has been licensed for the short-term in-hospital management of hypertensive emergencies, including malignant hypertension with end organ deterioration. When administered intravenously, the drug acts as an agonist at the dopamine D1 receptors, and also binds to a-adrenergic receptors. Its fast-onset vasodilating effect gives a rapid lowering of blood pressure.

Increasing numbers of bacteria are now resistant to at least one and, in some cases, most available antibacterial agents. While some agents have been created by modifying existing structures, there is a real need for truly novel antibiotics with new modes of action to prolong the effectiveness of our antibiotic arsenal. One such new chemical entity is linezolid (Zyvox, Pharmacia & Upjohn), which has a highly selective action on bacterial protein synthesis. Uniquely, it forms a complex that interferes with ribosomal protein synthesis, and is especially effective against Gram positive pathogenic bacteria. It is also active against pneumococci, even if they are resistant to penicillin.

Invasive aspergillosis is a potentially life-threatening fungal infection caused by the filamentous fungus Aspergillus fumigatus. It is most often seen in people with compromised immune systems, such as HIV/AIDS patients, organ and bone marrow transplant recipients, and people undergoing cancer therapy. Mortality rates can be as high as 90% in severe cases. Caspofugin acetate from Merck & Co is a novel antifungal agent that has been approved for the intravenous treatment of aspergillosis in patients who have not responded to, or are intolerant of, amphotericin B and itraconazole. It is a member of the echinocandin class of lipoprotein antifungal agents, which work by inhibiting the synthesis of ß-(1,3)-D-glucan, a component of fungal cell walls.

Two more additions to the collection of chiral switches were approved, both antihistamines. Desloratadine (Neoclarityn, Schering Plough) is the single isomer form of the company's loratadine (Clarityn); levocetirazine (Xyzal, UCB Pharma) is based on UCB's cetirazine (Zirtek). Both have improved efficacy and lowered side-effect profiles in the treatment of allergic conditions like hay fever.

post-operative pain

A new, strong analgesic intended for combating post-operative pain, lomoxicam (Xefo), has been developed by Nycomed Pharma, and is licensed to CeNeS Pharmaceuticals in the UK. It is a non-steroidal anti-inflammatory drug, and has been approved in parenteral form for the short term treatment of moderate post-operative pain, and pain associated with acute sciatica. The oral formulation has the additional indications of pain and inflammation in osteoarthritis and rheumatoid arthritis. As it inhibits both cyclooxygenase inhibitors, COX-1 and COX-2, it has a similar side-effect profile to other non-COX selective NSAIDs.

The treatment of migraine took a great leap forward with the introduction of the first of the triptan drugs, sumatriptan. These selective serotonin agonists, which act at the 5-HT1D receptors, can have an excellent effect on the symptoms of migraine, but not all patients respond to all triptans, and the earliest drugs were not orally available. A new member of the class which was approved last year is eletriptan (Relpax, Pfizer). It is orally available, and has been shown to have a good effect in patients who do not respond to sumatriptan. In clinical trials, two thirds of patients given a 40 mg dose had a two-hour headache response for at least two out of three attacks, rising to 72% for an 80mg dose. By comparison, the proportion for patients given placebo was only 15%.

topical formulations

The incidence of diabetes is rising at an alarming rate. Type I diabetes is the result of a deficiency in insulin that is treated with insulin injections; patients with Type II, or non-insulin dependent diabetes suffer from an impairment of the insulin release mechanism that is normally stimulated by the intake of food. Therapy for Type II diabetes is normally with oral hypoglycaemic agents, notably sulphonylurea drugs, which promote the release of stored insulin, or increase the activity of the insulin secretory cells in the pancreas.

Two new drugs that act in a similar way to sulphonylureas are nateglinide (Starlix, Novartis) and repaglinide (Prandin, Novo Nordisk). They open ATP-dependent potassium channels in the pancreas, which, in turn, leads to the opening of voltage-dependent calcium channels, stimulating the release of insulin from storage in the insulin-containing cell granules. Both are more effective than the sulphonylureas drugs.

Excessive facial hair is a potentially distressing problem for women, and a new drug that provides an alternative to hair removal regimes is eflornithine hydrochloride (Vaniqa, Bristol-Myers Squibb). It acts at the hair follicle, blocking the enzyme ornithine decarboxylase, which is needed for hair to grow, and is applied in a topical cream formulation to the affected area.

Trials showed that improvement was seen in as little as eight weeks, and in a clinical trial around a third of women reported a good reduction in the growth of the unwanted hair around the lips and under the chin, compared with 8% of those using placebo.

Slimming pills have had a very bad press over the years, from concerns about their addictive qualities to the serious side effects on the heart valves seen with the fenfluramine phentermine combination. But obesity is more than merely a cosmetic problem: the severely obese are at an increased danger of developing conditions such as diabetes and heart trouble. While not remotely a magic cure for the overweight, sibutramine (Meridia, Knoll) is an advance in the treatment of the clinically obese. The chlorophenyl derivative inhibits both serotonin and the reuptake of noradrenaline, and has been shown to reduce the appetite and food intake, leading to weight loss.