Longevity: a driver for drug discovery

With longer life expectancy come increased health problems. Over the past year this has led to a dramatic rise in new drugs that treat 'old-age' diseases

The vast arsenal of medicines discovered and developed by the pharmaceutical industry is one of the major factors behind the increase in average lifespan seen over the past few decades.But an ageing population brings its own problems, and as we are now less likely to die at an early age of infection, so more people are suffering from conditions - life-threatening or otherwise - that they might not otherwise have lived to experience. Cancer rates are rising, arthritis and osteoporosis affect ever larger numbers of people, and our increasingly unhealthy lifestyles contribute directly to the disease burden. So it is perhaps unsurprising that as many as half of all the new medicines approved in the past year are designed to treat these sorts of conditions.

preventive treatments

Osteoporosis is a particular problem for post-menopausal women, with the decrease in bone density it causes leading to an increased propensity to experience fractures. With preventive hormone replacement therapy now not being routinely prescribed because of side effect concerns, focus has to be on direct treatment of bone density reduction with drugs. Many of these drugs are bisphosphonates, and a further one to gain approval is Roche's ibandronic acid (Bonviva). The product decreases osteoclastic bone resorption and reduces the rate of bone turnover, without having a direct effect on bone formation. It has been shown to be particularly effective at reducing the risk of vertebral fractures in patients with postmenopausal osteoporosis, and also increases bone mineral density in those with osteopoenia. It has also been approved as a preventive treatment in high risk patients.

signs and symptoms

Another disease whose incidence increases with age is rheumatoid arthritis. Although its cause is unknown, sufferers generally have an excess of tumour necrosis factor α, which triggers inflammation as part of the normal immune system response. Overproduction of TNF-α can lead to the excessive inflammation seen in rheumatoid arthritis, and as it builds up in the joints, it can ultimately destroy them. A newly approved treatment that blocks TNF-α is Humira (adalimumab, Cambridge Antibody/ Abbott), a monoclonal antibody. It has a positive effect on the signs and symptoms of rheumatoid arthritis, slowing the progression of joint damage.

Parkinson's disease results from low levels of dopamine in the brain, and patients have trouble with mobility and speech because of the loss of control over movement that results.

The standard treatment is levadopa, which has a dramatic effect on the symptoms in the first instance, but within a year or two the effects wear off and symptoms return.

A newly approved product, Stalevo (Orion/Novartis), is a combination of levodopa and carbidopa with entacapone, which blocks the COMT enzyme that breaks levodopa down before it can reach the brain, leading to better control of symptoms for a longer period of time.

Three new cancer medicines were approved. Faslodex (fulvestrant, AstraZeneca) is designed to treat advanced metastatic breast cancer. While great strides have been made in the treatment of breast cancer in recent years, once it reaches an advanced stage and spreads to other sites around the body, it becomes extremely difficult to control or cure. Most breast cancers are hormone dependent, and the introduction of tamoxifen, which acts as a competitive antagonist for oestrogen within the breast, had a dramatic effect on survival rates.

But its side-effects, such as endometrial stimulation and cancer flare, can cause problems of their own. Fulvestrant does not cause these difficulties as it has no oestrogenic activity; rather, it binds to the oestrogenic receptors in the breast around a hundred times more strongly than tamoxifen, and as a result very few oestrogen receptors are found in the breast after treatment for several weeks.

A much rarer form of cancer, hairy cell leukaemia, is the target of Lipomed's Litak (cladribine), which had been granted orphan drug status by EMEA back in 2001. Cladribine is a purine analogue that acts as an antimetabolite. The pro-drug is rapidly taken up by lymphocytes and other haematopoietic cells and then activated, in which form it blocks the synthesis of new DNA and blocks DNA repair mechanisms. In addition, it blocks the enzyme ribonucleotide reductase, which is involved in the synthesis of new DNA. This ultimately results in cell death, caused by energy depletion.

anti-cancer drugs

Non-Hodgkin's lymphoma is a group of several closely related cancers that affect the lymphatic system. Radiotherapy is commonly used as a treatment in the early stages of the disease, often in combination with chemotherapy. However, initial response is all too frequently followed by a relapse, and remission periods between treatments get progressively shorter. Zevalin (ibritumomab tiuxetan, Biogen Idec/Schering) is a radioimmunotherapy, made by linking a monoclonal antibody to a radioactive isotope. The MAbs circulate in the body after administration until they reach the cancerous cells which they are designed bind to, delivering the cytotoxic radiation directly to the cells. Zevalin contains yttrium-90 attached to a murine MAb that targets the CD20 antigen on the surface of mature B cells and B-cell tumours.

cholesterol lowering

Barrett's oesophagus is a rare condition in which the normal lining of the lower part of the oesophagus is gradually replaced by stomach lining. It usually develops during the process of healing after a chronic injury to the oesophageal mucosa, particularly that caused by reflux of gastric juice in the oesophagus. If the reflux continues, the dysplastic changes can become more severe and, ultimately, lead to oesophageal adenocarcinoma. Axcan Pharma's Photobarr (porfimer sodium) has been licensed for the treatment of high-grade dysplasia, and has also been granted orphan status. It is a photosensitiser for use in dynamic phototherapy, and has been shown to reduce the likelihood of progression to cancer.

Severe nausea and vomiting are frequent side-effects of cancer chemotherapy treatment, so anticancer drugs are often administered alongside anti-emetic medicines. Emend (apripetant, Merck & Co) is a novel antiemetic, which is a selective high affinity antagonist of human substance P and neurokinin 1 receptors, unlike most previous antiemetics which targeted serotonin, dopamine and corticosteroid receptors.

High levels of cholesterol resulting from bad diet have been blamed in part for the rise in the incidence of heart disease, and a whole new therapeutic category - the statins - has been making vast profits for pharma companies in the past few years. A new, non-statin, cholesterol lowering agent from Genzyme, colesevelam (Cholestagel), has been approved to treat primary hypercholesterol-aemia. It is a non-absorbed lipid lowering agent that binds with bile acids in the intestine, impeding their reabsorption. This bile acid sequestration initiates a series of events that results in an increased clearance of LDL cholesterol from the blood, and increases HDL cholesterol levels.

body problems

Type II diabetes is also on the rise, again because of bad lifestyles. Avandamet (rosiglitazone/metformin) is a novel combination product from GlaxoSmithKline that combines the most widely used drug for treating Type II diabetes, metformin, with the insulin sensitiser rosiglitazone. Metformin reduces the amount of sugar the liver produces, and rosiglitazone decreases insulin resistance, allowing more sugar to enter, so decreasing both sugar and insulin levels in the blood.

A transdermal patch to treat urinary incontinence has been approved. The patch, from Nicoderm, contains oxybutinin, and can be used to treat urge incontinence and increased urinary frequency in patients with unstable bladders. Oxybutynin is a urinary antispasmodic, which acts as a competitive antagonist of acetylcholine at post-ganglionic muscarinic receptors, resulting in the relaxation of bladder smooth muscle. The patches deliver 3.9mg of the active over a 24-hour period, giving controlled relief.

antiviral agents

In the absence for a cure for AIDS or the virus that causes it, and the propensity of HIV to mutate and develop resistance to antiviral agents, new agents that counteract the virus are greatly needed. Three new ones were approved in 2003, all of which operate by different means of activity, and which provide new options for the cocktail of drugs that keeps the virus's activity at bay as the virus renders other drugs ineffective.

Gilead Sciences' Emtriva (emtricitabine) is an oral nucleoside reverse transcriptase inhibitor. Inhibition of reverse transcriptase was the first route by which the virus was attacked by drugs. This enzyme copies HIV RNA into new viral DNA, and interfering with this process - central to the replication of HIV - can reduce the viral load in a patient's body and increase the number of T-cells in the immune system, improving the patient's health as a result, as well as decreasing the likelihood of developing AIDS-related illnesses. Emtricitabine is a synthetic analogue of cytosine that has been phosphorylated by cellular enzymes, and competes with the natural substrate deoxycytidine 5'-triphosphate.

life threatening

The second route by which HIV is targeted is by inhibiting the protease enzyme. During replication of the virus, the protease cleaves two large viral encoded precursor proteins to give structural proteins required for the assembly of new virion, as well as three further enzymes essential for the replication process to continue. Bristol-Myers Squibb has developed a new orally available protease inhibitor, Reyataz (atazanavir) for use in combinations, and it is recommended that it is used alongside a low dose of ritonavir.

Fuzeon from Roche (enfuvirtide) works by a completely different mechanism, and is the first fusion inhibitor to gain approval.

It interferes with the virus's entry into cells by inhibiting the fusion of viral and cellular membranes by binding to the gp41 sub-unit of the viral envelope glycoprotein, preventing the conformation changes that are required for the fusion of viral and cellular membranes from taking place, and hence blocking the entry of the virus into the cells.

The drug is a linear synthetic peptide containing 36 amino acid residues, and is administered by injection.

Mucopolysaccharidosis I is a progressive, debilitating and life threatening disease. It is an inherited disorder, and sufferers have a deficiency of the lysosomal enzyme a-L-iduronidase.

These enzymes are required for the catabolism of glycosaminoglycans, and the missing enzyme catalyses the hydrolysis of terminal a-L-iduronidase, and the ultimate result is a build up of glycosaminoglycans (GAG) substrates throughout the body, leading to widespread cellular, tissue and organ dysfunction. Genzyme's Aldurazyme (laronidase) is designed to increase the catabolism of GAG substrates, and it has been shown to improve both pulmonary function and walking capacity in affected patients.

Advate (octocog alpha, Baxter) is designed to treat another inherited disorder, haemophilia. The product is a recombinant human coagulation factor VIII, which replaces human coagulation factor VIII in patients with haemophilia A. Factor VIII is normally present in the blood, and is essential for forming blood clots; it is absent in haemophiliacs. Replacement factor VIII to improve blood clotting capacity in haemophilia sufferers was originally produced from blood plasma; Advate is produced by recombinant DNA technology, and is indicated for both the treatment of bleeding and prophylaxis to prevent it in haemophiliacs.

Primary pulmonary hypertension affects maybe one or two people in every million a year, and it can also occur as a secondary problem to another systemic disease, such as systemic sclerosis, mixed connective tissue disease, and HIV infection, or it can be induced by drugs or toxins.

heart drugs

It involves vasoconstriction, vascular remodelling and thrombosis in situ, resulting in a progressive increase in pulmonary vascular resistances, which raises pulmonary hypertension. Death most often results from an increase in pulmonary artery pressure and right atrial pressure, and a decrease in cardiac output resulting from a failure of the right side of the heart. Schering AG's ilaprost is already available for other conditions such as severe Raynaud's phenomenon and late-stage inoperable peripheral arterial occlusive disease. It is now available under the trade name Ventavis to treat pulmonary hypertension. The synthetic prosta-cyclin analogue inhibits adenylate cyclase, increasing intracellular cyclic AMP levels.

A couple of further orphan products were also approved last year. Xagrid (anagrelide, Shire Pharmaceuticals) is intended for the reduction of elevated platelet counts in at-risk essential thrombocythaemia patients who are intolerant to their current therapy, or whose elevated platelet counts are not sufficiently reduced by it. The major problem that the overproduction of platelets in sufferers from this condition causes is the development of blood clots.

The imidazoquinazoline drug inhibits platelet formation by retarding the maturation of megakaryocytes, as well as reducing their size. It acts as an inhibitor of the enzyme cyclic AMP phosphodiesterase III.

biogeneric competition

Busilvex (busulfan) from Orphan Medical, marketed in Europe by Pierre Fabre, is designed for use before transplantation of haematopoietic progenitor cells, otherwise known as stem cells, or bone marrow. The infused product is administered in combination with cyclophosphamide, and it is an alkylating agent that destroys the original bone marrow before the transplant takes place, also causing a profound decrease in blood cells.

A final product that has gained approval, while not new, is definitely of great interest and importance. The growth hormone Omnitrop (somatropin) from Sandoz will, when it reaches the market in the next year or so, probably be the first biogeneric product to be sold. Thus far, biopharmaceuticals have been immune to generic competition, largely because of the difficulties involved in their production, and proving that they are identical to the reference product.

Increasing numbers of biological products are reaching the market and, despite the problems they present to the generics manufacturers, this is sure to be the first biogeneric of many.