The introduction of nces has been helped by regulatory improvements but potential blockbusters are thin on the ground. Dr Sarah Houlton reviews the new entrants targeting today's unmet needs
Pharma's profits have been largely driven by the big blockbuster drug for many years, but that is now changing. As the patents on today's big sellers expire, the potential huge money-spinners of the future just aren't being developed or approved. Regulators become ever more vigilant regarding effectiveness and potential side effects, and less likely to approve me-toos unless they have substantial benefits in terms of efficacy or side-effect profile, with many common conditions and diseases now more than adequately treatable with cheaper generic medicines.
Trials for new drugs become ever more expensive, too, as the authorities demand greater proof of safety. The pitfalls were amply illustrated by the problems Pfizer had with its "next big thing", the HDL cholesterol raising drug torcetrapib. Having spent an estimated $800m on developing the compound, it was suddenly pulled from the pipeline in December because of concerns about cardiovascular side-effects, leaving said pipeline looking decidedly thin.
While 20 new chemical entities and biological medicines were approved by the EMEA in 2006, there are few that one might imagine reaching blockbuster status. And even then, one that might - rimonabant (Acomplia/Zimulti) - is struggling to gain reimbursement in numerous European countries, including several potentially large markets such as Germany.
Rimonabant is one of a growing number of drugs being developed to treat the "lifestyle" conditions that largely result from people abusing their bodies through lack of exercise, smoking, or a poor or excessive diet. It was developed by Sanofi-aventis as a treatment for obesity, and selectively blocks the CB1 receptors that are important in the body's metabolism of glucose and fat. These are present in the brain and peripheral organs, such as the liver, adipose tissue, muscle and gastrointestinal tract. By blocking the CB1 receptors, over-activity in the endocannabinoid system is decreased. This recently characterised physiological system, which includes the CB1 receptors, is thought to play an important role in regulating body weight and controlling energy balance, in addition to glucose and lipid metabolism.
Type II diabetes is reaching epidemic proportions in the developed world, largely as a result of the growing number of overweight people. Eli Lilly's exenatide (Byetta) is the first of a new class of drugs, designed to mimic the effect of glucagon-like peptide in the body. This naturally-occurring incretin hormone stimulates the body to produce insulin as sugar levels rise, but it is not itself therapeutically useful because of its short half-life. Exenatide is a synthetic version of a peptide isolated from the venom of a desert lizard known as the Gila monster, which has a similar effect to the natural hormone, but is more stable and longer lasting.
Many diseases, from lung cancer to COPD, are common in smokers, and giving up smoking is by far the best way to cut the chances of getting seriously ill. Smokers can be helped to quit with nicotine replacement products, and some antidepressant drugs such as GSK's bupropion (Wellbutrin/Zyban) can also help, but Pfizer's varenicline (Champix) is completely different - it acts as a partial agonist at the nicotinic acetylcholine receptors. Nicotine itself is an agonist for these receptors, and this activity is at the root of its addictive nature. Varenicline thus helps prevent nicotine cravings, but also prevents the nAChR receptors from being activated, helping to reduce dependence.
Three new anti-infective medicines received positive opinions. Entecavir (Baraclude) from Bristol-Myers Squibb was developed to treat patients infected with the hepatitis B virus. It is a guanosine nucleoside analogue, which is efficiently phosphorylated in the body, and it competes with the natural substrate deoxyguanosine triphosphate. As a result, it inhibits DNA replication in hepatitis B polymerase at the priming, reverse transcription and DNA synthesis stages, thus reducing the viral load.
A second new antiviral drug, darunavir (Prevista, Janssen-Cilag), has been developed to treat HIV infection. Combination therapies that put together different classes of antiviral drugs have transformed HIV infection from a death sentence to a more manageable long-term condition, but because the virus mutates to become resistant to the drugs used to keep it at bay, new ones that have activity against resistant strains are much needed. Darunavir is a new protease inhibitor with potent antiviral activity, in particular against strains that have developed resistance to other drugs in the class. It should be useful in extending the usefulness of anti-HIV combination therapies in resistant patients.
The third new anti-infective, tigecycline (Tygacil) from Wyeth, is a new class of antibacterial agent. The tetracycline drug inhibits protein translation in bacteria by binding to the 30S ribosomal subunit, and blocking the entry of aminoacyl tRNA molecules into the A site of the ribosome, preventing amino acid residues from being incorporated into the growing peptide chains. As it is not affected by the two major resistance mechanisms for tetracyclines, efflux and ribosomal protection, it has activity against a broad spectrum of bacteria, and no cross resistance with other antibiotics has yet been seen. The drug is administered by intravenous infusion, and is indicated for complicated skin, skin structure and intra-abdominal infections caused by a number of susceptible strains.
Multiple sclerosis remains incurable and the precise causes are still unknown, but there are drugs that provide symptomatic relief in some patients. Another such treatment, Elan's natalizumab (Tysabri), has now been given a positive opinion. The drug is a humanised monoclonal antibody, and acts on the formation of the inflammatory brain lesions that cause the condition's symptoms. These lesions are thought to result from autoimmune responses involving activated lymphocytes and monocytes. These cells have the glycoprotein a-4 integrin, which plays a vital role in the adhesion of the cells to the vascular endothelium, and natalizumab is an a-4 integrin antagonist that can reduce the development of the brain lesions.
Another monoclonal antibody, ranibizumab (Lucentis) has also been approved. Licensed by Novartis from Genentech, it has been developed to treat age related macular degeneration. This is one of the most common causes of blindness in the elderly, and is characterised by the malfunction and death of light sensing cells within the macula of the eye. The result is a deterioration of central vision, with peripheral vision remaining good. Ranibizumab targets the angiogenesis that is at the root of the wet form of the disease, where new blood vessels form under the retina and macula. These can all too easily leak fluid or bleed, the result being the macula bulging and lifting up, distorting central vision.
While new medicines with blockbuster potential have become very thin on the ground, it's a completely different story for orphan drugs. The European orphan drug legislation, introduced in 2001, designed to provide incentives for companies to treat rare diseases, has been a big success, and 12 new orphan drugs were given positive opinions in 2006, representing 60% of all the treatments given the thumbs up.
Four of these are to treat cancers. Sorafenib (Nexavar, Bayer) is approved for advanced renal cell cancer, and is an orally available multikinase inhibitor targeting several serine/threonine and receptor tyrosine kinases. A number of these kinases are believed to be involved in angiogenesis, the process by which tumours develop their own blood supply, and preventing this activity means the tumours cannot thrive. It also decreases tumour cell proliferation.
Sunitinib (Sutent) from Pfizer was initially been licensed to treat metastatic gastrointestinal stromal tumours, and it has potential against other forms of cancer. Again an orally available small molecule drug, it inhibits the receptors for kinases such as vascular endothelial growth factor and platelet derived growth factor and thus, like sorafenib, both inhibits angiogenesis and reduces tumour cell proliferation.
The other two anticancer agents have been designed to treat leukaemias. Bioenvision's clofarabine (Evoltra) has been approved to treat acute lymphoblastic leukaemia (ALL) in children. It was developed with Genzyme and originally discovered by the Southern Research Institute, and is a nucleoside analogue that inhibits DNA synthesis at two critical points: DNA polymerase and RNA reductase. As a result, it damages cancer cells, and also prevents DNA repair, triggering the process of apoptosis, or programmed cell death.
Dasatinib (Sprycel) from Bristol-Myers Squibb is used to treat patients with chronic myelogenous leukaemia who have developed resistance to imatinib (Glivec, Novartis). It can also be used in ALL. Imatinib is a specific small molecule inhibitor of the BCR-ABL fusion gene, whereas dasatinib hits this target and also the Src kinase. Few patients achieve molecular remission with imatinib treatment, which implies that some stem cells persist, and resistance to it has appeared in a number of patients. Dasatinib has been shown to be active in many of the resistant patients.
Two of the new orphan drugs are for forms of epilepsy. Stiripentol (Diacomit, Laboratoires Biocodex) is an antiepileptic that is structurally unrelated to any other available treatments. It was recommended for conditional authorisation in combination with clobazam and valproate for the treatment of severe myoclonic epilepsy, otherwise known as Dravet syndrome, in infants. It inhibits cytochromes P450, and hence results in increased plasma concentrations of the other medicines it is administered alongside. The drug is also believed to increase gamma-aminobutyric acid transmission.
Eisai's Inovelon (rufinamide) is a broad spectrum anticonvulsant that is indicated for Lennox-Gastaut syndrome, a severe form of generalised epilepsy that develops in early childhood; it is caused by several brain disorders such as brain haemorrhage, encephalitis, metabolic abnormalities or developmental abnormalities of the brain. Licensed from Novartis, rufinamide reduces the recovery capacity of neuronal sodium channels after they have been inactivated. This limits neuronal sodium-dependent firing and results in anticonvulsant effects.
The remaining five new orphan drugs are indicated for disparate conditions. Encysive's sitaxentan (Thelin), for example, is to treat pulmonary arterial hypertension. The blood pressure in the pulmonary arteries of sufferers is permanently elevated, which damages the endothelial cells within the capillaries in the lungs and causes the blood vessels to constrict. It often leads to heart failure, and is difficult to treat. Sitaxentan is an orally available antagonist for endothelin A, which mediates blood vessel constriction and the growth of smooth muscle in vascular walls and has been shown to improve blood flow.
Orphan Europe's Cystadane (betaine) has been developed for homocystinuria, a rare genetic disorder involving faulty metabolism of methionine. It is characterised by elevated levels of homocysteine in the plasma and urine, and causes serious problems such as mental retardation and premature vascular disease. Betaine has been shown to be effective in reducing the toxically high plasma levels of homocysteine by acting as a methyl donor for the remethylation of homocysteine to methionine. Although betaine occurs naturally in foods such as beets, spinach, cereals and seafood, it is only present in them at low levels. By taking betaine in drug form, homocysteine levels are typically reduced by a quarter.
Pompe disease, otherwise known as glycogen storage disease Type II, is another rare genetic disorder. Those with the condition have a deficiency in the lysosomal enzyme a-glucosidase, which is used to break down the glycogen stores in the body. The accumulation of glycogen causes progressive muscle weakness, affecting various tissues such as the heart, liver, skeletal muscles and the nervous system. Genzyme's Myozyme (alglucosidase alfa) is a synthetic replacement for the missing enzyme produced by recombinant DNA technology, and is administered by intravenous infusion.
Another rare, fatal genetic disorder, Hunter syndrome, is treated by idursulfase (Elaprase) from Shire. The condition results from a deficiency of another lysosomal enzyme, iduronate-2-sulfatase, which is needed for the degradation of the glycosaminoglycans dermatan sulfate and heparan sulfate. The resulting accumulation of these two substances in cells throughout the body causes a range of developmental problems such as a large head, short stature and thick skin, and those with the condition are also prone to developing numerous other diseases such as obstructive airway disease and frequent pneumonia. The new drug is a recombinant form of the natural enzyme administered by intravenous infusion, which is used to replace the missing enzyme.
TopoTarget's Savene (dexrazoxane) is used to treat anthracycline extravasation. This is a relatively rare side effect of chemotherapy treatment with anthracycline drugs such as doxorubicin, daunorubicin and epirubicin, and occurs when the drug leaks out of a blood vessel or central line into the surrounding tissue, destroying healthy cells. Dexrazoxane inhibits DNA topoisomerase II, the target of the anthracyclines, at a different step in the catalytic cycle from the drugs themselves, locking the enzyme in a form that is no longer affected by the anthracyclines and preventing further damage.
The final new orphan drug is also designed to combat a side effect of another treatment. Deferasirox (Exjade) was developed by Novartis to treat chronic iron overload, which is a serious risk for patients with chronic anaemias, such as thalassaemia or sickle cell anaemia. These are frequently treated by regular transfusions of red blood cells, but this can lead to a dangerous and toxic build up of iron in the form of ferritin within the body. This can be fatal, especially if the iron accumulates in the heart or liver. Deferasirox is an iron chelator that has a far better side effect and administration profile than the available alternatives.
In addition to these 20 drugs, four new vaccines received positive opinions, three of them from Sanofi Pasteur MSD. Zostavax, a herpes zoster vaccine, was developed to prevent shingles. RotaTeq is a paediatric vaccine to prevent rotavirus infection - a virus that has a huge healthcare burden, particularly in the developing world, where it is a common child killer. And Gardasil is the first vaccine against various strains of the human papilloma virus. This virus is implicated as a cause of cervical cancer, and by preventing HPV infection it is hoped that cervical cancer can be eliminated.
The final vaccine, from GlaxoSmithKline, is not a final product but an exercise in preparedness. If the H5N1 avian influenza virus mutates into a form that is easily transmissible between humans, then a global flu pandemic is extremely likely. GSK's Daronrix flu virus is a mock up vaccine, which is awaiting the flu strain. Although it will still take some time to turn into an H5N1 vaccine - and manufacture it in huge quantities - by pre-approving the formulation the process has been speeded up.