As blockbusters wane and companies look to boost their pipelines through M&A activity, Dr Sarah Houlton reviews some of the niche drugs that have gained EMEA approval recently
The death of the blockbuster drug has been widely predicted in recent years, and certainly there's unlikely to be such a big seller as Pfizer's atorvastatin (Lipitor) in the future. Companies such as GlaxoSmithKline (GSK) have said that they will look to launch a greater number of smaller drugs in coming years to replace falling revenues as their blockbuster drugs lose patent protection. And there are few, if any, potential blockbusters in the list of drugs recommended for approval by EMEA's committee on human medicinal products last year mainly because they either target niche diseases or are antibiotics whose usage will be restricted to otherwise untreatable patients.
The rising health concerns about resistant superbugs, such as MRSA and C. difficile, have highlighted the desperate need for new antibiotics. Although the problem is far from solved and the answer will lie as much in prevention as cure two new antibiotics were given positive opinions in Europe last year, both of them licensed to Janssen-Cilag.
The first, ceftobiprole (Zevtera), will be licensed in the first instance to treat complicated skin and soft tissue infections. It is a fifth generation cephalosporin, and is active against MRSA and penicillin-resistant Streptococcus pneumoniae, and several other pathogens, both Gram positive and Gram negative; it is the first broad spectrum cephalosporin to be active against MRSA.
The intravenous antibiotic was initially discovered by Basilea the anti-infectives company spun out of Roche in 2000 and is marketed by the J&J subsidiary. The second, doripenem (Doribax), is a carbapenem with a very broad spectrum of activity against both Gram positive and Gram negative bacteria. Discovered by Japanese company Shionogi, and marketed in Europe by Janssen-Cilag, the intravenous antibiotic is licensed to treat nosocomial pneumonia, complicated intra-abdominal infections, and complicated urinary tract infections.
A new echinocandin antifungal agent from Astellas, micafungin (Mycamine) was given the go-ahead. It is designed to treat invasive candidiasis, and prophylaxis in patients susceptible to this infection, such as those undergoing bone marrow transplantation or who are liable to neutropoenia. The intravenous agent works by inhibiting the production of 1,3-b-D-glucan, a constituent of the cell walls of fungi.
The fourth new anti-infective is a non-nucleoside reverse transcriptase inhibitor for the treatment of HIV, etravirine (Intelence, Janssen-Cilag). Because the virus mutates into resistant forms, new antiviral agents are always needed to replace those that are no longer effective; this is a particular problem in HIV treatment as the drugs have to be taken for life, and not just a short course of a week or two. It was designed to retain activity against strains of HIV that have developed resistance against the two most commonly prescribed NNRTIs, nevirapine and efavirenz. It is taken twice a day, and prescribed to treatment-experienced patients in combination with other antiretrovirals including protease inhibitors.
Three new blood-thinning agents of various types were given the green light last year. Bayer's rivaroxaban (Xarelto) is a first in class molecule - it is an orally available direct inhibitor of Factor Xa, part of the coagulation cascade. This activity in turn inhibits the formation of thrombin and the development of thrombi. In the first instance, it has been licensed for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery. It is orally available, and needs dosing only once a day.
The second agent, dabigatran (Pradaxa, Boehringer Ingelheim), works on the next step of the cascade as it is a direct thrombin inhibitor; thrombin is the enzyme that converts fibrinogen to fibrin. Approved for the prevention of venous thrombotic events, again in those undergoing elective knee or hip replacement, it is dosed as the mesilate salt of the orally available prodrug dabigatran etixilate. It is given in once daily doses.
Prasugrel, developed by Japanese company Daiichi Sankyo and sold in Europe under the brand name Efient by Eli Lilly, is a little different as it is a platelet inhibitor. It is not the first of these drugs the class also includes the world's second biggest selling drug, Sanofi-aventis's clopidogrel (Plavix). Its initial licence will be for the prevention of atherothrombotic cardiovascular events in patients undergoing percutanous coronary intervention for acute coronary syndrome. It works by reducing the aggregation of platelets by binding to the P2Y12 receptors.
A new cholesterol lowering agent, Merck Sharp & Dohme's Tredaptive, is a nicotinic acid (better known as niacin, or vitamin B3) and a second molecule, laropipritant. Nicotinic acid reduces the levels of cholesterol and triglycerides in the blood and can reduce the risk of a further heart attack in people with high cholesterol who have already had a coronary.
However, it has a very common side-effect it frequently causes facial flushing, which the laropipritant is designed to counteract. The flushing is a result of nicotinic acid's stimulating effect on the biosynthesis of prostaglandin D2 in the skin, which acts as a vasodilator by hitting the DP1 receptors, and increases blood flow. Laropipritant reduces this vasodilation, and thus the flushing, by antagonising the DP1 receptors.
Ranolazine (Latixa) from CV Therapeutics is a novel drug designed to treat angina pectoris. However, its mechanism of action is uncertain. Initially, it was thought that it acted as a partial fatty acid oxidation inhibitor; this encouraged the heart to get its energy from glucose rather than fatty acids, which is a more efficient way of using oxygen. However, this effect is seen at higher plasma concentrations than were observed in clinical trials; it is now thought that it may reduce calcium load in ischaemic cells by inhibiting the late sodium current. It has no significant effect on the blood pressure or heart rate, unlike other angina drugs such as beta blockers and nitrates.
new orphans
The first of five orphan drugs to gain a positive opinion, Jerini's icatibant (Firazyr), is a bradykinin B2 antagonist that is used to treat the rare condition hereditary angioedema. Bradykinin forms in tissues in response to trauma, and its actions include dilating blood vessels and causing smooth muscle tissue to contract; too much bradykinin results in inflammation syndromes such as pain, swelling and overheating. Blocking the B2 receptors has a positive effect on the symptoms of hereditary angioedema. The drug is a 10 amino acid peptidomimetic compound, and is also being looked at as a treatment for other diseases where bradykinin is involved.
Another orphan drug, ambrisentan, being marketed by GSK as Volibris, is designed to treat pulmonary arterial hypertension. This condition results if the blood pressure in the pulmonary artery is too high, and has several damaging effects including narrowed arteries in the lung, blood clots, thickening of arterial walls and damage to the endothelial cells lining the capillaries in the lung. The heart then has to work harder, weakening its muscle, ultimately leading to heart failure. The drug acts as an antagonist of the endothelin A receptors, which are over-expressed in various forms of pulmonary vascular disease. It is orally available and can be dosed once a day.
A new antidepressant, agomelatine (Valdoxan, Servier) is an analogue of melatonin. It works as a melatonin agonist, and also acts as an antagonist at the 5-HT2c receptors, both of which actions are thought to have antidepressant activity. Its melatonin activity has a positive effect on sleep, but without daytime drowsiness. It also avoids the sexual dysfunction problems common with many other antidepressants.
Sepracor's eszopiclone (Lunivia) is an increasingly rare example of a chiral switch. Roche's zopiclone (Imovane), the original hypnotic, was not licensed in the US, but Sepracor's single isomer version was approved there a couple of years ago, and has now been given the go-ahead in Europe. The enantiopure version of the drug has fewer anticholinergic side effects than the racemate. It is an agonist of the benzodiazepine-GABA complex, and the recommended dose of 3mg is less than half of that recommended for zopiclone (7.5mg).
Another new drug that acts on the central nervous system is the antiepileptic lacosamide (Vimpat) from UCB. It works in a different way from existing antiepileptic drugs - it enhances the slow inactivation of voltage gated sodium channels, the membrane proteins that generate the neuronal action potential that causes neurons to release neurotransmitters. The inactivation prevents the sodium channels from opening and results in a stabilisation of the hyperexcitable neuronal membranes. It is licensed for use as adjunctive therapy in the treatment of partial onset seizures in epileptic patients over the age of 16.
Sugammadex (Organon's Bridion) is very different - it is designed to reverse the activity of another drug, the general anaesthetic rocuronium. It is a modified form of gamma-cyclodextrin, which is lipophilic on the inside and hydrophilic on the outside, and the thioether groups enlarge the cavity, which allows rocuronium to be encapsulated. By mopping up rocuronium atoms in this way, they are unable to bind to the acetylcholine receptors at the neuromuscular junction, reversing their anaesthetic effect. As it does not itself act on the ACh receptors, it gives much better cardiovascular and autonomic stability than traditional agents used to reverse anaesthesia.
A new drug to treat gout, febuxostat (Adenuric, Ipsen), is a selective non-purine inhibitor of xanthine oxidase. This enzyme is responsible for the formation of uric acid in the body, and when more of this acid is produced by the liver than can be excreted in the urine or too much is consumed in a rich diet and is not processed properly by the kidneys, the acid crystallises out in the joints. The result is swelling, inflammation, stiffness and pain. It is licensed for the management of chronic hyperuricaemia in patients who have already had deposition of urate or uric acid.
Lasofoxifene (Fablyn, Pfizer) is a selective oestrogen modulator that is used to prevent osteoporosis in postmenopausal women. The third generation SERM binds selectively to both alpha and beta oestrogen receptor sub-types, and has a better oral bioavailability than other SERMs. It may also have a preventive effect in breast cancer.
Three new anticancer agents were recommended, including Ferring's degarelix (Firmagon) for prostate cancer. It is an antagonist of gonadotropin releasing hormone, or GnRH, and these analogues inhibit the plasminogen activator system. This confers antiproliferative and anti-metastatic activity by suppressing gonadotropins, testosterone and prostate specific antigen in prostate cancer.
Azacitidine (Vidaza, Celgene) is licensed to treat two forms of blood cancer - myelodysplastic syndromes and acute myeloid leukaemia in adult patients not eligible for bone marrow transplantation. The drug is an analogue of the nucleoside cytidine, and it is incorporated into RNA during transcription and DNA during replication, inhibiting the enzyme methyltransferase.
The other new oncologic is an orphan drug for a rare form of the disease. IDM Pharma's mifamurtide (Mepact) is to treat non-metastatic osteosarcoma. This form of bone cancer is most common in children and young adults who are growing, as it generally develops from osteo-blasts. It is an immunomodulator that activates monocytes and macrophages, and it is thought that this may be the drug's mechanism of action. It is given by infusion.
Two other orphan drugs were also recommended for approval last year. Sapropterin (Kuvan, Merck KGaA), is designed to treat hyperphenylalaninaemia in people with phenylketonuria. This is a condition in which the body is unable to carry out its normal conversion of the amino acid phenylalanine to tyrosine, leading to an elevation of the levels of phenylalanine in the blood, which causes long-term neurological damage. Sapropterin, also known as tetrahydrobiopterin, is the cofactor required by the enzyme in this process. When dosed to patients with PKU, it reduces the levels of phenylalanine in the blood, and it should be used in conjunction with a diet that is low in phenylalanine.
The other new orphan drug is Amgen's romiplostim (Nplate), which treats the condition idiopathic thrombocytopenic purpura, in which patients have a low platelet count with no obvious cause. The drug is a genetically engineered fusion protein analogue of thrombopoietic growth factor that binds to the thrombopoietin receptor; the idea is that it reduces the body's ability to develop antibodies to this receptor. It stimulates the megakaryocytes to produce platelets more quickly than normal.
Despite the fact that Big Pharma is focusing heavily on biologics, this is one of just three new biologics that were recommended for approval last year. The other two are both designed to treat common autoimmune diseases. Tocilizumab (RoActemra, Roche) is a humanised monoclonal antibody against the interleukin-6 receptor which acts as an immunosuppressant. As IL-6 is one of the key cytokines in the inflammatory process, this first in class antibody is used in the treatment of rheumatoid arthritis.
Finally, ustekinumab (Stelara, Janssen-Cilag) is a monoclonal antibody targeted at two other interleukins, IL-12 and IL-23. Ustekinumab has initially been licensed for the treatment of moderate to severe plaque psoriasis which has failed to respond to other systemic therapies.