Prevalent infections beaten by new approvals
Sarah Houlton reports on the year's new approvals that have triumphed over some high-profile infections, as well as illnesses such as AIDS, diabetes and cancer.
Sarah Houlton reports on the year's new approvals that have triumphed over some high-profile infections, as well as illnesses such as AIDS, diabetes and cancer.
When just three new molecules had been given a positive opinion in the first five months of last year, it was looking like being a pretty bad year for the pharma industry. Things picked up as the year went on, and ultimately a total of 22 were given the green light, but many of the big name pharma companies were conspicuous by their absence from the list, with no new positive opinions for AstraZeneca or Bristol-Myers Squibb (BMS), while GlaxoSmithKline's only approval was a new infant vaccine.Those that did receive positive opinions included a mixture of niche products and orphan drugs, some fascinating new uses for old molecules and one or two novel medicines that could have widespread benefits. One that may have a big impact on the lives of patients is Exubera inhaled insulin. The short-acting insulin could replace many of the injections that Type I diabetics currently have to take, with only the long-acting insulin they take at night having to be injected.
Non-injected forms of insulin have been under development for some years, and Exubera represents a real breakthrough as the first to be given approval. It was developed by Nektar Therapeutics in collaboration with Pfizer and Aventis, and after a legal case brought on by the Sanofi takeover, in January Pfizer agreed to pay sanofi-aventis US$1.3bn for worldwide rights to the drug.
Exubera is a fast-acting dry powder formulation of human insulin, and trials showed it to be as effective as the injected form in achieving glycaemic control. It has also been approved for those with Type II diabetes whose condition is not adequately controlled by oral antidiabetic drugs and thus require insulin therapy.
Several novel anti-infectives have been approved. Serious invasive fungal infections can be extremely difficult to treat, particularly in immunocompromised patients, and Schering-Plough's Noxafil (posaconazole) was granted the go-ahead to treat infections that prove refractory to existing drug treatments, as well as patients that cannot tolerate initial therapies.
The novel triazole antifungal agent is dosed as an oral suspension and is active against a wide range of fungal pathogens, including yeasts and moulds. It offers a new treatment option for infections such as aspergillosis, fusariosis, chromoblastomycosis, mycetoma and coccidioidomycosis.
Hospital acquired infections such as methicillin-resistant S. aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) are frequently in the headlines, and Cubicin (daptomycin), developed by Cubist Pharmaceuticals and marketed in Europe by Chiron, is designed to treat soft tissue infections resulting from these bacteria. The cyclic lipopeptide antibacterial agent is administered by intravenous infusion once a day for seven to 14 days. It has a novel mechanism of action: binding to bacterial membranes in Gram positive organisms, causing a rapid depolarisation of membrane potential. This inhibits protein, DNA and RNA synthesis, resulting in bacterial cell death.
drug resistance
Aptivus (tipranavir) from Boehringer Ingelheim is a much-needed new anti-HIV drug, which has been licensed for use in combination with ritonavir. A non-peptide protease inhibitor, it works by blocking this enzyme, thus preventing the HIV replication process from reaching completion. In clinical trials, it was shown to be effective in treating patients with HIV whose virus had developed resistance to other therapies, such as saquinavir and indinavir. As the virus mutates to become resistant to existing drugs it is essential that novel medicines are created to replace those that become ineffective. A steady stream of new anti-HIV agents will thus be reaching the market in the next few years.
A new drug that is designed to replace antibodies in immunocompromised patients, such as children with congenital AIDS and recurrent infections, has been developed by Baxter. Kiovig (intravenous human immune globulin) is indicated for use in a wide range of primary immunodeficiency disorders caused by an incorrectly functioning immune system, as well as in conditions such as myeloma, chronic lymphocytic leukaemia, Guillain Barre syndrome and idiopathic thrombo-cytopenic purpura. It can restore immunoglobulin G levels to normal or near normal levels, helping to prevent and fight off infections.
While cancer remains one of the major focuses of global drug discovery efforts, just one new anticancer agent got the nod last year: Roche's Tarceva (erlotinib), which has been licensed to treat non-small cell lung cancer (NSCLC). The small molecule drug inhibits the epidermal growth factor receptor (EGFR), which is over-expressed in many forms of cancer. It is to be used as monotherapy in locally advanced or metastatic forms of NSCLC, and is given in tablet form.
Amgen's Kepivance (palifermin) is designed to combat a side-effect that can result from high-dose chemotherapy or radiotherapy. Oral mucositis often appears as painful ulcerative lesions and erythema in the mouth and throat, following mucosal tissue damage through an anticancer regime. It is frequently identified by patients as the most debilitating side-effect during treatment as it makes eating, drinking, swallowing and even talking difficult. The new drug is a human keratinocyte growth factor administered by intravenous injection that causes the proliferation, differentiation and migration of epithelial cells; notably those that are affected by oral mucositis.
Age-related macular degeneration (AMD) is one of the most common causes of irreversible blindness in the elderly. The cytokine vascular endothelial growth factor (VEGF) plays an important part in angiogenesis and is required for normal vascular development. Patients with AMD have high concentrations of VEGF, which has been implicated in blood retinal barrier breakdown and pathological ocular neo-vascularisation, in their eyes. Macugen (pegaptanib), a PEGylated modified oligonucleotide from Pfizer, is a selective VEGF inhibitor. Administered every six weeks by intravitreous injection, it slows the rate of decline of vision.
The incidence of asthma has increased dramatically in recent years. Commonly treated with reliever drugs like salbutamol and steroid preventer drugs, in severe cases these can prove ineffective. A new treatment for patients with severe persistent allergic asthma is Xolair (omalizumab) from Novartis, which, when used in addition to inhaled steroids, helps reduce the number of asthma attacks a person experiences. The drug is a recombinant DNA-derived humanised IgG1κ monoclonal antibody that selectively binds to and blocks human immunoglobulin E. It is given fortnightly by subcutaneous injection and has been shown to reduce exacerbations in many patients who are suboptimally controlled with inhaled cortico-steroids.
Parkinson's disease is a disorder of the central nervous system in which a deficiency of dopamine in the body leaves patients unable to control their movements reliably. Dopamine agonists are designed to compensate for this deficiency, and a new drug in this class, Neupro (rotigotine) from Schwarz Pharma, has been given a positive opinion. The drug is a non-ergoline dopamine receptor agonist and is formulated as a transdermal patch - the first Parkinson's disease treatment to be dosed in this way. It provides continuous dosing of the drug throughout the day, which should mean that its effects will remain stable, with no peaks or troughs of activity as a dose wears off.
muscle weakness
Another CNS disorder, narcolepsy, is the target of UCB Pharma's Xyrem (sodium oxybate). Narcolepsy is a combination of excessive daytime sleepiness with abnormal manifestations of REM phenomena such as cataplexy, sleep paralysis and hypnagogic hallucinations. Cataplexy is a common symptom, and involves a sudden episode of bilateral skeletal muscle weakness triggered by intense emotions. It is this that Xyrem is designed to treat. More recognisable as the recreational drug γ-hydroxybutyrate, or GHB, it is a CNS depressant that reduces excessive daytime sleepiness and cataplexy in patients with narcolepsy. However, its mechanism of action in the relief of cataplexy is unknown.
Procoralan (ivabradine) from Laboratoires Servier is the first selective and specific If inhibitor to be approved for the treatment of chronic stable angina pectoris in patients with normal sinus rhythm who have a contraindication or intolerance to beta-blockers. It acts by selective inhibition of the cardiac pacemaker If current that controls the spontaneous diastolic depolarisation in the sinus node and regulates heart rate. It gives a significant dose-dependent reduction in heart rate and reduces myocardial oxygen consumption. It is given in tablet form twice daily and is also being investigated for further indications, such as heart failure and acute coronary syndrome.
difficult diagnosis
Paget's disease is the second most common metabolic bone disease after osteoporosis. The resulting malfunction of the body's bone-building process causes pain, fractures and deformities. However, it is often difficult to diagnose and many patients remain untreated. A new drug, Aclasta (zoledronic acid) from Novartis, has been approved. It is a bisphosphonate drug with a strong affinity for bone mineral, which acts as a potent inhibitor of both normal and abnormal bone resorption. Administered by infusion, it breaks the cycle of excessive bone destruction, induced by osteoclasts, that results in skeletal problems.
Another, more familiar, bisphosphonate drug is being given a new lease of life by its approval in combination with vitamin D. The new formulation of alendronic acid, Fosavance from Merck Sharp & Dohme, is indicated for use in postmenopausal osteoporosis in women who are deficient in vitamin D. A deficiency in the vitamin, otherwise known as cholecalciferol, is associated with reduced calcium absorption, bone loss and increased risk of fracture. The combination of the vitamin with alendronate, which decreases the rate of bone loss, results in an increase in bone density in most patients. It is given in tablet form.
Two further familiar molecules have been given positive opinions for applications in pain control. The first, Duloxetin (duloxetine) from Lilly, is a selective serotonin and norepinephrine reuptake inhibitor that acts as an antidepressant and is also licensed to treat stress urinary incontinence. It has now been given the go-ahead as an agent for the management of pain associated with diabetic peripheral neuropathy - the nerve damage caused by high sugar levels. It is thought that if levels of serotonin and noradrenaline in the spinal cord are increased it will reduce the body's sensation of pain from the nerve damage.
The opioid analgesic fentanyl is commonly used to treat severe pain. A novel formulation, Ionsys, has been developed by Johnson & Johnson company Alza. It is indicated for the treatment of severe post-operative pain in a hospital setting and is to be marketed in Europe by sister J&J company Janssen Cilag. Ionsys is a compact, non-invasive self-contained pre-programmed analgesic system that is designed to adhere to a patient's upper arm or chest. It uses a low level electrical current to deliver the medication directly through the skin and into the bloodstream at the push of a button. It is the first needle-free iontophoretic patient-controlled transdermal system to receive marketing authorisation.
EMEA's orphan drug programme, intended to foster the development of medicines to treat rare diseases, provided two new products last year. The first of these, Naglazyme (galsulfase), is for enzyme replacement therapy in the condition mucopolysaccharidosis VI. It is a normal variant form of the polymorphic human enzyme N-acetylgalactosamine 4-sulfatase that is produced by recombinant DNA technology. The disease is caused by the deficiency of specific lysosomal enzymes that are required in the catabolism process, which results in the build-up of the enzyme's substrate in the body as well as widespread cellular, tissue and organ dysfunction. Naglazyme is administered by infusion and is intended to provide a replacement for the missing enzyme; thus preventing the damaging build-up of the substrate.
Sildenafil, the active in the second orphan drug, Pfizer's Revatio, is already extremely well known in its guise of Viagra. However, it has now been approved to treat pulmonary arterial hypertension. The rare, aggressive disease is characterised by dangerously high pressure in the blood vessels that lead from the heart to the lung, with symptoms including difficulty in breathing, dizziness and fatigue. If untreated, the average survival time from diagnosis is less than three years, but it is difficult to treat. The drug is an inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5) inhibitor in the smooth muscle of the pulmonary vasculature, where PDE5 is responsible for the degradation of cGMP. It increases cGMP within the pulmonary vascular smooth muscle cells, resulting in relaxation; and in patients with pulmonary arterial hypertension this can lead to vasodilation of the pulmonary vascular bed as well as vasodilation in the systemic circulation.
Two new infant vaccines also got the go-ahead. ProQuad from Sanofi Pasteur MSD is a combined attenuated live virus vaccine containing measles, mumps, rubella and chicken pox viruses. The other, GSK's Rotarix, is designed to protect against rotavirus, a very common infection in children that causes gastroenteritis and is particularly dangerous in developing countries - it is responsible for 600,000 deaths a year around the world. There are approximately 4.5 million cases of rotavirus gastroenteritis in children under the age of five in the EU every year. The vaccine is given orally, and can be co-administered with other common infant vaccines, including oral polio vaccine.
Vasovist (gadofosveset sodium) is a new contrast agent for diagnostics, rather than a medicine. It was developed by Schering as a blood pool contrast agent for magnetic resonance angiography. The gadolinium-based agent has been optimised for prolonged vascular enhancement; after intravenous injection it binds reversibly to human serum albumin in plasma, giving an extended imaging time window over currently available contrast agents.
The final positive opinion was given to something a little different: Yttriga (yttrium-90 chloride) from AEA Technology QSA, a β-emitter that is a precursor intended to be used for in vitro labelling of appropriate carriers for subsequent radionuclide therapy, rather than for direct use in patients.
