Drug approvals meet unmet needs

Sarah Houlton reviews last year's drug releases and reveals that there were far more drugs for unmet medical needs than for 'me-too' applications

The number of 'me-too' drugs being submitted to - and approved by - the regulatory authorities continues to drop, and as a result the number of approvals in 2004 is way below the number that were being given the go-ahead a few years back. Many of the drugs that were given positive opinions by EMEA in 2004 are targeted at real areas of unmet medical need, where there are either no effective treatments, or those drugs that do exist have limiting side-effects.

Cancer remains a major focus for drug discovery companies, with so many different potential interventions, and ever more therapeutic targets being discovered from our growing knowledge of the human genome and how it works. Four new anticancer agents were given a positive opinion in 2004 - two of them biological medicines.

Bevacizumab (Avastin, discovered by Genentech and marketed by Roche) is a monoclonal antibody, which has been approved in the first instance to treat metastatic carcinoma of the colon and rectum. It targets vascular endothelial growth factor (VEGF). This protein stimulates the formation of new blood vessels, which supply the blood that the tumour requires if it is to survive and grow. VEGF binds to receptors on nearby blood vessels and stimulates the growth of extensions to these vessels that dock into the tumour.

VEGF is secreted by hypoxic cells, including cancerous ones. It is also implicated in the process of metastasis, where tumours spread away from their primary site. The recombinant humanised monoclonal antibody bevacizumab was designed to prevent VEGF from binding to its receptors, which should inhibit both the tumour's growth and its metastasis.

cancer treatment

Another monoclonal antibody has also been given approval for the treatment of metastatic colorectal cancer. Cetuximab (Erbitux, Merck) targets epidermal growth factor receptors (EGFR) which, when stimulated, cause a cascade of signals that tell a cell whether to grow, divide or die. Cetuximab was developed to block EGFR, and hence stop abnormal signalling in malignant cells, preventing the abnormal growth of cells and, ultimately, the tumour shrinking. EGF receptors are found on the surface of a range of tumours, including bowel cancers, making them a good target for drug treatment.

Bortezomib (Velcade, Millennium) is a boron-containing small molecule drug, which has been approved for the treatment of relapsed and refractory multiple myeloma. The modified dipeptidyl boronic acid is a reversible inhibitor of the 26S proteasome in mammalian cells, a large protein complex that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis in cells.

Inhibiting the 26S proteasome prevents this targeted proteolysis, affecting multiple signalling cascades within the cell, which can lead to cell death and inhibit tumour growth. In the first instance, it is licensed for use in patients with multiple myeloma who have received at least two prior therapies and have demonstrated disease progression from their last therapy.

The fourth new anticancer agent, pemetrexed (Alimta, Eli Lilly), is another small molecule drug. It is indicated for use in malignant pleural mesothelioma and non-small cell lung cancer (NSCLC). Pemetrexed is an antifolate, with an antineoplastic effect that results from its disruption of the folate-dependent metabolic processes that are essential for cell replication. Mesothelioma is extremely difficult to treat, and pemetrexed, in combination with cisplatin, provides an option for patients with the cancer for whom surgery is not an option. It has also been approved as single therapy for locally advanced or metastatic NSCLC in patients who have received previous chemotherapy.

One of the major side effects of cancer chemotherapy is nausea and vomiting, which can be so severe that patients are unable to tolerate their chemotherapy regimens. As a result, it is very common for chemotherapy to be given in conjunction with an antiemetic medicine. Palonosetron (Aloxi, Helsinn Birex) is a new antiemetic with a prolonged action - it can work for up to five days after chemotherapy from a single intravenous dose. The drug is a 5-HT3 receptor antagonist, with little or no affinity for other receptors, and in trials it was shown to have improved complete response rates over both ondansetron and dolasetron.

A new serotonin and norepinephrine reuptake inhibitor, duloxetine, has been approved for both major depressive episodes and stress urinary incontinence. It is being marketed by Eli Lilly as Cymbalta for the former indication and Yentreve for the latter, and also by Boehringer Ingelheim as Xeristar and Ariclaim respectively. As an antidepressant, it acts on the physical symptoms of depression as well as the emotional ones, and in trial was shown to be superior to placebo in improving the state of health of depressive patients.

dual action

Its second indication, stress urinary incontinence, is the involuntary loss of urine with an increase in abdominal pressure caused by a physical activity such as coughing, laughing, sneezing, lifting or exercising. Around 97% of sufferers are female.

Serotonin and norepinephrine play a key role in normal urethral sphincter closure, and by increasing the concentration of these two neurotransmitters, duloxetine is believed to increase the tone and contraction of the urethral sphincter, helping to prevent accidental urine leakage during physical activities. It is the first oral drug to be approved that has been shown to have a significant effect on the number of incidences of urinary leakage.

A second drug to be given a positive opinion for a urinary disorder is darifenacin (Emselex, Novartis), which is indicated for the treatment of overactive bladder syndrome with symptoms of urge urinary incontinence, urgency and frequency. The once-daily treatment works by blocking the M3 muscarinic receptor, which is primarily responsible for bladder muscle contraction. The potent antagonist is very selective for the M3 receptors, and so has a low incidence of central nervous system and cardiovascular side effects.

In clinical trials, it was shown to reduce weekly incontinence episodes by up to 83%, and its onset of action began within two weeks of treatment being initiated.

Osteoporosis is a growing problem. Most common in postmenopausal women, hormone replacement therapy has a good protective effect but now women are being discouraged from taking HRT because of its potential adverse effects, and as a result the incidence is likely to grow. Previous drug treatments for osteoporosis, notably the bisphosphonates such as alendronate, have severe gastro-intestinal side effects.

Unlike the bisphosphonates, strontium ranelate (Protelos/Osseor, Laboratoires Servier) does not cause damage to the GI tract; its major side effect is nausea. It has dual action of preventing bone resorption and promoting bone formation when given alongside calcium supplements.

Psoriasis is an autoimmune condition, which is thought to be caused by the activation of T cells within the immune system. While topical corticosteroids, vitamin D analogues and systemic drugs such as methotrexate and cyclosporin can be used to treat it, these provide only symptomatic relief.

A new monoclonal antibody treatment, efalizumab (Raptiva; discovered by Genentech and commercialised by Serono) provides a potential solution. The recombinant humanised monoclonal antibody was designed to inhibit the adhesion of T lymphocytes to other cells. It is given subcutaneously, and impressive reductions in the severity of psoriasis plaques were seen in clinical trials.

Bivalirudin (Angiox, Medicines Company UK) has been approved as an anticoagulant and for percutaneous coronary intervention. The 20 amino acid peptide is a specific and reversible direct thrombin inhibitor, which prevents fibrinogen being cleaved into fibrin monomers, and also prevents the activation Factor XIII to Factor XIIIa, stopping fibrin from developing a covalently cross linked framework that stabilises the thrombus.

Secondary hyperparathyroidism in patients with chronic kidney disease is a progressive disease that is associated with increases in parathyroid hormone (PTH) levels and alterations the metabolism of calcium and phosphorus. Increased PTH levels stimulate osteoclastic activity, which causes cortical bone resorption and marrow fibrosis. Chronic kidney patients on dialysis with uncontrolled secondary hyperparathyroidism are at particular risk, and reductions in PTH levels have a positive impact on bone-specific alkaline phosphatase, bone turnover and bone fibrosis.

Cinacalcet (Mimpara/Parareg, Amgen) lowers PTH levels by increasing the sensitivity of the calcium sensing receptors on the surface of the parathyroid gland to extracellular calcium. This then also results in a decrease in serum calcium levels; previous drug therapies have had the major drawback of increasing calcium-phosphorus product.

Rasagiline (Azilect, Teva) is designed to treat the neurological condition Parkinson's disease. It is a selective monoamine oxidase B inhibitor, which is metabolised in the body to aminoindane, and has few of the amphetamine-like properties of its predecessor selegiline.

effect profiles

The mental disorder schizophrenia is a severe condition that can result in a loss of contact with reality and a breakdown in mental processes. The earlier antipsychotic drugs such as haloperidol and chlorpromazine can have side effects such as cognitive disorders, weight gain and impaired motor function, and as a result drugs with reduced side effect profiles, termed atypical antipsychotics, have been introduced. Another of these was given a positive opinion last year - aripiprazole (Abilify, Otsuka). Aripiprazole has a different mechanism of action from existing atypical antipsychotics, being a dual dopamine autoreceptor agonist and post synaptic D2 receptor antagonist. It is also thought to be a partial agonist for the 5-HT1A receptors, and an antagonist at the 5-HT2A receptors, which could be a factor in its overall efficacy and its good side effect profile.

Epilepsy is a very different brain disorder, in which electrical misfiring results in sudden seizures. There is a variety of different antiepileptic drugs on the market that reduce the incidence of seizures, such as sodium valproate, which is believed to mimic the action of GABA in the brain, and more recently atypical antipsychotics have reached the market, which have lower side effect profiles.

Zonisamide (Zonegran, Eisai) is unrelated to any of the currently available agents, being a sulfonamide drug. Its precise mechanism of action is unknown, but it is thought that it blocks sodium channels and reduces voltage-dependent, transient inward currents, which stabilises neuronal membranes and suppresses neuronal hypersynchronisation. It is indicated as adjunctive therapy in the treatment of partial seizures in adults with epilepsy.

Another new treatment for epilepsy, pregabalin (Lyrica, Pfizer), is a derivative of GABA, which cannot itself be used therapeutically as it does not cross the blood-brain barrier. Pregabalin is an analogue that can cross the barrier, and hence act directly on the central nervous system. It has been shown to reduce the incidence of seizures, and has also been approved to treat neuropathic pain.

Treating pain is also the focus of ziconotide (Prialt, Elan), a synthetic peptide based on a sequence from a peptide found in the venom of the marine snail Conus magnus. It is the first in a new class of non-opioid analgesics, which act by blocking the N-type calcium channels, an essential part of the nervous system's pain signalling. It has the advantage of having a lower incidence of side-effects than the opiates, and has been approved to treat severe, chronic pain, and also for intrathecal delivery.

encourage development

Ziconotide is one of five drugs given positive opinions last year that had been designated orphan drugs, providing further proof that EMEA's orphan drug procedures to encourage the development of medicines for rare conditions is working. Nitisinone (Orfadin, Swedish Orphan International) is another. It was developed to treat hereditary tyrosinaemia Type I, which is the result of a deficiency in fumarylacetoacetase (FAH), the final enzyme in the tyrosine catabolic pathway.

The disorder is characterised by progressive liver failure, increased risk of hepatocellular carcinoma, coagulopathy, painful neurologic crises, and renal tubular dysfunction resulting in rickets. Its symptoms usually become obvious before the age of six months. Nitisinone is a synthetic reversible inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase, an enzyme upstream of FAH in the tyrosine catabolic pathway. This prevents the accumulation of the catabolic intermediates whose toxic metabolites lead to liver and kidney toxicity.

Mitotane (Lysodren, Laboratoire HRA Pharmaceuticals) is another orphan drug, this time to treat advanced adrenal cortical carcinoma. The antineoplastic agent treats cancers in the adrenal cortex, which makes steroid hormones such as cortisol. By reducing the amount of adrenocorticoid hormones it produces, it starves those cancer cells whose survival is dependent on the hormones.

vaccine form

The final two new orphan drugs are both from Orphan Europe, and represent new uses for old substances. Ibuprofen (Pedea) has been developed to treat the congenital heart condition patent ductos arteriosus, and zinc acetate dihydrate (Wilzin) for the rare metabolic disorder Wilson's disease.

HIV remains incurable, and while the ultimate solution is likely to come in vaccine form, its rapid mutation means that antiretroviral drugs all too often become ineffective in patients infected with the virus. As a result, new drugs and combinations are needed if patients are to remain ahead of the virus.

One completely new medicine was approved last year - fosamprenavir (Telzir, co-developed by Vertex Pharmaceuticals and GlaxoSmithKline). Fosamprenavir is a protease inhibitor, which inhibits the protease enzyme that plays an essential part of the virus's life cycle. Inhibiting protease means that the virions produced by an infected cell do not reach maturity, and hence are not infectious. The new agent is a prodrug of the existing drug amprenavir, which has delivery issues because it is highly lipophilic and has low water solubility.

Fosamprenavir is a highly water soluble inactive phosphate ester, which is converted to the active non-phosphated form in the body. It has been found particularly effective when given in combination with low doses of the reverse transcriptase inhibitor ritonavir.

Positive opinions were also given on two formulated combinations for treating HIV infection. Also from GlaxoSmithKline is Kivexa (abacavir/lamivudine), which is the first once a day fixed dose combination of two nucleoside reverse transcriptase inhibitors (NRTIs). It is intended for use as part of a triple therapy alongside a protease inhibitor, and contains the two NRTIs in the same daily dosage as the existing single components.

Another two component formulation, Truvada, has also been approved. The product, from Gilead Sciences, is a combination of two other NRTIs - emtricitabine and tenofovir disoproxil. Again, it is intended for once-daily administration in combination with a protease inhibitor, and is designed to make adhering to the triple therapy regime more straightforward.