The novelty wears off

The appearance of fewer new medicines on the market is symptomatic of the problems facing the pharmacutical industry, says Dr Sarah Houlton, in her review of new products in 2002

The number of new medicines approved by EMEA in 2002 marks a continuation of the worrying trend of the past few years that fewer novel drugs are coming out of the pharmaceutical companies' pipelines and onto the market.

In part it is a result of the regulatory agencies being less inclined to approve medicines that are merely 'me-too' products with no obvious therapeutic benefits over existing treatments. But it also mirrors the problems facing the pharma industry itself: the escalating cost of research means companies are more likely to pursue only those drugs that are most likely to succeed. The recent spate of mega-mergers, too, is having an effect, with the consequent consolidation of research operations.

That said, a number of innovative treatments have been licensed over the past year. And, importantly, the fruits of EMEA's orphan drug policy, introduced in 1999, are beginning to appear, with four more being approved in 2002. Orphan drugs are those designed to treat rare diseases which, without incentives, would otherwise be unlikely to be pursued because of the low potential for returns from sales. Europe is way behind the US in this area, where similar regulations were put in place in 1983.

long-lasting effects

The first of these orphan medicines to get the go-ahead in 2002 was bosentan (Tracleer) from Swiss biotech company Actelion, for the symptomatic treatment of patients with pulmonary arterial hypertension. Actelion was set up by a group of researchers from Roche to exploit the discovery, made in 1987, that a substance secreted by the inner lining of the walls of blood vessels causes the blood vessels to constrict.

This substance, endothelin, plays an important role in the pathogenesis of vascular disorders, particularly hypertension, and both renal and cardiac failure. Bosentan is the first endothelin receptor antagonist to reach the market, and it provides a significant and long-lasting reduction in blood pressure.

Gaucher disease is caused by a deficiency of the enzyme β-glucocerebrosidase, which leads to the accumulation in the system of the enzyme's substrate, glucocerobroside. The cells that are most affected are the macrophages, which are common in the liver and the spleen, and these organs can become severely enlarged. Thrombocytopoenia and anaemia are also common problems, and bone marrow can be affected, with a decrease in bone density leading to skeletal abnormalities. Treatments include splenectomy, enzyme replacement therapy and bone marrow stem cell transplant, but a newly-licensed orphan medicine from Oxford GlycoSciences, miglustat (Zavesca), has been developed to match the rate of production of the substrate to the rate at which the enzyme degrades it.

Glucocerebroside is produced from ceramide by the enzyme ceramide glucosyl transferase, and this is reversibly inhibited by miglustat.

Another orphan condition for which a drug was licensed last year is hyperrammonaemia caused by a deficiency in the enzyme N-acetylglutamate synthase. Patients suffering from this rare congenital disorder of the urea cycle are unable to eliminate waste nitrogen from their bodies. It accumulates as ammonia, which is particularly toxic to the brain and can, in severe cases, result in reduced levels of consciousness, coma and death, and mental retardation is a common outcome for survivors. The condition can develop at any age. Orphan Europe has developed carglumic acid (Carbaglu) to treat it.

The drug is a structural analogue of N-acetyl glutamate, a vital activator of carbamoyl phosphate synthetase, the first enzyme in the urea cycle. Production of this compound is impaired in patients with the condition.

lifestyle drugs

The fourth orphan drug to gain market authorisation last year is pegvisomant (Somatovert) which, unusually for an orphan medicine, is from a large drug company – in this case Pharmacia.

It was designed to treat acromegaly, an increase in size of hands, feet and face as a result of the overproduction of the growth hormone somatotrophin resulting from a tumour in the anterior pituitary gland. The condition is usually treated by surgery or radiation.

Pegvisomant is the pegylated form of an analogue of human growth hormone that has been genetically modified to be a growth hormone receptor antagonist, and has been licensed to treat patients with acromegaly who have not responded adequately to previous treatments.

One area where we have seen me-too drugs rushing into development is erectile dysfunction. Until the advent of Pfizer's sildenafil (Viagra), the condition was little recognised, and certainly not talked about. Now, we have even had television adverts featuring the footballing great Pele urging the afflicted to seek help.

And, unsurprisingly considering the cash cow Viagra turned into, other drug companies have looked to develop their own versions. Two were approved in 2002: vardenafil (Levitra) from Bayer, and Lilly's tadalafil (Cialis).

Both work via the same mechanism as sildenafil, being phosphodiesterase Type 5 inhibitors, acting on the secondary messenger cyclic guanosine monophosphate. Sildenafil was initially developed as a treatment for angina and hypertension, and its effect on erections was discovered serendipitously. PDE5 is present in the corpus cavernosum, and is believed to play an essential role in inducing an erection.

The neurons release nitric oxide in the corpus cavernosum, activating soluble guanyl cyclase, which converts GTP to cGMP. If PDE5 is inhibited, then the conversion of cGMP from its active to its inactive form is prevented, resulting in levels of cGMP building up, and leading to an erection.

chronic disease

Another drug in an established therapeutic category is Pfizer's valdecoxib (Bextra/Kudeq/Valdyn). Valdecoxib is a COX-2 inhibitor, and has been licensed for the treatment of osteoarthritis, rheumatoid arthritis and, additionally, primary dysmenorrhoea.

COX-2 inhibitors are non-steroidal antiinflammatories, which were originally developed to overcome some of the gastrointestinal side-effects of the traditional NSAIDs like ibuprofen and ketoprofen. NSAIDs work by inhibiting the formation of prostaglandins, whose synthesis is controlled by the enzyme cyclooxygenase, or COX.

COX exists in two forms, of which COX-2 has the inflammatory effects, and COX-1 is thought to be implicated in the gastrotoxic side-effects.

The chronic forms of hepatitis, both B and C, are growing public health problems because they are all too rarely diagnosed, yet can cause severe health problems later in life. Two treatments were given marketing authorisation last year: adefovir dipivoxil (Hepsera) (Gilead Science) for hepatitis B, and Pegasys (Roche) for hepatitis C.

Hepatitis B is a serious liver infection, and if it is not cleared from the system within six months, can lead to chronic infection, and potentially cirrhosis, liver cancer and death.

Although there is a vaccine that can prevent hepatitis B infection, as many as 1.25m people in the US alone are believed to have the chronic form of the disease. Between a quarter and a third of these can be expected to develop some other form of liver disease as a result, and the virus is the leading cause of liver cancer.

developing versions

Gilead Sciences' adefovir dipivoxil (Hepsera) is an antiviral drug that has been licensed for the treatment of chronic hepatitis B. The nucleotide analogue is administered in tablet form, and clinical trials show that 80% of infected patients given the drug for 12 to 15 months had the levels of the virus in their systems reduced to undetectable levels. The drug is the ester prodrug of adefovir, an acyclic nucleotide analogue of adenosine monophosphate.

It is phosphorylated into the active metabolite in the body, and inhibits the virus's reverse transcriptase by competing with the enzyme's natural substrate, deoxyadenosine triphosphate, causing DNA chain termination after its incorporation in DNA.

Hepatitis C is recognised as the most common chronic blood-borne infection in the US, with 1.8% of the population believed to be infected. Most infected people are unaware they have the virus, as the majority suffer no symptoms even in the early, acute phase of infection. The virus remains in the system of over 80% of sufferers after the acute phase, giving rise to chronic infection which usually progresses very slowly, often over 10 to 30 years. If the virus is untreated, then serious consequences such as cirrhosis, liver failure or liver cancer can result. Roche's Pegasys (interferon α-2a) was licensed last year to treat hepatitis C. It is a covalent conjugate of recombinant α-2a interferon, with an approximate molecular weight of 20,000 with a single branched bis-monomethoxy polyethylene glycol chain attached.

Even if the virus is not cleared from the system by treatment, one of the benefits is a decrease in liver inflammation and scarring.

long-lasting effects

Another new antiviral agent is oseltamivir (Tamiflu) from Roche. Already available in the US, the oral antiviral medicine was developed to treat uncomplicated influenza up to two days after symptoms begin. The drug is a neuraminidase inhibitor, which inhibits the neuraminidase protein on the surface of the virus, preventing the virus from escaping from its host cell.

The growing problem of antibiotic resistance means there is a need for novel antibacterial agents to treat infections. One new antibiotic was licensed last year: ertapenem (Invanz), (Merck Sharp & Dohme) is for the parenteral treatment of moderate to severe infections caused by susceptible Gram positive bacteria, such as Staphylococcus aureus, Streptococcos agalactiae, S. pneumoniae and S. pyogenes.

Neutropenia, a drop in the level of infection-fighting neutrophil white blood cells, is a common side-effect of some forms of cancer chemotherapy, putting patients at risk of life-threatening infections. Amgen's pegfilgrastim (Neulasta) has been developed to counteract neutropenia. It is a covalent conjugate of recombinant methionyl human G-CSF and monomethoxy polyethylene glycol.

The hormone is a water-soluble 175 amino acid protein, and the pegylated product is administered by subcutaneous injection. It is a colony stimulating factor that acts on haemopoietic cells by binding to specific cell surface receptors, and as a result stimulating the proliferation, differentiation, commitment and end cell functional activation. The pegylated version of the hormone remains in the body for longer than the hormone product alone.

naturally occurring

A recombinant medicine for treating broken legs may seem like a concept straight out of science fiction, but that is just what Wyeth's InductOs (dibotermin alfa) is designed to do.

The recombinant human bone morphogenetic protein is a recombinant version of a naturally occurring human protein that induces bone growth. It is applied to an absorbable collagen sponge matrix which is surgically implanted into acute tibia fractures.

Developed by the Genetics Institute, now part of Wyeth, and co-developed with Japanese company Yamanouchi, it is aimed at the treatment of open tibia fractures, which can often prove a severe problem as the bone often does not heal satisfactorily of its own accord. Using the hormone implant reduces the need for further surgical interventions.

Severe sepsis is the destruction of tissues by disease-causing bacteria or the toxins they produce. The body is overwhelmed, and treatment is difficult; numerous products have been developed, only to prove, ultimately, ineffective. A further recombinant product to reach the market has been developed by Lilly to treat patients with severe sepsis who are at a high risk of death.

Xigris (drotrecogin alfa, activated) is a recombinant form of human activated protein C, a serine protease with the same amino acid sequence as the human plasma-derived glycoprotein. Activated protein C has an antithrombotic effect, inhibiting Factors Va and VIIIa, and it may also exert an anti-inflammatory effect by inhibiting human tumour necrosis factor production by monocytes, blocking leukocyte adhesion to selectins, and by limiting the thrombin-induced inflammatory responses within the microvascular endothelium. However, the specific mechanisms by which it increases the survival of patients with severe sepsis are not completely understood.

The ageing population means diseases of the elderly are an increasing public health problem, and the incidence of Alzheimer's disease is rising.

Memantine (Ebixa/Acura), Merz/ Lundbeck) is a NMDA receptor antagonist. The excitatory neurotransmitter glutamate plays an important part in the development of neurodegenerative diseases, and dysfunction of glutamatergic neurotransmission is implicated in neurodegenerative dementias such as Alzheimer's.

Chronically released glutamate has an excitatory effect, leading to the degeneration of cortical and subcortical neurons. Normally, the NMDA receptor is blocked by magnesium ions.

In learning processes, high levels of glutamate are released, allowing calcium to enter the cell, and the signal to be recognised by a secondary process.

However, the pathological, sustained release of low concentrations of glutamate displaces magnesium ions from the NMDA receptor channel, leading to a continuous influx of calcium into the cell. But, as the calcium level is already raised, the learning signal can no longer be detected and the symptoms of dementia result.

Memantine, unlike magnesium, is able to block the NMDA receptor in the presence of low levels of calcium, and is released during the learning process. The background noise of a steady level of calcium is no longer there, so the signal can be processed.

One of the distressing symptoms of hayfever is itchy, watering eyes. Alcon's olopatadine (Opatanol) was designed to reduce these symptoms. Administered as eye drops twice a day, it reduces the symptoms of allergic conjunctivitis caused by allergens such as pollen, pet hairs, pollution, dust mites and mould spores.

It is described as a relatively selective histamine H1 receptor antagonist, and an inhibitor of histamine release from the mast cells. Its systemic exposure on application to the eyes is low.

almost perfect

Finally, one product that, although it does not contain novel actives, is certainly worthy of note — Janssen-Cilag's Evra (norelgestromin-ethinylestradiol).

It is the world's first contraceptive patch, and was even described by Time Magazine as one of the best inventions of 2002. The small, thin, smooth patch is applied to the buttocks, abdomen, upper torso or upper outer arm, and is said to remain in place while swimming, bathing and showering.

A new patch is applied each week for three weeks then, as with the combined contraceptive pill, there is a week off. As Time says, all that is needed is to make the patch invisible, and then it will be almost perfect.