Research

Brain Teasers

Researching drugs for neurological drugs can be a very dicey affair, considering the mushrooming R&D costs and expensive failures, especially in the case of orphan neurological disorders. Aashruti Kak provides an update on the status of drug development across neurological disorders

Hundreds of millions of people worldwide are affected by neurological disorders. Due to the incredibly high global prevalence of these disorders the scope of research in the neurology segment is infinite for researchers and highly profitable for pharmaceutical companies.

As per Ramaraju Nallaparaju, Consultant, Healthcare Consulting, Datamonitor, India, in 2007, the global neurology market was worth $34.5 billion. Of the seven major markets, which account for 74 per cent ($25.5 billion) of the global market, US market was the largest with 64.5 per cent share ($16,434 million). The five European countries (France, Germany, Italy, Spain and the UK) had 27 per cent ($6,882 million) and Japan accounted for 8.5 per cent ($2,178 million). Both the US and the five EU markets have shown strong growth over the period 2004-07. However, with a CAGR of only 0.5 per cent , the Japanese market has remained flat over the same period. The top five neurological drugs companies-as measured in terms of 2007 revenues in the seven major markets-account for just over 43per cent of the total $34.50 billion 2007 neurological drug sales.

"The central nervous system (CNS) market in India is estimated to be around Rs 1,200 crore ($275 million), with major players in this segment being Sun Pharmaceuticals, Torrent Pharma, Abbot India, and Lundbeck India. Other players which are making major inroads into this market are Intas Pharmaceuticals, Micro and Sanofi-Synthelabo India, USV and Elder Pharmaceuticals," says Nallaparaju.

Common disorders

"Since five products are getting off-patent this year, new drug launches in same therapy classes will get affected. Reduced cash flow (from lower revenue realisation) will adversely affect R&D investments" - Ramaraju Nallaparaju Consultant, Healthcare Consulting Datamonitor India

Common neurological disorders include epilepsy, Alzheimer's disease and other dementias, Parkinson's disease, multiple sclerosis, insomnia, cerebrovascular diseases including stroke, migraine and other headache disorders, neuroinfections, brain tumours, traumatic disorders of the nervous system such as brain trauma, and neurological disorders as a result of malnutrition. The existing therapies for the some of the disorders are as follows:

Epilepsy-Epilepsy can be controlled with medication, but not cured, although surgery may be considered in difficult cases. There are about 12-14 drugs available in the market to treat epilepsy, which is characterised by recurrent unprovoked seizures-transient signs and/or symptoms due to abnormal, excessive or synchronous neuronal activity in the brain. "Sodium valproate, carbamazepine, phenytoin, lamotrigine, topiramate and leveritacetam (last three being newer drugs) are some of the most commonly used treatments. These drugs may work for some and not for others. Often even the newer drugs fail," says Dr Joy Desai, Consultant Neurologist, Jaslok Hospital, Mumbai.

Multiple sclerosis (MS)-MS is an auto immune brain targeted inflammatory disease in which the body's immune system changes and identifies the brain structures as being foreign, and therefore it attacks it. "MS may cause attacks that may lead to numbness is limbs, paralysis, visual, urinary or speech problems. So during the acute attack you are supposed to suppress it by giving an immunosuppressant, which commonly is intravenous (IV) steroids, which helps for the time being but after a few months the attacks recur someplace else in the body," informs Desai. Every attack leaves behind a disability which may be profound and may disallow a person from normal vision, imbalance etc. He adds, "To make sure that these recurring attacks die down you need an immunomodulator, which modulates the immune system such that it stops attacking itself too often. In the case of MS, immunomodulators that are currently in use are interferons."

Alzheimer's disease-The basic reason why Alzheimer's disease occurs is due to the depletion of a chemical called acetylcholine in the fundamental circuits that sub serve memory registration and retrieval. And if you supplement a drug that can augment the amount of acetylcholine in the brain then memory improves. "There is no absolute cure, but there are three medications that have been licensed for treatment to help their symptoms of the disease-rivastigmine, donepezil, galantamine," says Desai. Aricept (donepezil hydrochloride), produced by Eisai and co-marketed with Pfizer, was the first drug to be licensed in the UK specifically for Alzheimer's disease, followed by Exelon (rivastigmine) by Novartis Pharmaceuticals, Reminyl (galantamine), co-developed by Shire Pharmaceuticals and the Janssen Research Foundation, and Ebixa (memantine), produced by Merz and marketed in Europe by Lundbeck, which is the newest of the Alzheimer's drugs.

Parkinson's disease-Treatment for Parkinson's has evolved considerably over the last three decades. Existing treatments day can improve symptoms, delay onset of total physical dependence, hence delaying morbidity and mortality, which result due to progressive immobility. Levodopa (also called L-dopa) is the most commonly prescribed and most effective medication for controlling the symptoms of Parkinson's disease, particularly bradykinesia (slow movement) and rigidity. L-dopa is taken in combination with carbidopa (Sinemet) to increase its effectiveness and prevent or lessen side effects. Other treatments are dopamine agonists (Parlodel, Permax, Requip, Mirapex)-that activate dopamine receptor-taken alone or in combination with sinemet. Requip and Mirapex are newer medications, which are safer and more effective than the older drugs, Parlodel and Permax. Symmetrel, anticholinergics (artane, cogentin), eldepryl or deprenyl, Tasmar and Comtan (COMT Inhibitors) are other treatments for Parkinson's.

Orphan neurological disorders-Amyotrophic lateral sclerosis (ALS/Motor neuron disease) and Huntington's disease (HD) are two orphan neurological disorders. ALS, also known as Lou Gehrig's disease and Maladie de Charcot, is a progressive neurodegenerative disease associated with the loss of upper and lower motor neurons. "Sanofi-Aventis's Rilutek (riluzole) is the leading drug for ALS. Rilutek accounted for 84 per cent of the total ALS market value in 2006, across the seven major markets. Other drug classes, such as antidepressants and antispasm agents, are prescribed to treat specific symptoms and co-morbidities," informs Nallaparaju.

HD, on the other hand, is an autosomal dominant, inherited, neurodegenerative, neuropsychiatry disease which gives rise to progressive motor, cognitive and behavioral symptoms. Nallaparaju says, "Current pharmacological therapy of HD is limited to the management or alleviation of associated neurobehavioral or movement abnormalities. The market is almost entirely composed of off-label prescribing of narcoleptics, antidepressants and anti-Parkinson's drugs. Due to the comparatively cheap and highly genericised nature of these drug classes, the value in the six major markets (US, France, Germany, Italy, Spain and the UK) reached only $24 million in 2007."

Top 10 neurological brands in the seven major markets (based on the last three quarter sales in 2006) are-Aricept for Alzheimer's (patent expiring in 2010); Topamax for epilepsy (patent expiring in 2008); Lamictal for epilepsy (patent expiring in 2008); Ambien for insomnia (patent expired); Depakote for epilepsy (patent expiring in 2008); Avonex for MS (patent expiring in 2013); Lyrica for epilepsy (patent expiring in 2018), Copaxone for MS (patent expiring in 2014); Imitrex for migraine (patent expiring in 2008); and Kepprafor epilepsy (patent expiring in 2008. With some drug patents expiring this year and in the near future, the prospects of getting cheaper, and hence, more accessibility are bright.

"Among the top 10 neurological brands across the seven major markets, the leading drug class is anticonvulsants (Topamax, Lamictal, Depakote, Lyrica and Keppra). These are also approved for a number of psychiatric and pain indications, which significantly broadens their target patient population," says Nallaparaju. Among the anticonvulsants, Pfizer's Lyrica is the fastest growing neurological drug with a CAGR of approximately 400 per cent (2004-2007) and it sustained this rapid growth in 2006-07 with an annual growth of 50.7 per cent . "Five of the top 10 products are getting off-patent this year. With formulation and development expertise, global presence, and competitive pricing, Indian companies are poised to target the $8.8 billion market of these five drugs getting genericised," he adds.

Current ongoing research

"For epilepsy, we are doing clinical research for new drugs, mostly because there are patients that need them following the failure of standard treatments. These trials are sponsored by UCB," reveals Desai. "We have a new anti-epileptic drug called brivaracetam (generic), which is a new compound developed by UCB. Right now we are doing phase III for brivaracetam for epilepsy patients who are not responding to standard treatment," he adds. The drug may be put up for FDA licensing in 2010, so it might come into the market internationally by 2011. Johnson & Johnson is also developing a drug called carisbamate that it thinks is very promising, which may hit the market by 2010.

For MS there are newer immunomodulators that may be available two or three years from now. "There is a monoclonal antibody (mAb) called tysabri (natalizumab), which is undergoing studies in Europe and the US. Initially, when the drug was developed, there were two patients who had a very disastrous side effect and died-a condition called progressive multifocal leukoencephalopathy (PML). It has not happened again but it can be considered as a possible side effect. In all likelihood the drug will still get licensed," says Desai.

There is a vaccine that is being studied for Alzheimer's-beta amyloid vaccine. There is an abnormal deposition of a protein called beta amyloid (present in many structures of the nervous system) which, in Alzheimer's, goes under a structural change and gets deposited as a pathological process and forms what is known as neuritic plaque. So to target this part of the pathology researchers are trying to target a vaccine which can block the beta amyloid from getting deposited in the brain. However, according to a recent study by researchers in University of California (in the Journal of Neuroscience), the vaccine does what it is designed to do-clear beta-amyloid plaques from the brain-but does not seem to help restore lost learning and memory abilities, hence the need for complementary treatments that would be able to address the complexity of Alzheimer's disease.

Another significant development in Alzheimer's R&D is the recent liscencing deal between Pfizer and Medivation (a San Fransisco based biopharmaceutical company) to co-develop and market Medivation's drug Dimebon for Alzheimer's and Huntington's disease, which is currently in phase III trials. The results from the study should be out by 2010.

In mid 2007, a study featured in the journal Nature stated that a team of researchers at Northwestern University's Feinberg School of Medicine had found that isradipine, a drug widely used for hypertension and stroke, could restore dopamine neurons to their original healthy state in mice, hence benefiting susceptible cases of Parkinson's as well as those who are already affected by the disease. Another drug has been very recently found to slow the progression of Parkinson's. Researchers from Newcastle University found that rasagiline (also known as Azilect) can slow the development of the disease if given at an early stage. Both the above mentioned studies cannot be termed as conclusive; however, they do raise expectations of a new treatment for the disease.

There any other known and promising neurological drugs as well that are currently undergoing clinical trials in various companies.

Issues and trends

There are quite a few issues and limitations that pharma companies face in the R&D of neurological drugs across disorders. "Considering that among the top 10 products five of them are getting off-patent this year, new drug launches in the same therapy classes of these drugs are bound to get affected," reveals Nallaparaju. He continues, "The reduced cash flow (from lower revenue realisation) will adversely affect investments in R&D. There are chances of potential failure in the clinical trials, and availability of limited patient population (for recruiting in trials) of ALS and Huntington's disease." Additionally, he says that since novel therapies like cell therapy/gene therapy for Parkinson's disease are still in initial stages of development, it is likely that there would be regulatory resistance to the acceptance of such novel therapies.

There have also been controversies regarding the teratogenicity of some of the neurological drugs. For instance, carbamazepine has a potential teratogenic risk. A number of reports have described a slight increase in the risk of major congenital abnormalities, especially neural tube defects, among children of mothers with epilepsy treated with carbamazepine during pregnancy. If women are treated with a combination of carbamazepine and other anti-epileptic drugs, particularly sodium valproate, there is an increased risk without any doubt.

A new trend that is surfacing is the overlap of neurology and psychiatry, because of which there may be a dual approach required/implemented soon to deal with neurological disorders. "Because some of the psychiatric drugs are being used off-label in neurological disorders, this is quite possible. Also, some psychiatric drugs will be used in these conditions for the co-morbidities that the patients may be present with," says Nallaparaju.

Desai concurs, " Most of the anti epileptics are being used by psychiatrists to treat bipolar mood disorder based on the theory that bipolar depression is a sort of limbic epilepsy (epilepsy of emotions)." For example, sodium valproate is used off-licence by specialists as a mood stabiliser for treating people with the psychiatric illness, bipolar affective disorder. This use is not licensed, but the medicine has been shown to be effective for controlling episodes of mania in this condition, and for helping prevent future episodes of ill health. To understand better cases like how sodium valproate works as a mood stabiliser in bipolar disorder, neurologists and psychiatrists ought to work together.

Unmet needs

Globally, about 94 companies are developing products for various neurological disorders. From amongst them, some Indian companies like Glenmark are developing drugs for indications like migraine (pipeline drug-GRC6211). Glenmark has partnered with Eli-Lilly for development deals. Suven Life sciences has also partnered with Eli-Lilly.

As neurological disorders are age-related, an increasing ageing population will drive the growth of the market, and hence the R&D. The following indications posses high levels of unmet needs:

• Alzheimer's disease affects approximately 24 million people worldwide today, with the number predicted to reach 40 million by 2020. Further, current therapy has a modest symptomatic effect and does not significantly modify the course of this progressive neuro-degenerative disorder
• There is a significant need for an MS treatment with superior efficacy to current therapies with a less invasive and less time-consuming route of administration. There is also an unmet need for primary-progressive and secondary-progressive MS indications
• There is also need for a reduced dosing frequency or a less invasive therapy with good patient compliance
• In novel therapies for Parkinson's like cell therapy/gene therapy, initial studies have shown significant results in slowing the progression of the disease, this area needs to be explored more extensively.

Searching for the ‘Ideal’

"Philosophically, I think most disease cannot be reversed, you can only buy time. The key to developing new drugs for these disorders is to know what goes wrong and try to formulate a fix," says Desai. He adds, "The problem in degenerative disease is that we only know what happens as an end result, but we haven't yet understood what initiates it. If one can find the initiative event that triggers the disease chain, we can come close to finding a better treatment if not a cure."

Each drug is different. Desai says, "We need a medication that can be given orally and at the same time can pass the blood brain barrier and reach the nervous system to the target because the target is itself protected by the blood brain barrier." Another attribute can be that the drug should be specifically targeted, act only at the site where it is needed, for example it should only augment acetylcholine in the brain where it is needed and not else where in the body and produce side effects. "A drug that can reach the nervous system without losing its potency and has minimum side effects is what you are looking for," he says. Unfortunately, neurological diseases are so many that it will be difficult to form a common umbrella to give attributes to a drug and call it 'ideal'.

aashruti.kak@expressindia.com