Wednesday, March 12, 2008

A hopeful future for Parkinson's disease patients

As discussed in our recent feature Parkinson's Disease Market analysis and forecasts Parkinson's disease is the second most common neurological disorder, affecting approximately 4.1m people worldwide.

Parkinson's disease is a neurodegenerative disorders characterized by the progressive loss of dopaminergic neurons and hence pharmacotherapy centers on bringing dopaminergic activity back to normal. The range of options open to Parkinson's disease patients is however changing.

Treatment of Parkinson's disease currently includes the use of levodopa, COMP inhibitors and dopamine agonists

Levodopa - the Gold Standard: Since its introduction in the 1960s, levodopa has been considered the gold standard drug therapy for Parkinson's disease. Levodopa is a precursor to dopamine that, when given to people with Parkinson's, is converted into dopamine by nerve cells in the brain. The increase in dopamine may reverse many of the disabling symptoms of Parkinson's disease.

Treatment with dopamine itself isn't possible, because dopamine doesn't cross the body's blood-brain barrier. Levodopa, on the other hand, does cross this barrier, but only a small amount actually reaches the brain. Today levodopa is generally combined with carbidopa that targets levodopa to the brain (by limiting its activation in the periphery) increasing the therapeutic index.

During early treatment, side effects from carbidopa-levodopa therapy are usually not a major problem. However, the drug works less evenly and predictably as the disease progresses. As a result, some people may experience involuntary movements (dyskinesia), primarily when the medication is having its peak effects. The length of time for which each dose is effective may begin to shorten (wearing-off effect), leading to more frequent doses.

Another problem that may develop with long-term carbidopa-levodopa usage, the on-off effect, may cause Parkinson's-related movement problems to appear and disappear suddenly and unpredictably. Other side effects may include hallucinations and a drop in blood pressure when standing (orthostatic hypotension). Some people may experience nausea with carbidopa-levodopa therapy.

COMT inhibitors as adjuncts to levodopa: Catechol-O-methyltransferase (COMT) inhibitors are often used alongside levodopa. COMT inhibitors prolong the effect of carbidopa-levodopa therapy by blocking an enzyme that breaks down dopamine. Tolcapone (Tasmar) is a potent COMT inhibitor that easily crosses the blood-brain barrier. But because Tasmar has been linked to liver damage and liver failure, the drug is normally used only in people who aren't responding to other therapies. Entacapone is a COMT inhibitor that shares some of the properties of tolcapone but doesn't cross into the brain. It may help manage fluctuations in the response to carbidopa-levodopa in people with Parkinson's disease. Entacapone doesn't cause liver problems and is now combined with carbidopa and levodopa in a medication called Stalevo.

Dopamine agonists as important components of the Parkinson's disease arsenal: Although carbidopa-levodopa typically allows people with Parkinson's disease to extend the time they are able to lead relatively normal lives and in many cases is effective for a number of years other treatment options are required. Dopamine agonists are used both as adjuncts to carbidopa-levodopa therapy. Bromocriptine and Permax suffered problems with adverse effects in the past however other dopamine agonists such as romocriptine (Parlodel), apomorphine (Apokyn), pramipexole (Mirapex) and ropinirole (Requip) are all still used.

Selegiline as a strategy for delaying carbidopa-levodopa initiation: Selegiline (Eldepryl) is another commonly used therapeutic. This product is an MAO-B inhibitor that limits the breakdown of both naturally occurring dopamine and dopamine formed from levodopa. Selegiline may delay the need for carbidopa-levodopa for about a year, and when taken with carbidopa-levodopa, may enhance the drug's effectiveness.

Parkinson's disease represents a multi-billion dollar market for the pharmaceutical sector: In 2006, the global sales of Parkinson's disease therapeutics were $3.1bn up by 11% from $2.5bn in 2005. Revenues of approved Parkinson's disease drugs across the major markets (US, Japan, France, Germany, Italy, Spain and the UK) totaled over $2.2bn in 2006, with revenues expected to exceed $4.6bn by 2012.

While it may seem distasteful to some talking about a disease as distressing as Parkinson's in terms of dollars, the size of the Parkinson's disease market is driving pharmaceutical activity which will hopefully improve options available to patients. We are currently seeing a climate of change in this market. A number of key drugs are approaching the end of their patent life while other new products are about to enter the market.

The future of Parkinson's disease: The leading therapeutics expected to change the Parkinson's disease market dynamics will include GSK's Requip Once-daily ER, UCB-Schwarz's Neupro and Teva/Lundbeck’s Azilect. Requip ER received an approvable letter from the FDA in Dec. 2007, while at about the same time UCB filed for Neupro. Other key compounds predicted for success include Kyowa Hakko’s Istradefylline, Merck-Serono/Newron’s Safinamide.

The new wave of Gene/cell Therapy compounds that have revealed positive initial clinical data, thus Neurotrophic growth factors (NGF), either to be injected directly into the brain are also tipped for potential market success. Ceregene’s Neuturine, Neurologix’ GAD (glutamic acid decarboxylase) amongst other similar drugs, will add to the present Parkinson's disease therapeutics that will expand revenue growth in the long-term.

More information on Parkinson's disease: LeadDiscovery currently lists over twenty in depth reports on various aspects of Parkinson's Disease (click here) plus over 200 journal articles (click here). To keep track of all activity in the Parkinson's Disease arena subscribe to DailyUpdates-Neurodegenerative Diseases [see todays edition here]

Tuesday, March 11, 2008

The Return of Drug Discovery

The more observant amongst you will notice that this is the first offering from Advances in Drug Discovery for a fact one year. This is not to say that there has been a lack of advances over the past 12 months. Quite the opposite and our silence has been due to the efforts that we have been placing on redesigning our main site, LeadDiscovery to better cover drug discovery.

Just a few words on what we have been up to before we continue from where we stopped this time last year.

DailyUpdates, our alert service now highlights key research and breaking news across 12 different therapeutics channels. The service is now a key intelligence tool across the pharmasphere. DailyUpdates is now supported by a monthly service, UpdatesPlus which takes a deep dive into R&D activity providing detailed analysis on selected indications or drug classes. Our portfolio of PharmaReports, in depth pharmaceutical market research and pipeline analysis reports, has expanded with over 1,000 reports now on offer. All in all we now offer insight into drug discovery at increasing levels of if you need to track a particular area of drug discovery let us help you, we can!

Anyway enough of us and onto the blog.

Todays edition of DailyUpdates covers nearly 50 key journal articles published over the past couple of weeks, a selection of trials and all the most important news. One of the journal articles that we would like to highlight here looks at the therapeutic potential of AT-101 which is featured in a paper highlighted on DailyUpdates-Oncology.

Cottoning onto apoptosis...

Ascenta Therapeutics' AT-101 is an enantiomer of gossypol, a natural product of cotton. The molecule is an orally active inhibitor of the Bcl-2 family of anti-apoptotic proteins and is in Phase 2 cancer trials in a number of oncology indications.

Apoptosis, or programmed cell death represents a pathway targeted by multiple oncology therapeutic candidates. The Bcl-2 proteins (Bcl-2 stands for B-cell lymphoma) comprise the best known anti-apoptotic group. Proteins from this family are frequently over-expressed in cancer making the cells resistant to death signaled by natural or therapeutic stimuli. There are at least five well characterized members of the Bcl-2 family: those most implicated in cancer progression and resistance to conventional therapies are Bcl-2, Bcl-XL and Mcl-1. Over-expression of anti-apoptotic members of the Bcl-2 family are observed in the majority of Non-Hodgkin's lymphomas (NHLs) , contributing to intrinsic and acquired drug resistance. Since AT-101, inhibits each of these proteins there is strong proof of concept to support the development of AT-101 as a treatment of NHL.

NHL is the most common hematological malignancy and is comprised of around 30 different disease subtypes. Each of these present with a distinct set histological, genetic and clinical characteristics. Treatment options in NHL include chemotherapy, targeted therapies, stem cell transplantation and radiotherapy (see our recent feature Non-Hodgkin's Lymphoma - Is there room to emulate Rituxan's success?)

Rituxan-based regimens constitute the mainstay of first-line treatment options in several NHL subtypes. There is however a lack of consensus over the treatment of relapsed and refractory disease in most NHL subtypes. Refractory patients are poorly served by currently available treatment options. Consequantly the NHL late-phase pipeline is relatively active, with 10 Phase IIII drugs and 46 Phase II drugs.

In their upcoming paper in the journal Blood, Paolluzi et al characterize AT-101, one of these phase II candidates in B cell lymphoma. The IC50 for AT-101 was reported to be between 1 and 10 microM for a diverse panel of B-cell lymphomas. In a mouse model of drug resistant B-cell lymphoma, 35 mg/kg/day of AT-101 was safe and efficacious. The addition of AT-101 to cyclophosphamide and rituximab in a schedule-dependent manner enhanced the efficacy of the conventional therapy.

These data support the open-label, phase II trial of 52 NHL patients comparing rituximab with AT-101 and rituximab which commenced in the US in 2006.

LeadDiscovery currently featured 24 market research reports analyzing various aspects of NHL (click here for listing) and nearly 300 journal article selected for their importance to drug discovery (click here for listing). Interested readers can view our entire oncology portfolio here