GSK reviews CNS therapeutics

GlaxoSmithKline (GSK) has given an update on its compounds in development to treat Central Nervous System (CNS) disorders, a therapy area that represents approximately 20% of the company's total r&d pipeline.

The CNS seminar represents the first in a series of key therapy area updates that GSK will conduct once or twice a year to provide an in-depth look at segments of its research portfolio.

'Within a growing research pipeline of quality compounds that cross a wide range of disease areas, GlaxoSmithKline is building a strong stable of medicines with significant potential to fight neurodegenerative and psychiatric diseases. With '381, for example, we have a potential best-in-class pain medicine,' said Tachi Yamada, chairman of r&d at GlaxoSmithKline. 'Our scientists are developing a new oral treatment for multiple sclerosis, novel treatments for Alzheimer's disease and schizophrenia, and new ways to treat depression and anxiety. Our emerging CNS portfolio could potentially make a huge difference to the lives of millions of patients.'

pain

406381, a new dual-acting Cox-2 inhibitor, is active in pre-clinical models in both inflammatory and neuropathic pain. In Phase II studies for rheumatoid arthritis and osteoarthritis, 406381 had better efficacy in the treatment of pain than placebo. In some pre-determined endpoints involving head-to-head comparisons, it was more effective than celecoxib, the current market leader. An initial study in neuropathic pain also suggested efficacy in this difficult-to-treat condition. In these Phase II studies, the adverse event profile was similar to celecoxib, and the overall safety evaluation supports progression to larger studies of longer duration. The company will meet with regulatory agencies over the next few months to finalise Phase III development plans, and will then have better information on which to project a filing date for the product. GSK believes 406381 has the potential to become a class-leading medicine for the treatment of pain.

depression and anxiety

Radafaxine (353162), a potent metabolite of bupropion, continues in development as a treatment for depression. While results from Phase II clinical trials that evaluated lower doses of radafaxine did not meet primary end points for efficacy, the results of secondary endpoint analysis provide a basis for undertaking further clinical studies at higher doses. The target date for regulatory filing is 2007.

Importantly, in the completed Phase II trials for depression, weight loss was observed in obese individuals after 8 weeks compared with a small weight gain among patients on placebo. On the basis of these data, GSK is now planning to develop this compound for the treatment of obesity.

GSK is also continuing to investigate two novel approaches for the treatment of anxiety and depression. One explores the potential synergistic advantages of combining low doses of 597599, an NK1 antagonist, and a low-dose SSRI in the treatment of anxiety. A second approach focuses on 372475, a first-in-class, potent, and selective serotonin, noradrenaline and dopamine reuptake inhibitor being developed in partnership with NeuroSearch. With this compound, GSK expects significant efficacy in depression with the potential to also improve cognitive function.

multiple sclerosis

683699, being developed in collaboration with Tanabe, is expected to be the first oral integrin antagonist for the treatment of multiple sclerosis. In a recent study, oral 683699 matched the biomarker activity of intravenous Antegren - the latest advance in the treatment of the disease. The compound is in Phase IIb with filing expected in 2008.

Alzheimer's disease

GSK's 5-HT6 receptor antagonist, 742457, is highly brain penetrant, and has been shown to enhance neurotransmitters and improve learning and memory in pre-clinical models. The compound has recently completed Phase I testing, with Phase II expected to begin in 2005.

GSK is also investigating Avandia for the treatment of Alzheimer's disease in two clinical studies. Evidence suggests that PPARs (peroxisome proliferator activated receptors) play a role in modulating CNS inflammation and glucose metabolism, which may be important in Alzheimer's disease. Data already published supports the concept that Avandia has an effect against Alzheimer's. Therefore, GSK is conducting Phase IIb clinical trials with Avandia for the treatment of Alzheimer's disease, with data from the first study expected in 2005.

Schizophrenia

Talnetant is an NK3 antagonist for the treatment of schizophrenia. In Phase II studies, a small subset of patients with high exposures to the compound experienced good efficacy with a benign safety and tolerability profile, including lack of weight gain. A Phase II study is underway with a new formulation that permits higher dosing; data is expected in 2005. Recent data from this subset of patients also suggest that this compound has the potential to deliver a cognitive benefit, which is increasingly recognised as a major disability in schizophrenic patients.

2005-2007 CNS product filings

In addition to its promising CNS research compounds, GSK also showcased further opportunities for near-term momentum with late-stage assets and currently marketed products:

• Lamictal: Having seen encouraging results in preliminary efficacy studies, GSK is initiating a Phase III development programmeme for Lamictal for adjunctive treatment of schizophrenia. In addition, Lamictal for the acute treatment of bipolar disorder is expected to be filed in 2006. Lamictal XR, an improved once-daily formulation, will also be filed for treatment of epilepsy in 2006, and in 2007 for adjunctive treatment of schizophrenia and diabetic neuropathy.

• Entereg: Currently physicians lack treatments for post operative ileus (POI), a bowel impairment occurring after abdominal and other surgery that can be a major contributing factor to patient discomfort (including nausea, vomiting, bloating and constipation). POI can often prolong hospital stays, and may pose additional costs to payers. Entereg (alvimopan) has been shown to accelerate gastrointestinal (GI) recovery following abdominal surgery, allowing patients to be ready to leave hospital sooner. The FDA has accepted for review an NDA for Entereg in the management of POI. The FDA action date is April 25, 2005.

Entereg also appears to reduce the lower GI side effects of opioids without interfering with the analgesic effects on the central nervous system. In clinical trials, Adolor and GSK are studying Entereg for opioid-induced bowel dysfunction - the constipation and the associated symptoms of chronic opioid use - as well as chronic constipation. Phase IIb studies are ongoing, and NDA submissions are targeted for 2007.

• Trexima for Migraine: Developed in collaboration with Pozen, Trexima, an innovative formulation combining the active ingredient in Imitrex - the current market leader - and naproxen sodium, is expected to provide superior efficacy compared with each of the individual components alone. In a Phase II trial, the combination of Imitrex and naproxen sodium relieved pain more effectively than either agent administered alone, both at the 2-hour time point, and on a sustained basis from 2-24 hours. Filing is expected in the second half of 2005.

• Requip/Adartrel in Restless Leg Syndrome (RLS): RLS is the third most common cause of sleep disturbance. Treatment often focuses on symptom control, rather than on the underlying condition; 50% of patients on medication are not treated effectively. Phase III clinical data show that Requip/Adartrel reduced leg movements and improved outcome measures like sleep and quality of life, in some cases within one week of treatment. Requip/Adartrel was approved in France in July 2004; GSK expects to gain US approval for the treatment of RLS in the first half of 2005.