Glaxo announces cull that could get partners squirming

GlaxoSmithKline today became the latest pharma major to announce a shake up of its research activities alongside annual results, joining the likes of AstraZeneca and Pfizer, all of which have displayed a new willingness to take the knife to previously sacrosanct R&D budgets.

There is no doubt that big pharma’s productivity needs improving – outside of vaccines the last blockbuster Glaxo launched was the ill-fated diabetes pill Avandia in 1999, although a couple of recent launches are forecast to just about top the magical $1bn mark in a few years time. Today, the company revealed some areas it plans to focus on in an attempt to improve this productivity, whilst singling out others to exit, news that could prompt a couple of partners, namely Neurocrine Biosciences, NeuroSearch and possibly Actelion, to shift nervously (see table below).

Feel my pain

In a shake up to work on central nervous system therapy areas, Glaxo said today it is planning to cease discovery research in selected neuroscience areas, including depression and pain, and focus on neurodegenerative and neuroinflammatory diseases such as Alzheimer’s disease, multiple sclerosis and Parkinson’s disease.

The company believes the prospects for successful registration and launch of differentiated medicines are greater in these areas. This is certainly supported by a number of examples from the areas to be exited, where regulators are becoming increasingly hard to please. For example the trials and tribulations of Vanda’s Fanapt, which finally won surprise approval last year, and the significant hold ups seen with the “abuse resistant” pain drugs developed by Purdue Pharma and King Pharmaceuticals.

According to pipeline data from EvaluatePharma, Glaxo is involved in 36 R&D projects in the CNS area, ranging from research projects to phase III, some in-licensed but mostly derived internally.

The company’s statement does not necessarily mean all work on these projects will immediately grind to a halt. However, when it comes to go/no-go decisions, it is likely the bar will be raised considerably higher to justify continued investment.

Under threat?

The table below highlights drugs that could be subject to much greater scrutiny in the future. The most advanced, Gepirone ER, is certainly a case in point, as the tortuous regulatory pathway it has travelled means the drug was probably already on the “to abandon” list, even before Glaxo decided to exit depression.

It was in-licensed in February 2007, just before its developer Fabre-Kramer was about to file for approval in the US for major depressive disorder (MDD). A non approvable letter was issued in response; the FDA has never been very impressed with the drug, as this followed an earlier non approvable letter in 2004.

In terms of other projects under the microscope Neurocrine possibly has the most to lose. The two companies have an ongoing project researching corticotropin releasing factor (CRF1) receptor antagonists, with two candidates in phase II. Results from a trial of 561679 in MDD are due by the end of the year.

NeuroSearch also has a research project with Glaxo in this area, which has been running for six years now, having been amended in January 2009. The Danish company is responsible for work up to phase IIa, suggesting the collaboration is unlikely to be scrapped, although NeuroSearch may find Glaxo more reluctant to take on future work.

Trouble sleeping

The table below also includes drugs outside of pain and depression, but that could be considered equally problematic in terms of regulatory hurdles. In particular is insomnia, an indication that has derailed numerous candidates in the last few years. Glaxo’s exposure to this area is mainly with Actelion’s almorexant.

The Swiss company is shouldering 60% of the cost of the phase III programme, and news is awaited on a second pivotal trial, which is due to start this year. Nothing has yet been listed on www.clinicaltrials.gov.

The deal Glaxo signed to get its hands on this product was significant, SFr150m upfront with an eye-watering biodollar total of SFr3.3bn ($3.1bn); the fact that this sum was very backend loaded illustrated the risk associated with the project.

Results from the first phase III trial were announced late last year but failed to ignite much excitement, in fact flagged safety observations prompted a fair amount of concern (Actelion’s lack of sleep safety information wakes up critics, December 21, 2009).

Until confirmation that Glaxo is continuing to support this project is received, Actelion and its investors would be forgiven for feeling nervous in the wake of today's R&D shake up.

GlaxoSmithKline CNS projects potentially under review
Product Indication Summary Pharmacological Class Strategy Deal Partner/ Product Source
Phase III Gepirone ER Depression [Phase III] 5-HT1A (serotonin) agonist In-licensed Fabre-Kramer Pharmaceuticals
Almorexant (ACT-078573) Insomnia [Phase III]; Obesity [Pre-clinical] Orexin receptor antagonist In-licensed Actelion
Phase II 823296 Depression [Phase II]; Generalised anxiety [Abandoned - Phase I] Neurokinin-1 antagonist Organic -
876008 Social anxiety disorder [Phase II]; Irritable bowel syndrome (IBS) [Phase II];  CRF-1 receptor antagonist In-licensed Neurocrine Biosciences
842166 Pain [Phase II] Non-cannabinoid type 2 agonist Organic -
372475 Attention deficit disorder/hyperactivity (ADD/ADHD) [Phase II]; Generalised anxiety [Abandoned - Phase II]; Depression [Abandoned - Unclassified] SNRI & dopamine reuptake inhibitor In-licensed NeuroSearch
649868 Insomnia [Phase II] Orexin receptor antagonist In-licensed Human Genome Sciences
561679 Depression [Phase II]; Generalised anxiety [Phase II]; Irritable bowel syndrome (IBS) [Abandoned - Phase I] CRF-1 receptor antagonist In-licensed Neurocrine Biosciences
239512 Dementia, senile [Phase II]; Schizophrenia [Phase I]; Alzheimer's disease [Phase I] H3 receptor antagonist Organic -
Phase I 163090 Depression [Phase I]; Generalised anxiety [Phase I] 5-HT1 (serotonin) antagonist Organic -
424887 Depression [Phase I]; Generalised anxiety [Phase I] Neurokinin-1 antagonist & SSRI Organic -
729327 Schizophrenia [Phase I] AMPA antagonist Organic -
NSD-788 Generalised anxiety [Phase I]; Depression [Phase I] GABA modulator In-licensed NeuroSearch
1014802 Bipolar disorder [Phase I] Sodium channel antagonist Organic -
1018921 Schizophrenia [Phase I] Glycine transport inhibitor Organic -
1144814 Schizophrenia [Phase I] Neurokinin-1 & neurokinin-3 antagonist Organic -
NSD-721 Generalised anxiety [Phase I]; Epilepsy [Pre-clinical]; Pain [Pre-clinical] GABA modulator In-licensed NeuroSearch
1482160 Pain [Phase I] Purinergic ATP receptor antagonist Organic -

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