Therapeutic focus - Huntexil at spout of dry Huntington's disease pipeline


NeuroSearch’s release of positive phase III data on its Huntington’s disease drug, Huntexil, was an encouraging development for patients but also demonstrated how dry the pipeline is for this neurodegenerative condition.

Huntexil, a dopaminergic stabiliser, is the first of two candidates currently in phase III trials to announce results, the other being Medivation's Dimebon. Behind that only one candidate is reported to be in phase II, where it has lingered since 2003 and has been the subject of a legal tussle between the research partners, Teva and Proneuron, over trials for amyotrophic lateral sclerosis (ALS).

Rare disease, poor prognosis

Huntington’s disease is a genetic condition that causes neurodegeneration. Patients carry a dominant mutation that codes a protein called huntingtin to damage specific areas of the brain, particularly in the basal ganglia that plays a key role in movement and behaviour control.

It is more common in people of Western European ancestry, where prevalence can be 3 to 7 per 100,000. An estimated 100,000 people worldwide are stricken with the disease, and about 8,000 live in the US.

Symptom onset typically occurs between ages 35 and 44, and patients can typically expect a lifespan of about 20 years after onset. Although Huntington’s disease is not fatal, death occurs frequently as a result of pneumonia caused by inhaling food and heart disease.

First therapies

Before Lundbeck premiered the vesicular monoamine transporter 2 inhibitor Xenazine in the US in November 2008, there were virtually no drugs specific to the disease, the symptoms of which include involuntary movements, cognitive decline, and emotional and mental health problems. Drugs used to treat symptoms of the disease have included dopamine antagonists, the antipsychotic haloperidol and the glutamate antagonist amantadine.

Xenazine treats chorea, a type of involuntary writhing movement associated with the condition. For a product treating a small population, Xenazine is a valuable one to Lundbeck. It will have worldwide sales of $380m in 2014, $366m of which will be generated by Lundbeck in the US market, according to EvaluatePharma’s consensus forecasts.

The only other Huntington’s-specific drug marketed anywhere in the world is anti-hyperlipidaemic ethyl icosapentate, in Japan, where it is marketed in that indication by the Indian drugmaker Lupin. As an anti-hyperlipidaemic it is marketed under the name Epadel.

However, when Amarin brought ethyl icosapentate to European regulators they sought more efficacy data, prompting the company to withdraw its marketing application at the end of 2009.

Dry pipeline

NeuroSearch released data from its European phase III trial MermaiHD demonstrating that Huntexil at a twice-daily 45mg dose is statistically superior to placebo in improving voluntary and involuntary motor control, as well as eye movement and dystonia (NeuroSearch redeems itself with impressive Huntington’s phase III data, February 3, 2010).

In announcing the phase III trials, NeuroSearch executives made no indication when they would file for a marketing application as they said they were awaiting the results of a North American trial called HART, due later this year.

Behind Huntexil in the late-stage pipeline is Dimebon, a combined acetylcholinesterase inhibitor/NMDA receptor antagonist. Therapies in the acetylcholinesterase inhibitor and NMDA receptor antagonist classes are already in wide use to treat the symptoms of Alzheimer’s disease.

Dimebon is in phase III for both Huntington’s disease and Alzheimer’s disease. In Dimebon’s Huntington’s trial, which began in July 2009, researchers are measuring as primary endpoints cognitive, behavioural and functional tests, rather than the motor functions that NeuroSearch is measuring in its Huntexil trials.

Analysts are forecasting a bright future for Dimebon, with worldwide sales of $328m in 2014 for Pfizer, although the bulk of these revenues will be generated from the drug's use in Alzheimer's; Dimebon could receive regulatory approval in both settings by the end of 2011.

In the early pipeline, Teva and Proneuron's high molecular weight co-polymer version of glatiramer acetate, the active ingredient in blockbuster MS drug, Copaxone, is believed to still be in phase II trials, where it has lingered since 2003 as the two companies have fought in court over the drug's development for ALS.

Four candidates are in phase I. One, NBI-99854 from Neurocrine Biosciences, is in the same pharmacological class as Xenazine. Novartis is preparing a phase II trial of 60 patients for AFQ056, according to PBT2 from Prana Biotechnology is a beta amyloid aggregation inhibitor also in phase II trials for Alzheimer’s disease. And Raptor Pharmaceuticals' DR Cysteamine, a lysosomal transport modulator, is being tested for renal failure and liver disorders.

Xenazine’s launch in 2008 surely was good news for patients suffering from Huntington’s disease and gives them hope in controlling some of its more challenging symptoms, while the positive results for Huntexil must bring further hope. Yet a very dry pipeline and no sign of a drug that will reverse the effects of the disease must be a continuing source of disappointment and frustration.

Huntington's disease - marketed products and clinical pipeline WW sales ($m) - across all indications
Status Product Company Pharmacological class Lead Indications 2010 2014
 Marketed Xenazine Lundbeck/Biovail Vesicular monoamine transporter 2 (VMAT2) inhibitor Huntington's disease [Marketed] 137 380
Ethyl Icosapentate Lupin Signal transduction inhibitor Huntington's disease [Marketed] - -
Phase III Dimebon Pfizer/Medivation Acetylcholinesterase inhibitor & NMDA receptor antagonist Alzheimer's disease [Phase III]; Huntington's disease [Phase III] - 328
Huntexil NeuroSearch Dopaminergic stabiliser Huntington's disease [Phase III]; Schizophrenia [Phase I] - -
Phase II Glatiramer acetate (TV-5010/Cop-1) Teva Pharmaceutical Industries/Proneuron Biotechnologies CNS agent Amyotrophic lateral sclerosis (ALS) [Phase II]; Huntington's disease [Phase II] - -
Phase I AFQ056 Novartis Metabotropic glutamate receptor 5 (mGluR5) antagonist Fragile X syndrome [Phase II]; Parkinson's disease [Phase II]; Huntington's disease [Phase I] - 10
NBI-98854 Neurocrine Biosciences Vesicular monoamine transporter 2 (VMAT2) inhibitor Huntington's disease [Phase I]; Schizophrenia [Phase I] - -
PBT2 Prana Biotechnology Beta amyloid aggregation inhibitor Alzheimer's disease [Phase II]; Huntington's disease [Phase I] - -
DR Cysteamine Raptor Pharmaceuticals Lysosomal transport modulator Renal failure, chronic [Phase II]; Liver disorders [Phase II]; Huntington's disease [Phase I] - -

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