HD could attract ‘big pharma' investment

Death usually occurs after 15-20 years, because of a general decline in motor and cognitive function, and in particular choking. Given the relatively small number of patients with HD, ‘big pharma' have been reluctant to commit significant resources to drug discovery in this field. However, with a genetic test freely available for this disorder, a shift in ‘big pharma' thinking towards niche conditions, and developments in the understanding of the disease, Datamonitor central nervous system (CNS) senior analyst Dr. Terence McManus suggests “big pharma looks again at what could be a lucrative market”.

Highly genetically linked disease

Huntington's disease is a highly genetically linked disease, which is inherited in an autosomal dominant fashion. Therefore, each person whose parent has HD is born with a 50/50 chance of inheriting the mutated huntingtin gene. Anyone who inherits this gene will, at some stage, develop the disease. A single autosomal gene coding for a mutated form of the protein, huntingtin, causes the neurodegeneration observed in HD.

Genetic tests that can show whether someone has inherited the mutated gene are widely available, Dr. McManus says. “According to the US National Institute of Neurological Disorders and Stroke (NINDS) there are 30,000 US patients suffering from HD. A similar prevalence of 1/10,000 is believed to occur in the major European countries.”

Current pharmacological therapy is limited to alleviating symptoms

Current pharmacological therapy for HD is limited to the management or alleviation of neurobehavioral or movement abnormalities associated with the disease. No disease modifying, disease slowing or neuroprotective agent is currently approved or used to treat HD. Antipsychotics are frequently used to partially suppress chorea (signature movement disorder of the disease) and help control psychiatric abnormalities, such as agitation, hallucinations, or psychotic delusions common in these patients. However, little scientific development has been achieved in symptomatic treatments over the last few years. Although the Federal Drug Authority (FDA) in the US has recently approved Prestwick Pharmaceuticals tetrabenzine for HD patients, this treatment has been available in some EU countries for a number of years.

However, pharmaceutical companies may have underestimated the commercial potential of developing HD drugs, Dr. McManus says. “With a strong genetic link and a freely available genetic test, prophylactic treatment with a disease modifying drug could be possible in Huntington's disease in the future.”

The NINDS estimates that at least 150,000 patients – beyond its stated 30,000 US symptomatic Huntington's disease patients – have a 50% risk of developing the disease. This translates to 75,000 individuals who will at some point develop the disease in the US or approximately 150,000 individuals across the six major Huntington's disease pharmaceutical markets (6MM) of the US, France, Germany, Spain, Italy and the UK.

As the current treatments are symptomatic, these 150,000 individuals are not treated for HD, Dr. McManus says. “Although the genetic test is available, many patients do not take the test, and remain in the dark about whether they will develop the disease or not. This would change significantly if a disease modifying treatment became available. In fact, the hope that such a drug will be developed within their lifetime may be a reason why some HD families continue to have children, rather than stopping the disease line at their generation,” he says.

Big pharma could be attracted by revenue potential of incorporating pre-symptomatic patient pool

Pharmaceutical companies developing disease-modifying treatments may be able to enlarge their target market by including pre-symptomatic patients. With neurodegeneration believed to start many years before the first symptoms are observed, justification for pre-symptomatic prescribing is clear. In addition to this, the age of symptom onset may be linked to the length of the mutated genetic region, a characteristic that can be evaluated by existing genetic tests, Dr. McManus says. “It is conceivable that in the future, if the motivation of a disease modifying treatment was present, estimation of age of onset may aid in evaluating when a patient should start treatment.”

If all patients with a positive genetic test were prescribed a disease modifying treatment at a cost of US$20,000 per patient per year (upper end of the price range for a disease modifying orphan CNS drug), the total potential market could be up to $4.2 billion across the 6MM. Clearly not all patients would receive treatment, however, a treatment rate of greater than 24% could be possible, resulting in a blockbuster market i.e. generating over a billion dollars revenue per year. The financial carrot of a blockbuster market would encourage more R&D investment from ‘big pharma', thereby improving the quality of treatment available for HD patients.

Several drugs in development could contribute to creating blockbuster market

Amarin Corp's Miraxion (LAX-101) is an ultra-pure EPA (Eicosapentaenoic acid, a fish oil) currently in Phase III development. In November 2007, Amarin met with the US FDA following the completion of a comprehensive data review from its large-scale Phase III studies. The FDA indicated that one additional Phase III trial demonstrating robust results, in conjunction with the confirmatory evidence from the existing clinical data might be sufficient to support a New Drug Application.

Medivation's Dimbon is an orally available small molecule that is believed to block the mitochondrial permeability transition pore (MPTP), the glutamate NMDA receptor and cholinesterase activity. The MPTP appears to be a new clinical target for tackling neurodegeneration. The drug is currently being investigated for Huntington's disease in a Phase II trial, the first patient in this trial was treated in July 2007. The results of this Phase II trial will be required before assessment of Dimbon's commercial potential can be evaluated. Dimbon is also being investigated in a Phase II trial for use in Alzheimer's disease.

Avicena's HD-02 (ultra-pure creatine) may be a good candidate for prophylactic use. As a metabolic modulator with already established widespread use and manageable side effects, incorporation into a pre-symptomatic patient's diet as a food supplement may be viable. It may be too early to predict the clinical profile of HD-02, and the commercial viability of such a drug is also questionable. However, the pharmaceutical magazine R&D Directions selected HD-02 as one of the "100 Great Investigational Drugs of 2007" in the March issue. Avicena are also developing ultra-pure creatine preparations for Parkinson's disease and Amyotrophic Lateral Sclerosis.

Huntington's disease – an analog for future direction of Alzheimer's & Parkinson's disease therapy

In addition to representing a new pharmaceutical market, this disease may prove to be a model disease for other neurodegenerative diseases with much greater patient populations and commercial potential, such as Alzheimer's and Parkinson's disease. In these larger markets there is a clear movement towards earlier diagnosis via biomarkers and treatment with disease modifying drugs, Dr. McManus says:

“The uptake of disease modifying drugs prior to symptom onset in Huntington's disease could indicate how much stakeholders such as healthcare payers, patients and physicians are willing to treat diseases such as Alzheimer's and Parkinson's disease if biomarkers identify the disease prior to the evolution of traditional symptoms in the future,” he says.