Glimmers of hope in Huntington's must not be overstated


Two novel agents being tested in Huntington’s disease yielded results from mid-stage studies this week, prompting big jumps in the share prices of the companies that own the drugs: Raptor Pharmaceutical and Prana Biotechnology.

Although the data were encouraging, the 40% advance in valuations that both experienced overstates the importance of these findings. Like Alzheimer’s, efforts to find effective therapeutics that might be able to slow, halt or even reverse the devastating neurological decline that this disease wreaks are still very much a work in progress. And much firmer evidence that either of these drugs works is still needed to confirm that real progress has been made (see tables below).

Clinical stage Huntington’s research has been marked more by setback than step forward over the last few years, with notable failures including Neurosearch’s Huntexil and Medivation’s Dimebon (Therapeutic focus – Two steps back for Huntington’s disease, April 11, 2013).

Despite that it is encouraging to see that commercial companies, including Prana and Raptor, are still pursuing various avenues. Only this week Omeros announced that it had started a phase II study with its PDE10 inhibitor, OMS824. The second such agent to be tested in this use – after Pfizer’s PF-02545920 – the company hopes that its more potent inhibitor of the target enzyme will be able to show a bigger impact on cognition and psychomotor functions.

Interim results due later this year should give an insight into the approach’s future. Following the inconclusive results from Raptor’s RP103 and Prana’s PBT2, a disappointing finding would leave the mid-stage pipeline very bare.

Active mid-late stage Huntington trials underway evaluating potentially disease modifying agents 
Status Company/Sponsor Product Pharmacological class Enrollment Acronym Primary Completion Date NCT ID
Phase 3 Huntington Study Group, MGU & University of Rochester High dose creatine Amino acid therapy 650 CREST-E 01/06/2016 NCT00712426
Phase 2 Teva Pharmaceutical Industries Huntexil Dopaminergic stabiliser 400 - 01/01/2015 NCT02006472
Prana Biotechnology PBT2 Tau aggregation inhibitor 109 Reach2HD 01/07/2013 NCT01590888
Pfizer PF-02545920 Phosphodiesterase X (PDE10) inhibitor 56 - 01/11/2015 NCT01806896
Raptor (Centre Hospitalier Universitaire d'Angers) RP103 Cystine-depleting agent 96 CYST-HD not available 2010-019444-39 
Omeros OMS824 PDE10 inhibitor 120 H2 2014 not available

Unfortunately, both Prana and Raptor had to rely on data mining to find the bright spots in their data.

Prana reported top line results from a trial called Reach2HD that recruited 109 patients and tested two doses of PBT2 against placebo, over six months, with the primary aim to evaluate the safety and tolerability of the agent.

The Australian company has yet to unveil the actual data, but said the primary endpoint, the frequency of adverse events, was met. Efficacy was also measured as secondary endpoints via eight separate tests, but only one yielded positive results, and only just: in the high dose group, patients showed a significant improvement on one measure of executive function called the Trail Making Test Part B (p=0.042 at 26 weeks). On the executive function composite score, which incorporated a second measure, a trend to improvement was seen across all patients given the high dose, while a significant improvement was seen with mild disease patients.

The company is now planning a phase III trial to confirm these results, but it is hard to see how firm conclusions can be drawn about the drug’s efficacy before this is done, or full data from the phase II study scrutinised.

Masking efficacy?

Raptor meanwhile announced top line results from a planned 18 month analysis of an ongoing three year phase II/III trial of RP103, delayed release cysteamine, which the company is already selling as a treatment for cystinosis, under the brand name Procysbi.

The study – run in France by independent investigators - recruited 96 patients who received the drug or placebo; 89 completed the 18 month phase. Data to date revealed only a positive trend towards slower progression of Total Motor Score – a measure of disease progression – in patients given the active drug.

However the company highlighted that a subset of 66 patients who were not taking Xenazine did show a significant slow down; patients were allowed to continue their baseline medicines throughout the trial.

Xenazine is approved to treat the chorea caused by Huntington's, and Raptor speculated that the effects of the drug might have masked the benefits of RP103 in patients who were taking it throughout the study. The company intends to talk to regulators about these results, and investor enthusiasm about the results will have been prompted in part by hopes that it will be allowed to market the drug based on these findings.

However given that the mechanism of action of RP103 is not fully understood, or why this sub group seemed to respond, it is seems highly unlikely that regulators will sanction this without a further phase III study, or at least full three year data.

For patients

Like Alzheimer’s, Huntington’s is a poorly understood disease with little definitive knowledge of the molecular drivers of its progression or biomarkers that might be helpful in the development of potential therapies. As such, the early signals of efficacy seen in these trials have to be treated with caution.

As such, both Prana and Raptor face a difficult task to prove more conclusively the benefits of their respective agents. For the sake of patients desperate for progress, their progress to date should not be overstated.

To contact the writer of this story email Amy Brown in London at or  follow @AmyEPVantage on Twitter

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