Therapy Focus - One Step Forward But Two Steps Back In Huntington's

by: EP Vantage

The path towards developing a therapy for Huntington’s disease continues to be rocky, with clinical setbacks aplenty. The only project currently filed with regulators, Teva’s (NYSE:TEVA) Austedo, received a complete response letter earlier this year, and data on the most advanced clinical projects have been far from compelling.

A few have been trudging along in the clinic for several years, but novel compounds are starting to emerge (see table below). An antisense approach from Ionis (NASDAQ:IONS) could be the first truly disease-modifying treatment; phase II data could come next year. And the private group Vaccinex is developing what it claims is a first-in-class antibody. It will, however, still take a good few years to understand the real potential of these new agents.

Mountain to climb

Huntington’s is an inherited genetic brain disorder caused by the expansion of the CAG trinucleotide sequence in the huntingtin gene. The resulting mutant huntingtin protein is toxic and gradually destroys neurons, resulting in the progressive loss of mental faculties and physical control.

Companies have struggled for years to develop anything better than Lundbeck’s (OTCPK:HLUYY) Xenazine, one of only a handful of Huntington’s drugs on the market in the US. It is approved for the symptomatic treatment of the chorea associated with the disease, but has a poor safety profile and a black box warning of depression and suicide.

Teva’s Austedo is a deuterated version of Xenazine, and is arguably the closest to market of the current crop of Huntington’s therapeutics. It is awaiting approval, but in a complete response letter in May regulators requested examination of blood levels of certain metabolites.

Next in line is Raptor’s (NASDAQ:RPTP) Procysbi, but this failed to meet its primary endpoint in the phase II/III Cyst-HD trial at the end of last year. The company claimed that the results were clinically meaningful enough to warrant a pivotal study, and is looking for funding and partnering options.

Behind these the most advanced asset is Teva’s pridopidine, phase II results on which are expected in the next couple of months (Upcoming events – Testing lirilumab in leukaemia and pridopidine in Huntington’s, July 21, 2016). Pridopidine was previously called Huntexil and owned by Neurosearch, which took it to phase III, but results were not conclusive and the FDA requested a further trial.

In with the new

Despite setbacks novel compounds are finding their way into development. Relatively new to the pipeline is IONIS-HTTRx, an antisense project designed to reduce production of the malformed huntingtin protein.

A phase I/IIa trial of IONIS-HTTRx started in July 2015 and has a primary completion date of March 2017. The dose escalation study has enrolled 36 patients with early-stage disease who will receive the therapy intrathecally as an injection directly into the cerebral spinal fluid.

Ionis says this is the first project designed directly to target the causes of the disease to enter clinical trials. Roche (OTCQX:RHHBY) licensed it back in 2013. An advance here would be encouraging not only for Huntington’s but for antisense technology.

Another new approach is Vaccinex’s VX15/2503. The phase II Signal trial is testing this in 84 patients with late prodromal disease or early Huntington’s, and started in June 2015. An interim analysis is expected in the third quarter with full data in 2018.

VX15/2503 is a first-in-class anti-semaphorin 4D (SEMA4D) antibody. SEMA4D triggers activation of microglia and astrocytes, the innate inflammatory cells of the CNS. Chronic activation of these cells has been implicated as a disease mechanism in Huntington’s, multiple sclerosis and other neurodegenerative disorders.

Selected projects in the late-stage Huntington’s pipeline


Pharmacology class



Phase III


Cystine-depleting agent

Raptor Pharmaceutical

Cyst-HD, NCT02101957


Dopaminergic stabiliser

Teva Pharmaceutical

Price-HD, NCT02006472

Phase II


Phosphodiesterase X inhibitor





Phosphodiesterase X inhibitor




Tau aggregation inhibitor

Prana Biotechnology



Antisense therapeutic

Roche/Ionis Pharmaceuticals







Anti-semaphorin-4D/CD100 MAb


Signal, NCT02481674



Teva Pharmaceutical/Active Biotech

Legato-HD, NCT02215616


V1a receptor antagonist

Azevan Pharmaceuticals


Triheptanoin/Triheptanoin Oil

Metabolic disease agent


Trihep3, NCT02453061


VMAT2 inhibitor

SOM Biotech

Phase II proof of concept study starting Q3

The mid-stage pipeline still contains Pfizer’s (NYSE:PFE) PF-02545920 and Prana’s (NASDAQ:PRAN) PBT2, both featured when EP Vantage last delved into the area two years ago (Glimmers of hope in Huntington's must not be overstated, February 21, 2014).

PF-02545920 is in a 272-patient phase II trial due to end in September, according to A 12-month extension study is also under way. PF-02545920 is a phosphodiesterase X inhibitor, and Pfizer will be hoping that it does not go the same way as Omeros’s OMS824, which is in the same class.

A phase II trial of OMS824 was put on hiatus two years ago owing to an undisclosed safety signal seen in a rat study (Omeros shareholders smell a rat, October 22, 2014). Its development has since resumed in Huntington’s, but with a dosing limitation, and a new phase IIa trial is being designed.

In fact, dosing restrictions have been put in place in a number of Huntington’s trials. In February 2015 Prana's PBT2 was put on partial clinical hold by the FDA, cutting the dose, because of neurotoxicology findings in a dog study.

And the highest dose of Teva’s laquinimod had to be dropped in the Legato-HD trial after cardiovascular events were seen in two separate multiple sclerosis studies. Legato-HD is now testing two lower doses, and has a primary completion of August next year.

A market for the taking

A quick scan of preclinical Huntington’s products shows 15 based on RNA interference, antisense or gene therapy. As these technologies remain largely unproven, it will take some time before their real potential becomes apparent and many will likely fail.

Despite the setbacks the sheer number of projects in early and mid-stage development demonstrates the interest in the area. For now, however, this elusive commercial opportunity remains untapped.

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