Victories in Huntington’s disease few and far between, but resolve remains undimmed

The Huntington's disease (HD) community was cheered by the FDA’s approval last month of Austedo (deutetrabenazine), the deuterated tetrabenazine analogue from Teva Pharmaceutical Industries Ltd., to treat chorea, the involuntary, random and sudden, twisting and/or writhing movements associated with HD. (See BioWorld Today, April 5, 2017.)

The vesicular monoamine transporter 2, or VMAT2, inhibitor was the star asset in Teva's 2015 acquisition of La Jolla, Calif.-based Auspex Pharmaceuticals Inc. for $3.2 billion. The first deuterated product approved by the FDA, Austedo was advanced using the 505(b)(2) pathway, referencing a process in which metabolically sensitive hydrogen atoms are replaced with the non-radioactive isotope deuterium to provide a pharmacokinetic profile that allows for lower doses and, thus, an improved safety profile. (See BioWorld Today, Dec. 18, 2014, and March 31, 2015.)

"It's been an exciting time," Michael Hayden, Teva's president of global R&D and chief scientific officer and a long-time HD researcher, told BioWorld Insight. "Huntington's has been described as one of the most disastrous diseases known to man."

That disaster is transferred from one generation to the next, so far with no options to alter its progression. A safer, more effective therapy for chorea at least helps to tamp down one of HD's first visible signs.

"These patients often are seen as drunk when they walk down the street," Hayden explained. "They're inappropriately arrested. They're embarrassed for their families and their children, and they become quite socially isolated. Chorea represents a very significant symptom."

Austedo's reference drug, tetrabenazine, (Xenazine, H. Lundbeck A/S), is an oral monoamine depleter that, in 2008, became the first compound green-lighted by the FDA specifically to treat HD, also for the manifestations of chorea. (See BioWorld Today, Aug. 18, 2008.)

But the drug came with the risk of serious side effects – notably, sedation, depression and an increased risk of suicide in a condition where suicide is already a risk factor. Because it's metabolized much more slowly, Austedo minimizes those effects. The FDA's initial complete response letter sought additional data on the drug's metabolites, he pointed out, and the highly publicized black box warning on the drug's label was not due to the frequency of depression but solely to the 505(b)(2) pathway and its reference to the parent compound.

"There was never any question on efficacy," Hayden said. "And depression is not increased with deutetrabenazine. It's exactly the same as placebo. In the trial, it was actually 4 percent and placebo was 7 percent. Most of the side effects seen with tetrabenazine are not seen in Austedo."

'There's a momentum right now'

When tetrabenazine was approved, researchers in the field were confident that a cure for HD was just around the corner. The genetic cause had been exposed more than a decade earlier with the discovery that expansion of the cytosine-adenine-guanine, or CAG, triplet repeats in the gene coding for the huntingtin (HTT) protein resulted in an abnormal protein, gradually damaging cells in the brain. Few would have predicted that the next FDA nod would take nearly another decade and essentially result in a next-generation version of the same product.

The HD community has since tempered its expectations but not its optimism. Louise Vetter, president and CEO of the Huntington's Disease Society of America (HDSA), called Austedo's approval "very meaningful" in alleviating some of the most debilitating symptoms of HD and pointed out that the drug's successful development "reinforces the continued clinical interest in solutions for HD. We're particularly heartened that the FDA is continuing to move forward in their commitment to seeking therapies for HD."

Although the pace of therapeutic development has been slow, "there's a momentum right now, which is heartening," Vetter told BioWorld Insight.

The diversity of therapeutic approaches and players – from symptomatic relief to potentially curative gene therapy, small biotech to big pharma – "gives me more confidence in the ability for meaningful solutions to continue to develop for HD families," she said. "HD has proven itself to be a challenging foe, and we need to have a lot of shots on goal."

Certainly, HD is an indication that's been marked by more failure than success. Of approximately 140 trials of HD drug candidates conducted over the years, 80 were completed – 46 of those phase I or II studies – eight terminated and one suspended, with the status of another 20 unreported, according to Cortellis Clinical Trials Intelligence. Only nine completed trials were phase III studies, including those for the two approved products. Three others were part of the 600-patient pivotal program for Amarin Corp. plc's candidate, Miraxion, which was abandoned when it failed to show statistically significant difference compared to placebo. (See BioWorld Today, April 25, 2007.)

Another was the phase III flop of dimebon (latrepirdine), advanced by then-independent Medivation Inc. of San Francisco and then-partner Pfizer Inc., of New York, which missed its primary efficacy endpoints. The asset subsequently fell short in Alzheimer's disease (AD), as well. (See BioWorld Today, April 12, 2011, and Jan. 18, 2012.)

Paris-based Sanofi SA advanced its amyotrophic lateral sclerosis drug, riluzole (Rilutek), into a phase III HD study but also discovered the compound showed no benefit compared to placebo, according to Cortellis.

'A disease that inexorably progresses'

That leaves another Teva asset, pridopidine, still standing among pipeline prospects with a completed phase III in HD. In September 2012, the Jerusalem-based pharma acquired the drug, earlier called Huntexil and ACR-16, from Denmark-based Neurosearch A/S – which had conducted the late-stage trial – for about $26 million. Last year, Teva reported that a phase II trial of the sigma 1 receptor agonist showed a statistically significant impact on HD progression at 52 weeks compared to placebo. (See BioWorld Today, May 25, 2011, and Sept. 20, 2016.)

"Austedo is only our first foray into Huntington's disease," Hayden emphasized. "We recognize that there are 40,000 patients in the U.S., and the biggest issues for patients are symptoms and functional decline. This is a disease that inexorably progresses, and we're exploring other ways to slow functional decline."

He cited laquinimod, another HD candidate in the company's pipeline that was discovered by Active Biotech AB, of Lund, Sweden. In 2004, Teva inked a $92 million partnership for the asset, initially a multiple sclerosis (MS) candidate that advanced to a third pivotal study in 1,800 patients with relapsing-remitting MS. That indication ran into problems last year, however, when 1.2-mg and 1.5-mg doses triggered nonfatal cardiovascular events in eight patients, prompting Teva and Active to shift development in MS to the primary progressive form and to amend the design of a phase II study in HD. (See BioWorld Today, June 16, 2004, April 20, 2011, and Jan. 5, 2016.)

Frustrations have piled up in earlier trials, as well. Pfizer suffered another disappointment in HD with PF-2545920, a phosphodiesterase 10 (PDE10) inhibitor. In December, the company terminated a phase II study of the asset after finding no significant difference when compared with placebo on co-primary endpoints.

Cancellation of that program indirectly affected Omeros Corp., which was advancing OMS-824 (OMS-643762), the lead from a series of PDE10 inhibitors, to treat diseases that affect cognition, especially schizophrenia and Huntington's chorea. But in 2014, the Seattle-based company suspended a phase II dose-escalation study in HD over FDA concerns about higher-than-expected blood levels of the drug in a concurrent rat study. Although the company continued to work with the FDA, it did not resubmit a phase II request to the agency and, in November 2016, said the decision to resume development would be made after Pfizer reported outcomes from its phase II trial of PF-2545920. (See BioWorld Today, Oct. 22, 2014.)

Hayden acknowledged the line-up of failures and their relationship to clinical flops in the larger neurodegenerative space. In fact, HD researchers are borrowing from the lessons learned in other fields. Like AD, they are looking at individuals who carry the HTT mutation but are not yet ill to understand changes that take place early in the disease. Like cancer, they are considering how to design combination drug approaches.

"There's tremendous plasticity in the brain," he said. "It's often the last drop that spills the cup, but there's been a lot of damage on the way, which means exploring not only symptomatic approaches but also addressing the primary and secondary causes.

"This is a tough road," Hayden added. "Our approach is to think about the commonality of pathways. Even though there are different causes to Huntington's, Parkinson's, [amyotrophic lateral sclerosis] and Alzheimer's, when you get beyond the secondary effect there are a lot of shared pathways. We're focusing on pathways that can be neuroprotective and can decrease neuro-inflammation, and we're using Huntington's disease as a model."

'A bellwether event for the HD community'

The HD field is not bereft of other players. Thirty trials are underway, according to Cortellis, mostly under the auspices of academic researchers. And nearly five dozen assets remain at the discovery or preclinical stage at familiar names such as Sangamo Biosciences Inc., Wave Life Sciences Ltd., Benitec Biopharma Ltd. and PTC Therapeutics Inc. as well as with newcomers such as Brainvectis SAS, Capo Therapeutics Inc. and Vybion Inc.

This month, Wave Life priced a $100 million public offering with the goal of moving its first three candidates into the clinic in central nervous system and neurological disorders. Two of them, WVE-120101 and WVE-120102, focus on HD, each designed to target a distinct patient population – together comprising more than two-thirds of Huntington's patients – in an allele-specific approach. Each drug is directed to a different disease-associated single nucleotide polymorphism (SNP) within the HTT gene, with WVE-120101 taking aim at rs362307 (HTT SNP-1) and WVE-120102 targeting rs362331 (HTT SNP-2). (See BioWorld Today, April 13, 2017.)

Both candidates are designed to knock down the mutant HTT allele while sparing the healthy allele – a key distinction from perhaps the most closely watched asset in HD: the antisense oligonucleotide inhibitor, IONIS-HTTRX, which Ionis Pharmaceuticals Inc. is advancing in collaboration with Roche Holding AG, of Basel, Switzerland. Part of a 2013 alliance between the companies to hunt for cures to brain disorders, the candidate moved into a phase I/IIa study in patients with HD in July 2015. The randomized, placebo-controlled, dose-escalation study is evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple ascending doses of IONIS-HTTRX in patients with early stage HD. (See BioWorld Today, April 9, 2013.)

"We're certainly watching the progress of Ionis' trial with great interest, as that is the first gene-modifying approach that's moved into a clinical study," Vetter said. "That's a bellwether event for the HD community."

IONIS-HTTRX works by knocking down both mutant and healthy, or wild-type, HTT. The company also has an antisense approach targeting HTT expression that could lend itself to a more personalized therapy. That program, part of a long-time partnership with Genzyme Corp., a unit of Sanofi, now includes a trio of early stage assets, according to Cortellis. (See BioWorld Today, Jan. 9, 2008.)

Although potentially curative efforts are important, in the meantime individuals with HD need treatments to address characteristics of the disease, from the movement disorders to complex psychiatric and cognitive symptoms.

"HD is a really complicated neurodegenerative disease," Vetter said. "There's a lot of room for therapeutic development on multiple fronts while looking for ways to potentially slow or halt disease prevention."

In that respect, Austedo's approval "is good news for individuals in the sense that it gives their doctors another treatment option," said Robi Blumenstein, president of CHDI Management Inc., which provides administrative, management and contracting services to the privately funded not-for-profit CHDI Foundation Inc. "It's not a revolutionary breakthrough, but it's potentially a good addition to the therapeutic toolkit."

And Austedo isn't likely to be a one-off approval followed by another 10-year drought, Blumenstein said.

"There's been a lot of work on more mechanistic approaches specifically geared to Huntington's disease," he told BioWorld Insight. "Although, unfortunately, it's been 24 years since the gene was discovered, now there are a number of different approaches in or coming toward the clinic. That's quite different from what we saw in the past."

EARLY TRIALS NOT 'GROUNDED IN THE BIOLOGY' OF HD

In addition to the technology from Ionis, of Carlsbad, Calif., Blumenstein cited the zinc finger protein transcription factor, or ZFP-TF, agonist in development by Dublin-based Shire plc and Sangamo, of Richmond, Calif., and an RNAi effort targeting motor neuron diseases underway at Voyager Therapeutics Inc., of Cambridge, Mass., as particularly interesting technologies. For long-time champions of HD research, the breadth of approaches is a welcome sight.

"There's a little bit of the dark side to the discovery of the gene," Blumenstein admitted.

When the cause of HD was discovered, many thought the biggest challenge was solved – an assumption likely made across other orphan indications following similar Eureka moments, he observed. In HD, researchers quickly set about building genetic models and looking for quick fixes, such as existing drugs that could be repurposed or natural products that were thought to have neuroprotective benefits. Those efforts distracted the field from trying to gain a better mechanistic understanding of HD itself: how to connect the HTT protein to the phenotype seen in individuals with the disease.

"Because that didn't take place, a lot of the early drug trials weren't grounded in the biology of Huntington's disease," Blumenstein said, calling early models of the disease "a little bit of a red herring" in the context of how HD played out in humans.

Today, Huntington's is well-described clinically, with documented endpoints that can be used to monitor disease progression. A share of credit for advancing that research belongs to the CHDI Foundation, which has alliances with a global network of biotechs and academic institutions, including past or ongoing collaborations with companies such as Evotec AG, Vertex Pharmaceuticals Inc., Galapagos NV, Galenea Corp., Albany Molecular Research Inc., Shire, Sangamo and Ionis. The organization has been involved in at least eight compounds that have advanced to discovery, preclinical or human trials, according to Cortellis.

CHDI has assembled a management team of more than 50 scientists and professionals, who support a network of some 700 scientists in academic and industrial labs around the world. The organization instituted a set of standardized criteria to evaluate molecular targets, pathogenic mechanisms and therapeutic approaches, and scientists selected as collaborators work closely within its network toward common research and development objectives. In addition to managing internal drug programs and working in partnership with biopharmas, CHDI also directly funds academic and contract research work and works closely with advocacy organizations such as HDSA.

Last year, CHDI joined with the Critical Path Institute (C-Path) to establish a broad-based consortium to define regulatory pathways and expedite the approval of HD therapies. The effort, known as the HD Regulatory Science Consortium, or HD-RSC, emerged from conversations between CHDI staff and C-Path scientists about how to better address the unmet medical need in HD.

"As HD research moved downstream toward the clinic, it became obvious to us that it would be good to define a regulatory pathway for HD, generally, for the benefit of the community," Blumenstein said. "Once the scientific tools were developed, how should we work with regulators to get the tools validated for use by sponsors? The idea was to get this done now so we're not holding up the process when good opportunities arise to test new candidates."

The organization also sponsors Enroll-HD, which began as a global observational study of HD families but evolved into a platform to enable clinical research that now encompasses some 14,000 people.

"We cannot do any of this without the involvement of patients and families," Blumenstein said. "We view them completely as our partners in this effort. One of the things the HD community has demonstrated over the years is the ability to enroll large, high-quality trials. It's never good enough because we'd like to do them faster, but that's certainly not because of a lack of interest on the part of patients."

'We have to support multiple flowers blooming'

Huntington's remains a disease not only with a serious unmet medical need but also one that carries a heavy psychological burden, Hayden pointed out.

"The number of people affected is much more than the patients who are symptomatic," he said. Because so many family members know they are destined to develop the disease, "it's like an iceberg effect of people who are not visible but deeply affected by the illness."

So what does a new approval and the percolation of research mean for the future of HD drug development? Although experts no longer expect a magic bullet, as they might have in years past, small successes are building hope for bigger breakthroughs.

"Different approaches are needed," Hayden said. "There are technical barriers still to be overcome, and it's impossible actually to predict where the precise breakthroughs will come. We have to support multiple flowers blooming. We're committed for the long haul."

"I like to think that we're standing at the doorstep of a new frontier," Vetter said. "That said, we still need to be able to chew gum and walk at the same time, so we'll continue to see the chipping away at symptomatic treatments, and that's important, as well. The next five years are pivotal."

Failures in the field also offer directions for future research, Blumenstein said, singling out Pfizer's PDE10 miss.

"There's a lot of PDE10 biology in Huntington's disease," he observed. "Although that trial was negative, because it was well-designed we're going to learn a lot from it, and there will be more of that over the next five years."

As with any neurodegenerative disease, trials in HD take many years, "and I can't say with certainty that within five years there will be new drugs approved and on the shelf," Blumenstein added. "But at the very least, we will learn a lot more about the human biology that will be really valuable going forward."

"The Year’s New Drugs & Biologics" is an annual two-part feature in Drugs of Today, a journal published by Clarivate Analytics. Part I provides a comprehensive look at the previous year’s new approvals and launches, while Part II offers insight into important news and issues affecting the pharmaceutical industry. Click here to download a free copy of Part I and Part II of "The Year's New Drugs & Biologics" for 2016 now.