‘Inequality is unsustainable’: a view of the quest for Huntington’s disease treatments from the Global South

(I dedicate this article to the worldwide HD community as we mark Huntington’s Disease Awareness Month in many countries around the planet.)

 

Both the COVID-19 pandemic and the quest for treatments for rare and genetic diseases have laid bare deep social divisions across the world, and it behooves the scientific establishment to help resolve this ethical dilemma, says a leading Brazilian Huntington’s disease clinician.

 

“The world should not be divided between those who have money and those who don’t,” Mônica Santoro Haddad, M.D., a neurologist with 33 years’ practice at the Universidade de São Paulo (USP) School of Medicine, told me in an April 30 Zoom interview about the 16th Annual HD Therapeutics Conference. “The pandemic has already shown us that. This inequality is unsustainable.”

 

Dr. Haddad has assisted HD patients from 600 families at the USP neurology clinic and her private office. A participant in the 2013 Therapeutics Conference in Venice, Italy, and 2014 meeting in Palm Springs, CA, she watched all of this year’s three-day virtual event (April 27-29) online. The conferences are sponsored by CHDI Foundation, Inc.

 

“What we’re witnessing in Brazil [regarding the pandemic] is immoral – Brazil in relationship to the world and Brazil in general,” Dr. Haddad observed, speaking in her native Portuguese. “Two categories of people have been created: those with the vaccine, those without the vaccine.”

 

A South American giant struggles

 

Sadly, Brazil ranks second in the world behind the United States with more than 428,000 COVID-19 deaths.

 

As a history professor, I have dedicated much of my career to the study of Brazil, a country that I consider my second  home; my wife is Brazilian, and her extended family is there. Along the way, I have witnessed the development of the Associação Brasil Huntington and built ties to its leaders.

 

A major country of the Global South – the world’s developing countries – Brazil has an estimated 20,000-plus afflicted individuals and an active HD movement. An enthusiastic group of some 30 Brazilians took part in #HDdennomore, Pope Francis’ special audience with the HD in May 2017. Francis, a native of Argentina, is also the first pontiff from the Global South.

 

However, although Brazil’s medical system has gained international recognition for past vaccine campaigns and its model fight against AIDS, during the pandemic the country has lacked hospital beds, cemetery plots, and basic supplies. Like Donald Trump, Brazilian President Jair Bolsonaro denied the crisis, downplayed the dangers, and actively denounced such measures as mask-wearing.

 

In addition, Brazil has fallen victim to the international inequities in the rollout of vaccines. Both U.S. President Joe Biden and former Brazilian president Luiz Inácio Lula da Silva – a likely candidate in the 2022 presidential election – have backed waiving COVID-19 vaccine patents to assure global access.

 

Brazil’s deep internal disparities have led to inadequate vaccine distribution to the poor and marginalized.

 

Recognizing similar, longstanding neglect in other South American countries, the humanitarian organization Factor-H has continued to assist abandoned HD families during the crisis.

 

Providing everybody access to medicines

 

Echoing her concerns about COVID-19, Dr. Haddad affirmed the need for a “change in the paradigm” regarding rare and genetic diseases like Huntington’s.

 

As in the U.S. and elsewhere, fear and denial frequently underlie Brazilians’ decisions to avoid genetic testing and facing the terrible medical and social challenges posed by the disease. Many Brazilians have “prejudice against disease” in general, Dr. Haddad told me in a 2013 interview.

 

However, the trend against testing might be shifting for the younger generations, and could also change among older groups when the overall outlook for treatments has improved, Dr. Haddad wrote in a May 14 WhatsApp message. Clinical trials seeking presymptomatic HD gene carriers will require testing, she added.

 

Like medical professionals in many countries, Dr. Haddad believes genetic testing is a personal decision, with the procedure governed by established protocol and with professional medical and psychological support.

 

As of April 2021, the Brazilian government has required all private health plans and insurance to cover genetic testing. This represented a “small advance,” Dr. Haddad asserted in our Zoom interview, because health advocates want to see the country’s free public health service also provide that benefit.

 

For Dr. Haddad, for HD to be defeated, inequality must diminish.

 

“The question is: is it ethical to diagnose someone with one of those diseases and not have a treatment available?” Dr. Haddad said. “This is a question that I discuss with my patients and with my colleagues.”

 

She added: “It is certainly not ethical to have a treatment that not everybody has access to.”

 

The HD Therapeutics Conference left her with her “hope battery recharged” and confident that a treatment is possible, Dr. Haddad said.

 

 

Gene Veritas interviewing Dr. Mônica Haddad (screenshot by Gene Veritas, aka Kenneth P. Serbin)

 

Advocating for open science

 

At the close of the conference, Dr. Haddad was inspired by the presentation by featured speaker Aled Edwards, Ph.D., who in 2004 founded the Structural Genomix Consortium (SGC), which practices and advocates for open sharing of scientific information, particularly as it applies to protein science, chemical biology, and drug discovery.

 

Dr. Edwards, the SGC CEO and a scientist based at the University of Toronto, spoke on “HD drug discovery in the public domain – a model for CHDI.” A breath of “fresh air,” Dr. Edwards’ talk pointed the way to reducing inequality, Dr. Haddad told me.

 

“What we would also like to do is develop a drug discovery ecosystem that prioritizes affordability and global access, and, of course, to do this in collaboration with industry,” Dr. Edwards stated. “Now this might sound naïve, but I’d like to emphasize there’s quite a bit of drug discovery experience in the SGC and in our network.”

 

Dr. Edwards presented examples of researchers who have followed the open science model – including 16 “HD open science programs” that share science “as they go,” with some even blogging about their findings. He highlighted the work of Rachel Harding, Ph.D., an SGC researcher and postdoctoral fellow at the University of Toronto who achieved the “very challenging” task of purifying the huntingtin protein to a “resolution that is practically useful” to other scientists.

 

Dr. Harding has widely shared both the protein and reagents (compounds that facilitate chemical reactions) that enable the making of the protein, ultimately aiming to inform the discovery of potential HD drugs, in particular so-called small-molecule drugs, Dr. Edwards explained.

 

Discussed at the Therapeutics Conference, these drugs become distributed very evenly across the whole body, including the brain, whereas several drugs in other current or recently completed clinical trials need to be injected directly into the brain or via spinal tap.

 

“This is a really fantastic contribution to the public good that these folks have made,” Dr. Edwards said of Dr. Harding’s team.

 

Sharing science as they go: Huntington's disease "open science champs" as presented by Dr. Aled Edwards, at upper right (screenshot by Gene Veritas)

 

Seeking more efficient drug discovery

 

Dr. Edwards underscored a key point: despite spending $300 billion globally each year on research and development and producing many hugely successful drugs, the biomedical field is highly inefficient. “We need to do better as a society,” he asserted.

 

“For many diseases – Huntington’s, Parkinson’s, Alzheimer’s – we don’t even know the molecular mechanism of the disease, let alone how to design a therapeutic strategy,” Dr. Edwards said, adding that a system in which the “first past the post gets the money” in designing drugs has required “the pricing of medicines at levels that are unaffordable for most people on the planet.”

 

Dr. Edwards displayed data demonstrating how globally most research focuses on the familiar rather than explore new, potentially crucial areas of biology. Similarly, in industry, companies pursue drugs in parallel rather than collaborate, wasting valuable resources, he added.

 

SGC is working against the grain, trying to create the way for a new scientific culture. The SGC never files for patents “as a core principle,” Dr. Edwards explained. “All of the work we do goes into the public domain, including the reagents that we make.”

 

If labs and companies openly shared data before doing the final crucial test on a potential drug in a Phase 3 trial, the field could not only save money, but test multiple drugs at the same time, he said.

 

Rather than rely on patents, the system should take advantage of federal laws that give companies protection from competition for a fixed period, generally five to twelve years, Dr. Edwards affirmed. The law provides even longer periods for orphan and pediatric drugs.

 

Supporting the public good

 

“There is no law of physics that says industry has to invent a drug,” Dr. Edwards said. “That’s the social system that we’ve put in place. Let’s imagine a different system.”

 

To “walk the walk about open drug discovery,” SGC established the Agora Open Science Trust, a registered charity in Canada modeled on Newman’s Own Foundation, which funnels profits from food products with the picture of the late Academy-Award-Winning actor into philanthropy.

 

Dr. Edwards described its goal: “To support open science and the public good, and price new medicines to ensure global access. Whether you’re a rich American or live in Thailand, you’re going to get the medicine at a price you can afford.”

 

In its first project, Agora has focused on children’s cancers. As of yet the trust has not announced a plan for an HD drug program, although Dr. Edwards and the above-mentioned HD open science researchers have an abiding interest in finding treatments.

 

Indeed, regarding those treatments, Dr. Edwards concluded that “if we do it as a collective, we’ll get further faster.”

 

 

Dr. Aled Edwards explains the creation of for-profit drug companies to fund the Agora Open Science Trust, whose mission is to ensure global, affordable access to new medicines (screenshot by Gene Veritas).

 

Knowledge belongs to the world

 

If Dr. Edwards and SGC achieve their goals, they will have a place in history, Dr. Haddad observed. The emphasis on sharing data will “democratize” knowledge, she added.

 

“It’s obvious that a company does things to earn money,” Dr. Haddad continued. She noted, however, that Dr. Edwards is asking scientists and others to put their vanity aside to help the suffering.

 

Brazil has not yet hosted, and may not host in the future, any sites for the major HD clinical trials, Dr. Haddad pointed out. She noted that the local HD community attempted to bring to Brazil the historic Phase 3 gene silencing clinical trial by Roche, which reported the unfavorable results at the HD Therapeutics Conference. In South America, Roche ran the trial in Argentina and Chile.

 

“We did the paperwork to try to include a Brazilian research center, and because of questions raised by an ethics committee and political and legal issues, we were unsuccessful,” Dr. Haddad explained. “Brazil did not permit genetic material [from the clinical trial] to be sent out of the country.”

 

For now, Dr. Haddad said, Brazilians can at least look forward to the possibility of their government’s authorization of the drug Austedo, approved by the U.S. Food and Drug Administration in 2017 for chorea, the involuntary movements that occur in many HD-affected individuals.

 

At this time, Brazil’s lack of participation in clinical trials of drugs that aim to slow or stop the disease is “not important,” Dr. Haddad concluded. Echoing Dr. Edwards – and the hope of thousands of Brazilian HD families anxiously awaiting the arrival of effective treatments but fearful that the country might not be able to afford them – she added: “The knowledge obtained belongs to the world.”

‘The first at-bat is never a grand slam’: how Huntington’s disease drug research has matured with the Roche and Wave setbacks

Despite the disappointing clinical trial results reported last week by Roche and Wave Life Sciences, Huntington’s disease drug researchers see an upside: they are using the data collected to achieve new insights, offering renewed hope of effective treatments.

 

The news of these setbacks produced one of the most heartbreaking moments of the last several decades for the HD community and researchers.

 

“That kind of news, I hope it’s okay to say: it sucks!” said Robert Pacifici, Ph.D., the chief scientific officer for CHDI Foundation, Inc., of the Roche and Wave trial data. “All of us who hold out so much hope and recognize that there are so many families who so desperately are waiting for much needed relief and therapies – it knocks the wind out of you.”

 

The companies made their first formal scientific presentations of their data at the start of the CHDI-sponsored 16th Annual HD Therapeutics Conference, held virtually from April 27-29. A nonprofit virtual biotech, CHDI focuses solely on developing Huntington’s therapies.

 

Roche confirmed that its drug tominersen failed to alleviate symptoms in its Phase 3 clinical trial; patients receiving the highest of two possible doses may have done even slightly worse than those on placebo. Two early-stage Wave trials failed to meet the goal of reducing the amount of mutant huntingtin protein in the trial participants – an objective already achieved by Roche in an earlier tominersen trial. (Click here to read more.)

 

Dr. Pacifici offered his assessment of the Roche and Wave data and the state of HD drug research in a wide-ranging, 46-minute Zoom interview with me after the close of the event.

 

Dr. Robert Pacifici moderates panel discussion of huntingtin-lowering clinical trial results with Dr. Vissia Viglietta of Wave Life Sciences and Dr. Scott Schobel of Roche (screenshot by Gene Veritas, aka Kenneth P. Serbin)

 

Gaining perspective

 

“My reaction though, now that I’ve come back down to earth, is really not one of surprise,” Dr. Pacifici said. “Drug discovery, as we’ve discussed many times, is a really tough business. The probability of success on any given endeavor is incredibly low.”

 

Dr. Pacifici used a baseball metaphor to explain: “How often does the first batter get up to the plate and hit a grand slam home run? A grand slam, never, because you need to load up the bases with three people. Even a home run is incredibly rare.”

 

The “name of the game” in discovering effective treatments is to carry out as many trials as necessary, “doing it well, failing, but making it a good failure that we can learn from so that subsequent efforts have a much higher chance of success,” Dr. Pacifici explained. “And we continue to snowball and build on that so that we can learn the things to do better, the things that we can do differently, or the things that we should stop doing altogether because we now have confirmed that those are not viable lines of investigation.”

 

The accumulation of experience through research and clinical trials, including the crucial participation of patient volunteers, has produced “an incredibly positive thing,” Dr. Pacifici observed.

 

“Look at how the field has matured,” he said. In the past, scientists would have kept a trial running for three years, waiting for patient improvement, only to discover that “the drug really didn’t even have a chance of working” because it hadn’t done what it was “tasked with doing, which is lowering huntingtin levels.”

 

Now the process is moving “faster” and is “better informed,” Dr. Pacifici said.

 

Watch the entirety of my interview with Dr. Pacifici in the video below.

 

Huntington's disease drug research now a 'mature field' from Gene Veritas on Vimeo.

 

Huntingtin lowering still in the running

 

Dr. Pacifici commented on the critical topic of lowering (reducing) the mutant huntingtin protein, the first strategy aimed at HD’s genetic cause. Scientists believe that the mutant protein is a main driver of the disease. In mouse studies, lowering that protein led to a disappearance of symptoms, and, beginning with the Roche trial, researchers have sought to achieve similar results in humans. Thus, until now, lowering mutant huntingtin has been seen as the potentially most promising path to a treatment.

 

Both Roche and Wave used a type of drug known as an antisense oligonucleotide (ASO), an artificial strand of DNA. Other firms and labs are also investigating ASOs.

 

“When two of those things don’t move forward simultaneously, it’s perfectly reasonable to ask the question, ‘Well, is this one of those times where we’ve learned that this approach is not going to work?’” Dr. Pacifici asked. “I can say unequivocally that that’s not yet the case. There are just too many things that factor into how a drug needs to do its job that remain unanswered.”

 

He said that possible key factors affecting the outcomes of the Roche and Wave trials include the stage of disease of the participants, the concentration of the drug tested, and the proper distribution of the drug within the brain. The particular characteristics of the drugs selected could have also impacted the outcome, he added.

 

Another possible explanation involves the design of the trials, the techniques for measuring patient response, and biomarkers (signs of disease and a drug’s effects).

 

In addition, even though Roche’s tominersen reduced the level of mutant huntingtin protein in trial volunteers’ cerebrospinal fluid, researchers still do not know whether the samples of protein actually came from the brain and, if so, cells relevant to HD, Dr. Pacifici cautioned. Scientists also lack other critical details about those samples; for example, they could be fragments, he said.

 

Crucially, the “interim analysis” of the Roche data at the Therapeutics conference did not demonstrate whether lowering huntingtin can help people feel, function, or survive better, Dr. Pacifici observed.

 

Even a “whisper of efficacy” would have validated the huntingtin-lowering approach and “prepared the path for subsequent trials with gusto and confidence,” he continued, adding, however, that “the opposite is not true. We still have great hopes that this is a viable mechanism of action.”

 

Wave plans to start a trial of a third ASO later this year. Roche has also stated that it will continue to explore drugs for HD.

 

Exploring other avenues

 

Because the effectiveness of huntingtin-lowering remains an open question for the field, Dr. Pacifici renewed his call to redouble and diversify drug-hunting efforts.

 

Dr. Pacifici noted that other potential huntingtin-lowering approaches are in the works using non-ASO compounds, while others propose different methods of delivery, including a pill. In the Roche and Wave trials, participants received the drug via spinal tap.

 

“If we were in a fantasy world of the 20th new treatment for Huntington’s coming, you would worry about things like convenience: ‘I’d like to have a pill instead of an injection,’” Dr. Pacifici said. “‘I’d like to have a pill I can take once a day. I’d like to have a small pill that’s easy to swallow.’”

 

However, Dr. Pacifici observed, “we’re not at that stage yet.” Even so, “very critical advantages” exist in exploring different modes of delivery, he said.

 

Indeed, another possibility emerged at the conference. A scientist from pharmaceutical giant Novartis presented research on its drug branaplam, a pill used to treat spinal muscular atrophy (SMA), which causes severe muscle weakness in children. Novartis researchers discovered that Branaplam also reduced the amount of the huntingtin protein in a study of SMA patients. Novartis plans a trial of branaplam in HD patients, with details expected in the coming weeks and over the summer (click here to read more).

 

Like other so-called small-molecule drugs, branaplam becomes distributed very evenly across the whole body, including the brain, whereas a drug like an ASO tends to concentrate where it is administered, Dr. Pacifici explained. He added that small-molecule drugs can be dosed “creatively” – for example, weekly instead of daily – to maximize the “beneficial effect” and allow the person a rest from the drug.

 

(I will explore the quest to develop this type of HD drug in a future article.)

 

Dr. Rajeev Sivasankaran of Novartis presents data demonstrating the effect of the drug branaplam on huntingtin RNA in a study of spinal muscular atrophy patients (screenshot by Gene Veritas).

 

Sharing knowledge rises all boats

 

Dr. Pacifici emphasized that success in the fight against HD ultimately depends on the sharing of scientific information – even negative research results that private companies are loathe to reveal to protect their egos and their stock prices.

 

He cited the presentation by featured speaker Aled Edwards, Ph.D., the founder and CEO of the Structural Genomix Consortium, which practices and advocates for open sharing of scientific information, particularly as it applies to protein science, chemical biology and drug discovery. Dr. Edwards spoke on “HD drug discovery in the public domain – a model for CHDI.”

 

“I think the HD field will benefit by everybody realizing how difficult this problem is,” Dr. Pacifici concluded. “It’s not giving up a competitive advantage by being transparent about what happened. It’s sharing data. That knowledge rises all boats. Everybody needs to know about these things.”

 

Sharing of data and other knowledge has also been one of CHDI’s trademarks as a nonprofit. Dr. Pacifici pointed to specifics: knowledge about the disease, potential treatments, biomarkers, and clinical outcome measures (the techniques for measuring patient response).

 

With such sharing, he asserted, everybody will have an increased chance of success.

 

Refusing to do so will “doom us to the same failure we see in other neurodegenerative fields that have outspent us and been at this a lot longer than we have.” 

Roche confirms tominersen as ineffective, while Triplet provides key details for trial of drug to slow major driver of Huntington’s disease

 

Following up on news that it had halted dosing, Roche has confirmed that its historic GENERATION HD1 clinical trial, aimed at the genetic causes of Huntington’s disease, failed to improve symptoms in study participants.

The disappointing trial outcome for the drug candidate tominersen was revealed on April 27 by Scott Schobel, M.D., M.Sc., Roche’s medical leader of GENERATION HD1, at the virtual 16th Annual HD Therapeutics Conference, sponsored by CHDI Foundation, Inc., the nonprofit virtual biotech focused solely on developing HD treatments and a collaborator in the effort.

 

More than 1,000 people registered for this greatly anticipated meeting.

 

“Nobody wanted this result,” Dr. Schobel said in his online talk, the first scientific presentation describing why an independent review committee had recommended, and Roche accepted, that GENERATION HD1 be halted. “This is a setback, and it’s a setback which is emotional. It’s a setback which we all feel, because, after being able to lower the huntingtin protein for the first time, there’s a lot of hope in that.”

 

An opportunity to learn

 

Dr. Schobel displayed a series of slides demonstrating tominersen’s lack of effect on trial volunteers, who showed “progressive decline,” reflected in key measures of cognition and control of bodily movements. Observations by physicians also showed “increasing severity” of disease in the participants, Dr. Schobel said.

 

Still, he said the researchers established a “new setpoint for the field”: reducing the level of the mutant protein in the early-stage tominersen clinical trial.

 

That achievement was a historic first, and many HD scientists still believe that this strategy can lead to an improvement in symptoms. However, it now remains for potential future trials to demonstrate that huntingtin-lowering can actually help patients.

 

Roche is “compelled” to use the trial results “as an opportunity to learn,” Dr. Schobel said. The company still has a “wealth of data” to analyze regarding tominersen and its implications for the huntingtin-lowering approach. The firm will share results with the HD community.

 

The Huntington's Disease Society of America will hold a webinar at noon Eastern time on April 29 with an update for the community on the Roche results. (Click here to register.)

 

 

Dr. Scott Schobel of Roche displays slide demonstrating decline in volunteers' condition in the GENERATION HD1 clinical trial at the 16th Annual HD Therapeutics Conference (screenshot by Gene Veritas, aka Kenneth P. Serbin)

 

Drug candidate’s target chosen

 

On this first day of the three-day conference, Irina Antonijevic, M.D., Ph.D., the chief medical officer at Triplet Therapeutics, Inc., revealed key details of the firm’s drug program to develop a genetic strategy that contrasts sharply with the idea of lowering the huntingtin protein. The firm also issued a press release.

 

Dr. Antonijevic focused on Triplet’s efforts to slow or stop a key driver of HD, somatic expansion, the mutant huntingtin gene’s tendency for continued expansion with age.

 

Triplet’s research exploits continuing breakthroughs in HD genetics, also the topic of this year’s Therapeutics Conference. Those advances have revealed that so-called modifier genes linked to the speeding or slowing of somatic expansion can hasten or delay the age of HD onset by just a few years or by as many as 40.

 

Triplet scientists and others believe that the longer that expansion, the more toxic the gene and its product, the huntingtin protein, become.

 

Building on these developments, in 2020 Triplet announced its drug candidate TTX-3360, aimed at slowing or stopping somatic expansion.

 

In her conference presentation, Dr. Antonijevic announced that the specific biochemical target of TTX-3360 is the modifier gene MSH3, involved in the maintenance and repair of DNA.

 

In studies of mice, Triplet has demonstrated safe and effective lowering of MSH3 using TTX-3360. Additional safety studies were done in nonhuman primates.

 

Injection directly into the brain

 

Like the Roche drug, TTX-3360 is an antisense oligonucleotide (ASO), a synthetic modified single strand of DNA. Both the early-stage trial of tominersen and GENERATION HD1 delivered ASOs via spinal tap.

 

However, Dr. Antonijevic announced that TTX-3360 will be introduced into the brain using an intracerebroventricular (ICV) injection. The ICV device is a small reservoir implanted at the top of the head with a catheter going into the brain. ICVs have been used in medical treatments since the 1960s, including injection of anti-cancer drugs.

 

Dr. Antonijevic explained that, in contrast with the spinal tap – whereby an ASO had to travel along the spine before entering the brain – the ICV will permit Triplet to get its drug deeper into the brain, including areas severely affected by HD.

 

With spinal taps, patients can experience pain and inflammation during dosing because of scarring that results from repeated dosing, Dr. Antonijevic asserted. The ICV permits easy withdrawal of cerebrospinal fluid (which bathes the brain) for monitoring of drug safety and efficacy, she added.

 

The ICV also allows for rapid dosing – perhaps even at home – whereas the spinal tap requires a visit to a doctor’s office, Dr. Antonijevic pointed out.

 

(According to one scientific article, an ICV can remain in place for life. However, long-term usage is not well understood. The device should be monitored for leakage or failure. If necessary, the device can be removed or replaced.)

 

At the HD Therapeutics Conference, Dr. Irina Antonijevic of Triplet Therapeutics discusses a slide comparing two methods of drug delivery: spinal taps (intrathecal injections) and intracerebroventricular injection (screenshot by Gene Veritas)

 

Triplet aims to file an investigational new drug application with the U.S. Food and Drug administration (and/or a clinical trial application in Europe or Canada) by year’s end for a Phase 1/2a study of TTX-3360, which will address primarily the safety and tolerability of the compound. Triplet will recruit presymptomatic and early symptomatic individuals for the trial.

 

Triplet also announced a pledge of one percent of its equity to a “patient support fund,” to be managed independently, to support patients suffering from HD and other, similar disorders, known as repeat expansion disorders. The fund will help patients and families secure access to care and therapies.

 

(For background on the Triplet clinical trial program, click here. Stay tuned to this blog here for further coverage of the conference.)

 

(For additional coverage of the conference, click here).

With PROOF-HD in the lead, the Huntington’s disease drug pipeline is still ‘full of hope’ (Coping with disappointing clinical trial results – Part II)

 

Despite the recent disappointing news about two fundamental programs seeking Huntington’s disease treatments, significant drug-discovery initiatives proceed steadily. They include two major clinical trials: KINECT-HD, sponsored by Neurocrine Biosciences, and PROOF-HD, backed by Prilenia Therapeutics.

 

As reported in Part I of this two-part series and a previous article, Roche announced that it had halted dosing in its historic Phase 3 gene silencing clinical trial, followed by Wave Life Sciences’ revelation that a similar effort to reduce the level of mutant huntingtin protein had fallen short.

 

In all likelihood, these drug candidates – at least the current version of them – will not become HD treatments.

 

However, other candidates abound.

“Our pipeline is full of hope,” said George Yohrling, Ph.D., the chief scientific officer for the Huntington’s Disease Society of America (HDSA), in a March 25 webinar held to address the devastating clinical trial news. “Our pipeline is deep and diverse.”

 

The HD research community “has not put all their eggs” in the Roche “basket,” Dr. Yohrling explained. “We know what causes the disease, and it’s the expansion of the huntingtin gene and the expression of this mutant protein. There is a wide array of approaches that we are using to tackle that. We’re hopeful that one or many of them will prove efficacious and modify the course of the disease.”

 

Advancing programs

 

Although two Wave drug compounds failed in early-stage trials, the company plans to start a trial of a third compound later this year.

 

Both Roche and Wave are scheduled to make the first scientific presentations about their recent results this week at the greatly anticipated 16th Annual HD Therapeutics Conference, April 27-29, a virtual event because of the COVID-19 pandemic. The research community is confident that a deep analysis of these studies will guide its next steps in the quest for therapies.

 

Researchers and companies are investigating dozens of distinct designs for the type of drug used by Roche and Wave, an antisense oligonucleotide (ASO).

 

Using surgery to inject its drug directly into the brain, Uniqure has started the first-ever HD gene therapy safety trial in a small number of trial participants.

 

Triplet Therapeutics aims to start a Phase 1 clinical trial in the second half of this year of a unique ASO targeted at stopping the mutant huntingtin gene’s tendency for continued expansion with age (click here  to read more).

 

Genetic modification is not the only approach under study, however. Several other firms have Phase 2 programs in the works to treat symptoms and reduce disability due to HD, and Neurocrine expects to complete KINECT-HD – its Phase 3 trial of a chorea-reducing drug called valbenazine – by year’s end. Chorea is the involuntary movements that afflict many people with HD. (On KINECT-HD, also click here.)

 

Two similar drugs for chorea – Xenazine and Austedo – are the only HD drugs approved by the U.S. Food and Drug Administration (FDA). They do not stop progression of the disease.

 

A big goal: helping HD people function normally

 

A second major study, called PROOF-HD, is currently underway, led by the Huntington Study Group (HSG), and sponsored by Prilenia. This is a Phase 3 trial (the final step before a drug can be approved by the FDA) of a drug called pridopidine, which is proposed to improve function in people in the early stages of HD.

 

PROOF-HD stands for “PRidopidine Outcome On Function In Huntington Disease.”

 

The clinical trial investigators believe that, if tested successfully, pridopidine would help early-stage HD-afflicted individuals maintain the ability to function normally in five key areas: occupation/employment, managing personal finances, performing household chores, performing activities of daily life (such as bathing and dressing), and the ability to live in a home environment. These five domains comprise the Shoulson-Fahn Total Functional Capacity Scale (TFC), developed almost 40 years ago, and used daily in HD clinics and research studies since then.

 

“The bigger the effect, the better,” Prilenia CEO Michael Hayden, M.D., Ph.D., said in an April 1 interview about pridopidine with Evaluate Vantage. “But any significant change in TFC would be regarded as meaningful. There’s never been a drug that has had any impact on TFC.”

 

Dr. Hayden is one of the world’s foremost HD scientists (click here to watch our 2011 interview at the Therapeutics Conference.) Prior to founding Prilenia in 2018, Dr. Hayden served as the president of global R&D and chief scientific officer at Teva Pharmaceutical Industries, Ltd. from 2012-2017, where he oversaw ongoing research on pridopidine. He is also a professor at the University of British Columbia and a senior scientist at the Centre for Molecular Medicine and Therapeutics, having mentored over 100 graduate students.

 

In a January 28 HDSA webinar, Sandra Kostyk, M.D., Ph.D., a professor Ohio State University and the co-principal investigator for PROOF-HD in the U.S., pointed out that individuals’ Total Functional Capacity ranges from zero (severely reduced function) to 13 (full function). In early and mid-early HD, people on average lose about one point on the scale a year, she explained.

 

In later stages of the disease, TFC may be less reflective of the rate of decline, Dr. Kostyk continued.

 

A slide from the January 2021 HDSA webinar on the PROOF-HD trial illustrating the Total Functional Capacity Scale and the effect of  pridopidine (screenshot by Gene Veritas, aka Kenneth P. Serbin)

 

Stopping the house from burning down

 

As an HD gene carrier who saw his mother devastated by the disease, I have most feared losing my ability to function normally.

 

In three previous clinical trials of pridopidine, carried out between 2008 and 2018, both the original developer of the drug and Teva failed to achieve the goal of reducing HD persons’ difficulties with both voluntary and involuntary movements. At that time, scientists thought that pridopidine affected levels of dopamine, an important chemical in the brain affecting movements in both HD and Parkinson’s disease.

 

However, additional analysis (done after the trials) showed that patients taking the study drug showed a slower decline in TFC than expected from previous studies. “In early patients with Huntington disease we have shown that the functional capacity may be maintained,” Dr. Hayden observed in a January HSG podcast. “There also appears to be an improvement and less deterioration in patients with early HD.”

 

Referring to research conclusions published in the Journal of Huntington’s Disease last December and co-authored by Dr. Hayden and five others, he asserted that the stabilized TFC results were the “first time that this has ever been shown in any analysis for any drug. This was exciting.” Significantly, the FDA accepts TFC as a way of measuring drug efficacy in HD clinical trials, he added.

Those observations now require confirmation in PROOF-HD, Dr. Hayden said.

 

Also, he continued, pridopidine “appears to have beneficial effects around protecting neurons,” whatever the injury might be. The goal, he said, is to prevent these brain cells from dying – one of the major symptoms of HD.

 

“You want to treat them before they've died,” he explained. “If you're trying to stop a fire taking care of a house, you don't want the house to be burned down. And that's why treating early becomes effective because there are still injured neurons, but not dead neurons.”

 

In the HDSA webinar, Dr. Kostyk referred to pridopidine as a possible “disease-modifying intervention – something that slows the course of the disease.” The data indicate that early-stage HD patients could obtain “long-term beneficial effects” from an approved pridopidine drug for five years or more, she said.

 

That could buy valuable time for older asymptomatic individuals like me and the HD community in general as we await other gene-modifying or huntingtin-lowering drugs.

 

Prilenia: seeking to soothe the impact of disease

 

Dr. Hayden explained the name and goals of Prilenia: “Prilenia, which comes from pri, as in pridopidine, and lenia, which comes from the Greek, to sooth or to cure. It's an aspiration that we can have some impact on soothing some aspects of this disease and potentially others as well.”

 

Privately held and based in Israel and the Netherlands, in 2020 Prilenia raised $68.5 million to support PROOF-HD and also a Phase 2/3 trial in sufferers of amytrophic lateral sclerosis (ALS).

 

The ALS trial is currently enrolling participants at 54 sites across the US.

 

Pridopidine taken as a pill

 

For HD sufferers, Pridopidine has another major advantage: whereas ASOs so far have been injected into the spine and Uniqure’s drug has been infused via brain surgery, pridopidine in the PROOF-HD trial is very conveniently dosed in a 45-milligram pill – a hard gelatin capsule – taken twice daily (click here for official details of the trial). 

 

Pridopidine has been extensively studied in several previous clinical trials over more than a decade, with more than 1,300 people taking the drug, most of them with Huntington’s, Dr. Kostyk said. As a result, researchers have high confidence in its safety, she added.

 

Other HD research projects and biopharmaceutical firms are seeking so-called small molecule drugs that can enter cells easily and be taken as a pill.

 

A key receptor in the brain

 

Dr. Hayden and his colleagues now believe that the benefits of pridopine are due to its ability to activate the sigma-1 receptor (S1R). “It’s highly selective and fairly potent,” Dr. Hayden explained about the action of pridopidine on S1R in response to a question that I posed about the drug’s basic mechanism during his presentation at the 27th Annual HSG Meeting (held online) in October 2020.

 

Dr. Hayden observed further that ample data demonstrates that activation of S1R leads to protection of neurons. Deficiencies in S1Rs leads to disease. He cited the case of patients lacking the S1R gene, resulting in juvenile onset ALS.

 

“The activation of the sigma-1 receptor has multiple mechanisms of action that should lead to neuroprotection in HD and help stabilize cell function,” stated Dr. Kostyk, noting that S1Rs are plentiful in the striatum – the inner core of the brain where HD is especially devastating – and in the cortex, the large outer area of the brain in charge of thought, language, and consciousness.

 

“One could think of the role of S1R as being like that of a high school guidance counselor,” Martha Nance, M.D., director of the HDSA Center of Excellence at Hennepin HealthCare in Minneapolis, MN, wrote me in an e-mail. “When the receptor is turned on, materials, molecules, and traffic within the cell flow as it should, and the cell stays healthy, much as the counselor helps students in trouble to be safe, find resources to keep healthy, and stay in school. Supporting S1R early in the course of HD might help more brain cells to remain healthy and function well for longer.”

 

A relatively easy trial seeking practical results

 

Initiated last October, PROOF-HD investigators hope to enroll a total of 480 clinical trial volunteers by year’s end at 30 sites in the U.S. and Canada and 30 more in Europe. Over 15 months, half will get pridopidine, and half will get a placebo. Patients must have a diagnosis of HD, be 25 or older (no upper age limit), and have a TFC score of at least 7, in line with the project’s goal of testing the drug in the earlier stages of the disease.

 

Participants will undergo measurements of their TFC, cognition, quality of life, and motor symptoms (difficulties with voluntary and involuntary movements). They will also get blood and safety tests. All participants can take part in the potential extension of the trial, with everybody receiving the drug. Dr. Kostyk described PROOF-HD as an “easy” trial, with no brain scans or spinal taps (used in the Roche trial, for instance). The study design has been adapted to accommodate the challenges posed by COVID-19.

 

PROOF-HD emphasizes practical results. “What’s most important for us it to get an agent out that’s working,” Dr. Kostyk said, and “not necessarily” the kinds of measurements used in other trials in order to demonstrate how the drug works.

 

A separate trial might be designed later for later-stage HD-afflicted individuals, Dr. Hayden said.

 

For more information on PROOF-HD, click here or call 800-487-7671.

 

A potential major step forward

 

“Our overall goal is to get this agent FDA-approved as soon as possible so that we can start using it in individuals affected by Huntington’s disease,” said Dr. Kostyk. The more quickly patients enroll in the study, the sooner it will be completed, hopefully by late 2022 or early 2023.  Because this is a Phase 3 trial, if it is successful, the next step will be an application to the FDA for approval as a drug that doctors can prescribe.

 

Andrew Feigin, M.D., the HSG chair and principal investigator in the U.S. for PROOF-HD, said in the HDSA webinar that Prilenia has also shown interest in a possible future trial involving pre-symptomatic individuals like me.

 

Past skepticism about pridopidine focused on the lack of hard evidence that the drug could really slow HD progression (click here to read more). However, that debate came before the discovery of a clearer picture of pridopidine as a potential protector of neurons.

 

As will all clinical trials, the Huntington's community will be rooting for success in PROOF-HD. Although pridopidine may not cure HD, enabling people to have a few more years of normal daily function would be a major step in the quest to manage this complex disease.