‘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.”