After abrupt shutdown of Triplet Therapeutics, Huntington’s disease community regroups in the fight for therapies

 

Triplet Therapeutics, Inc., a Cambridge, MA-based start-up that aimed to transform the treatment of Huntington’s disease and related disorders, has shut down, citing a lack of new investment partners and the discovery that its proposed HD drug caused adverse effects in animal tests.

 

On October 11, Triplet CEO Nessan Bermingham announced the company’s closure on his LinkedIn page. The abrupt closure was another piece of tough news regarding potential therapies for HD.

 

In March 2021, Roche and Wave reported negative trial results for drugs aimed at reducing the toxic mutant huntingtin protein in patients’ brains. These drugs are antisense oligonucleotides (ASO), a synthetic modified single strand of DNA that can alter production of certain proteins.

 

Triplet’s strategy

 

Triplet had designed its own ASO, but with a different strategy: to stop the deleterious expansion of the mutant huntingtin gene (click here to read more). Known as somatic expansion, this process drives the disease and can hasten the onset of symptoms. By slowing this expansion, Triplet had hoped that its drug would head off the disease early.

 

Triplet scientists and others have viewed this approach as a more effective alternative to the “huntingtin lowering” strategy devised by Wave, Roche, and others.

 

Capitalizing on recent groundbreaking HD genetics research, Triplet, founded in late 2018, developed the only clinical trial program to slow or stop somatic expansion in HD. Triplet also had hoped to develop treatments for others among the 50 rare conditions with somatic expansion, which, like HD, are called repeat expansion disorders.

 

 

Brian Bettencourt, Ph.D., Triplet's former senior vice president for research, explains a slide illustrating the firm's pathway to a potential HD drug at the 15th Annual HD Therapeutics Conference, 2020 (photo by Gene Veritas, aka Kenneth P. Serbin).

 

“It is with great sadness we announce the closure of Triplet Therapeutics,” Bermingham wrote on LinkedIn.

 

The “underlying science of targeting repeat expansion disorders” remains “a viable approach from our vantage point,” Bermingham wrote. However, crucially, in animal studies, the data from Triplet’s HD drug “reflected prior experiences” with ASO toxicity in the central nervous system – a reference to the Roche and Wave results.

 

Specifically, the ASO showed signs of harming neurons (brain cells). “As a therapeutic modality, given Roche’s data, our data, lack of efficacy from Wave products, our belief is that neurons may be particularly sensitive to antisense oligonucleotides,” Bermingham told STAT.

 

Triplet secured $59 million in initial financing and investment. After the bad news in 2021 from Roche and Wave, Triplet struggled to raise the money needed for its planned next step: an early phase clinical trial of its ASO. “The clinical data really put a chill on the overall interest or risk perceived within Huntington’s disease,” Bermingham noted.

 

SHIELD HD continues to provide key data

 

To provide data about the disease for the clinical trial it was planning, Triplet has run a separate, two-year study, without a drug, of approximately 70 presymptomatic and early-disease-stage carriers of the HD mutation. Called SHIELD HD, the study involves cognitive testing, brain MRI scans, blood tests, and examination of cerebrospinal fluid drawn from spinal taps (click here to read more). The sites are Canada, France, Germany, the United Kingdom, and the U.S.

 

In March, Triplet scientists presented a preliminary analysis of this data at the 17th Annual HD Therapeutics Conference, sponsored by CHDI Foundation, Inc., the virtual nonprofit biotech focused exclusively on developing HD therapies. CHDI is the largest private funder of HD research.

 

SHIELD HD may end in the next few months. In Bermingham’s announcement about the closure of Triplet, he said that CHDI, “a great partner and patient advocate,” stepped in to help SHIELD HD sites complete their work.

 

Triplet’s representatives are now seeking potential partners to continue the company’s research, including a new plan for a clinical trial.

 

Assessing risk

 

In an online interview with me on October 21, Irina Antonijevic, M.D., Ph.D., the former chief medical officer of Triplet, explained that discovering toxicity of the ASO in the animal studies surprised the firm’s researchers. However, she emphasized that the toxicity was “minimal” at therapeutic dose levels, with the animals not suffering any functional loss.

 

As noted publicly, Triplet had also developed several, more potent backup ASOs, Dr. Antonijevic said. The more potent the drug, the smaller the dose needed, therefore reducing the chance of toxicity or an adverse effect, she added.

 

Nevertheless, in a more risk-averse investment climate, Triplet could not find the necessary partners to carry on its clinical trial program with the added concern about the toxicity, Dr. Antonijevic observed.

 

“I think that they are just sort of very different risks,” she said. “Somebody takes maybe a risk to say, ‘Maybe this drug has a risk, but I have a disease, and I know what this disease will do to me.’”

 

For a drug company, the risk involves “investing millions” and waiting years to see if there is a return on investment, she said.

 

Tweaking drug safety, efficacy, and delivery

 

Triplet’s experience revealed how the field of HD drug development needs to tweak the safety, efficacy, and delivery of ASOs into the brain. Despite the challenges, a number of other firms and many researchers believe ASOs merit more study and clinical trials.

 

Roche has developed a revised clinical trial plan, including lower and thus potentially less toxic doses of its ASO. It will start a second trial of that ASO in early 2023.

 

Wave, building on its failed 2021 early stage trials of two ASOs, put a third drug into another small, early phase trial. Unlike the previous drugs, this Wave ASO successfully reduced the mutant huntingtin protein. Also, for the first time, it did this without lowering the level of the healthy protein – something that occurs with the Roche drug.

 

“This is, as far as we know, the first time anyone has ever selectively lowered only one copy [of a total of two] of a protein inside of a human body,” the HD science site HDBuzz commented on Sept. 30.

 

The method of delivery is important for all drugs, especially for ones introduced into the brain. The Roche and Wave trials use spinal taps (intrathecal injections). Triplet had projected using an

injection via a small reservoir implanted on the top of the brain. The firm uniQure is injecting its drug using brain operations.

 

Developing a pill

 

Drug developers point out that the most convenient HD drug would be a pill – taken orally, at home, and without medical assistance. These drugs are known as small molecules.

 

Several firms have embarked on small molecule clinical trial programs for HD.

 

An important trial of one of these small molecule drugs, a huntingtin-lowering pill developed by Novartis, was halted in August for safety reasons. Some of the trial volunteers on the drug developed problems with their nerves, known as peripheral neuropathy.

 

FDA requests more data from PTC

 

On October 18, another firm enrolling people in a clinical trial for a small molecule, PTC Therapeutics, Inc., was asked by the U.S. Food and Drug Administration (FDA), to provide further information before allowing a clinical trial of its HD drug, PTC518. PTC announced that enrollment is ongoing for the planned 12-month Phase 2 trial in several European countries and Australia.

 

Both branaplam and PTC518 are so-called splicing molecules.

 

“PTC pioneered the development of splicing molecules and we have learned about the essential elements to successfully develop these molecules,” Jeanine Clemente, the senior director of corporate communications at PTC, wrote me in an October 20 e-mail in response to my questions about the FDA decision. “We cannot comment on the FDA’s thoughts regarding branaplam or splicing molecules, in general.”

 

However, Clemente pointed out that PTC518 is highly specific and selective for the huntington gene.” She added that, in many important ways, “PTC518 is different than branaplam.”

 

HDBuzz also noted that PTC518 “may have more ideal drug properties, compared to branaplam.”

 

The FDA has asked PTC for additional data to support the dose levels and duration proposed in the trial, Clemente wrote.

 

Clemente added that PTC enrolled its trial entirely with patients outside of the U.S., including approvals to conduct the study at all proposed dose levels. “There have been no treatment-associated adverse events reported to date,” she stated. “We will continue to work with the FDA to potentially enable enrollment of U.S. patients in the trial.”

 

Keeping perspective in a difficult fight

 

Triplet will host a podcast later this year to discuss the “birth, life and death” of the firm, CEO Bermingham stated in his announcement of the closure.

 

The HD community must keep the Triplet shutdown – and all news regarding the ups and downs of the search for HD therapies – in perspective, noted Martha Nance, M.D., the director of the Huntington’s Disease Society of America Center of Excellence at Hennepin County Medical Center in Minneapolis.

 

“We would not do research if we already knew all the answers,” Dr. Nance wrote me in an October 18 e-mail. “HD patients and families have bravely faced their difficult disease for generations, and the doctors and scientists are doing their best, along with patients and families, to find a brighter path.”

 

As an asymptomatic HD gene expansion carrier who has not yet participated in a clinical trial, I had high hopes for the Triplet program, with its focus on attacking the disease in the early stages. I was deeply saddened to hear that the firm closed. I also felt in the gut once again the hard reality of marshalling resources – including financial support – for combating rare diseases.

 

Companies like Triplet are venture capital-funded businesses pursuing high-risk, high-reward endeavors, and many such endeavors fail. So we are fortunate to have a nonprofit like CHDI as a backstop.

 

Dr. Nance’s wisdom reminded me of the need to join with my fellow HD and rare disease advocates to regroup in the fight for therapies.

 

“Finding a solution to brain cell death in HD is not easy,” she observed. “And as we edge closer to an answer, each failure seems more dramatic. It would be nice if the answer would just reveal itself, if the answer to HD was simple and easy, but we will not let the setbacks of the last two years prevent us from moving forward.”

‘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.” 

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.

In the pandemic, we need to rediscover patience and grasp our responsibility

In this time of pandemic, the virtue of patience is paramount. So is the need to grasp our impact on the history of the planet and its effect on our lives. We who are afflicted with rare diseases have already had to learn many hard life lessons, which apply to the vital efforts to confront the coronavirus. 

As we mark Huntington’s Disease Awareness Month, we recall how many in the HD and other neurological and rare disease communities have demonstrated great fortitude and also patience as we await effective treatments. Since learning of my mother’s diagnosis with HD in 1995 and my positive test for the mutation in 1999, I have worried about the inevitable onset of symptoms and yearned for a successful clinical trial to produce a drug to stave off the disease or ameliorate it.

“HD warriors” like my mother and caregiver father (both deceased) have had to confront the disease on a daily basis for a decade or longer. 

Drugs like tominersen, the gene-silencing compound now in a historical Phase 3 clinical trial run by Roche, require painstaking development and often well over a decade to reach the market.

The tominersen project began in 2007, and Roche expects to analyze Phase 3 data in 2022. (Tominersen was previously known as RG6042 and, before that, as IONIS-HTT_Rx.)

The best-case scenarios for an effective and safe COVID-19 vaccine for the general public point to some time in 2021. 

“What people don’t realize is that normally vaccine development takes many years, sometimes decades,” Dan Barouch, M.D., a virologist at Beth Israel Deaconess Medical Center in Boston, stated in a news report. “And so trying to compress the whole vaccine process into 12 to 18 months is really unheard-of.”

A vaccine might never be found; after decades of intense research, science still has not developed one for AIDS.

Drug development requires precision and patience.

Possible hope from new drug development approaches

That said, by dint of biomedical progress (but lacking overall preparedness for a pandemic), the current worldwide effort could take place more rapidly than previous drug-development work.

With positive results in the very early stage of its vaccine program, drug maker Moderna, Inc., is using an RNA-based approach to attempt to block the actions of the coronavirus.

Ionis Pharmaceuticals, Inc., the developer of tominersen, is also looking into ways its drug technology “could benefit COVID-19 patients, first by looking at our existing pipeline to see if any clinical or preclinical drugs would have a use in treatment in either the disease, or more likely the complications of the disease arising from the acute respiratory syndrome,” Eric Swayze, Ph.D., the firm’s senior vice president of research, wrote in an e-mail to me on May 8. Ionis designs drugs using antisense oligonucleotides (artificial strands of DNA), a form of gene silencing technology.

“In the 2002/2003 SARS epidemic we did done some work with ASOs targeting both the coronavirus itself as well as host factors, and had preliminary hints of activity [effect],” Swayze added. “Because of this, we are making newer generation ASOs targeted to the SARS-CoV-2 [COVID-19] virus as well as host factors that contribute to the infection and disease. 

“We plan to work with collaborators who have the capability to test our lead ASOs in virus cultures. We believe that our recent pulmonary program advances position us to quickly move forward, provided that our drugs look promising. However, we feel this remains a high-risk discovery project, with many challenges ahead.”

Behind the reaction against lockdowns

However, despite the need for a long-term fight against COVID-19, only a few weeks after lockdowns began, tiny groups of purported “protestors” appeared demanding to “open up” states. They were egged on by President Donald Trump, who has declined to marshal national resources against the virus, and organized by conservative groups.

I have wondered: What if Americans had wanted to give up only three weeks after the 1941 attack on Pearl Harbor?

The initial impatience about COVID-19 was clearly politically motivated. Since then, some criticism of lockdowns results from growing economic hardship: with a 14.7 percent unemployment rate, the U.S. has lost the greatest number of jobs since the Great Depression of the 1930s. In addition, many small business owners have had to curtail their work or even shut down completely.

The pain hits professors and students

The economic pain has hit American universities such as my employer, the University of San Diego (USD), which switched to remote, online instruction in mid-March. Confronting an unexpected deficit, the president has announced a 50 percent cut in retirement benefits and a salary and hiring freeze.

There is no consensus nationally on how to resume classes in the fall, with leaders of different campuses struggling with uncertainty. The nation’s largest public university, California State University, for example, has announced, that its campuses will move nearly all instruction online.

With USD’s dependence on tuition for institutional survival and its reputation for high-quality instruction in relatively small classes in small classrooms, the administration has launched a still inchoate plan to reopen for the fall semester early, in mid-August. According to administrators, because of the loss in student fees, going remote again would extend losses by tens of millions of dollars, forcing possible layoffs and furloughs of some instructors and employees, an increased teaching load for the main faculty, and other types of cutbacks.

Many professors, including myself, fear returning to campus so soon; in normal times, packed dorms, classrooms, and other facilities (and student parties administrators can’t control) provide ideal conditions for a virus to spread. Though young people are less likely to suffer from coronavirus symptoms, some do get serious cases, and asymptomatic people can of course spread the virus to others more vulnerable.

Universities and their employees will seek to implement social distancing, testing for COVID-19, and other measures. Ultimately, depending on the course of the pandemic, many might have to resort again to remote learning.

We cannot return to ‘normal’

In fact, three in four Americans have supported social distancing and wearing masks.

Without good health, we are restricted economically, as the HD community knows so well.

I believe that the impatience comes in part from our culture of instant gratification, epitomized by online shopping and overnight delivery. Another part relates to political orientation, with Republicans favoring a more rapid opening than Democrats (for one analysis, click here).

I think many people – myself included – wrongly thought that, after a month or two of lockdown, we would return to “normal.”

However, as New York Governor  Andrew Cuomo put it on April 1, “I don’t think we get back to normal. We get to a new normal.” As a result of the crisis, society will undergo a “transformation,” and we must assure that it be “positive and not negative,” Cuomo urged.

“I fear that the resumption of normality would signal a failure to learn,” commented Pulitzer-Prize-winning medical writer Siddhartha Mukherjee, M.D. “We need to think not about resumption but about revision.”

He added, with reference to how the drive for instant success has exacerbated the pain of the pandemic: “To what extent did the market-driven, efficiency-obsessed culture of hospital administration contribute to the crisis?”

The perspective of Big History

Cuomo echoed the point that professional historians like me make to students and readers of our books: history is ever-changing, often with great progress, but also devastating setbacks, including world wars, plagues, and inhumane practices like slavery.

I teach a course called “Big History: From Cosmos to Cannibals,” which begins with the start of the universe and ends with the dawn of the modern era: Europeans' conquest of the Americas, beginning in the late 1400s and quickly causing epidemics of Old World diseases in which tens of millions of native Americans died in the hemisphere – a very poignant point of comparison with the pandemic this past semester. A field that has emerged recently, Big History embraces the idea that human development must be understood in the context of physics, biology, evolution, and the transition from small bands of hunter-gatherers to cities with millions of people.

Over the past several years, my classes have focused on how we now live in the Anthropocene, an era in which humans have taken control of the earth’s systems (atmosphere, oceans, land, life, and others).

Human agency has led to global warming, probably a more daunting challenge to humankind than coronaviruses, and many other threatening phenomena.

Human control has contributed to the crisis

In fact, some commentators have asserted that the pandemic has resulted from the humans’ super-control of the earth and our encroachment on the last vestiges of nature in areas such as the Amazon rainforest (for some examples, click here, here, and here).

Deforestation (for cash crops and cattle), mining, a growing population, and the expansion of urban areas have put the environment and the species therein under greater stress, making them more susceptible to viruses and zoonosis (jumping of a virus from one species to another, including humans).

Human domination of the planet has intensified over the past several decades. I witnessed the devastation firsthand of the Amazon in 1988 and 1990, during my time in Brazil as a graduate student. I saw gold prospectors who penetrated the deepest recesses of the forest, using clandestine airstrips. I also viewed up close how many square miles of trees had been cut down.

Above, using modern equipment, men prospect for gold by excavating the floor of the Amazon rainforest in Brazil, 1988 (photo by Gene Veritas, aka Kenneth P. Serbin). Below, Gene Veritas (wearing sunglasses) with workers at the mining site (personal photo).

Reconnecting with ourselves, and the planet

In my Big History course just concluded this semester, we were all deeply saddened by the onset of the pandemic. However, in the context of history, a devastating viral outbreak was highly likely. Leading scientists have also warned the world for decades.

The pandemic serves as a global alarm. The Earth is a system, and it is crying out against our dangerous intrusions into rainforests and other attacks on the environment. Ironically, with the decrease in vehicle traffic, the vast reduction in pollution gives us a glimpse of the air quality we once had and must achieve again to stem the tide.

A key lesson of my Big History course is that the modern world led humans to think they were separate from nature, but, in reality, we are ever more interconnected. The pandemic will perhaps force humanity to rediscover our identity (for some, a spirituality) of being one with nature. We are part of the Earth, not over and above it.

As Dr. Mukherjee pointed out, the virus has laid bare many things, such as the inequality of our health system. It has also laid bare our impatience. To overcome the virus, we need to regain patience and, along with it, humility and respect for the planet.

As Dr. Mukherjee and others have urged, we also need to learn from this crisis and make better policy choices for future threats of all types.

(Disclosure: I hold a symbolic amount of Ionis shares.)