With ‘great promise’ for treating Huntington’s disease, four drug programs press ahead (Part II)

 

At the recent 20th Huntington’s Disease Therapeutics Conference in February, four pharmaceutical companies provided updates on their key clinical trial programs, demonstrating that they had overcome basic safety hurdles and revealing plans to have their drugs potentially approved as therapies (treatments) for delaying the progression of HD symptoms.

 

All four programs use drugs to lower the amount of harmful mutant huntingtin protein in the brain cells of patients.

 

In the first of two articles on these programs, I described the projects of PTC Therapeutics and Roche.

 

In this article, I cover the presentations made by Wave Life Sciences and uniQure.

 

These updates took place during the conference’s first session on February 25, the first day of the three-day event.

 

In a post-conference interview Robert Pacifici, Ph.D., the chief scientific officer for CHDI Foundation, Inc., the conference sponsor, told me that that there is “great promise” regarding these four programs’ potential HD therapies.

 

Attacking only the bad protein, preserving the good one

 

Jane Atkins, Ph.D., Wave’s senior vice president for portfolio strategy and program management, provided an update on the company’s groundbreaking program.

 

Like Roche’s tominersen, Wave’s WVE-003 is an antisense oligonucleotide, an artificial strand of DNA that blocks or lowers the production of the huntingtin protein.

 

However, whereas tominersen and PTC’s votoplam (a splicing modulator) reduce both the mutant and normal huntingtin protein, Wave’s drug is uniquely allele-selective: it attacks just the bad protein and allows the good one to carry out its essential actions unhampered.

 

Clinical trials for drugs usually go through three phases. If the last is successful, the drug can receive approval from the U.S. Food and Drug Administration (FDA).

 

In 2021, in small clinical trials, precursors WVE-120101 and WVE-120102 failed to reduce the bad protein. Wave then developed WVE-003, which entered a clinical trial that same year.

 

At the conference, Dr. Atkins reported that in June 2024 the Phase 1b/2a SELECT-HD study of WVE-003 produced positive results, “including the first allele-selective silencing in any disease.”

 

“A growing body of literature” supports the importance of the good huntingtin protein, she explained, as it sustains the health of brain cells.

 

Slowing the shrinking of the brain

 

In the clinical trial, the bad protein was reduced as much as 46 percent in some volunteers, exceeding the overall goal of 30 percent, Dr. Atkins said, noting that the drug was safe and well-tolerated.

 

Significantly, the study also demonstrated a slowing in the atrophy (shrinking) of the caudate, a key part of the brain dramatically affected in HD, leading to a decline in cognition, function, and movement, Dr. Atkins said. Such atrophy occurs before symptoms appear, she noted, so being able to observe this change early makes the atrophy a good measure of a drug’s effectiveness.

 

The slower shrinking “was the first time this was shown in the clinic,” Dr. Atkins said. “We were super-excited to see this.”

 

With these promising results, Wave plans to put WVE-003 into a combined Phase 2/3 clinical trial, Dr. Atkins said. The company later this year expects to seek FDA approval of the trial. Wave proposes to use caudate atrophy as a primary endpoint, that is, a main measure of WVE-003’s effectiveness.

 

Wave is also investigating WVE-003’s potential impact on somatic expansion, Dr. Atkins said. Somatic expansion is the tendency of the mutant huntingtin gene to continue expanding over time. Many scientists now believe that this process triggers HD symptoms.

 

Somatic expansion is understood as a two-step process where expansion of the gene (step 1) triggers disease (step 2) that drives HD. Wave believes that lowering the bad protein selectively (with WVE-003) is likely to address the second step.

 

As with tominersen, WVE-003 is administered via a spinal tap. Votoplam is a pill.

 

 

Dr. Jane Atkins of Wave Life Sciences displays a slide demonstrating the slowing of caudate atrophy in the WVE-003 clinical trial (photo by Gene Veritas, aka Kenneth P. Serbin).

 

uniQure drug slows disease progression in trial

 

David Margolin, M.D., Ph.D., uniQure’s vice president for clinical development, gave a presentation on the latest developments regarding AMT-130, the firm’s gene therapy drug that reduces the levels of both the good and bad huntingtin protein.

 

In the uniQure clinical trial, a neurosurgeon injects AMT-130 directly into the brains of the volunteers under the guidance of an MRI. As a gene therapy, AMT-130 requires just this one application. (Watch the uniQure video about how AMT-130 is administered here).

 

This small, long-term uniQure Phase 1/2 trial began in 2020. As of April, the number of participants had reached 45, including people from the U.S. and Europe.

 

An interim analysis in mid-2024 showed that “AMT-130 high dose … strongly and significantly reduced disease progression,” Dr. Margolin pointed out. Another analysis found “substantial reduction in risk of clinically meaningful worsening,” he added.

 

As patients continue to go through the trial and beyond, with follow-up, “with every data cut we see… a promising treatment effect becoming more and more evident,” Dr. Margolin said.

 

 

Dr. David Margolin of uniQure presents data illustrating the slowing of HD disease progression in the AMT-130 clinical trial (photo by Gene Veritas).

 

Hoping to accelerate approval

 

The positive results have led uniQure to seek acceleration of FDA approval for AMT-130.

 

Because of HD’s status as a rare disease, in 2017 uniQure received the financially beneficial orphan drug designation from the FDA for AMT-130. In 2019, FDA granted AMT-130 fast track status to further facilitate development of the drug and expedite review.

 

As explained by Dr. Margolin at the conference, in 2024 the FDA defined AMT-130 as a regenerative medicine advanced therapy (RMAT).

 

This category includes life-threatening diseases such as HD. Dr. Margolin said it is applicable to new kinds of drugs such as gene therapy, cell therapy, and tissue-engineered products, and it further accelerates FDA review.

 

In achieving this designation, uniQure presented to the FDA the data from the Phase 1/2 trial, and the FDA agreed that this data can serve as the primary basis for a drug application, Dr. Margolin said.

 

Dr. Margolin indicated that this determination means that uniQure will not need to put AMT-130 into a Phase 3 trial.

 

“An additional investigational study will not be required,” he emphasized. “That accelerates by several years the timeframe in which AMT-130 might become available to a wider U.S. cohort of patients.”

 

Swaying the FDA to be more flexible

 

Because of the lack of therapies that modify the course of this rare and devastating disease, the uniQure project and the company’s dialogue with the FDA have indicated the willingness of the agency to allow flexibility in clinical trial programs and a faster timeline.

 

Dr. Margolin’s talk title included the phrase “alignment on a US Regulatory Path Via RMAT.” Alignment with the FDA could lead to an “accelerated approval” for AMT-130, he observed.

 

Dr. Margolin asserted that uniQure’s dialogue with the FDA “has meaningfully advanced HD regulatory science.”

 

In response to a question from Dr. Pacifici about the negotiations with the FDA, Dr. Margolin stated that uniQure hopes that the lack of disease-modifying therapy is “swaying FDA to be more liberal than they have been in the past.”

 

Dr. Pacifici asked what additional studies uniQure will conduct if it secures the accelerated approval, which would still be only conditional.

 

Dr. Margolin replied that uniQure will discuss that matter with the FDA.“Importantly, even an accelerated approval means the drug will be available to patients,” Dr. Margolin stressed. “It does constrain promotional materials in certain ways, but would have no relevant impact on its potential availability and accessibility to U.S. patients.”

 

A Breakthrough Therapy designation

 

AMT-130 gained RMAT designation because it is a gene therapy. Since the conference, the AMT-130 program has made yet further progress.

 

On April 17, uniQure announced that the FDA granted Breakthrough Therapy designation to AMT-130.

 

“Receiving Breakthrough Therapy designation underscores both the urgent need for effective treatments for Huntington’s disease and the encouraging interim data demonstrating that AMT-130 has the potential to slow disease progression,” said Walid Abi-Saab, M.D., chief medical officer of uniQure, in a press release. “We look forward to working closely with the agency to bring AMT-130 to the Huntington’s disease patient community as quickly as possible.”

 

As explained in the press release, Breakthrough Therapy designation for AMT-130 means that the drug “may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s).” 

 

The firm expects to provide a further FDA update this quarter. In the third quarter, it aims to present data on AMT-130 to support its potential drug application submission.

Triplet Therapeutics aims to transform the approach to treating Huntington’s disease, similar disorders

Huntington’s disease causes complex symptoms and attacks the brain ­– the most difficult organ to access with drugs. Thus, current remedies only help manage symptoms. They do not stop the disorder from progressing and, ultimately, causing death.

 

Now, building on groundbreaking research into the genetic roots of HD, Triplet Therapeutics, Inc., is taking a bolder stance: restoring the idea of transformative treatment onto the agenda by directly attacking the disease's underlying causes.

 

Founded in late 2018, Cambridge, MA-based Triplet aims to start a clinical trial in the second half of 2021 for a potential drug, for now called TTX-3360, targeted at stopping the mutant huntingtin gene’s tendency for continued expansion with age. That expansion compromises brain cells and triggers disease. Using the same mechanism, Triplet hopes to develop transformative treatments for many of the more than 50 other so-called repeat expansion disorders (REDs). For REDs of the central nervous system, it would use the same drug as for Huntington’s.

 

The DNA that comprises the mutations of many REDs – as with Huntington’s – occurs in triplets of the letters of the genetic alphabet. This helped inspire Triplet’s name. But other repeats, from 3-12 letters long, have also been described. Also as in HD, the DNA in other repeat expansion disorders grows longer and thus may cause disease.

 

“There's a lot of the genome that we actually don't know about, and a lot of putative genes there that, frankly, we don't know functionally what they do,” Triplet founder and CEO Nessan Bermingham, Ph.D., said in a January interview on the podcast BioBoss. “So, I think of the opportunities in our industry as we think about treating disease is very much going in and trying to actually understand and segment these regions of the genome to understand how targeting them may actually prevent or treat or cure disease.”

 

The efforts for treatments have taken “significant steps forward,” Dr. Bermingham observed.

 

Triplet secured $59 million in initial financing and investment. The company’s scientific advisory board includes key researchers in the fight against Huntington’s such as Harvard University geneticist James Gusella, Ph.D., the leader of the team that discovered the huntingtin gene in 1993, and Sarah Tabrizi, FRCP, Ph.D., a professor at University College London and one of the chief medical collaborators in the development of the historic Phase 1/2a HD gene-silencing clinical trial run by Ionis Pharmaceuticals, Inc., followed by an in-progress Phase 3 trial run by Roche (discussed below).

 

Triplet has also consulted with CHDI Foundation, Inc., the nonprofit virtual biotech dedicated solely to developing HD therapies (drugs and/or other treatments) and sponsor of the 15th Annual HD Therapeutics Conference in February. Produced by former NBC-TV foreign correspondent and global Huntington’s advocate Charles Sabine, this year’s conference highlights video featured Triplet and its senior vice president for research, Brian Bettencourt, Ph.D. Dr. Bettencourt was the lead scientist in the design of TTX-3360.

 

As I wrote nine years ago, preventing onset in premanifest (presymptomatic) gene HD gene expansion carriers like me has been the “Holy Grail” not only for Huntington’s, but other neurological disorders, given that brain damage starts many years before visible symptoms occur. 

 

“To hear what has been up and coming in the past five years and to hear what Triplet Therapeutics has been doing is so exciting for somebody like me who is premanifest and who has kids, one who is at risk,” said leading advocate Lauren Holder, 34, during her July 22 interview of Irina Antonijevic, M.D., Ph.D., Triplet’s chief medical officer, on the Help4HD Live podcast.

 

Above, Brian Bettencourt, Ph.D., Triplet’s 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 (photo by Gene Veritas, aka Kenneth P. Serbin). Below, Nessan Bermingham, Ph.D., Triplet founder and CEO (Triplet photo).

 

Leveraging trailblazing insights of HD genetics

 

As a December 2019 news release stated, Triplet is “leveraging insights of human genetics to target the underlying cause” of REDs.

 

Those insights from genetic data collected over decades in more than 9,000 people affected by HD have changed standard thinking about Huntington’s genetics. This type of broad-ranging study is known as GWAS, genome-wide association study. 

 

“My company, Triplet Therapeutics, was quite literally founded based on the information that came out of the Huntington’s GWAS,” Dr. Bettencourt said in his interview with Sabine. “The GWAS provided us a really, really rich list of good gene targets for drugs.”  These genes modify the age of onset and progression of HD.

 

“The research in HD has really driven the research in this entire field,” Dr. Antonijevic told me in an interview via Zoom on October 4. From 2009-2010, she served as CHDI medical director. Later, she worked for Wave Life Sciences, which is conducting an HD clinical trial with a drug similar to the one developed by Roche for its historic clinical trial. 

 

Dr. Antonijevic pointed to the “trailblazing” work of Harvard University HD genetics researchers Dr. Gusella, Marcy MacDonald, Ph.D., and Jong-Min Lee, Ph.D. With others, they demonstrated why people with the same repeat length in the huntingtin gene can experience widely different ages of onset (click here to read more).

 

This might very well explain why HD struck my mother in her late 40s, turned her into a debilitated, mere shadow of herself by her late 50s, and took her life at 68, while I, with the same degree of mutation, have reached 60 essentially healthy, without motor onset, and able to function normally.

 

Somatic expansion: a driver of disease

 

The disease-causing expansion of the relevant portion of the huntingtin gene is the trinucleotide repeat CAG, letters in DNA alphabet. The expansion over an individual’s lifetime is known as somatic expansion or somatic instability. The breakthrough in HD genetics has 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.

 

Most of the modifiers contribute to the maintenance and repair of DNA, which, in general, helps cells remain healthy. Scientists call this process the DNA damage response (DDR) pathway.

 

“We tend to think of DNA as a fixed blueprint, an overarching plan for the biological bricks and bridges that constitute our cells, organs, and bodies,” a recent HDBuzz article explained of somatic instability. “But like any good plan, DNA is actually dynamic and adaptable.” 

 

Roche/Ionis achievement a ‘stimulus’ to other companies

 

Like Roche’s historic, in-progress Phase 3 gene-silencing clinical trial (GENERATION HD1), the Triplet program will use an antisense oligonucleotide (ASO), a synthetic modified single strand of DNA that can alter production of certain proteins.

 

In its Phase 1/2a trial, the Roche ASO successfully reduced the amount of mutant huntingtin protein in participants’ cerebrospinal fluid (CSF), obtained from lumbar punctures (spinal taps). The CSF bathes the brain. Roche researchers are looking hard for biomarkers (signs of disease and a drug’s effectiveness) in the CSF. Triplet and other research programs are also studying CSF. 

 

Roche and its partner Ionis, which designed the drug candidate Tominersen over nearly a decade, did the scientific heavy lifting required to develop the first HD ASO and administer it safely to clinical trial volunteers using lumbar punctures.

 

To date, Roche has not reported any serious adverse effects after the many lumbar punctures done on the hundreds of volunteers in its clinical trial program. The company expects to complete GENERATION HD1 and start analyzing data in 2022.

 

“The demonstration in a clinical study that a drug can lower mutant huntingtin levels was a critical development for the field,” Ignacio Muñoz-Sanjuán, Ph.D., the CHDI vice president for translational biology, told Sabine in the HD Therapeutics Conference highlights video. “It really provides stimulus to many other companies to use similar approaches and similar methodologies to try to establish treatments that really benefit the life of patients.”

 

Ionis has also been studying the control of somatic expansion as an additional Huntington’s therapy. Researcher Jeff Carroll, Ph.D., presented on this topic at the HD Therapeutics Conference. In July he co-published a paper on this subject with a team of researchers, including two Ionis scientists. The research demonstrates that lowering the huntingtin protein with an ASO in mice and human neurons in a lab (but not yet in a clinical trial) decreases somatic expansion and may also decrease the size of the expansions.

"We remain committed to finding effective treatments for Huntington's disease and are investigating multiple targets beyond lowering of huntingtin in our drug discovery group and with academic collaborators," Frank Bennett, Ph.D., Ionis executive vice president and chief scientific officer, wrote me in an October 12 e-mail.

 

Taking the foot off the disease accelerator

 

Dr. Antonijevic indicated that Triplet has leveraged publicly available knowledge gained from the Roche/Ionis program and others to plan Triplet’s development program.

 

“I think it is great to see that there is trial activity,” she said. “Ultimately the more trials with different approaches there are, the better the chance that there will be a treatment for the patient.”

 

Dr. Irina Antonijevic (Triplet photo)

 

However, Dr. Antonijevic pointed out a key difference between Triplet’s approach and Tominersen: lowering the amount of the mutant huntingtin protein does “nothing” to block the harmful expansion of the huntingtin gene, because it does not “touch the DNA.”

 

As with all ASOs, the Triplet approach blocks the action of RNA. However, Triplet’s drug will act “upstream” of the mutant, disease-causing gene itself by targeting another gene that promotes huntingtin’s somatic expansion, Dr. Antonijevic explained. 

 

“This is why we say it’s upstream: it affects the huntingtin gene at the DNA level,” she observed. “This is where we think it matters. The continuously increasing toxicity of the mutant gene is stopped, because the expansion at the DNA level is stopped.”

 

At the HD Therapeutics Conference, Dr. Bettencourt drew a contrast between the huntingtin lowering done by the Ionis/Roche ASO and Triplet’s targeting of somatic expansion. Huntingtin lowering is like “putting a brake on the process,” he said. As a result, the drug is “not dealing with the constant foot on the gas, whereby the DNA repeat is continuing to expand.” Triplet is different: “our therapies quite simply seek to remove that foot on the gas,” with the DNA no longer expanding, he said.

 

Dr. Brian Bettencourt (Triplet photo)

 

Drug candidate now ready

 

Triplet announced the selection of its ASO drug candidate, TTX-3360, in July. “TTX” stands for Triplet; 3360 is the number of the molecule.

 

Triplet very quickly developed its ASO because of “luck and expertise combined,” Dr. Antonijevic told me, explaining that TTX-3360 has been tested in animals, including non-human primates (monkeys). “We are excited to move it forward.”

 

To help select candidate compounds, Dr. Bettencourt stated at the Therapeutics Conference that Triplet relied on computational screening, experiments in animals, and tests in cells derived from HD patients. The company has also used siRNAs, small interfering RNA molecules, to test potential drug targets.

 

In its studies in non-human primates, one of Triplet’s test drugs was safe, well-tolerated, and had significant “knockdown” (reduction, a desired positive effect) on the targeted gene, Dr. Bettencourt added.

 

Dr. Antonijevic stated that TTX-3360 will target a modifier gene, but did not reveal which one. The modifier gene itself is “not pathologic,” she added. However, by reducing this gene’s expression as a protein that acts on the huntingtin gene, Triplet hopes the deleterious expansion of the huntingtin gene will slow or stop.

 

Triplet has not yet announced how it will deliver TTX-3360 in in the Phase 1/2 trial.

 

“Ultimately what we think is most important is that we get the drug to those areas in the brain that are important to target when treating an individual with Huntington’s disease, and we will let the science drive what the right delivery is,” she said.

 

SHIELD HD: preparing for a clinical trial

 

Before Triplet can launch a study of its drug aiming to cure HD, it wants to understand in greater detail how the disease progresses. It also wants to confirm existing biomarkers and measure new ones to help track the effectiveness of its drug. 

 

Under Dr. Antonijevic’s leadership, last May Triplet initiated SHIELD HD, a critical, two-year “natural history study” of approximately 60 HD gene expansion carriers to help prepare the Phase 1/2 clinical trial of TTX-3360 that the firm hopes to launch in the second half of 2021. Triplet is recruiting volunteers in Canada, France, Germany, the United Kingdom, and the U.S.

 

“SHIELD HD” aligns with some of the letters in the study’s longer scientific name, “but ultimately it reflects that we think of our approach as a protection from the disease,” she told me. 

 

A natural history study involves no “intervention or treatment,” she added. “We are studying the disease as it would normally progress, using clinical [observation] and biomarkers. So, it is really the natural course of the disease.”

 

As part of the study, Triplet scientists are analyzing volunteers’ CSF, MRI brain scans, blood, and data from cognitive tests, including HD-CAB, a refined “cognitive assessment battery” developed with input from the U.S. Food and Drug Administration and researchers predominantly for premanifest individuals, Dr. Antonijevic said in the Help4HD Live interview.

 

“It is really a performance test,” Dr. Antonijevic told advocate Holder. “This is something that does not require the physician or the investigator to assess a patient, but it is the individual who performs the test.”

 

The cognitive tests provide a “snapshot in time” of the individual’s decline because of HD and measures change over time, Dr. Antonijevic continued. “It’s really more objective than, for instance, a rating scale.” (Physicians use rating scales to determine a person’s level of HD.)

 

The study is also measuring DDR gene expression and the brain protein neurofilament light chain, the latter a marker of disease progression. SHIELD HD participants are also evaluated by a physician. Increasing somatic expansion in HD models was associated with elevations of neurofilament light chain, Dr. Bettencourt noted in his conference talk.

 

A slide from Dr. Bettencourt's presentation explaining SHIELD HD (screenshot by Gene Veritas)

 

Participants before official onset

 

Because of Triplet’s ultimate goal to prevent onset of symptoms, SHIELD HD is enrolling volunteers who have not yet experienced motor onset ­– the involuntary movements and problems with gait that form the classic criteria for diagnosing HD but have been called into question over the past few decades.

 

As Dr. Antonijevic told advocate Holder, studies of postmortem HD brains demonstrate that somatic expansion occurs many years before motor onset.

 

“There are a number of symptoms that are measurable, trackable, and predictable long before motor symptom onset,” Dr. Bettencourt noted at the Therapeutics Conference. He described the three groups of individuals under study in SHIELD HD as “prodromal,” “peri-manifest,” and “manifest.”

 

Prodromal refers to a period of years before motor onset, during which gene carriers have already shown some cognitive and emotional symptoms. Within the prodromal period, peri-manifest signifies the start of so-called “soft” motor symptoms. Manifest individuals have an official diagnosis of HD.

 

(For an in-depth discussion of premanifest and early-HD stages, click here.)

 

Aiming to improve clinical trial design, researchers continue to refine definitions of onset and disease progression. For instance, IBM has produced a model of the disease with nine stages instead of the traditional three. The traditional stages are after motor onset and do not include the first two of early-stage categories indicated above. 

 

SHIELD HD volunteers can do Phase 1/2 trial

 

Significantly, eligible SHIELD HD participants can later participate in the TTX-3360 Phase 1/2 trial, Dr. Antonijevic explained to Holder. This will enable the clinical trial investigators to compare an individual’s performance in SHIELD HD, with no drug, to a period on treatment. 

 

“This can be statistically a very powerful tool to measure the effect of a therapy,” Dr. Antonijevic observed.

 

Triplet projects the trial as a Phase 1/2 so that it can test for the crucial safety and tolerability typical of a Phase 1 but also perform measurements that could “tell us a little bit more about the mechanism of our drug,” Dr. Antonijevic told me. “We’ll be looking at the totality of data from this Phase 1/2 study to inform the subsequent study.”

 

Helping hundreds of thousands of patients

 

Triplet’s leadership has emphasized how the company’s search for an HD drug might work for other REDs, the repeat expansion disorders. These include myotonic dystrophy type 1, fragile X syndrome, familial amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxias as well as dentatorubral-pallidoluysian atrophy.

 

Large-scale genetic studies such as the Huntington’s GWAS “have revolutionized the way we identify the underlying genetic drivers of repeat expansion disorders,” CEO Bermingham stated in the news release about SHIELD HD. “Our targeted approach is based on results from these studies with our internal research providing insight into the central role the DDR mechanism plays in these diseases. Our approach has the potential to address a broad range of repeat disorders addressing unmet medical needs for hundreds of thousands of patients.”

 

As Bermingham stated in the BioBoss podcast, the potential now exists to treat large numbers of diseases with the same drug.

 

According to Dr. Antonijevic, the number of REDs is actually increasing: scientists are discovering new disease genes, and a growing number of existing disease genes are now known to undergo somatic instability. She believes that ranking them by number of affected people is not helpful, in part because for each diseased person there can be many more asymptomatic gene carriers.

 

For example, there are an estimated 41,000 HD-affected individuals in the U.S., and more than 200,000 at risk for having inherited the gene. Some 140,000 people in the U.S. suffer from myotonic dystrophy type 1, and, Dr. Antonijevic noted, additional people are at risk. Myotonic dystrophy type 1 symptoms include skeletal muscle weakness and myotonia (difficulty relaxing muscles after use), cardiac dysfunction, respiratory dysfunction, excessive daytime sleepiness, cataracts, and other abnormalities.

 

The focus on a one-drug-for-all approach distinguishes Triplet from other companies that have developed ASOs against a specific disease gene, she added.

 

Previously, scientists have sought a way to address energy loss in HD-affected brain cells and other disorders such as epilepsy as a possible path to a common drug to correct the problems in bioenergetics (click here and here to read more), but without success so far.

 

To further its strategy, on August 18 Triplet announced that it would take part in a large international natural history study of myotonic dystrophy type 1 aimed at deepening understanding of the disorder and developing therapies.

 

Rescuing neurons – and people

 

Despite the COVID-19 pandemic, SHIELD HD – the natural history study ­– is “definitely on schedule,” Antonijevic told me. Dr. Bettencourt said that Triplet plans to provide a report on its research, including SHIELD HD, at the 2021 HD Therapeutics Conference.

 

Triplet’s plan for a Phase 1/2 trial of TTX-3360 in 2021 is exciting news for the HD community and beyond – not just for individuals with diseases caused by repeat expansion disorders, but for the hundreds of thousands of asymptomatic gene carriers (like me) fearful of their futures.

 

As Dr. Antonijevic said to Holder, “We think that, by intervening early, we could rescue more neurons and have ultimately hopefully a greater therapeutic benefit.”

 

The Triplet drug development program became possible because of the decades of research by scientists around the globe – and the participation of thousands of HD families in research studies.

 

A growing number of companies are competing to develop HD therapies. However, thanks to CHDI’s nonprofit role, academic researchers, and the overall ethos of the HD cause, researchers have collaborated in remarkable ways.

 

The HD community can take great comfort and pride in the hope that its efforts can potentially benefit so many other rare and neurological disease communities.

 

More than ever, #CureHD can become a dream fulfilled.

 

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

Ionis scientists provide initial assessment of successful Phase 1/2a Huntington’s disease trial and discuss next steps

After announcing December 11 that Ionis Pharmaceuticals’ gene-silencing drug for Huntington’s disease safely reduced the production of the toxic HD protein, company officials analyzed the firm’s successful Phase 1/2a clinical trial and discussed the next step: larger trials that are designed to test IONIS-HTT_Rx’s efficacy in alleviating symptoms by modifying the course of the disease.

I met with two lead scientists from Ionis’ HD team at company headquarters in Carlsbad, CA: Frank Bennett, Ph.D., Ionis senior vice president of research and the franchise leader for the company’s neurology programs, and Anne Smith, Ph.D., the Ionis director of clinical development and the individual responsible for the day-to-day management of the trial.

Drs. Bennett and Smith stressed that, because the two-year trial ended just last month, they could provide only an initial assessment of the results. The company plans to present detailed clinical trial findings at medical conferences in early 2018 and then publish the results in scientific journals.

Ionis will transfer administration of the next clinical trial phases to Roche, a key partner in the project since 2013. Roche now holds the license to IONIS-HTT_Rx, will lead further development, and handle all potential sales. Phase 1/2a took place in Canada, England, and Germany, but the next phase will have sites in the U.S. and other countries, to be determined next year by Roche. Ionis will continue to play an advisory role in the project.

“We are very appreciative of the community, and the patience that the community has exhibited,” Dr. Bennett said. “We understand how important this is for the HD community. We’re very pleased it’s going forward. The community has been very respectful towards the company and has allowed us to conduct this study in a way that was very robust.”

Drs. Bennett and Smith focused on how the trial revealed a reduction in the mutant huntingtin protein that “substantially exceeded our expectations,” according to the December 11 press release. The key, initial piece of trial data came from the measurement of the protein in the HD patients’ cerebrospinal fluid (CSF). Other trial data such as brain scans and blood samples will become available later.

IONIS-HTT_Rx and other Ionis drugs are antisense oligonucleotides (ASOs, artificial strands of DNA), which alter the expression of genes. In August 2016, Ionis and its partner Biogen actually halted a Phase 3 trial of an Ionis ASO in infants with spinal muscular atrophy (a motor neuron disease) because the drug was extending their lives. The FDA (Food and Drug Administration) approved the drug, with the commercial name SPINRAZA, in December 2016.

In October, Ionis and Biogen won a biotechnology prize for SPINRAZA (click here to read more). Ionis is also collaborating with Biogen to develop a drug for amyotrophic lateral sclerosis (Lou Gehrig’s disease).

Dr. Frank Bennett (left) with Gene Veritas (aka Kenneth P. Serbin) and Dr. Anne Smith (photo by Kristina Bowyer, Ionis)

Following are key excerpts from the interview.

Compelling changes in mutant huntingtin levels

GV: How did patients react to the intrathecal administration of the drug, that is, via a spinal tap?

AS: We didn’t hear from any of the physicians that there were any difficulties. There was probably some nervousness, but there were few side effects, and that ones they had were manageable. I think it’s telling that all 46 patients completed the trial.

GV: What was observed in the HD patients in this trial?

AS: We’re still in the process of getting these next waves of data in. That will come out over months. It’s important to recognize that the trial just ended in November. But at this stage we did see a promising safety profile, meaning that we didn’t have any clinical concerns with the drug.

We saw clear, compelling changes in mutant huntingtin levels in the CSF. It was sort of gravy in this study. It’s designed as a safety study. We didn’t know when we entered the study whether we’d be able to even measure mutant huntingtin in CSF. But it is the best evidence of target engagement that we have – meaning that it is evidence that the drug is doing what it ought to do.

We were pleased that the assay [lab test] was developed to the point that we could use it to measure mutant huntingtin. The test is relatively new and fortunately came online at about the right time that we needed it.

The label from the first vial of the Phase 1/2a clinical trial, administered in London, September 2015 (photo by Gene Veritas)

GV: The reductions of mutant huntingtin “substantially exceeded” your expectations. To what extent?

FB: When we began the program with Roche, we picked a target level of reduction of mutant huntingtin in CSF, and, based upon that, we would decide to go forward with the program [into the next phase].

We put the mutant huntingtin data at the top of the list, because it was the data that was going to drive a business decision from Roche, but also, importantly, it was the data that would help them design the next study. So we prioritized that as being the first thing we would look at. It’s the basis for telling us what are the doses that we should be using for the next study.

GV: So can you specify the amount of mutant huntingtin reduction?

FB: We’re going to save that for a medical meeting.

Phase 1/2a too early for improving symptoms

GV: You project from your pre-clinical animal studies that the level of reduction in the brain itself should be greater than what is seen in the CSF, correct?

FB: Yes. An important nuance for the community is that the level of reduction that we’re seeing in CSF is not a one-to-one correlation with the level in [brain] tissue, which is where you want the drug to be working. We haven’t proven it in patients, but we’re very confident that it will translate [into higher levels of reduction in the brain].

AS: We’ve tested this drug in several species and are able to understand that relationship between what you see in CSF versus what you see in [brain] tissue, which is why it was really important this assay [CSF measurement] was online. It really is a window into the brain.

To understand that relationship in animals, the animals have to be sacrificed, to measure the level in the [brain] tissue. So we won’t ever ‘prove’ it in humans, so to speak, but we have a good understanding of it through the animals. And that it’s consistent from species to species is comforting. We can draw a conclusion about what’s likely happening in the human.

GV: Many in the HD community want to know: in this trial, did you see any signs of disease modification? Were there any hints at all from the doctors or from the data?

AS: We get anecdotal reports from physicians, but this is a population with a high placebo effect. These are motivated and excited physicians and patients as well. So I wouldn’t read anything into that. It’ll be several months before we have an understanding, though I would really caution any expectations along those fronts, because this is a short-term study.

We’re not expecting to see any sort of disease modification, just because of the way the study was designed. We dosed for three months, but it wasn’t even full drug effect for three months, because you build up the effect. This is the precursor to what would be long-term dosing.

GV: Have you observed whether there was also a reduction in the wild type (normal) huntingtin protein that all HD patients also have?

FB: There isn’t a good assay [lab test] for measuring wild type at this point. We have the samples, and once the assay is robust enough, we’ll look at it. The team is working on it, as well as others.

GV: Were there any surprises in the data that you’ve seen so far?

FB: It’s only surprising that it’s worked as we predicted it would [laughter]. Oftentimes when you go from pre-clinical to clinical, things don’t quite work out as well. But the drug is doing what it should be doing, which is lowering mutant huntingtin in cerebrospinal fluid. I think it’s all very positive from that perspective.

Phase 2 versus Phase 3

GV: What have you learned that will be helpful in planning phase 2?

FB: We asked a lot of the sites and the patients – because we collected a tremendous amount of data from them – for data that will be useful in designing a Phase 3 trial. We wanted to figure out which of the clinical outcome measures, which of the imaging measures, is actually reproducible, robust, and sensitive, to make sure it’s not “noisy” data.

AS: Another important learning will be whether there are differences from site to site. In a multi-site, multi-country trial, if a particular test just doesn’t translate well to German, for example, then we’ll have learned that. We can spare Roche from collecting data that are difficult to interpret, because they’re difficult to operationalize across sites and countries.

GV: You said “Phase 3” and not Phase 2. Why?

FB: Yes. At this point, Roche has not made a final decision on the next step. One of the options being considered is going right to a Phase 3 study. There’s a trade-off. You can do a smaller Phase 2 study – get more data that make it more probable that you’ll be successful for the Phase 3 – or you can go directly to a Phase 3 study. Those are the decisions that Roche is looking at right now very carefully.

The plus side is: if they go right to Phase 3, it would accelerate getting the drug to market. When we’ve reviewed with them the size of the study and the time of the study, there’s not a big difference between doing a Phase 3 and doing a more traditional Phase 2 first. It’s more expensive to go right to Phase 3, but it would save a lot of time.

GV: For an entity such as the FDA, is it okay to go from a Phase 1/2a to a Phase 3?

FB: The FDA will pay a lot of attention to the safety of the drug which – so far, knock on wood – looks very good. And then they leave it to the sponsor whether they want to risk the program. They may advise – because they ultimately want the drug to be successful, too – that this isn’t the best thing to do, but ultimately that’s the drug company’s decision. Roche will engage with the FDA.

GV: What is leading Roche to think it could maybe go directly to a Phase 3?

FB: It’s safety and tolerability [shown in Phase 1/2a], and the fact that we now know what dose of the drug produces this level of huntingtin lowering. Without that, they wouldn’t be able to go to Phase 3, but with that data, you could say that “this dose” should then produce “this level” of huntingtin lowering.

GV: Going straight to Phase 3, how much shorter would the whole program be?

AS: It’s definitely in the years.

FB: Yes, because if they were to do a Phase 2 study first, it would probably take three years to enroll and run. Roche wants to get this drug to patients as quickly as possible, assuming it works. They understand the disease. They understand the need for the patients.

GV: Whether Phase 2 or 3, when would the next study begin?

FB: I would anticipate towards the end of next year.

An important milestone

GV: What is the historical significance of the Ionis breakthrough?

FB: It’s an important milestone for the Huntington’s community. The mutation in the huntingtin gene was described in 1993. This is the first drug to go into clinical trials that is directly on target. It addresses the cause of the disease. We’re extremely excited that we’re actually seeing this basic science and all the work that NIH and other agencies have funded over the last 25 years now being translated into something that could actually have an impact for Huntington’s patients.

This bodes well for other neurological diseases. It has potential to markedly change how we treat those diseases. Perhaps this technology platform [the Ionis gene-silencing approach] would be beneficial for them as well. For patients out there overall, this is extremely important.

(For additional information about next steps in the IONIS-HTT_Rx program, click here for a Q & A with Dr. Ed Wild, an advisor and investigator of the program. You can also read a FAQS from the Huntington's Disease Society of America by clicking here.)

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

(In the video below, watch my report on the December 11 Ionis announcement.)

News from Ionis: drug reduces toxic Huntington's protein, trial may jump straight to Phase 3! from Gene Veritas on Vimeo.