5 Huntington’s Therapies to Watch

 

A fatal, highly hereditary illness with no disease-modifying treatments, Huntington’s is long overdue for a therapeutic win. Here, BioSpace looks at five candidates that could change the trajectory for patients.

Huntington’s disease has perplexed researchers for decades. Despite being one of the first genetic neurodegenerative illnesses for which science was able to pinpoint the causative gene, modern medicine is still searching for a disease-modifying treatment for this formidable foe.

“Here we are, decades later, and we still don’t know what to do with that information to prevent people from having decline from all the different functions of the brain and ultimately dying from the illness,” David Shprecher, movement disorder director at Banner Sun Health Research Institute, told BioSpace.

Huntington’s, which is caused by a CAG repeat in the first exon of the huntingtin (HTT) gene, generates a triad of symptoms: motor, cognitive and behavioral. While patients can develop severe issues with anxiety and obsessive-compulsive disorder, it is complications from the motor symptoms—including difficulty swallowing and falls—that are usually the cause of death, according to Shprecher.

“The problem is we don’t fully understand why the gene mutation causes damage to the brain,” he said.

Clinical trials are another challenge, he continued, with only about 41,000 symptomatic patients in the U.S. and many not at a stage where they’re eligible to participate. Geographic barriers are also significant as most trials are conducted at major academic centers and require in-person assessments.

“There’s been a real push to use a lot more telehealth and biometric remote technology” to allow more access to these important trials, Shprecher said.

While the Huntington’s community has experienced multiple letdowns over the last four years, biopharma is not giving up. Several companies, including Prilenia Therapeutics, uniQure and Sage Therapeutics are hopeful that their approaches can make a tangible difference for patients.

Here, BioSpace reviews five investigational drugs that could change the trajectory for patients with Huntington’s disease.

Prilenia Therapeutics

Pridopidine

Prilenia Therapeutics announced in September that the European Medicines Agency has accepted its Marketing Authorisation Application for pridopidine, a “highly selective and potent” agonist of the sigma-1 receptor.

Topline results reported in April 2023 from the Phase III PROOF-HD study revealed a miss for pridopidine, which failed to meet the primary and key secondary endpoints. However, further analysis of the data showed that the candidate elicited clinically meaningful efficacy in patients not taking anti-dopaminergic and chorea medications.

The Huntington’s community had been hopeful of pridopidine’s potential to treat Parkinsonian symptoms experienced by patients, Shprecher said, as these are not addressed by any current treatments. However, he added, “there would be very few Huntington’s disease patients eligible for a trial if it excludes both of those types of medications.”

Sage Therapeutics

Dalzanemdor

Sage Therapeutics is developing dalzanemdor, a potentially first-in-class positive allosteric modulator of the NMDA receptor, for cognitive impairment associated with Huntington’s. The Cambridge, Mass.–based biotech reported data in June from a small, Phase II trial in which there was a “small numerical difference” between dalzanemdor and the placebo as measured by the HD-Cognitive Assessment Battery composite score on day 28, with the company also noting that other “prespecified analyses” showed potential positive signals.

Huntington’s watchers, however, were not impressed. In a note to investors at the time, William Blair analysts called the results “underwhelming” and said they “remain cautious” on dalzanemdor and “do not view the small numerical changes as definitive” based on the results of this study.

Sage is gearing up to report data from the Phase II DIMENSION study of dalzanemdor in Huntington’s later this year, a win it needs after the drug failed to show efficacy in Alzheimer’s and Parkinson’s.

uniQure

AMT-130

Dutch biotech uniQure is developing a microRNA gene therapy, AMT-130, which is delivered deep inside the brain to inhibit the production of the mutant HTT (mHTT) protein. In July 2024, the company reported 24-month interim data from its Phase I/II trial of AMT-130 in 29 patients showing a dose-dependent slowing of disease progression.

“We believe this is the first clinical trial of any investigational medicine for Huntington’s disease to show evidence of a potential long-term clinical benefit and reduction of a key marker of neurodegeneration,” Walid Abi-Saab, chief medical officer of uniQure, said in the press release at the time.

AMT-130 has been granted orphan drug, Fast Track and Regenerative Medicine Advanced Therapy designations from the FDA, and uniQure has scheduled a Type B meeting with the regulator for later this month to discuss the potential for an accelerated development pathway, according to its Q3 earnings report.

Wave Life Sciences

WVE-003

Wave Life Sciences is developing the first allele-specific silencing therapy for Huntington’s. An antisense oligonucleotide, WVE-003 targets a nucleotide polymorphism present on the mHTT mRNA while leaving healthy huntingtin intact.

In June 2024, Wave reported that the candidate significantly and selectively reduced levels of the mHTT protein in a Phase Ib/IIa trial. After 24 weeks, treatment with WVE-003 led to a 46% drop in mHTT levels in patients’ cerebrospinal fluid versus placebo.

While the program was initially partnered with Takeda, the larger pharma stepped back from the collaboration last month. Now taking WVE-003 forward itself, CEO Paul Bolno told BioSpace that Wave has “initiated engagement” with regulators regarding a clinical development path that could support accelerated approval.

Roche and Ionis

Tominersen

Roche and Ionis Pharmaceuticals are partnered on the development of tominersen, which is currently being studied in a Phase II clinical trial of patients with prodromal and early manifest Huntington’s disease.

In previous clinical trials, tominersen was shown to lower levels of toxic mHTT by blocking its production. The antisense oligonucleotide is administered through a lumbar puncture into the cerebrospinal fluid.

Tominersen’s development journey has not been without challenges. In March 2021, Roche discontinued a Phase III trial of the candidate in manifest Huntington’s disease after a pre-planned data review by an unblinded Independent Data Monitoring Committee. The recommendation was related to tominersen’s potential benefit/risk profile for patients, Ionis said at the time.

Roche and Ionis are going all in on Huntington’s. In addition to the mid-stage tominersen trial, Roche paid its longtime partner last year for two RNA-targeting programs targeting Huntington’s and Alzheimer’s disease.

https://www.biospace.com/drug-development/5-huntingtons-therapies-to-watch

After Decades of Failure, First Disease-Modifying Huntington’s Treatment on Horizon

 

The past four years have brought disappointment for the Huntington’s community, but optimism is growing as companies including Prilenia and Wave Life Sciences eye paths to approval of therapies that could address the underlying cause of the disease.

Thirty years after the discovery of the huntingtin gene—and following several high-profile failures—a new crop of Huntington’s disease therapies is nearing the R&D finish line, all aiming to be the first disease-modifying treatment for this intractable, and ultimately fatal, disease.

While symptomatic treatments exist to treat Huntington’s, which is caused by a CAG repeat in the first exon of the huntingtin (HTT) gene, patients are still waiting for the type of breakthrough seen recently in another neurodegenerative disease, Alzheimer’s. Unfortunately, work toward this goal has hit notable potholes and dead ends, with clinical disappointments for Roche and Wave Life Sciences as well as an axed program from NeuBase Therapeutics and the shuttering of Huntington’s-focused Triplet Therapeutics.

But now, after decades of trial and error, the space appears to be gaining momentum. Wave, along with Prilenia Therapeutics and uniQure, are all charting out a pathway to regulatory approval, while PTC Therapeutics, Sage Therapeutics and Roche and Ionis are moving forward with mid-stage clinical trials.

“I think it’s very encouraging, really healthy,” Ignacio Munoz-Sanjuan, chairman of Rumi Scientific and president of the Huntington’s-focused non-profit Factor-H, said of the current R&D pipeline.

The Long Road for Huntington’s

Thirty years may sound like a long time, but Munoz-Sanjuan noted that “we haven’t been particularly successful” at developing disease-modifying therapies for neurodegenerative disorders. So the apparent lack of progress in Huntington’s, he said, is “probably true for most genetic disorders of the nervous system.”

This has only recently begun to change, he told BioSpace, pointing to the approvals of Biogen and Ionis’ Spinraza and Novartis’ Zolgensma in spinal muscular atrophy and Biogen and Ionis’ Qalsody for SOD1-amyotrophic lateral sclerosis (ALS) —both diseases with genetic underpinnings.

Paul Bolno, president and CEO of Wave, concurred, adding that “the translation from understanding what drives pathology to ultimately developing therapeutics that interrogate that is often . . . in some ways a long road. You need the convergence of the understanding of genetics, and you need the convergence of the technology with which to interrogate that.”

A Pathway to Approval

In September, Prilenia announced that the European Medicines Agency had accepted its marketing authorization application for pridopidine in Huntington’s disease. Prilenia’s submission is the first for an investigational drug with the potential to impact Huntington’s measures of clinical disease progression, according to the company’s press release. Prilenia expects an opinion from the Committee for Medicinal Products for Human Use in the second half of 2025, according to a company spokesperson.

As for the FDA, the spokesperson told BioSpace in an email that the company “remain[s] in an ongoing dialogue with them and hope to be meeting with them in the near future to understand how they view the potential pathways forward.”

Pridopidine is a “highly selective and potent” agonist of the sigma-1 receptor, which is highly expressed in the brain and spinal cord and regulates several key processes that are commonly impaired in neurodegenerative diseases.

In April 2023, Prilenia shared that pridopidine missed the primary endpoint in the Phase III PROOF-HD study, failing to reach statistical significance on the Unified Huntington Disease Rating Scale-Total Functional Capacity scale. However, a prespecified analysis that excluded participants taking anti-dopaminergic drugs and chorea medications showed “clinically meaningful and nominally significant benefits” with pridopidine.

“When we looked then at those off of anti-dopaminergics, then we got a very different picture,” Prilenia CEO Michael Hayden previously told BioSpace. In terms of total functional capacity, this subgroup of patients remained stable for at least a year, and as for motor function and cognition, “we saw improvement,” he said. “That was exciting because no [Huntington’s] drug had ever shown improvement in any of these functions.”

Munoz-Sanjuan suggested that the EMA might request another Phase III trial before approving pridopidine. “We’ll see how the regulatory agencies respond to such a restricted group of people,” he said.

Meanwhile, Bolno said Wave has “initiated engagement” with regulators regarding a clinical development path that could support accelerated approval for WVE-003, a potentially first-in-class antisense oligonucleotide that targets a single nucleotide polymorphism found on mutant HTT mRNA. Wave has “lean[ed] on a lot of growth in the field of oligonucleotides,” to develop the first allele specific silencing therapy for Huntington’s, he told BioSpace.

In June 2024, Wave announced that WVE-003 significantly and selectively reduced levels of the mutant HTT protein in a Phase Ib/IIa trial. After 24 weeks, the therapy elicited a 46% drop in mutant HTT levels in patients’ cerebrospinal fluid versus placebo. WVE-003 also preserved wildtype HTT levels throughout the 28-week assessment period.

“I think [we’re having] an impressive impact on engaging the target,” Bolno said. This is important because “when we think about accelerated approval, the first step is you’ve got to show that your therapeutic engages the target [mutant HTT].”

Additionally, Wave demonstrated the first-ever data showing a correlation between the reduction in mutant HTT and slowing of atrophy in the caudate nucleus, a feature of Huntington’s detected on imaging, Bolno said.

He pointed to recent data showing that “for the first time now you can look at changing caudate with clinical outcome measurements.” This type of correlation is a key factor for the FDA accelerated approval, which is granted on the basis of a surrogate endpoint that is reasonably likely to predict clinical benefit.

“If we could use clinical imaging as a surrogate, I think we can expedite medicines that are disease-modifying for Huntington’s patients very quickly,” Bolno said.

Like Wave, uniQure is moving forward in the regulatory process for its gene therapy AMT-130, announcing in its Q3 earnings report last week that it has scheduled a Type B meeting with FDA for later this month to discuss the potential for an accelerated development pathway.

After failing to impress investors with Phase I/II data for the candidate in December 2023, uniQure rebounded in July with updated data from the study showing that AMT-130 significantly slowed the progression of Huntington’s disease in a dose-dependent manner. After 24 months of observation, a higher dose of the gene therapy slowed disease progression by 80% relative to the external controls, according to uniQure.

AMT-130 also elicited a significant reduction level of neurofilament light chain—a key marker in neurodegenerative diseases—which dropped by 11% in patients’ cerebrospinal fluid, compared with the external controls. These results nabbed AMT-130 the first-ever Regenerative Medicine Advanced Therapy (RMAT) designation for Huntington’s disease, which comes with the opportunity for the Type B meeting with the FDA.

And the Huntington’s pipeline doesn’t end there. In June 2024, PTC Therapeutics reported positive interim results from a Phase II study of PTC518, a small molecule based on the biotech’s splicing platform. Roche and Ionis Therapeutics are collaborating on tominersen, an antisense oligonucleotide designed to reduce the production of all forms of the HTT protein. Sage Therapeutics is developing dalzanemdor, a potentially first-in-class positive allosteric modulator of the NMDA receptor, for cognitive impairment associated with Huntington’s. As the company recently halted dalzanemdor’s development in Alzheimer’s and Parkinson’s, Sage is banking on early data in Huntington’s expected later this year.

The Ideal Huntington’s Therapy

Munoz-Sanjuan said that the programs targeting the HTT protein are “receiving a lot of excitement.”

In terms of an ideal therapy for Huntington’s, he said preferential lowering of mHTT and broad distribution throughout the brain are key. “You’re going to see that each one of these modalities and routes of administration has disadvantages compared to the ideal profile,” he said. “An ideal profile will be an oral drug that lowers mutant huntingtin selectively. That doesn’t exist today.”

When it comes to leveraging the accelerated approval pathway for Huntington’s, Munoz-Sanjuan was supportive but urged caution. “We need to make sure that these therapies are really safe if we don’t want to be in a situation like some of the Alzheimer’s drugs where there’s a lot of reported side effects, including deaths that [were] maybe worse . . . than what the trials actually initially reported,” he said. Ultimately, Munoz-Sanjuan said, “I think the field has advanced a lot in the last decade.”

Bolno agreed. “I do think we’re on the precipice.”

https://www.biospace.com/drug-development/after-decades-of-failure-first-disease-modifying-huntingtons-treatment-on-the-horizon

US ordered TSMC to halt shipments to China of chips used in AI applications

 The U.S. ordered Taiwan Semiconductor Manufacturing Co to halt shipments of advanced chips to Chinese customers that are often used in artificial intelligence applications starting Monday, according to a person familiar with the matter. 

The Department of Commerce sent a letter to TSMC imposing export restrictions on certain sophisticated chips, of 7 nanometer or more advanced designs, destined for China that power AI accelerator and graphics processing units (GPU), the person said. 

The U.S. order, which is being reported for the first time, comes just weeks after TSMC notified the Commerce Department that one of its chips had been found in a Huawei AI processor, as Reuters reported last month. Tech research firm Tech Insights had taken apart the product, revealing the TSMC chip and apparent violation of export controls.

Huawei, at the center of the U.S. action, is on a restricted trade list, which requires suppliers to obtain licenses to ship any goods or technology to the company. Any license that could aid Huawei's AI efforts would likely be denied. 

TSMC suspended shipments to China-based chip designer Sophgo after its chip matched the one found on the Huawei AI processor, sources told Reuters last month. 

Reuters could not determine how the chip ended up on Huawei's Ascend 910B, released in 2022, viewed as the most advanced AI chip available from a Chinese company. 

The latest clampdown hits many more companies and will allow the U.S. to assess whether other companies are diverting chips to Huawei for its AI processor. 

As a result of the letter, TSMC notified affected clients that it was suspending shipments of chips starting Monday, the person said. 

The Commerce Department declined comment. 

A spokesperson for TSMC also declined to comment beyond saying it was a "law-abiding company...committed to complying with all applicable rules and regulations, including applicable export controls." 

The Commerce Department communication -- known as an "is informed" letter -- allows the U.S. to bypass lengthy rule-writing processes to quickly impose new licensing requirements on specific companies.

Ijiwei, a Chinese media site covering the semiconductor industry, reported on Friday that TSMC notified Chinese chip design companies it would suspend 7 nanometer or below chips for AI and GPU customers beginning Nov. 11. 

The action comes as both Republican and Democratic lawmakers have raised concerns about the inadequacy of export controls on China and the Commerce Department's enforcement of them. 

In 2022, the Commerce Department sent is-informed letters to Nvidia and AMD restricting their ability to export top AI-related chips to China, and to chip equipment makers like Lam Research, Applied Materials and KLA to restrict tools to make advanced chips to China.

The restrictions in those letters were later turned into rules that apply to companies beyond them.

The U.S. has been delayed in updating rules on tech exports to China. As Reuters reported in July, the Biden administration drafted new rules on some foreign exports of chipmaking equipment and planned to add about 120 Chinese companies to the Commerce Department's restricted entity list, including chipmaking factories, toolmakers, and related companies.

But despite plans for an August release, and later tentative target dates for publication, the rules still have not been issued.

https://www.msn.com/en-us/news/technology/exclusive-us-ordered-tsmc-to-halt-shipments-to-china-of-chips-used-in-ai-applications-source-says/ar-AA1tNZ19

'Trump, Putin speak as Biden plans to lobby Trump to stick with Ukraine'

 U.S. President-elect Donald Trump spoke with Russian President Vladimir Putin and advised him not to escalate the Ukraine war, a source familiar with the conversation told Reuters on Sunday, as President Joe Biden plans to urge Trump not to abandon Kyiv.

Trump and Putin spoke in recent days, said the source. Trump spoke with Ukrainian President Volodymyr Zelenskiy on Wednesday. Trump has criticised the scale of U.S. military and financial support for Kyiv, vowing to end the war quickly, without saying how.

Ukraine's foreign ministry said it was not informed in advance of the call between Trump and Putin and subsequently could neither endorse or object to it.

"We do not comment on private calls between President Trump and other world leaders," said Steven Cheung, Trump's communications director, when asked about the phone call, which was first reported by The Washington Post.

The Russian embassy in Washington did not immediately respond to a request for comment.

Republican Trump will take office on Jan. 20 after defeating Vice President Kamala Harris in the Nov. 5 presidential election. Biden has invited Trump to come to the Oval Office on Wednesday, the White House said.

U.S. National Security Adviser Jake Sullivan said on Sunday that Biden's top message will be his commitment to ensure a peaceful transfer of power, and he will also talk to Trump about what's happening in Europe, in Asia and the Middle East.

"President Biden will have the opportunity over the next 70 days to make the case to the Congress and to the incoming administration that the United States should not walk away from Ukraine, that walking away from Ukraine means more instability in Europe," Sullivan told CBS News' "Face the Nation" show.

Sullivan's comments came as Ukraine attacked Moscow on Sunday with at least 34 drones, the biggest drone strike on the Russian capital since the beginning of the war.

When asked if Biden would ask Congress to pass legislation to authorize more funding for Ukraine, Sullivan deferred.

"I'm not here to put forward a specific legislative proposal. President Biden will make the case that we do need ongoing resources for Ukraine beyond the end of his term," Sullivan said.

UKRAINE FUNDING

Washington has provided tens of billions of dollars worth of U.S. military and economic aid to Ukraine since it was invaded by Russia in February of 2022, funding that Trump has repeatedly criticized and rallied against with other Republican lawmakers.

Trump insisted last year that Putin never would have invaded Ukraine if he had been in the White House at the time. He told Reuters Ukraine may have to cede territory to reach a peace agreement, something the Ukrainians reject and Biden has never suggested.

Zelenskiy said on Thursday he was not aware of any details of Trump's plan to end the Ukraine war quickly and that he was convinced a rapid end would entail major concessions for Kyiv.

According to the Government Accountability Office, Congress appropriated over $174 billion to Ukraine under Biden. The pace of the aid is almost sure to drop under Trump with Republicans set to take control of the U.S. Senate with a 52-seat majority.

Control of the U.S. House of Representatives in the next Congress is not yet clear with some votes still being counted. Republicans have won 213 seats, according to Edison Research, just shy of the 218 needed for a majority. If Republicans win both chambers, it will mean the majority of Trump's agenda will have a significantly easier time passing through Congress.

Republican U.S. Senator Bill Hagerty, a Trump ally who is considered a top contender for secretary of state, criticized U.S. funding for Ukraine in a CBS interview.

"The American people want sovereignty protected here in America before we spend our funds and resources protecting the sovereignty of another nation," Hagerty said.

The 2-1/2-year-old war in Ukraine is entering what some officials say could be its final act after Moscow's forces advanced at the fastest pace since the early days of the war.

Any fresh attempt to end the war is likely to involve peace talks of some kind, which have not been held since the early months of the war.

Moscow's forces occupy around a fifth of Ukraine. Russia says the war cannot end until its claimed annexations are recognized. Kyiv demands all of its territory back, a position that has largely been supported by Western allies.

https://www.aol.com/news/biden-discuss-trump-top-us-160901728.html

Philippines' Marcos signs tax reform law to lure foreign investment

 Philippine President Ferdinand Marcos Jr. signed into law on Monday a bill lowering corporate income tax rates and granting more fiscal incentives to qualified companies, in a move aimed at enticing foreign investors to do business in the country.

Despite being one of Asia's fastest-growing economies, the Philippines has been a laggard in the region in attracting foreign direct investment because of foreign ownership restrictions, high power costs and poor infrastructure.

United Nations data show $6.2 billion in foreign direct investments flowed into the Philippines last year, smaller compared to Singapore's $159.7 billion, Indonesia's $21.6 billion and Vietnam's $18.5 billion.

Called the Corporate Recovery and Tax Incentives for Enterprises to Maximise Opportunities for Reinvigorating the Economy, the law lowers the income tax rates of registered business enterprises (RBEs) to 20% from 25%.

The measure, which changes and builds upon a 2021 law, allows RBEs, or companies registered with investment promotion agencies, to benefit from enhanced deductions, including a 100% additional deduction for power expenses, to help firms cope with high power costs in the Philippines.

It extends tax perks for strategic investments for up to 27 years from 17 years and clarifies the exemptions companies can claim for sales taxes. It also institutionalises the allowance for up to 50% of employees in RBEs to work from home while still keeping their incentives.

"This was a hard fought and hard won bill...," Marcos said in a speech, adding its broad scope will help in the Philippines' planned economic transformation.

The Philippines expects to lose 5.9 billion pesos ($100.89 million) in tax revenue from the new law from 2025 to 2028, according to a document prepared by the president's communications office.

https://money.usnews.com/investing/news/articles/2024-11-10/philippines-marcos-signs-tax-reform-law-to-lure-foreign-investment

South Korea state-run think tank sees need to loosen monetary policy

 A South Korean state-run think tank said on Monday that monetary policy needed to be loosened in accordance with the slowing trend in inflation, which has weakened to a near four-year low that is well below the central bank's target.

"There is a need to adjust the degree of restrictiveness in monetary policy to prevent inflation from staying below the price stability target of 2% for a long period of time," the Korea Development Institute said in a report.

The institute often conducts research for the government but rarely gives specific policy suggestions. Market participants tend to regard policy advice from the think tank as the views of the finance ministry.

Inflation, which hit the slowest pace since early 2021 at 1.3% in October, has been on a slowing trend since 2023 amid high interest rates and is expected to continue weakening for at least some time, the think tank said.

South Korea's central bank last month cut interest rates for the first time since mid-2020 and flagged there was room to reduce further, giving some relief to households that have faced the highest borrowing costs in 16 years.

https://money.usnews.com/investing/news/articles/2024-11-10/south-korea-state-run-think-tank-sees-need-to-loosen-monetary-policy

Becoming Solution-Focused

 We give energy to what we focus on.

If we focus on negative outcomes, we energize our worries and fears.

If we focus on problems, we fuel our sense of being broken.

What is in your trading journal?  What is in your thoughts after a losing trade?

That is what you are energizing.

This is why it is so very important to focus on your best trading and learn from your successes.

When your trading problems are *not* occurring, that is often when you are doing something right.

Once you focus on what you're doing right, you become solution-focused.

Success follows when we identify our solutions and turn them into habits.

Suppose you identified one thing each day that you did well in your trading and made it a goal to repeat and extend the next day?

What we focus on each day compounds and becomes our reality.

No solution-focused trader has ever gone on tilt.

When we are solution-focused, we grow the best within us.

 Brett Steenbarger, Ph.

https://traderfeed.blogspot.com/2024/11/becoming-solution-focused-in-our-trading.html