Huntington’s disease continues to baffle Biopharma

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It’s 100% deadly, strikes its victims in the prime of life, and has businesses with potential cures shutting down or spinning their wheels with trial stops and failures.

Huntington’s disease may well top the list of incurable neurodegenerative diseases.

In October alone, Atlas Venture-funded Triplet Therapeutics shut down, citing recent failures in space, NeuBase halted development of its Huntington program, and PTC Therapeutics suspended the US arm of a trial. phase II following a request for additional data from the FDA.

So what are all these companies up against?

Multiple approaches

Researchers take multiple shots to achieve breakthrough in Huntington’s disease. The therapies in development aim to be neuroprotective, reduce mHTT, and deliver a complexly balanced payload to the cortex and striatum, the areas of the brain where disease is most prevalent.

Gene silencing with antisense oligonucleotides (ASO), AAV gene therapy, and gene splicing are just a few of these approaches.

Dr. Robert Friedlander_UPMCDr. Robert Friedlander, MD, is the chair of the Department of Neurological Surgery at the University of Pittsburgh and UPMC and a pioneer in this field. He said there are challenges to the neuroprotective approach.

“With a stroke… you have an injury and the injury goes away, and then you try to salvage what you can. In chronic neurodegenerative diseases, you have a mutant protein that gets expressed (over and over again) and you get sick ( over and over again),” he said. “You can prevent the downstream pathways, but you still get sick.”

Friedlander, also chairman of NeuBase’s scientific council, said the impact of this strategy, and others being evaluated, will be limited “unless you turn off the root cause – toxicity.”

A balance exercise

Most current approaches attempt to suppress mHTT. But the presence of wild-type huntingtin (wt)HTT in the body makes knocking out the gene a precarious balancing act.

“We know wild-type huntingtin is neuroprotective,” Friedlander said. “It helps in the production of BDNF (brain-derived neurotrophic factor); it is important for mitochondrial function. It does many things that are good for the cell.

So removing too much could be harmful. And selectively getting rid of the mutant version of the gene while preserving the wild type is a real challenge. Friedlander speculates that approaches that are not allele-specific are unlikely to work.

However, there are different schools of thought on the importance of wtHTT.

Stuart Peltz_PTC TherapeuticsStuart W. Peltz, Ph.D., Founder and CEO of PTC, said HTT is “probably necessary for embryonic development…but after that it’s not as critical.” He pointed to preclinical models where wtHTT was suppressed and animals survived.

Peltz doesn’t recommend eliminating all wtHTT, but “even a small amount is probably enough”.

Another challenge is that Huntington’s disease is a diffuse brain disease. Michael Hayden, Ph.D., CEO of Prilenia Therapeutics, said this makes engaging targets difficult.

“Many of the approaches taken have not reached all areas of the brain that are affected by the disease,” he said. BioSpace. “Intrathecal injection doesn’t reach all parts of the brain at the dose you would expect to get an appropriate reduction in huntingtin. If you go intrastriate, you don’t involve other parts of the brain.

Reaching the deep part of the brain is a challenge. This is why some have attempted to inject a drug intracranially into the striatum. But, in addition to toxicity, it may still not be possible to achieve full distribution of the drug throughout the brain.

Although primarily affecting the brain, Friedlander noted that Huntington’s disease is a whole-body disease that affects other organs, including the heart, muscles, and pancreas. As such, the ideal treatment would be “systemic therapy that crosses the blood-brain barrier,” he said.

In early 2021, Wave Life Sciences shelved its two lead ASO candidates for Huntington’s disease when they failed to achieve therapeutic effect. Dr Michael Panzara, chief medical officer at the time, suggested it was because an insufficient amount of the drug hit the target.

Toxicity issues have plagued several companies over the past two years. In March 2021, Roche halted a phase III trial of tominersen. After showing great promise in phase II, the drug ultimately failed to achieve greater efficacy than placebo and actually led to poorer results when given more frequently.

In August, Novartis halted a phase II trial of branaplam due to early indications of side effects, including peripheral neuropathy.

Regulatory attention

PTC’s drug, an orally bioavailable molecule that leverages the company’s splicing platform to reduce HTT production, is currently on hold pending further data in the United States. Meanwhile, the trial continues in Europe and Australia.

“The FDA is a conservative agency,” Peltz said. “All the other regulatory agencies let us use our preclinical data. The FDA, on the other hand, has requested additional data from us to support the proposed dose level and duration for PIVOT-HD.

There are currently two drugs approved to treat Huntington’s disease, and neither is disease-modifying. During his time as CSO at Teva Pharmaceuticals, Hayden led Austedo, a treatment for chorea associated with HD, until it was approved in 2017. The other, tetrabenazine, also treats chorea.

It’s also a bit of a niche space, according to Hayden.

“Compared to ALS, there are fewer drugs in development, so it hasn’t caught the eye,” he said. This despite substantial worldwide prevalence. Huntington’s disease affects about 100,000 people, but if you consider those with a genetic predisposition, that number rises to 400,000, Hayden said. “It’s not a rare disease.”

A way forward

But the situation is not hopeless.

“The pipeline is filling up,” Hayden said. “We know that we will probably need a cocktail of drugs, just like you have for [multiple sclerosis]ALS and for many cancers.

Michael Hayden_ PrileniaFor Hayden, the ideal therapy for the central nervous system components of the disease is “oral medication that is safe and tolerable and has targeted engagement throughout the brain.”

Prilenia is developing pridopidine, the only drug in phase III development for Huntington’s disease. Pridopidine activates the sigma-1 receptor, a highly expressed protein in the brain that regulates several cellular mechanisms common to neurodegenerative diseases. Activation of S1R reduces cellular stress and inflammation.

Studies have shown that Pridopidine prevents neuronal cell death and strengthens and improves the connections between neurons. The drug demonstrated a strong safety profile throughout its development. The Phase III trial only saw a 7% dropout rate, Hayden said. Prilenia expects top-notch results at the start of the second quarter of 2023.

Biomarkers have struggled to emerge in neurodegenerative diseases as they have in oncology.

“Researchers continue to identify additional biomarkers that could, if validated, be used for different disease stages,” Hayden said, referring to a forthcoming paper that suggests, “a new set of biomarkers which could be examined in the LCR”.

NeuBase was developing an allele-specific peptide nucleic acid (PNA) targeting CAG. The drug selectively binds to the mutated mRNA to reduce or prevent the production of mHTT. The approach differs from an ASO in that it is more neutral in its charge, more stable in circulation, and is not immunogenic, Friedlander noted.

The company was making progress in having both a brain and systemic effect without affecting wtHTT, Friedlander said, before the program was discontinued due to financial considerations.

NeuBase is evaluating options to move the drug forward, including partnerships or even developing a new company, he shared.

Paul Bolno_Wave Life SciencesAnd Wave tries again with a new and improved ASO. Paul Bolno, MD, President and CEO, explained that WVE-003 incorporates the new chemical modifications of the company’s PN backbone. These have been shown in preclinical and clinical studies to enhance the potency and durability of its molecules.

Additionally, “WVE-003 is engineered to preferentially lower mHTT by targeting a single nucleotide polymorphism (SNP3) that occurs on the mHTT transcript and is not present on the wtHTT transcript,” Bolno said. BioSpace. An estimated 40% of adults with Huntington’s disease carry SNP3 in association with the Huntington mutation.

WVE-003 is being evaluated in the Phase Ib/IIb SELECT-HD study. Wave presented data in September showing early signs of lower mHTT in CSF. Wild-type HTT was retained at both doses, the company reported.

“Our data told us we had a signal. We have a targeted engagement,” Bolno said.

Wave expects additional biomarker and safety data from expanded single-dose 30, 60, and 90 mg cohorts in the first half of 2023.

Sharon D. Cole