Two pharmaceutical companies have halted clinical trials of gene targeting therapies for Huntington’s disease (HD), following disappointing drug performance.

The researchers had hoped that the treatments – known as antisense oligonucleotides (ASOs) – would be a game-changer for HD, an incurable genetic disease that affects cognition, behavior and movement. But back-to-back announcements from Roche, headquartered in Basel, Switzerland, and Wave Life Sciences in Cambridge, Mass., Have dealt a devastating blow to those affected by the disease.

“I was really shocked, really in tears,” says Marion, a woman in London with HD, who was part of one of the trials. “We didn’t see it coming at all. I felt really scared and worried about my future. Marion has requested that her last name not be disclosed to protect her privacy.

In mid-March, Roche announced the discontinuation of a phase III study of its ASO drug, tominersen. A week later, Wave Life Sciences announced that it would halt development on two of its HD ASOs that were in clinical trials I / II.

“The Roche trial in particular left the community quite devastated,” says Cath Stanley, chief executive of the Huntington’s Disease Association, a UK advocacy group that supports people with the disease. “There has been so much positive noise around him, both from researchers and clinicians and from the pharmaceutical company itself. I think the community was really drawn to this hope.

Protein issues

ASOs are short strands of DNA or RNA that alter the production of specific proteins by binding to RNA sequences made by defective genes. The gene involved in Huntington encodes a protein called huntingtin that is active in the brain. In people with HD, this gene repeats a short piece of its sequence – the CAG nucleotide combination – too many times. Roche and Wave Life Sciences were developing compounds aimed at lowering levels of the resulting mutant form of huntingtin.

Optimism around the drug Roche skyrocketed after the Phase I / II trial showed tominersen significantly lowered levels of mutant huntingtin in cerebrospinal fluid, without serious side effects. But following a planned review of the data earlier this year, an independent expert panel recommended that the trial be stopped early, concluding that the drug’s potential benefits did not outweigh its risks.

On April 27, at a conference hosted by the CHDI Foundation – an American HD research organization – Roche revealed that the trial was halted because tominersen failed to show greater efficacy than placebo. – and when administered more frequently, it led to deterioration of results.

“The saddest possible result”

The tominersen phase III trial tested 2 dosing regimens: 120 mg of the drug – the highest safe dose based on previous trials – given every 8 weeks or every 16 weeks.

Roche reported that after 69 weeks, patients on the eight-week diet experienced a greater decline than those in the placebo group, with worsening results in areas such as motor function and cognition. Participants in the 16-week treatment group performed better than those in the 8-week arm, but experienced no overall benefit compared to those given a placebo. Those in the treatment group also showed larger increases in the size of fluid-filled chambers in the brain called ventricles – a process that typically occurs in people with untreated HD – than those who received a placebo.

“This is the saddest outcome possible,” says Claudia Testa, a neurologist at Virginia Commonwealth University in Richmond, who received consulting fees from Wave Life Sciences. “It is clearly the right decision to stop the dosage, although I am sure it is not the result that everyone was hoping for.”

Several factors could have contributed to tominersen’s failure, according to Sarah Tabrizi, a neurologist at University College London and one of the Roche trial investigators. The drug suppresses production of the healthy, mutant form of huntingtin, and low levels of normal protein may have caused problems. Other possibilities are that the ASO did not reach the right parts of the brain, or that the disease simply progressed too far in the trial participants for the drug to be of benefit.

Tabrizi adds that it will take several months of additional analysis to identify what went wrong. Roche’s results were preliminary and important data is still being evaluated.

Optimism kept

The Wave Life Sciences trials tested ASOs that leave the healthy version of huntingtin intact by targeting small mutations that only occur in the faulty gene, known as single nucleotide polymorphisms (SNPs). These occur in a subset of people with HD.

But two of those compounds failed to dramatically lower mutant huntingtin levels in early Phase I / II trials, leading the company to abandon their development. The results of these trials suggest that “we did not get enough medicine where it needed to be effective,” says Mike Panzara, the company’s chief medical officer. This is a different problem from that seen with tominersen, which reduced levels of the mutant protein but did not appear to slow disease progression.

Wave has a third Huntington’s ASO in development, which tracks a different SNP and features chemical changes that improve the potency and ability of the drug to achieve its goals.

And although hopes for gene therapy for Huntington’s disease have been dashed – at least temporarily – researchers are eagerly awaiting the results of a large phase III trial of an ASO for motor neuron disease (lateral sclerosis). amyotrophic or ALS). What happened with tominersen is not of concern for this trial, says Don Cleveland, a neuroscientist at the University of California, San Diego and consultant for Ionis Pharmaceuticals in Carlsbad, Calif., Who both developed this drug. and the tominersen. This is because unlike the early trials with tominersen, the Phase I / II trial of the drug ALS showed signs of slowing disease progression in people with a rapidly progressive form of ALS.

“I think we have reason to be cautious optimist,” says Cleveland.