The upcoming Phase 3 trial of RG6042 will test whether lowering the levels of a mutant form of huntingtin (mHTT) translates into functional, motor and cognitive benefits for people with Huntington’s disease.
Potential benefits could also help advance gene-silencing approaches in other neurodegenerative diseases.
“Deep down, we all feel like this is doable,” George Yohrling, senior director at the Huntington’s Disease Society of America, said in a Nature news release written by Asher Mullard. “We’ve got this.”
The GENERATION HD1 study (NCT03761849) of Roche and Ionis Pharmaceuticals’ experimental therapy, formerly known as IONIS-HTTRx, is enrolling participants to assess whether RG6042 delays disease progression.
Huntington’s is characterized by trinucleotide repeats — expansions of the CAG sequence of neucleotides, the building blocks of DNA — in the huntingtin gene (HTT) and production of a mutant form of the huntingtin protein (mHTT), which is toxic to cells. The greater the number of these repeats, the earlier the disease starts and the more severe it is.
Roche and Ionis believe that gene-silencing compounds are able to prevent the accumulation of these toxic fragments and could modify the course of the disease.
“It’s very exciting that we are not just addressing the symptoms of the disease, but that we may be getting at the underlying disease process itself,” said Samuel Frank, neurologist at Harvard Medical School and investigator on the Phase 3 trial.
Though the scientists still need to determine whether this strategy will be able to target all forms of HTT, the best delivery routes and how early the treatment needs to be started, Yohrling is optimistic. “I don’t want to get too excited, but it’s hard not to,” he said. “I’m very hopeful that this will move us in the right direction.”
The potential efficacy of targeting mHTT was suggested as early as 2000, when researchers showed that deleting mHTT in mice could reverse motor symptoms of Huntington’s. The development of oligonucleotides — small DNA or RNA strands made in the laboratory — has made it possible to transfer these findings to humans.
Scott Schobel, clinical science leader for Roche’s RG6042 program, said: “The remarkable aspect of that evolution is that even a mere six years ago, it would have seemed like science fiction that we could go into a human with a mutated gene and lower the production of a toxic protein safely and sustainably.”
RG6042 is an investigational antisense oligonucleotide treatment designed to target and destroy all forms of mHTT. Besides CAG repeats, RG6042 is also intended to target single nucleotide polymorphisms (SNPs) — variations in a single nucleotide — observed in patients with Huntington’s.
However, by knocking down wild-type, or normal HTT, RG6042 could have safety limitations, as the normal huntingtin protein has key functions such as neuronal survival and function of mitochondria — the cell’s power plants.
“But we certainly feel good about our total lowering approach,” Schobel said. “So far it’s been safe in animals and our early clinical experience was positive in terms of the drug being safe and well-tolerated.” Roche and Ionis opted for this strategy “with careful consideration of safety, tolerability and potency.”
Other pharmaceutical companies are developing different approaches. Wave Life Sciences and Takeda are targeting mHTT RNA specifically. WVE-120101 and WVE-120102 each target SNPs linked to CAG expansions. Although such an approach would require multiple treatment candidates to help all patients, it could be safer than non-selective HTT therapies.
Voyager Therapeutics and uniQure are following a different path. These companies are developing microRNA-based strategies to silence HTT and mHTT expression. Unlike the other companies, whose therapies are delivered via spinal tap, Voyager and uniQure designed their modified viral vectors to be delivered directly into the brain.
Results of a Phase 1/2 trial of RG6042 (NCT02519036) in 46 adults with early-stage Huntington’s showed that treatment with RG6042 lowered the levels of mHTT in the cerebral spinal fluid by up to 60%. This difference corresponds to a 55% to 85% reduction of mHTT in the cortex, the outermost layer of the brain, and 20% to 50% in the caudate, a deeper region.
Although this Phase 1/2 study of RG6042 was not designed to assess function, a subsequent analysis showed that lowering mHTT appeared to correlate with improvements in motor, cognitive, and functional scores. “That was encouraging to us,” Schobel said.
Frank Bennett, Ionis’ senior vice president of research, said: “A 40-60% reduction in mHTT is not subtle. If there’s that same signal in the larger trial, that’s going to be impressive.”
The Phase 3 trial will have two primary goals — total functional capacity in the U.S. and the composite Unified Huntington’s Disease Rating Scale in Europe, which tests movement, cognitive ability and daily functional ability — to monitor clinical benefit.
Frank said, “If there can be a change in a potential biomarker like mHTT, and the preponderance of evidence shows that there is some other type of functional or symptomatic improvement as well, there’s a much stronger case from a regulatory perspective.”
Fourteen biotech and pharma companies, including Ionis and Roche, have been working to identify endpoints that better track neurodegenerative disease progression, such as magnetic resonance imaging to measure brain atrophy, and positron emission tomography imaging to assess metabolic activity in the brain.
“We are changing how we’re thinking about the disease and we’re changing how we’re thinking about treating the disease,” said Ariana Mullin, executive director of the Huntington’s Disease Regulatory Science Consortium (HD-RSC) at the Critical Path Institute.
Roche and Ionis’ Phase 3 trial will test RG6042 for two years in 660 patients with “manifest” disease. Regardless of whether the therapy shows efficacy, the scientists could then aim for earlier treatment of Huntington’s, Frank said, as lack of therapeutic benefit could be due to treating people whose disease is too advanced.
Unlike similar strategies for patients with Alzheimer’s, the much lower prevalence of Huntington’s means that there are fewer patients to be enrolled in clinical trials and a narrower commercial opportunity. As a result, scientists may need to extend trial duration to have longer treatment periods.
“That’s more likely to happen versus going back and looking at a drug earlier in the course of the disease,” Bennett said.
Despite the optimism with current treatment candidates, developing new treatments for Huntington’s may require combining HTT-lowering approaches with compounds that target other aspects of the disease.
“[Ten] years from now we’re going to look at Huntington’s more like we look at HIV,” Frank commented. “Until we find something that will ‘cure’ this disease, we have to pursue all avenues.”
Looking at other neurodegenerative diseases
Besides Huntington’s, the Phase 3 trial of RG6042 may also help advance gene-silencing candidates for other neurodegenerative diseases. Data on how well these potential therapies reach the brain could be valuable, but the implications may even lead to changing the timing of treatment for these diseases.
Early findings with spinal muscular atrophy treatment Spinraza (nusinersen, by Biogen) revealed that the benefits could go beyond delaying disease progression by also reversing its course. “This suggests that if you tackle neurodegenerative diseases early enough, you might be able to see reversal of symptoms,” Bennett said.
Biogen and Ionis are partnering in an upcoming Phase 3 trial in patients with familial amyotrophic lateral sclerosis, which will test the SOD1 gene-silencing compound Ionis-SOD1RX (BIIB067). The partners’ C9orf72 gene-silencing Ionis-C9Rx (BIIB078) is in Phase 1 stage.
Biogen and Ionis are also developing IONIS–MAPTRx (BIIB080) to investigate whether knockdown of tau — which forms characteristic intracellular tangles in the brain — is beneficial in treating Alzheimer’s disease.