By Sara LaJeunesse and Daniel O. Claassen
Antisense oligonucleotides hold promise for treating Huntington disease.
Once considered to be unsuitable for therapeutics because of their ineffectiveness in reaching their target and lack of tolerability in patients, antisense oligonucleotides (ASOs) have made a big comeback and now hold promise for altering the course of Huntington disease (HD). ASOs are short pieces of chemically modified DNA that bind to RNA transcripts. Those designed to engage the huntingtin gene seek to prevent generation of the toxic mutant huntingtin protein (mHTT) by inducing degradation of the transcript. This is the protein that is thought to be responsible for neurodegenerative progression of people with HD.
There are two RNA-targeted approaches currently in development for HD. Both seek to reduce HTT gene expression, but they contrast in their delivery and dosing. siRNAs (small interfering RNAs), such as those used in RNA interference (RNAi), are delivered via viral vectors. siRNAs must be delivered directly into the brain, and dosing is targeted to subcortical regions like the thalamus and striatum. This procedure only has to be performed once.
In contrast, ASOs are able to be delivered throughout the nervous system using an intrathecal injection. While this is a chronic, long-term dosing schedule (approximately every 2 months), “you just put these molecules into cerebral spinal fluid and they distribute throughout the CNS where they enter cells and do their magic,” says Amber Southwell, assistant professor at the University of Central Florida. ASOs appear to be better at getting to the cortex than to subcortical areas.
ASOs In Development
In 2018, Roche licensed an ASO-based drug, which is now named RG6042, from Ionis Pharmaceuticals. RG6042 is a non-selective ASO, meaning that it will reduce both mutant huntingtin and wild-type huntingtin. The company has initiated a Phase 3 clinical trial in Europe, Canada, and the United States. Preliminary data demonstrate that the drug successfully reduces the amount of mHTT in the cerebrospinal fluid, suggesting that it may be reduced in the brain—the first time any medicine has done so—and that it may even result in clinical improvements.
In the double-blinded study, participants will undergo intrathecal injections every two months and be randomized to one of three treatment study arms: 120 mg of RG6042 every two months (eight weeks), 120 mg of RG6042 every four months (placebo during alternating procedures), or placebo every two months.
According to Scott Schobel, associate group medical director and clinical science leader for the HD program at Roche, this study design was recently amended following preliminary nine-month data from the open-label extension of the Phase I/IIa study, which showed effects on lowering mutant huntingtin protein levels in the cerebral spinal fluid that support the exploration of less frequent dosing. “Based on the totality of the data, including safety and tolerability, there appears to be no overall advantage to treating monthly versus every two months,” says Schobel. “We believe this will make study participation less demanding for patients, families and healthcare providers.”
Schobel adds that if the clinical development program is successful and RG6042 is ultimately granted regulatory approval, the entire HD community will need to transform itself to be able to effectively and efficiently administer this treatment. “This will require a lot of work, and strong collaboration across patient groups, medical societies, medical institutions, and companies like Roche and Genentech,” he says. “We look forward to partnering with the entire HD community to think about and address these challenges at the appropriate time.”
The issue of whether reductions in wild-type huntingtin will result in clinically relevant safety concerns is somewhat in question, but encouraging results from Phase I work have not shown clear safety issues to date. “There’s a complex interplay between loss of wild-type huntingtin and toxicity from mutant huntingtin,” says Southwell. “I think that getting rid of mutant huntingtin is more important than preserving wild-type huntingtin in terms of being beneficial to disease in the short term; however, over the long term, I think reduction in wild-type huntingtin has the potential to reduce the beneficial effect of lowering mutant huntingtin.”
Other approaches attempt to use selective ASOs that only suppress mHTT. Wave Life Sciences, for example, has two selective ASOs under development. Both are currently in Phase I, with results expected by the end of 2019.
Challenges of Disease Modifying Clinical Trials and the Border Wall
Clinical trials that test the hypothesis that any therapy will slow or stop the progression of disease are challenging on many fronts. How long should the trial go? How is disease progression defined? How can one account for biological variability in disease presentations and course? What methods are best for defining clinical changes?
A clinical trial outcome should be a measure that is clinically meaningful. By the FDA’s definition such an outcome measures how a patient feels, functions, or survives. Unfortunately, with Huntington disease, measuring such an outcome can take years or even decades to show a clear difference. Historically, the UHDRS motor score has been used as a marker of motor progression in HD, and has been useful in VMAT-2 inhibitor trials. In the case of ASO trials, this outcome measure fails to capture the breadth of HD symptoms, like the cognitive and psychiatric changes that are well described.
Karl Kieburtz, professor of neurology, likens this problem to the current border security debate.
“When we talk about ‘disease modification’ it’s a little bit like talking about a ‘border wall,’” he says. “Patients, families, investigators, regulators…everybody knows that with Huntington disease, the disease gets worse over time, people become disabled, and die. Everyone wants a treatment that stops or slows this process. That is like saying everyone wants border security. When we start saying a treatment slows or stops the inexorable progression to disability and death, needs to be a ‘disease-modifying’ treatment, it is like saying we need a ‘border wall’ for border security. Then the debate becomes about the ‘wall,’ rather than focusing on how to define and measure HD disability. It’s like saying the only way to get border security is to build a wall, and we start debating something; in my view, that is a distraction.”
How do we measure, in aggregate, the disabling quality of Huntington disease? Or turn it around, how do we measure the abilities that are important to patients over time so we can say this group of people is doing better than that group of people? “Total motor score alone probably does not fit the bill,” says Kieburtz. Because if the motor score gets better, what does that mean? How do we know if a person is doing better just because their scale score is better? This issue is a very important hurdle to cross in order to get therapies that improve HD in the long run.”
We also want to think about treating HD before it becomes disabling, perhaps before symptoms even begin, says Kieburtz. Accelerated approval, one of the FDA’s expedited approval programs, is one mechanism that allows for use of an outcome which is not a clinically meaningful outcome, but which is reasonably likely to predict a clinically meaningful outcome. Such outcomes could be used in individuals before symptoms develop. “In Huntington disease, one could imagine reducing the production of mutant huntingtin could be a biological measure which might be reasonably likely to predict a clinical outcome,” says Kieburtz.
For instance, a trial in pre-manifest patients with no observable clinical symptoms to manage may use mutant huntingtin levels as a measure that is reasonably likely to predict a clinical measure. “That can, in certain circumstances, be used as a substantial measure of efficacy, which is used in lieu of a clinical outcome measure,” says Kieburtz.
A Worldwide Problem
Further complicating global studies are apparent differences of opinion between the U.S. (FDA) and European Medical Agency (EMA) on what is needed for drug approval The FDA and EMA are largely aligned but have definitively different perspectives on the issues of how to determine clinical efficacy. For example, European approval of a therapy for marketing considers the magnitude of benefit of a drug versus approved drugs for that indication, as well as versus placebo. In the U.S., the standard of evidence is a comparison to placebo alone.
In HD, the differing approach of the FDA and EMA is evident in the differing endpoints for the GENERATION-HD1 study in Europe and the U.S. The primary outcome in the U.S. will be the Total Functional Capacity (TFC) compared to placebo. In Europe, the primary outcome will be the composite Unified Huntington’s Disease Rating Scale (UHDRS) versus placebo. This score combines the TFC, UHDRS motor score, symbol digit modality test, and Stroop Word Reading. “There’s usually a different perspective on composite measures at the FDA, with concerns about how to interpret them,” says Kieburtz. “EMA is traditionally not so concerned with the potential shortfalls of a composite measure.”
There is certainly a lot of optimism for ASOs. “Reducing mutant huntingtin is the only thing I would expect to have benefit to every aspect of HD,” says Southwell. “I think with an effective huntingtin-lowering therapy, we may even see recovery of function in people with HD. Studies in mouse models of HD show that stopping or reducing production of mutant huntingtin in mice that are already symptomatic results in their recovery, sometimes all the way to normal function.”
Southwell reminds us that these approaches, while promising, are not cures. “There’s no such thing as a cure for Huntington disease, and even if you have a therapeutic treatment that completely prevents onset of disease, you haven’t cured it,” she says. “The only cure would be full-body genome editing to correct the mutation, which is complete science fiction.”
Are ASOs an answer that the HD community has been waiting for?
Everyone, around the world, and across all borders, hopes so.