Exploring the use of antisense therapy for neurodegenerative diseases: an interview with Frank Bennett

Written by Sharon Salt, Editor

Frank Bennett is the Senior Vice President at Ionis Pharmaceuticals (CA, USA). He is responsible for research at Ionis and is the Franchise Leader for Neurological Programs there, including both research and development activities within the neuro program. Dr Bennett has been with the company research programs for 29 years.
What led to your interest in developing antisense oligonucleotides (ASOs) as therapeutic agents for neurodegenerative diseases?

We’ve always had an interest in neurological diseases, however, when we first began and founded the company we felt that there were some questions we needed to address before we tackled neurological diseases. Thus, we decided to focus on viral infections where it was known what causes the disease. In addition, oncology was an area we were focusing on and as this was new technology, we thought it was perhaps important to study the technology in a disease where the risk–benefit ratio favored accepting more risk associated with the drug.

Once we established the technology (approximately 15 years ago), we began exploring neurological diseases. One project that we started on early was a collaborative project working with Don Cleveland’s group at the University of California San Diego (CA, USA). The initial set of studies focused on trying to develop a drug for a genetic form of amyotrophic lateral sclerosis (ALS), which worked very well. Consequently, we decided to expand into other neurological diseases based on the preclinical data that we were observing, which demonstrated that antisense drugs could be safely administered to animals and distributed broadly throughout the CNS.

From these results, we expanded our internal efforts, including working on spinal muscular atrophy (SMA) and ultimately resulted in the approval of SPINRAZA®, the first and only drug to treat SMA, 2 years ago.

The work on IONIS-HTTRx in patients with early-stage Huntington’s disease (HD) made the headlines recently – could you tell us more about this? What are the next steps for the trial?

We reasoned that if you were to reduce the amount of mutant huntingtin, the toxic protein in HD patients, then this would be therapeutically beneficial for the patients. Subsequently, through a lot of preclinical work, we were able to document that we could use antisense technology to reduce the production of this toxic protein.

In mouse models our antisense drug improved motor function and cognitive abilities. We were then able to advance this drug into clinical trials in 2015, which was an early Phase I/II study in patients with early stage HD. We believed that it was important to study the drug in a relatively healthy population of Huntington’s patients in order to better understand the safety profile of the drug with minimal confounding disease symptoms. The study was set up as a dose-escalation study where we observed increasing doses with each cohort of patients. They were treated with four intrathecal injections of the drug once a month. The patients were then followed for an additional 5 months where we looked for any signs of safety, as the purpose of this study was to document the safety and tolerability of the drug.

As part of the study, we also wanted to determine whether the drug was doing what it was designed to do – which is to reduce the mutant huntingtin protein. Consequently, we used an assay to measure mutant huntingtin protein in the CSF of patients so that each time a patient received a dose of the drug, we could collect CSF samples and were able to observe whether the drug was affecting the levels of mutant huntingtin protein.

“…this was the first drug for the patient population that’s ever been developed that was really on target; we’re affecting the production of the protein that causes their disease.”

In the data that was collected, we saw a dose-dependent reduction in mutant huntingtin protein in these patients. The study also met its primary objective for safety and tolerability – this was the first drug for the patient population that’s ever been developed that was really on target; we’re affecting the production of the protein that causes their disease.

This is why there is a lot of excitement around this, as this was 25 years after the gene was discovered that we reported this data. This really does give hope to the community that we’re on track to develop a therapy that has the potential to benefit patients.

How could this therapy be applied to treat other neurodegenerative diseases?

As I mentioned previously, we have another antisense drug that’s approved for the treatment of SMA. Thus, we already know that this technology can be used to treat other neurodegenerative diseases. In this instance for SMA, the drug had a remarkable benefit for patients. Not only was it able to slow disease progression but actually, it reversed the disease – patients started getting better with treatment.

We haven’t yet demonstrated this for HD patients. Just slowing or stopping the progression of HD would be a big win, as there is no treatment that can significantly do this. But we hope that, as with SMA, we can improve disease symptoms in these patients and not just stabilize the disease. Perhaps one day we may even be able to treat patients who are genetically diagnosed before they have symptoms and prevent or substantially delay disease onset.

“…there’s a number of other neurodegenerative diseases caused by triplet repeat expansion or mutated toxic proteins. Having this dominant gain-of-function mutation, we may be able to directly translate what we learn from HD to target some of these other diseases…”

Taking HD as an example, there’s a number of other neurodegenerative diseases caused by triplet repeat expansion or mutated toxic proteins. Having this dominant gain-of-function mutation, we may be able to directly translate what we learn from HD to target some of these other diseases, such as spinal cerebellar ataxias or myotonic dystrophy. There’s a whole list of around 20–30 diseases caused by a repeat expansion like that found in HD. Recently, there’s been a repeat expansion identified that’s associated with familial forms of ALS, which accounts for around 8–10% of all ALS cases.

Again, we’re using our technology to target this dominant gain-of-function mutation in that disease. We’re also targeting proteins that are associated with genetic forms of Alzheimer’s disease and Parkinson’s disease. Although these are different targets, they’ve all been associated with a gain-of-function in these other proteins that seem to be contributing to the neurotoxicity that’s observed.

Currently, there are also other clinical developments being made for ASO therapy in other neurodegenerative diseases beyond Huntington’s – are you able to tell us more about this, such as any preliminary findings that you can share with us?

We have four other drugs that are currently in clinical trials. We have the HD drug; SMA, which is an approved therapy now; and a drug that targets familial forms of ALS by targeting SOD1. The latter is winding up its initial clinical studies and we expect to report updates either at the end of 2018 or the beginning of 2019.

Additionally, we also have a drug in clinical trials that is targeting tau or MAPT for Alzheimer’s disease and also for various tauopathies. This is only just starting clinical trials and we’re conducting dose-escalation studies for this. We anticipate reporting updates on this in approximately 18–24 months.

It’s also worth mentioning that we have a pipeline of four additional drugs that are in the process of starting clinical trials. The trials are yet to begin, however, these drugs are going through preclinical toxicity studies and we hope to start clinical trials for these over the next 12 months or so.

At the “Genetic Therapies in Neurodegeneration” symposium at University College London (UK), you mentioned using a non-allele selective ASO approach in Huntington’s patients to be able to target more patient populations around the world. Is this strategy also being utilized for other neurodegenerative diseases?

Yes, so the work that we’re doing on spinal cerebellar ataxias is non-allele selective. The approach for our ALS therapy targeting C9orf72 selectively targets the gene that contains the mutation and is more allele-selective; however, the majority of our other projects are targeting the general protein rather than selectively targeting the mutant form.

What are the challenges involved with using a non-allele selective ASO approach? How could these be overcome?

The basis for this concern is that if you completely knockout huntingtin in mice embryos, it’s lethal; however, if you have an adult animal, you can knock it out and it has very minimal effect in the adult animal.”

There is a theoretical concern that reducing the total amount of huntingtin protein could produce adverse effects. This is something that we’ve looked into very carefully, both ourselves and our partner Roche (Basel, Switzerland). We are very comforted by a number of data points that give us a reason to believe that in the adult patient population, there should not be any deleterious effect for reducing huntingtin protein.

The basis for this concern is that if you completely knockout huntingtin in mice embryos, it’s lethal; however, if you have an adult animal, you can knock it out and it has very minimal effect in the adult animal. Once you have developed a nervous system, it seems to be less critical and this is one of the reasons why we’re not as concerned with doing a non-allele selective knockdown approach. It’s important to recognize that our drugs don’t knockout a gene, so we don’t completely eliminate it but instead, we reduce the expression.

Are there any ASOs in development for treating neurodegenerative diseases that you feel particularly optimistic about?

Everything mentioned previously I’m optimistic about. I’m extremely pleased with where we are at with the HD therapy because it’s the first drug to really demonstrate on-target effects. We still need to go through the next steps of demonstrating that it has clinical benefit to the patient but I’m optimistic that we’ll get there with the current drug.

The SOD1 approach for ALS is still in the very early stages but ALS has been a disease where there have been 60 or 70 clinical trials in the last 10 years with 100% failure rate. I’m optimistic that we’ll demonstrate some benefit for the patients and for the first time, demonstrate that ALS is a treatable disease, as we’re on target for what is causing the disease in patients. We’re not curing it by any means – and this applies to any of the diseases we’re looking into – but we’re developing therapies that provide benefit to the patient.

Finally, where do you anticipate the field will be in the next 10 years?

Overall, I think I see us executing on our technology platform, as we’ve demonstrated that our antisense technology can be used to treat neurological diseases.”

I predict that there will be a number of drugs on the market for treating neurological diseases that up to this point have been untreatable and basically palliative therapy. We’ll begin to focus on making it more convenient for the patient, thus, looking at devices that can make the delivery of the drug easier for them. This would allow us to approach a broader patient population.

Overall, I think I see us executing on our technology platform, as we’ve demonstrated that our antisense technology can be used to treat neurological diseases. I also see multiple drugs approved and available to patients over the next 10 years.

We’re extremely thrilled with where we are at with the program and we are delighted with how the technology has been performing. It’s created a lot of excitement within the neurodegenerative field and we finally see some hope now, after decades and decades of not having effective therapies for these patients. We still need to prove it, so I want to be cautious that it’s not in the bag yet but I’m optimistic that we will get there.

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Disclaimer
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Neuro Central or Future Science Group.