Research news

The Huntington’s Disease community faced more disappointing news this week as Wave Life Sciences shared that they will discontinue development of two ASOs they had been testing in people with HD. Designed to decrease harmful huntingtin protein while keeping the healthy form intact, these experimental therapies unfortunately did not have the expected huntingtin-lowering effect. Wave will not move forward with these two ASOs, but is planning a clinical trial of a third ASO with new and improved chemistry. Let’s talk more about what this means, what’s next for Wave, and how this relates to the recent news from (Roche)[https://en.hdbuzz.net/300].

What was the aim of the PRECISION-HD1 and 2 trials?

Wave developed ASOs (antisense oligonucleotides) called WVE-120101 and WVE-120102 which they hoped would specifically lower the harmful form of huntingtin made in people with HD. ASOs work by interfering with the genetic message telling cells in our body to make a specific protein molecule. The ASOs developed by Wave specifically target the message for the harmful form of the huntingtin protein, preserving the message for the healthy form, so only levels of harmful huntingtin should be lowered. This differs from other huntingtin lowering approaches, such as those used by Roche and uniQure, which lower both the healthy and the harmful forms of huntingtin. Scientists at Wave think this is important as the healthy huntingtin protein remains to do its job properly, whilst the harmful form of the protein is eliminated so it can't misbehave.

During the PRECISION-HD1 and PRECISION-HD2 trials, up to 88 participants per trial received four monthly doses of ASO or placebo, delivered by injection into the spinal column. These relatively short Phase 1b/2a trials were testing safety and the drugs' ability to lower harmful huntingtin - they were not designed to measure effects on symptoms of HD. At the end of the trial, participants could decide to continue receiving monthly doses of the drug - this is known as an open-label extension. While the dosing period for the PRECISION-HD1 and PRECISION-HD2 trials had already ended, each study had an open-label extension ongoing.

So what happened in these trials?

On March 29th, Wave shared a press release sharing the key findings from the PRECISION-HD trials. Unfortunately, in the PRECISION-HD2 trial, there was no significant change in the levels of the harmful huntingtin protein in trial participants treated with WVE-120102, compared to those treated with placebo. In the open-label extension study, in which participants continued to receive monthly doses of ASO, some for nearly a year, only very small reductions of harmful huntingtin protein were measured.

The PRECISION-HD1 study began a little later than the PRECISION-HD2 study, and though dosing of WVE-120101 had finished, Wave needs a few more months to include the highest dose group in their analysis. However, based on the data they have from lower doses, similarly disappointing huntingtin-lowering results were seen for the PRECISION-HD1 trial. For this reason, Wave will discontinue development of WVE-120101 and WVE-120102. Participants in the open-label extension studies will have a final follow-up visit, but there will be no further doses.

Based on side effects in the drug and placebo groups, both drugs were safe and well tolerated, with a small percentage of participants who experienced severe side effects. However, neither ASO did in humans what it was designed to do: lower mutant huntingtin levels.

What's next for Wave?

Another piece of more promising news shared in the press release was that Wave plans to move forward with a trial of a third ASO to target harmful huntingtin, called WVE-003. With less-than-encouraging results from the PRECISION-HD studies, why move forward with this third candidate?

Wave has learnt a lot from these trials and they think they can improve their chances for success with WVE-003. One key difference between WVE-003 and the earlier ASOs, WVE-120101 and WVE-120102, is the improved chemistry of this new ASO, which uses Wave's "next-generation PN backbone chemistry." Essentially this means there are changes to the ASO molecule structure which should hopefully make the drug perform better in patients. The upcoming trial of WVE-003 will test its safety and potency for huntingtin-lowering, similar to the PRECISION-HD1 and 2 trials.

The Phase 1b/2a clinical trial for WVE-003 will begin in 2021. Similar to other Wave ASOs, participants need a specific signature in their genetic code in order for the therapy to work, a tiny spelling difference between the healthy and expanded copies of the huntingtin gene, called a SNP. The SNP needed for WVE-003 treatment is found in 40 % of adults with HD, so all potential participants will need to be tested for the presence of this SNP before they can be enrolled in the trial. People who participated in the PRECISON-HD1 and 2 trials will be offered the opportunity to undergo SNP screening for potential enrolment in the WVE-003 trial.

How does this relate to the news from Roche last week?

Although the timing is extremely unfortunate, the Roche and Wave announcements are completely separate and not scientifically connected in any way. The PRECISION-HD trials had completed dosing, and Wave stated many months ago that the key results would be shared by the end of the first quarter of 2021. Dosing in the Roche GENERATION-HD1 trial came to an unexpected halt, and that news could not have affected Wave’s timeline.

There's another important distinction between the two announcements: The results of the Wave studies showed that the WVE-120101 and WVE-120102 ASOs did not lower huntingtin protein in spinal fluid, even at the highest doses tested. Roche’s drug tominersen DID lower levels of huntingtin in patients’ spinal fluid in early trials, but development stopped based on findings midway through a longer and larger Phase 3 trial testing its effect on symptoms.

One possible reason that the PRECISION-HD trials struggled to lower huntingtin is that these ASO drugs used an older chemical structure. But the technology moves fast and is constantly improving, which is why there's hope that upcoming trials of WVE-003 could have a better outcome.

Onward once more

Although this has been a disappointing time for the HD community, this is by no means the end of the road for huntingtin lowering therapies. We still have very limited information about exactly why the (Roche trial)[https://en.hdbuzz.net/300] was halted, but details are forthcoming and will help to shape future trials. We'll learn from the PRECISION-HD trials, too, as the results are analyzed in greater depth and shared at upcoming scientific conferences and in future publications. There's still widespread evidence that targeting the HD gene at its source is a powerful approach, and there are many different ways that researchers and companies are exploring huntingtin-lowering: dozens of distinct drug designs, and multiple routes of delivery. There are also many additional therapeutic avenues that focus on other aspects of HD biology or aim to tackle a particular symptom.

The global HD community came together this week in an extraordinary way to seek support, share information, and talk about how to move forward, emotionally and scientifically. We continue to celebrate the heroes who participated in these trials and who are among the pioneers of huntingtin-lowering in people. We had all hoped for a better outcome for the PRECISION-HD trials, but we will move forward with a wealth of new knowledge. To quote Dr. Sarah Tabrizi of University College London in her comments to families about last week's news, "This is science, and science has to strive for the truth." We'll be here to report those truths as they arise.

Very sad news was announced today as Roche and Ionis declared that the large ASO study they're running in Huntington's disease patients has been halted early. Importantly, no specific new safety concerns were raised so far, but nevertheless dosing of the study drug, tominersen, as well as the placebo, has been stopped prematurely. What does this mean, and where do we go from here?

Background - what's this trial doing?

Roche and Ionis have developed tominersen which is a type of drug called an antisense oligonucleotide, more commonly referred to as an ASO. ASO therapies are able to reduce the levels of specific protein molecules by interfering with the genetic message which normally tells the cells of our bodies to make that protein. In the case of tominersen, this ASO drug interferes with the huntingtin protein genetic message. Tominersen treatment lowers the levels of both regular and Huntington's disease versions of the huntingtin protein.

This is not the first tominersen clinical trial. Before getting to this phase III study, tominersen was first tested in a Phase I/II trial where it was assessed for safety and shown to lower the levels of huntingtin protein in HD patients. The aim of this current phase III trial, also called the GENERATION-HD1 trial, was to work out if tominersen was effective, not only at lowering huntingtin protein in a larger group of patients, but also if it helped improve signs of HD in patients already showing symptoms.

What happened?

On March 22nd, 2021, a press release from Roche revealed that the phase III study of tominersen had halted dosing on the advice of the Independent Data Monitoring Committee (iDMC). This committee is a group of independent experts who have been monitoring the data from the ongoing study since it began.

These data monitoring committees play a very important role in clinical trials - their job is to act as a neutral party by looking at the data emerging from the trial, without an interest in the trial outcome. So, by design, these committees are totally separate from the patients, physicians and drug companies involved in running the study. Their sole job is to monitor the trial periodically to determine whether or not it should continue.

In general, these committees are asking two kinds of questions - first, are there any unexpected safety concerns emerging? If, for example - all the people receiving a drug had started to have some very weird symptom, this committee would see that and order the trial halted. Secondly, these committees can determine whether ongoing trials look extremely unlikely to have any benefit for the patient participating.

For example, earlier HD studies of several drugs have been halted by this kind of early analysis because the data suggest that the patients are extremely unlikely to benefit from the drug. If folks's HD symptoms are clearly not getting better, then the risk/benefit calculation for giving experimental drugs to people has shifted, and it may no longer be worth it to continue the trial.

What do we know?

What we know is very limited, which is important to remember for the next few weeks and months. All the important facts we know from the press release come from these few sentences:

"The decision was based on the results of a pre-planned review of the data from the Phase III study conducted by an unblinded Independent Data Monitoring Committee (iDMC). The iDMC made its recommendation based on the investigational therapy’s potential benefit/risk profile for study participants. No new or emerging safety signals were identified for tominersen in the review of the data from this study."

That tells us a couple things. First, that there's no new "safety signals" - meaning no new bad medical outcomes for the people in the trial. If there had been, say, sudden heart attacks in patients getting the drug (there weren't!!), this press release would have to tell us that. So, thankfully for the families participating, there's not yet any sign of scary new symptoms that emerged.

Second, the press release says that they decided to halt dosing in the trial because of the "investigational therapy’s potential benefit/risk profile for study participants." So how could the benefit/risk profile have changed if there's not scary new symptoms that emerged? Bottom line - we don't know yet. However, hypothetically speaking, it could be that the drugs worsen HD symptoms. Or, hypothetically, it could be that the drug just doesn't make HD symptoms better, in a way that is obvious to someone who has access to all of the data, and so it's not worth the risk of exposing people to a new drug because the benefits aren't clear.

Importantly - not even the researchers at Roche and Ionis know the answer to those hypothetical questions right now. When things like this happen, the independent committees have to make their decisions and let everyone know at once. So, until you see another HDBuzz story about this, tune out any noise you hear about these results - there's a huge amount we just don't know.

What do we not know, and when will we know it?

Why have we gotten this cryptic press release for something so important? Unfortunately, the way this works is that when trials are halted like this, there's an initial press release that's released as soon as the companies found out about the news. This is both so that the patient community can be informed, and to prevent shenanigans with people learning the news and selling stocks, or other inappropriate things.

As an example, after today's news Ionis's stock fell by nearly 19%, representing more than a billion dollars worth of value lost. In the wrong hands, early access to this information could be mis-used.

For the patient community, this means that when we hear bad news like this, there's always a baffling gap between this initial warning that something hasn't gone right, and learning the details of exactly what's happened. This is incredibly frustrating, but just how it goes when we hear things like this.

Is HTT lowering a bad idea?

We're likely to see a lot of discussion - and rightly so - about whether lowering huntingtin protein is a bad idea. Based on all the science we had at the time, we believed it was right to run this trial. And we have this incredible new set-point, which is that we know we can lower huntingtin protein in HD patients. So when we design the next trials - and there will be more trials - we're not going back to square one, but rather a point at which we know that lowering huntingtin in patients is possible.

What's next?

Until we see the data, there's no way to predict what will happen next. But here are some ideas that are sure to be discussed: first, should we be trying to treat HD patients earlier, even before they have advanced symptoms? Second, should we be trying to only lower mutant huntingtin protein (as Wave Life Sciences is currently trying to do in their ongoing study)? Third, should we be trying to lower huntingtin more or less than we did in this trial? You can bet that folks at Ionis and Roche are talking about this right now, as are other HD scientists around the world.

Meanwhile, even though dosing has been permanently stopped in the GENERATION-HD1 trial, Roche intends to continue monitoring participants to measure the longer term safety and effects of tominersen.

Gratitude for patients, physicians and companies

This trial was an enormous undertaking. The HD patients who volunteered in these early trials are forever HD heroes who took on significant risk for themselves on behalf of the entire HD community. Researchers in basic science labs, at both Ionis and at Roche, worked tirelessly to design the best possible drug for testing. And everyone who worked in clinics around the world to test the drug labored relentlessly to see if the drug worked. Everyone involved - families, scientists and physicians - wanted another outcome, but we just didn't get it this time.

Onwards

There's no doubt about it - this is a sad day for the HD community. HDBuzz is feeling sad and disappointed right along with you. But this trial was run in a way that is going to help us better understand how to design the next trial, and what we learn from this setback will be incredibly informative for the worldwide HD research community. And this community - both HD families and HD scientists - have proven that they can do hard stuff together, so we'll shake ourselves off and do it again. And we'll keep doing it until HD is no longer a threat to ourselves and our loved ones.

Families around the world are being impacted by COVID-19, but hope is on the horizon in the form of revolutionary new vaccines which were developed in record time. How is the coronavirus impacting HD families, and should they be worried about any of the vaccines coming to market? Should HD patients get the vaccine? We'll unpack this below, but the short answer is - absolutely, yes!!

HD and infectious disease

Making it through everyday life for Huntington's Disease families can feel like a marathon. The stress induced by the coronavirus has made things even tougher. HD patients often struggle with isolation, and being stuck in and out of lockdown only compounds these feelings of loneliness. Accessing regular medical care to deal with HD-related issues is also much more challenging, when doctors offices and hospitals can feel very threatening and scary.

In a series of incredible breakthroughs, infectious disease scientists were able to develop a number of highly effective vaccines for the coronavirus in record time. As 2021 gets underway, we find ourselves with several vaccines that have been approved by regulators, with several more on the way.

For good reasons, HD families are nervous about anything that could impact the well-being of their loved ones with HD. So should they encourage the HD patients they love to get a vaccine? Below, we unpack some of the concerns that HDBuzz has heard from the HD community about the coronavirus and vaccines, but if you just want the short answer - our strong opinion is that anyone who is eligible for the vaccine should get it, including HD patients.

mRNA sounds scary?

One concern voiced by the community is that several of the new vaccines - tested and sold by Pfizer/BioNTech and Moderna - rely on a novel technology called messenger ribonucleic acid (or mRNA). At HDBuzz we're often talking about mRNA in the context of Huntingtin lowering trials, such as those using ASOs, which we've talked about a lot here and here. These drugs target a specific mRNA in our cells - the one that tells them how to make the Huntingtin protein - for destruction.

If drugs like ASOs target mRNA to try and cure HD, and these vaccines have mRNA in them, should we be worried? No! mRNA is one of the most common types of components of our cells, each of which contains literally tens of thousands - if not hundreds of thousands - of different types of mRNAs. mRNA messages are plentiful in almost all living things so we safely ingest mRNA all the time when we have fruits and vegetables and other foods, at much higher levels than anything that is in mRNA vaccines.

If our cells contain a vast library of mRNAs, the Huntingtin lowering drugs that we're hopeful about are like sneaking into the library, taking one book off the shelf and tearing it up. The new vaccines that rely on mRNA technology are like sneaking an entirely new book - one that teaches our cells how to recognize the coronavirus - and quietly putting it on the shelf.

How can fast trials properly assess new vaccines?

But what about the fact that these vaccines were tested so quickly, doesn't that mean that they're not as rigorously tested as other drugs? Thankfully, the answer to this is a clear no. The initial development of the coronavirus vaccines did happen very quickly, but this was in fact building upon a huge foundation of work on mRNA vaccines, prepared for by many years of work by scientists around the world who were making mRNA vaccines for other illnesses who could then apply their technology to help fight the pandemic.

All of the available vaccines have been very carefully tested and have been shown to meet very strict safety criteria determined by different independent drug agencies, like the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). It is true that this happened faster than normal, but the corners cut to speed up the process were mainly bureaucratic rather than scientific. Because there was such an urgent need for the vaccine, all of the different players involved in making, testing and assessing the vaccines, worked very closely together and removed administrative roadblocks which often slow down the approval of new medicines.

The reality of HD and infections

HD is a demanding illness for families and the added complications of dealing with COVID infection for a person with HD or their caregiver can really add to the daily struggles which they might face. Although people with HD are not at any increased risk of contracting COVID, having COVID is certainly to be avoided as far as possible.

We still know very little about whether people with HD are affected by COVID infection worse than other groups of people but the data for the wider populations has shown that COVID can have devastating effects in otherwise healthy people. It is important we all do our best to stop the spread of this disease by following public health advice to stay home as much as possible, wash our hands, follow social distancing rules and wear face masks - things we are probably all too familiar with now one year into this pandemic.

Vaccines are another important part of stopping COVID infection in its tracks. COVID vaccines have been shown to be some of the most effective vaccines scientists have made to date with over 90% efficacy in some cases! There is no data to suggest that HD patients specifically should not get the vaccine, which was tested in a very broad range of people and has now been administered to huge swathes of the populations in countries like the USA and Israel. So far, the groups who are advised to hold off from getting the vaccine are people who are immunocompromised and those who have allergies to ingredients in the vaccines. This means that most people with HD have the green light to go ahead and get vaccinated.

What do the doctors say?

We spoke with some expert HD doctors to hear what they think about the COVID vaccines.

"We are incredibly fortunate to be living in an era in which medical science has advanced to the point that we have vaccines less than a year into a pandemic. I and my colleagues in the Cardiff HD centre have now been vaccinated and I’m delighted to see that our local HD community are starting to be offered the vaccine. COVID-19 is a nasty condition and, especially considering what we now know about its impact on the brain in some individuals, it is clear that having the vaccine is far safer than catching COVID-19." - Professor Anne Rosser PhD FRCP

"To be vaccinated is to be given a superpower - the ability to defeat an enemy you haven't even met. I volunteered for the clinical trial of the AstraZeneca vaccine and have been spending all my free time since Christmas eve vaccinating the people of London. The choice to consider isn't between the vaccine and nothing, it's between the vaccine and covid, which is the biggest threat currently facing the HD community. The vaccines are safe, incredibly effective, and pose no special risks to people with HD now or in the future. We need to do everything we can to get all our HD family members protected and safe from covid, so that we can get back to fighting HD together." - Professor Edward Wild MA MB BChir FRCP PhD

"Patients and their families are asking about Covid-19 and Huntington’s disease. We are learning more and more about the pandemic and the vaccines to prevent the infection. There is a lot that we know and a lot that we do not know. Covid-19 is a potentially fatal condition. There are risk factors that make it more dangerous including older patients and those with other medical problems. Patients with Huntington’s disease are more likely to become sicker due to Covid-19 if they become infected. We do not have data about this in detail, but most physicians agree that HD patients should do everything that they can to prevent infection. I encourage all my patients to get approved vaccines when they are available. There are some risks to the vaccines, but these are minimal compared to getting the infection. There is no indication that taking medications for the treatment of HD will make someone more susceptible to the infection or make their condition worse. There is also no indication that any of the investigational drugs that are being tested for HD either for symptomatic improvement or reducing the rate of progression will make HD patients worse or increase the risk of getting Covid-19. In balancing risks and benefits, In summary, get vaccinated as soon as possible." - Mark Guttman MD FRCPC

""The science supporting the approved COVID vaccines is compelling. They are safe and effective, and while not tested specifically in the HD population, I would still encourage people in HD families to consider being vaccinated if they are offered." - Professor Victor Sung MD

The bottom line

The science shows very clearly that the COVID vaccines are safe, effective and our best chance at combating this pandemic.