October 2020 - Branaplam

While developing a drug called branaplam for patients with SMA, the pharmaceutical company Novartis discovered that it could hold promise for people with HD. The FDA has granted a special status called Orphan Drug Designation to branaplam.

Branaplam was originally developed for the treatment of the neurological disorder spinal muscular atrophy (SMA) and is still under clinical investigation for this purpose. Branaplam works by interfering with how genetic messages are processed in cells and can increase the levels of a protein called SMN2. Boosting levels of SMN2 helps SMA patients who have lower levels of this protein which is the underlying cause of the disease in many cases.

Interestingly, it seems that branaplam also reduces the levels of the huntingtin gene message and the huntingtin protein. This is what huntingtin-lowering therapies all aim to do and is how many researchers and companies hope to treat Huntington’s disease.

The huntingtin-lowering therapies currently in clinical trials need to be given through spinal injections or brain surgery. Unlike these, branaplam is a small molecule drug, which means it can be taken as a tablet. If Novartis can show that branaplam is an effective treatment for HD, this would mean that it could be given as a pill, a more convenient option for HD patients!

February 2021 – GPR52

Scientists have found new leads for how to reduce the levels of the Huntington’s disease (HD) protein by targeting a protein called GPR52. A team of researchers working in Shanghai, China developed small drug-like molecules which lower huntingtin protein levels in HD tissue culture models and in HD mouse models. Treatment with their molecules was also shown to improve the HD mouse symptoms.

New avenues for huntingtin lowering

Huntingtin-lowering therapies are heralded by many researchers and clinicians as a very promising avenue for treatment of HD. People with HD have a longer or expanded CAG number in their HD gene, huntingtin. This means that throughout the body and brain they make a different, longer form of the huntingtin protein. This expanded protein is thought to be responsible for many of the symptoms we observe in people with HD.

The idea of huntingtin-lowering therapies is that if you reduce expanded huntingtin, you might also get rid of its toxic effects. There is evidence in lab HD models that huntingtin-lowering can slow or improve HD symptoms, but we await the results of ongoing clinical trials before we can be sure that the same effect will be observed in patients.

What has GPR52 got to do with huntingtin lowering?

GPR52 is part of a family of proteins called G-protein coupled receptors that sit on top of cells and receive messages, similar to a satellite dish. These types of receptors are commonly targeted by FDA-approved drugs. This gives scientists optimism that using new medicines to target members of this receptor family, like GPR52, could be safe and effective.

GPR52 was first identified by scientists as a protein of interest for HD in a genetic screen. A genetic screen can be thought of as a scavenger hunt, where scientists look at different genes one-by-one to see how they might, in this case, change signs of HD. Scientists then used genetic tricks in the lab to delete the GPR52 gene or to lower the levels of GPR52 protein, and this helped to improve signs of HD in cells and flies. A team of researchers in Shanghai, China, recently took this one step further and tried reducing the levels of GPR52 in mice. In this recently published research, they show that reducing GPR52 reduces the levels of huntingtin, indicating that GPR52 would be a good candidate to target with small molecules for huntingtin-lowering therapies.

Targeting GPR52 with small molecules lowers huntingtin and improves symptoms in HD lab models

The scientists describe the development of small molecules which stick on very tightly to GPR52 but not other proteins in our cells. These type of properties of a small molecule suggest that down the road this potential therapy could be very specific and avoid other unwanted effects. The best or lead molecule identified in this study, called Comp-43, was then used in a variety of different experiments to test how well it worked for huntingtin-lowering and reducing signs of HD-related damage and improving behaviour.

They first showed that Comp-43 could reduce huntingtin levels and preserve the health of mouse nerve cells in a dish. Following this exciting result, the scientists went on to test Comp-43 in HD mice. Critically, Comp-43 could cross the blood brain barrier in mouse models and lower huntingtin levels in some brain regions. This suggests that if Comp-43 was developed into a medicine in the future, people with HD might take it as a pill. Mice treated with Comp-43 had improved symptoms when tested on laboratory tasks that measure their movement and coordination, like a log-rolling exercise called the Rotarod or their ability to cross a balance beam. They also showed that mice treated with Comp-43 had more and healthier brain cells.

So, what’s next for GPR52 in HD research?

All of the data available in the literature to date indicates that GPR52 is a very promising drug target for huntingtin-lowering therapies but there are still many hurdles to cross before we are treating patients with GPR52 targeting molecules. Many therapies work well treating HD in cells in a lab dish or in different animal models of HD but don’t necessarily go the distance in safely treating people with HD.

It is not yet apparent what additional effects targeting GPR52 might have, beyond changing huntingtin levels and HD symptoms. GPR52 has important jobs to do in our nervous system and may play a role in dopamine signalling, chemical messages that affect mood, movement, and motivation. Sustained targeting on GPR52 by this type of huntingtin-lowering therapy might have side effects which we just haven’t yet observed in the shorter treatment experiments completed to date.

It should also be noted that targeting GPR52 lowers the levels of both normal and expanded huntingtin. We know that targeting both forms of the protein with other therapies such as Roche’s tominersen, which is also non-selective, is safe in the trials completed to date, but targeting expanded huntingtin while preserving normal huntingtin is still the goal for many researchers.

Nonetheless, small molecule targeting of GPR52 represents an exciting new way to lower huntingtin levels and we expect to see answers to many of these outstanding questions in future studies.

March 2021 - Tominersin

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.

Update – HD Therapeutics conference

Roche presented their data from the failed clinical trial, showing that at the doses and time points looked at, the ASO had no positive effect on patients- in comparison to a placebo. Basically, their symptoms did not improve because of the dosing, in fact at one dosing level, symptoms seemed to get worse. Whilst we do not fully understand the implications of this for future trials, Roche has committed to sharing the data to help improve trial design and HD drug research.  This has been disappointing for the HD community, however, there is a lot of exciting research in the pipeline that will benefit from all the data gathered.

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