On May 5th, PTC Therapeutics released results from their ongoing Phase 2 PIVOT-HD clinical trial for PTC-518, now called votoplam. Excitingly, they announced that this trial met its primary endpoint - votoplam was shown to lower huntingtin protein levels. We also learned more about the safety of this drug and some insights into how it might be changing biomarkers and symptoms of HD. Let’s get into it.

What is votoplam?

Votoplam belongs to a class of drugs known as splice modulators. The drug can be taken as a daily pill - a convenient and non-invasive method of delivery. The drug is a chemical that changes how the RNA message molecule, which encodes the instructions for making the huntingtin protein, is processed. The drug triggers the RNA message to be degraded, and as a result, less huntingtin protein is made.

The drug is not selective, which means that it lowers the levels of both the regular form of the huntingtin protein, as well as the expanded form that people with HD make. Votoplam acts systemically - this means it works throughout the whole body, not just in the brain and central nervous system like many of the other huntingtin-lowering therapies in development. In the ongoing Phase 2 trial, the pill is being tested at 5 and 10 milligram (mg) doses compared to placebo, in two different groups of people with HD; those with Stage 2 disease and those with Stage 3 disease.

The initial trial was designed to only be 12 months long, with data readouts at 12 weeks and 12 months. Then all folks were allowed to remain on votoplam in an “open label extension”, aka OLE - this is where people continue to take drug, or switch from placebo to the drug, while still be followed in the trial to get a better idea of the long term effects the drug may be having.

Endpoints in Clinical Trials

At the beginning of the clinical trials process, a series of outcomes are established that define the things that the drug maker thinks should happen in people as a result of being given a drug. Kind of like a game of billiards, where players have to call the shots before they take them. It shows intent throughout the process. These defined outcomes are called “endpoints”. This is in addition to safety parameters, which are paramount in all stages of clinical trials, and even after a drug is approved.

In a Phase 2 trial, we are generally testing to see if the drug is doing what it is designed to do based on the pre-defined endpoints, in ways we can precisely measure. In the case of votoplam, the primary endpoint was lowering the amount of huntingtin protein.

Additional measures then test if the drug might actually be benefiting disease. For the PIVOT-HD trial, PTC are usings various clinical tests to measure the progression of HD. In addition, PTC are collecting data that measures the biological progression of disease. For that, they’re using MRI to measure the volume of the brain, which we know decreases as the disease progresses. They’re also measuring neurofilament light protein (NfL), which is an indicator of the health of neurons. We know NfL levels rise as brain cells are lost to HD and the disease progresses.

“On May 5th, PTC Therapeutics released results from their ongoing Phase 2 PIVOT-HD clinical trial for PTC-518, now called votoplam. Excitingly, they announced that this trial met its primary endpoint - votoplam was shown to lower huntingtin protein levels. ”

What the PIVOT-HD Data Says, So Far…

In this update from PTC, they shared the data from all participants at the 12 week and 12 month timepoints, as well as some early data from folks who have reached the 24 month time point.

Safety

The most important take home message is that the drug continues to appear to be safe - there were no Serious Adverse Events (SAE) caused by votoplam. This has halted previous trials for HD in the past, so this is great news for the HD community.

Huntingtin Lowering

Secondly, the levels of huntingtin protein are indeed being lowered by votoplam. PTC shared data showing that for people taking votoplam, huntingtin levels are being lowered through the 12 month mark. This is really the make-or-break metric since huntingtin lowering was the primary endpoint for this trial.

Whether they measured in blood or spinal fluid, PTC saw that the higher dose of the drug lowered huntingtin more. This dose-dependent effect was confirmed for participants with Stage 2 or Stage 3 HD.

In the May 5th update, they hadn’t yet analyzed the 24 month samples for huntingtin levels, so that’s something we’ll be looking for in a future update.

Biomarkers

Next up - NfL. Nfl has become a critical biomarker for HD. It’s a well established way to measure the health of neurons in the brain for HD and other brain diseases. The data at 12 months was not presented for all participants so we don’t have an overall picture.

Instead, data were broken down to divide participants by HD-ISS stage. This sub-group analysis suggests that perhaps there is a slightly more positive effect in people with Stage 2 HD, but the data is less clear for people with Stage 3 HD. The good news is that they didn’t see any of the NfL level “spikes” recorded in other trials investigating other types of huntingtin-lowering drugs.

In folks who have been taking this drug for 24 months, levels of NfL in blood samples were found to be lower than expected. This data might suggest that votoplam may be having a protective effect on brain cells in a longer timeframe. Typically, we would expect an increase in NfL levels of about 12% per year in someone with HD. For people on votoplam, NfL levels decreased 9% for those on 5 mg and decreased about 14% for those on 10 mg. This is very promising data but it is important to note that this finding is from a much smaller number of participants than the 12 month data, so it should be interpreted cautiously. Additionally, everyone at the 24 month time point was in Stage 2 of disease at the start of the trial.

Brain MRI Scans

“In folks who have been taking this drug for 24 months, levels of NfL in blood samples were found to be lower than expected. This data might suggest that votoplam may be having a protective effect on brain cells in a longer timeframe. ”

Another piece of data that PTC shared were changes in brain volume. These data were harder to interpret - at 12 months, there didn’t seem to be a clear trend of how votoplam could be influencing changes in brain volume.

This could be for several reasons that make brain volume changes tricky to measure, like the influence of brain cell loss vs. brain swelling. If there is brain inflammation, it could look like volume is higher, but it may not be for a good reason. Another variable here could be timing - 12 months might just not be long enough to see meaningful changes in brain volume. So the jury is still out on how votoplam could be influencing brain volume.

Clinical Readouts

Another set of data that was tricky to interpret were the clinical readouts. To determine how votoplam may be influencing progression of HD, PTC looked at:

• Total Functional Capacity (TFC) - a collection of tests that measures someone’s ability to live and function independently.
• Total Motor Score (TMS) - a clinical assessment of HD-associated movement symptoms.
• The Symbol Digit Modalities Test (SDMT) - which asks people to match numbers to symbols to measure visual attention and thought processing speed.
• The Stroop Word Reading test (SWR) - which measures the ability to concentrate through cognitive interference.
• The Composite Unified Huntington’s Disease Rating Scale (cUHDRS) - a sensitive collection of all the above tests that measures the ability to function day-to-day while also assessing movement control, capacity to pay attention, and memory. Since cUHDRS is a collection of TFC, TMS, SDMT, and SWR, its score can be influenced by each of the separate readings.

Overall, cUHDRS seemed to improve slightly for people with less advanced, Stage 2 disease at 12 months. The improvements appeared to be primarily driven by the TMS and SDMT, suggesting these modest improvements were related to movement and thinking. However, SDMT improvements were only seen in the higher (10 mg) dose group.

For people with more advanced, Stage 3 disease, the results were less clear at 12 months. The cUHDRS showed a very small improvement for folks in this group on the low (5 mg) dose, but those on the higher (10 mg) dose didn’t see the same improvement. There also wasn’t a clear indication for what specific metrics were driving the cUHDRS scores.

For the data we have from the Stage 2 folks who have reached the 24 time point so far, the clinical readouts look similar - there are favorable improvements in cUHDRS which appear to be happening in a dose-dependent manner. In these data, this positive trend seems to be driven by improvements in TFC and SDMT, suggesting improvements in functional capacity and cognition. However, the improvements for TMS from 12 months didn’t hold, meaning changes in movement symptoms don’t seem to be driving the improvement here like we saw at 12 months.

Pharmacology: Dose Matters

An interesting question that arises from this update is how much huntingtin lowering do we need? The modest clinical benefits suggested by the data from PIVOT-HD are happening with 24% (low dose) to 39% (high dose) huntingtin lowering. This suggests that perhaps we don’t have to lower huntingtin levels as much as we previously thought - to around 50%. But it also begs the question - if we lower huntingtin more with votoplam, will we see stronger clinical effects?

For those with Stage 2 disease, PTC saw some signs of clinical improvements at the low dose (5 mg), which seemed to improve further at the high dose (10 mg), suggesting that maybe more drug and more lowering could be better. However, for folks at Stage 3, the results didn’t suggest that more drug had a better outcome - this could be due to several reasons. It may be that people at Stage 3 are taking different medications that influence the clinical tests being measured. For example, medication for chorea-related movements could influence motor tests. Or, the results might suggest that the earlier we treat people, the more effective the drug will be. Another possibility moving forward it that we may need to tailor a drug’s dose to the stage of disease of the person being treated.

For now, the data showing differences in Stage 2 and Stage 3 open up the question: does votoplam have a different clinical effect based on disease stage? As we continue to collect more data from the PIVOT-HD trial, it could help guide inclusion criteria for potential future clinical trials.

“For now, the data showing differences in Stage 2 and Stage 3 open up the question: does votoplam have a different clinical effect based on disease stage? As we continue to collect more data from the PIVOT-HD trial, it could help guide inclusion criteria for potential future clinical trials. ”

Lessons for Other Drugs in Trials or Pending Trials?

A further important finding from this update is that non-selective lowering of both the regular and expanded huntingtin protein seems to be fairly safe. This is good news for other so-called “total huntingtin” lowering approaches being developed or in the clinic, such as tominersen and AMT-130.

Another important question this trial brings up is brain vs. body - how important is it to target huntingtin lowering throughout the body, or just in the brain? How much does expanded huntingtin created outside the brain contribute to Huntington’s disease? And, are there other disease-related effects caused throughout the body? To answer these questions, it will be important for scientists to compare votoplam clinical trial data to other huntingtin-lowering approaches that specifically target the brain.

Cautious Optimism

While the new data from PIVOT-HD is promising, there are still data to analyze and unanswered questions. For example, we’re still waiting on huntingtin lowering data from the 24 month time point. Additionally, the effects on some of the clinical endpoints measures still aren’t entirely clear, but are trending in what appears to be a positive direction for some groups.

However, the data presented in the May 5th update appears to continue to give green flags for votoplam. This positive news could lead PTC to enter discussions with the FDA for a potential accelerated approval of votoplam, using the metrics defined in December, but the company didn’t indicate if this was the path they would be taking. Their next hurdle is to do more data analysis and digest the data with their new partner Novartis to determine the next steps for votoplam.

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