Putting it in print: a clinical trial trying to rein in runaway pruning

HDBuzz coverage of research and therapeutic efforts in Huntington’s disease (HD) has increasingly highlighted genetic approaches to treatments, like huntingtin-lowering (targeting the toxic protein) and somatic instability (targeting the expansion of the CAG number in the disease-causing gene). But all the while, there have been other efforts to target the “downstream” biology of HD – the stuff that happens within the brain and body over time as a result of having the HD gene.

In particular, HD can affect how well the immune system works within brain cells. A recent publication presents the results of a clinical trial led by Annexon Biosciences that tested an immune-targeted drug (ANX005, also called tanruprubart) to treat a small group of adults with HD, with the aim of correcting this immune system imbalance.

Annexon shared these results with the community way back in June of 2022 after the completion of the trial, and we mentioned their approach in a 2023 Buzz article, but despite positive findings, there hasn’t been much momentum for tanruprubart as a possible treatment for HD. Nevertheless, peer-reviewed publication is an important milestone that involves significant effort, and suggests that HD remains on the company’s radar. Let’s talk about the study findings and why next steps can sometimes take a while.

Science to Suppress Synaptic Snipping

Annexon’s efforts in developing new drugs have focused on a branch of the immune system that becomes overactive in HD. Specialized immune support cells called microglia make up about 10% of the human brain. Their job is to investigate damage and infection, clean up debris, and coordinate the brain’s response to injury.

One of the microglia’s maintenance jobs involves “pruning” the connections between neurons. These touchpoints, known as synapses, are constantly changing to accommodate growth, experience, and learning, so unnecessary or damaged connections must be removed. At earlier stages of life, when the brain is changing rapidly, this is an especially active process. The pace of this synaptic pruning slows down the more we age. But in people with HD, the microglia can become overactive, potentially eliminating useful cell-to-cell touchpoints and disrupting communication.

*Touchpoints between neurons, known as synapses, must be “pruned” to accommodate growth and change.*

Microglia are guided to synapses by a “tagging” process known as complement, a key part of the immune system. The “on” switch for this tagging is a protein called C1q. Annexon’s drug, ANX005 (now tanruprubart), interferes with C1q. The goal is to prevent too much tagging of synapses, in hopes of reining in overzealous synaptic pruning. Ultimately, the idea is that this could help preserve connections between neurons and promote healthier communication networks in the brain.

An Open Label Design

This was a small study involving just 28 people with HD, all of whom received tanruprubart. When everyone in a clinical trial receives the drug and no one gets a sham treatment or placebo, it’s known as an “open label” study. Participation depended on age (over 18), CAG number, and a specialized “independence score” that is a part of the Unified Huntington’s Disease Rating Scale (UHDRS). Some participants were presymptomatic, and some had early HD symptoms.

Everyone visited a clinic at the beginning of the study for the first blood infusion of tanruprupart, a second 5 or 6 days later, and then again every 2 weeks for up to 6 months. After that, the infusions stopped, but participants had regular follow up visits for another 3 months to continue studying the safety and the effects of the drug. At some visits they gave blood or spinal fluid samples, or performed tests of movement and thinking.

Because this was the first time that tanruprubart was tested in people with HD, the primary objective (main goal) of the study was to study safety and tolerability. Every clinical study must report what side effects or serious medical events each participant experienced, and whether anyone chose to stop for these reasons.

In addition to safety, the study recorded the amount of tanruprubart found throughout the body and how long it stayed there, and looked at whether the drug was working as planned. To do this, the researchers measured levels of different proteins, like C1q, the immune tagging “on” switch that tanruprupart blocks, as well as other parts of the tagging machinery. The study also measured levels of NfL, which can be a sign of damage to neurons.

All of these measurements and observations are detailed in this new publication so let’s get into what the researchers found.

*Too many tags can cause microglia to be overzealous with their pruning.*

Side Effects And A Successful Shot On Goal

The key findings were that tanruprubart seemed to be safe in people with HD, and that side effects were generally manageable. All of the participants developed an uncomfortable or itchy rash after the first infusion of the drug. They were offered remedies to prevent or soothe the rash for later injections, but needed them less as time went on.

When a drug affects the immune system, there can be a risk of triggering autoimmune-like symptoms. In this study, these effects appeared in a few people who already had signs of having a very active immune system before even receiving the drug. Three people left the study for this reason, but their symptoms went away after stopping the drug, which is good news.

Another important finding was that tanruprubart did what it was designed to do, decreasing levels of C1q and other proteins involved in tagging and pruning synapses. In theory this means that the microglia should have focused less energy on pruning connections between neurons!

Some data was less clear. A biomarker of overall brain health, called NfL, had pretty variable levels, so that part was hard to interpret. Typically, we would hope NfL levels would go down if brain health was improving but there was no clear trend to suggest this had happened.

Some Systems Are Snippier

When Annexon’s clever math whizzes were analyzing the data, they did what’s known as a post-hoc or after-the-fact analysis. They split the folks participating in the trial into two groups based on how active parts of their immune system were at the beginning of the study. They measured levels of complement system proteins, and saw that some people already had higher immune activation, while others had less. In other words, some people began the study with a more overactive pruning system than others.

These participants who started with higher levels of complement activity seemed to have some possible clinical benefit from tanruprubart. Over the 9 months of the study, their performance on movement and thinking tests and day-to-day abilities remained stable compared to what is predicted from studies that follow people with HD over time. This was measured through a combination score called the cUHDRS and a measure of day-to-day function called Total Functional Capacity (TFC).

It’s very important to note that these results were based on only 12 people in the “high complement” group and 11 people in the “low complement” group, a very small sample size. This study was also not designed to measure if the drug gave any benefit; it focused on safety. As we will continue to reiterate with every small-scale data announcement, promising early results warrant cautious optimism and justify larger studies.

So… What’s The Holdup?

As we said at the outset, this paper follows up on news from 2022. It’s one thing to announce the top-line data: news that a drug is safe, works as designed in the body, and shows potential for benefit. It’s another thing to dive into the nitty-gritty details and publish these findings in a peer reviewed journal – a coordinated effort that can sometimes span years.

In fact, there’s an entire industry (known as medical communications) focused on the clinical trial publication process, ensuring that scientific findings, especially those involving human participants, are accurately, thoroughly, and thoughtfully reported. It may feel anticlimactic in 2026, but when a publication comes to fruition, we think that’s worth highlighting.

*Creating a research publication is a coordinated effort that can sometimes span years.*

There are lots of reasons that companies might choose not to focus their energies in a particular direction (like HD), even when the data is promising. Funding and strategic priorities play a role – it’s tremendously expensive to see a drug from discovery through approval, and it sometimes takes the support of a bigger company to run a bigger trial.

Overactivation of the complement system is a feature of other diseases, and Annexon has prioritized testing tanruprubart in people with conditions like Guillain-Barré syndrome, where it has also shown encouraging results, so HD may simply be on the back burner.

Easter Eggs and Takeaways

In summary, the main findings in this paper – that tanruprubart appears safe, works as designed, and shows promise in a small group of people with HD – might seem like old news, but it’s important to acknowledge the publication of these findings.

If you have a super keen eye for HD news (and if you caught this, we’re genuinely impressed), you might have noticed something odd. In public-facing communications from Annexon and in clinical trial databases, this study was labeled as Phase 2 or Phase 2a, whereas the recent publication calls it Phase 1b. It’s not a different trial – it’s simply that phase definitions aren’t completely standardized and can blur a little depending on the conventions of reporting, registries, and publications. What phase would come next is not yet clear.

Finally, in recent correspondence with company representatives, HDBuzz learned that Annexon remains engaged in HD, so we hope to hear more about plans for tanruprubart in the near future.

Summary

A recently published study tested tanruprubart (ANX005), a drug that targets the immune system in HD.
The drug blocks C1q, a protein within a part of the immune system, known as complement, that helps tag synapses for removal by support cells.
In HD, this system may become overactive, leading to excessive “pruning” of connections between neurons and disrupted brain communication.
The trial included 28 people with HD and used an open-label design (everyone received the drug). The main goal was to test safety and understand whether it was hitting its target.
Tanruprubart was generally safe, though all participants experienced a rash after the first infusion, and a few developed autoimmune-like side effects which later resolved.
The drug successfully reduced levels of C1q and related complement proteins, showing it hit its intended target.
In a subgroup of participants with overactive pruning systems, there were hints of clinical stability, but the numbers were very small.
Despite promising early findings, no larger HD trial has followed.
Annexon has focused on other diseases (like Guillain-Barré syndrome), where the drug has also shown encouraging results.
The company says it remains engaged in HD, but future plans are unclear.

Putting it in print: a clinical trial trying to rein in runaway pruning

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