Clinical Considerations and Impact of Newly Approved Zilganersen for Alexander Disease

In early September, the FDA approved zilganersen injection (Zanvastro; Ionis) for the treatment of Alexander disease in pediatric and adult patients, marking the first approved therapy for the disease and the first antisense oligonucleotide approved for any leukodystrophy. The decision was based on a multicenter, randomized, controlled phase 3 study enrolling 49 pediatric and adult patients 2 years of age and older, in which patients treated with zilganersen showed significantly better walking speed at 61 weeks compared with untreated controls.

Amy Waldman, MD, is the Medical Director of the Leukodystrophy Center and a pediatric neurologist at Children's Hospital of Philadelphia, where she has been one of the leaders of the clinical development of zilganersen and cares for patients with Alexander disease and other leukodystrophies. Following the approval, NeurologyLive^® sat down with Waldman to discuss what the drug is, how it works, and what clinicians need to know as they begin incorporating it into practice.

In this Q&A, Waldman explained zilganersen's mechanism as an antisense oligonucleotide targeting GFAP RNA, walked through the key clinical and safety considerations for treating patients across a wide range of phenotypes and ages, addressed what the approval means for future drug development in leukodystrophies, and shares her call to action for the clinical community on diagnosis and long-term care.

NeurologyLive: For clinicians who might be unfamiliar with this drug, provide a little bit of background on what zilganersen is and how it operates.

Amy Waldman, MD: Zilganersen is an antisense oligonucleotide that binds to the GFAP RNA. When it binds, it triggers RNase H1-mediated cleavage of the GFAP RNA, which reduces the expression and decreases the amount of protein being made in the astrocytes.

This being the first FDA-approved therapy for Alexander disease, what considerations should clinicians keep in mind when discussing this therapy with patients and families?

This is very exciting for the community, not just for Alexander disease. It is the first time that an ASO or any treatment is available for Alexander disease. It is the first ASO for leukodystrophy. It really speaks to the proof of concept that you can either get the body to make more of a protein or make less of a protein, the latter of which we're doing in this case. It is the first therapy targeting the glial cells as opposed to the neurons. So, there are a lot of ways that this therapy gives hope for diseases beyond just this one.

But specifically for Alexander disease, I will mention that Alexander disease is very clinically heterogeneous. The heterogeneity is with respect to the clinical symptoms, which vary by age of onset. Across the age span, patients with Alexander disease look quite different. In younger patients, they have developmental delays, seizures, and macrocephaly. In older individuals, they have a lot of gross motor challenges, balance difficulties, and more brainstem-related findings.

This is a drug that is approved broadly for all patients across the age span and all phenotypes. It's very important for neurologists and primary care physicians to get to know the patient, get to know what this disease means for them, what their clinical symptoms are, and think beyond the brain.

A lot of the symptoms are affecting other parts of the body, and many physicians don't realize that they're brain-mediated. For example, vomiting is very common in Alexander disease because the dorsal medulla in the brainstem is our vomiting center. A lot of patients think it's a GI issue when it is, in fact, related to the underlying disease. Or dysphagia from bulbar weakness or even sleep apnea from different pathways being affected in the brainstem. I really encourage physicians to get to know each individual patient's symptoms, what to look for, and to monitor these patients very closely.

And when you give a new drug, you then have more of an understanding of what the benefits are. Is the patient showing improvements, or more importantly, is the patient remaining stable? Many patients throughout the trial were stable, and we can't expect a drug to always improve a disease if you have brain atrophy. A lot of patients with Alexander disease have atrophy of different regions of the brain, and we're not going to bring back those cells. So, making sure a patient is remaining stable on therapy is really the primary goal, even though I know so many patients want to see improvements.

Can you run through the safety profile of zilganersen and what physicians should keep in mind when administering it?

The drug was actually very well tolerated. It really does have an excellent safety profile. I saw many patients after anesthesia and after their lumbar punctures, and they were doing very, very well. Overall, the safety profile is incredibly favorable. We did see from time to time, in patients receiving zilganersen but also in patients in the control arm, things that you would expect after anesthesia or after a lumbar puncture, some occasional vomiting and headache, but nothing that didn't resolve either on its own or with some symptomatic therapy.

There was a patient with aseptic meningitis who was able to be rechallenged with the drug and did quite well. I will also remind families and physicians that we used atraumatic needles in this trial to try to limit some of the post-LP headaches, and it was very successful in that sense. Using atraumatic needles makes it a little more technically challenging, but does result in a lower rate of some of those typical post-LP complications.

Going back to vomiting, which was common after anesthesia, sometimes we ask is that the underlying disease, a response to anesthesia, or some other reason? This just goes back to really understanding the disease. Increased intracranial pressure is something that occurs in Alexander disease, and we more commonly see elevated opening pressure when a spinal tap is performed.

Sometimes we're seeing some high pressures in Alexander disease that are related to the disease itself, not necessarily the treatment. When you do the lumbar puncture and someone has elevated opening pressure, especially younger children, they need to be closely monitored for vision changes or other symptoms related to that. It's a known thing about the disease, but it could be confusing for a physician who goes to do a spinal tap, sees elevated pressure, and doesn't have an etiology for it.

What are some of the downstream impacts this approval has on those with Alexander disease and the wider leukodystrophy community?

I feel like it provides hope for so many other disorders. If an ASO is successful for one disease, could it apply to my disease as well? Reminding patients that we don't just pick, I'm going to do a gene therapy, I'm going to do an ASO, I'm going to do CRISPR. It really gets to the biology.

If there's a disorder where you have to turn on a gene or turn off a gene or increase or decrease the amount of protein being made, that lends itself to this type of treatment. Whereas if you have a disease where there's an enzyme deficiency, it comes back to the underlying biology. But for the safety profile and for the proof of concept, it really does open the doors for other disorders to say we can use this therapy successfully and safely in patients with disorders that affect multiple different areas within the brain, not just the neurons.

If you had to give a call to action to the clinical community, what more needs to be done to further the conversation around treating, diagnosing, and caring for patients with Alexander disease going forward?

First and foremost, we have to improve our diagnostic odyssey and accuracy. Recognizing patients with the disease is going to be first and foremost. It's much easier in the pediatric space because clinical seizures often lead to imaging, which leads to the diagnosis. But it gets a little more challenging in older individuals where they have more gait disturbances and people will get an MRI but not necessarily know how to interpret some subtle findings on the scan.

So, making sure that we are accurate in our diagnoses first and foremost. But then also understanding the heterogeneity within the disease and some of the variety in clinical symptoms and disease trajectories. How some patients seem to progress more quickly than others, and some regions of the brain are affected in some individuals more than others. Now it's really about trying to understand how the treatment works across all these different phenotypes and learning more about the long-term effects of the drug and knocking down GFAP in general.

Is there any cutoff for patients who may not be eligible for this drug, or who may be too far progressed?

Currently, no, thank goodness. One of the nice things about how this trial was designed is that it had broad inclusion criteria. We weren't restricted to patients of a certain age or a certain phenotype, and to the credit of the company in designing this trial, there really was a broad indication for treatment. I have had the pleasure of seeing patients of all ages go through this trial with success, and so I'm thrilled that I don't have that heart-wrenching discussion like we do in other leukodystrophies where I say, you're too progressed for treatment. Right now, there is no limitation, and anyone with the disorder would qualify for treatment.

Transcript edited for clarity.