NeuroVoices: Darcy Krueger, MD, PhD, on Ganaxolone, Genetics, and Drug Development for Tuberous Sclerosis


The director of the Tuberous Sclerosis Clinic at Cincinnati Children’s provided insight on promising drug developments for tuberous sclerosis complex and other notable priorities within the space.

Darcy Krueger, MD, PhD

Darcy Krueger, MD, PhD

Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in the TSC1 or TSC2 gene and is characterized by the growth of numerous benign tumors in parts of the body, including skin, brain, kidneys, and other organs. The disorder can cause a wide variety of symptoms, many of which include seizures and developmental delays. Most patients are treated with either everolimus (Afinitor; Novartis) or cannabidiol (Epidiolex; Genentech), which received FDA approval in 2018 and 2019, respectively.

Ganaxolone, an investigational neuroactive steroid that acts a positive allosteric modulator of both synaptic and extrasynaptic GABAA receptors, recently showed that it could be a potential add-on therapy for refractory epilepsy in patients with TSC. In a phase 2 setting, participants (n = 23) experienced a median 16.6% (95% CI, 59.1% to ­–18.8%) reduction in TSC-associated seizures, with 30.4% (7 of 23) achieving at least a 50% seizure frequency reduction.

Senior author Darcy Krueger, MD, PhD, claims that while drug development for this space is among the top priority, there are several other aspects that need continued research, including expanding more on the role of genetics. At the 2021 American Epilepsy Society (AES) annual meeting, December 3-7, in Chicago, Illinois, Krueger, the director of the Tuberous Sclerosis Clinic at Cincinnati Children’s, sat down to discuss the pulse of TSC research. As part of a new iteration of NeuroVoices, he discussed the phase 2 results, progress made in recent years, and what a phase 3 trial of ganaxolone would look like.

NeurologyLive®: Can you provide an overview of the phase 2 trial and its major take-home points?

Darcy Krueger, MD, PhD: The phase 2 trial was to look at a novel medication, ganaxolone, in how it may help people with intractable epilepsy, specifically tuberous sclerosis. Ganaxolone is a medication that targets the GABAA receptor, but it does it in a way that’s different than most of our other GABAA targeting seizure drugs. It’s not like phenobarbital, diazepam, clonazepam, clobazam, which are medications we’re more familiar with that target this pathway. It was an open-label trial where every patient enrolled received medication and were treated for several months. We evaluated both how well the dosing was working, in terms of any adverse effects we needed to watch out for, as we move forward into future clinical trials. They wanted to get some sort of idea on how well it was working in our patients with tuberous sclerosis who have difficult to treat epilepsy.

Is drug development currently the top priority in the TSC field right now?

I don’t think it’s the number 1 priority, but it certainly continues to be a high priority. We are also still working on how to better utilize the existing drugs as far as the timing and dosages involved. And we’re looking outside of traditional medications as a way to treat tuberous sclerosis, whether that be behavioral therapies for some of the neuropsychiatric components of tuberous sclerosis, or gene therapies, which there’s been a lot of talk about. We see that those technologies are moving forward, and we haven’t ignored that, we just knew there were some key mechanistic problems that had to be solved for gene therapy for everybody. Once those were solved, we were immediately going to be positioned to take advantage and start to get in that mode of gene therapy. I don’t know if we can say what’s most important but still, medication development, looking at new ways to treat epilepsy as we better understand epilepsy, is important for tuberous sclerosis.

How has genetics played a role in TSC, and how can we expand on that?

We’ve known the causative genes for tuberous sclerosis for a couple of decades. While there still remain cases of people with tuberous sclerosis for which we cannot make a confirmed genetic diagnosis, we still believe that the same genes are likely involved in some way or another. I thought it was fascinating that at AES we saw new a way of how we do traditional genetic testing. Why would they not pick up a genetic mutation when that gene is still involved? It can be involved in mechanistic control where the gene gets turned on or off. In this case, it was a mechanism that disrupted the process of making proteins once the gene was copied. I found that fascinating and got me to think more about that.

As far as our knowledge of genes in tuberous sclerosis, we’ve known generally that mutations in TSC1 and TSC2 can influence the likelihood [of tuberous sclerosis], but not necessarily specify what somebody’s risk for severe manifestations. We continue to refine that. That’s going to continue to move forward. One of the other areas that is fascinating is that we know that TSC1 and TSC2 are just a small set of genes in a whole instruction set that form the brain and tell it what to do. There are multiple researchers within the TSC community, as well as the epilepsy community, that are looking at the interplay between other genes that may be involved in some other rare epilepsy or genes that we see influence severity across multiple epilepsies. We have investigators looking to see where those genes play specifically with TSC1 and TSC2 to dictate severity. That’s going to be a huge leap forward in the genetic area for tuberous sclerosis.

Can you provide insight on a potential phase 3 trial of ganaxolone?

Enrollment has not begun, but the design of the trial is essentially complete. There may be some minor modifications as we get to the finish line before enrolling. It’s a phase 3, placebo-controlled, blinded trial. This is the type of trial that takes what we see in phase 2 and says, “this data looks promising,” to the type of data where the FDA says, “yes, this works, and you’ve proven that its safe and how it should be used.” Those are the things the FDA and other regulatory agencies around the world look for. They only come through a phase 3 design, which is what this will be.

Transcript edited for clarity.

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