RARE Daily

Inhibiting Electrical Activity in Rare, Seizure Disorders

July 27, 2023

CDKL5 deficiency disorder (CDD) is a serious and rare, genetic condition characterized by early onset and difficult to control seizures, as well as severe neuro developmental impairment. Last year, the U.S. Food and Drug Administration approved Marinus Pharmaceuticals Ztalmy to treat seizures associated with CDD, the first FDA approved therapy for the condition. Marinus is seeking to expand the use of Ztalmy in other seizure disorders including tuberous sclerosis complex and Lennox-Gastaut syndrome. We spoke to Alex Aimetti, chief scientific officer of Marinus, about Ztalmy, how it works, and the efforts to expand its use to other seizure disorders.

Daniel Levine: Alex, thanks for joining us.

Alex Aimetti: Thanks for having me, Daniel.

Daniel Levine: We’re going to talk about rare epilepsies, Marinus Pharmaceuticals, and its therapies, Ztalmy, which won approval last year for seizures associated with CDKL5 and is in development for other indications. Let’s start with CDKL5 deficiency disorder. For people not familiar with the condition, what is it?

Alex Aimetti: Yeah, certainly. CDKL5 deficiency disorder is a rare developmental and epileptic encephalopathy, which occurs in approximately one in 40,000 live births, which results in about 100 newborns each year. Here in the United States, it was named after the cyclin-dependent kinase-like 5, or CDKL5 gene, which is responsible for providing instructions to create a protein involved in brain development and function. The disorder is typically caused by mutations or alterations in the CDKL5 gene, which ultimately results in the production of a non-functional CDKL5 protein. In this disease state genetic testing is required to make an accurate diagnosis, and you know, certainly today we’re seeing a huge momentum within the epilepsy genetics world ultimately leading to increased testing, but I certainly think that there’s some additional work in education that can be done here to ensure complete diagnosis in these patients.

Daniel Levine: How does this condition manifest itself and progress?

Alex Aimetti: Yeah, so certainly seizures are one of the earliest, and by far most prominent features of CDKL5 deficiency disorder. They typically begin in infancy, often within the first few months of life and these seizures can be diverse in both seizure type as well as severity, and they oftentimes are difficult to control and may require multiple medications or alternative treatments. Now, we’re still learning a lot about the natural history of the disease and the evolution of the symptoms and comorbidities to really understand how the disease progresses. One thing that data would suggest that in cases where patients do have an early beneficial response to anti-seizure medications, it’s often that the efficacy wanes around three to six months. Therefore, there just continues to remain this need for an effective anti-seizure medication that offers a durable response.

Daniel Levine: And prior to the availability of Ztalmy, how are patients generally treated and what was their prognosis?

Alex Aimetti: Certainly. Currently there is no cure for CDKL5 deficiency disorder. Treatment primarily focuses on managing the symptoms and providing supportive care. Now specific to epilepsy, treatment is primarily based on seizure types and really weighing the clinical benefits and risks of any specific treatment option. Again, there’s strong evidence that suggests that CDD-associated seizures are highly refractory to previously available anti-seizure medications. Again, continuing to highlight that large unmet need in which we studied clinically.

Daniel Levine: Seizures are a common feature of CDKL5. For people who don’t live in a household with someone who has this type of disorder, the impact of these episodes can often be underappreciated. What kind of frequency and duration do these seizures occur with?

Alex Aimetti: Yeah, so patients with CDD experience very frequent and often severe seizures. In fact approximately 80 percent of patients experience daily seizures with approximately the remaining 20 percent experiencing weekly to monthly seizures. And as imagined, these seizures are detrimental to patient and family, quality of life, patient safety, and have potential long-term impacts.

Daniel Levine: Well, there’s also physical impact on the brain from seizures. What is the long-term physical impact that continued seizures have on the brain?

Alex Aimetti: Yeah, t that’s a great question and that certainly remains a hot area of research even today. It’s certainly believed that ongoing uncontrolled seizures could negatively impact cognitive function, brain structuring, connectivity, and ultimately lead to developmental delays. As a result, we truly believe that effectively treating seizures early could likely lead to improved non-seizure outcomes down the road, but then again, further research is certainly needed to definitively say.

Daniel Levine: And you mentioned impact on the whole family. What goes on in a household when a child has a seizure like this?

Alex Aimetti: Yeah. Not surprisingly, seizures are highly disruptive to daily life. They may cause children to miss school, therapy, and potentially other activities. These disruptive seizures can ultimately affect a family’s balance of good days with CDD, which are days with fewer seizures means that families can interact more easily with their child, feel more comfortable leaving the house for an afternoon or the park, or for dinner, for example.

Daniel Levine: Ztalmy is approved for this indication. What is Ztalmy?

Alex Aimetti: So Ztalmy is a neuroactive steroid that was the first drug to be specifically approved by the FDA for the treatment of seizures associated with CDD in patients two years of age and older. It is the first approved anti-seizure medication of this drug class called neuroactive steroids and provides a potentially exciting alternative to existing anti-seizure medications.

Daniel Levine: What are neuroactive steroids? Are these naturally occurring in the brain?

Alex Aimetti: So, they are, and in fact, ganaxolone is a synthetic analog of, or Ztalmy is a synthetic analog of a naturally occurring endogenous neuroactive steroid called allopregnanolone. And these molecules primarily act as positive allosteric modulators of GABAA receptors in the brain.

Daniel Levine: So, for a layman, what happens when they use Ztalmy? How does it work?

Alex Aimetti: Yeah, exactly how Ztalmy works to treat seizures and CDD is not fully understood, but it is thought to reduce seizures by enhancing the activity of GABA, which is an inhibitory neurotransmitter in the brain. So, more specifically, Ztalmy is a positive allosteric modulator of GABAA receptors, and we believe that it works to increase the inhibitory GABAergic tone through modulation of both synaptic and extra synaptic GABAA receptors. And I highlight that because this is unique to other GABAergic mechanisms and the action at the extra synaptic receptor could play an important role in the treatment of refractory epilepsies.

Daniel Levine: You say it’s unique. So how do epilepsy medications typically work?

Alex Aimetti: Yeah, so epilepsy is really just an imbalance of excitatory or inhibitory signaling within the brain. So, different anti-seizure medications can reduce excitation or increase inhibitory tone. A lot of the GABAergic compounds, including benzodiazepines, increase inhibitory tone or GABAergic tone within the brain. Ganaxolone and the class of neuroactive steroids is similar in the sense of how it acts on the GABAergic system. What makes it unique, relative to other GABAergic compounds such as benzodiazepines, is that action at the extra synaptic receptor, again, which we think can have potentially an important role in refractory epilepsies.

Daniel Levine: And what’s known about the safety and efficacy of Ztalmy from the studies that have been done to date.

Alex Aimetti: So, the study that led to Ztalmy’s approval was called the Marigold study. in this study, Ztalmy was assessed in a phase 3 placebo controlled global study in patients with CDD. This study enrolled 101 patients in this ultra-rare disease, which we think is exciting. And these patients were aged two to 19. The patients had a median approximately 50 seizures per month during the baseline period, despite being on and trying multiple anti-seizure medications, just really highlighting that unmet need. In the clinical study Ztalmy significantly reduced the monthly seizure frequency over a 17 week treatment period. Those that took Ztalmy experienced a four times greater reduction in seizure frequency of 31 percent compared to placebo of 7 percent. Also in this study, the most common side effects of Ztalmy were somnolence, fever, drooling in seasonal allergy. Now, that was the basis for ultimate approval. I think one thing that’s also worth noting here is that after patients left the double-blind phase of the study, they were enrolled into an extension and we now have data out to beyond two years. As I mentioned earlier, what the data would suggest in the literature, albeit through retrospective studies, is that efficacy of previously used anti-seizure medications likely wanes after three to six months of trial. We have data on 50 patients out to two years, and in those 50 patients, albeit in an open-label study, we’re seeing approximately a median reduction of 50 percent of their seizures relative to baseline, providing some preliminary evidence that Ztalmy could have a durable response over time, which again, requires further exploration.

Daniel Levine: There are a large number of rare neurodevelopmental conditions that have seizures as a feature. How much commonality is there across seizures and how well do we understand the underlying mechanism that causes them?

Alex Aimetti: Yeah, this is a good question, and the exact pathophysiology of these various diseases and how they lead to seizures is well understood for some conditions, but there still remains a lot to learn for others. However, with that said, the general mechanisms that lead to seizures are generally consistent between various diseases. And again, these existing anti-seizure medications really try to counteract those mechanisms such as increased excitation or loss of inhibitory tone.

Daniel Levine: There’s a big problem with seizures being intractable to existing medications. What’s known about Ztalmy beyond CDD?

Alex Aimetti: We believe that Ztalmy, or we call it ganaxolone as it’s called in its investigational indications, really could have the potential anti-seizure effects in a variety of patient populations. Pre-clinically, it’s been shown to have broad spectrum anti-seizure effects, which does give us confidence to study it in multiple patient populations. Currently, it’s being studied in a phase 3 study in tuberous sclerosis complex, which is another rare genetic epilepsy with predominantly focal seizures. And we’re looking to read out those data by mid-year next year. And lastly, we are currently in the planning stages of a clinical development program in Lennox Gastaut syndrome or LGS.

Daniel Levine: You’re also working on a second generation formulation of Ztalmy. How does that differ from the first generation?

Alex Aimetti: So, we’re certainly very excited about Ztalmy and the benefits we hope it’ll bring to CDD patients. However, with that said, we believe that there are attributes that we think we can improve upon with a new formulation. Specifically, there are some pharmacokinetic enhancements that we’re aiming to achieve that we hope will lead to both improved efficacy and tolerability and potentially even convenience with twice-a-day dosing. Now we’re still in the research stage of the new formulation development, and we’re currently conducting our phase 1 studies, and if we’re successful in achieving the attributes that we’re aiming to achieve, we hope to plan to study the new formulation in the Lennox Gastaut patient population.

Daniel Levine: So, would that have to do with some kind of time release formulation or the way it’s absorbed?

Alex Aimetti: Right now, in our second generation product portfolio, we have a few different approaches we’re taking. The first one is specific to formulation development where we think various excipients could help improve our oral bioavailability and absorption leading to some of those enhanced pharmacokinetic properties that I talked about. A little bit further behind that, in an earlier stage research phase, we are considering some pro-drug developments of ganaxolone that we think could potentially play an important role with some newer generation oral formulations down the road.

Daniel Levine: Having been through this process of bringing a rare disease therapy to market, what have you learned about overcoming the development and regulatory hurdles and things that you might be able to share with others trying to do the same?

Alex Aimetti: Yeah, we certainly have learned quite a few things during the early days of this launch. And just one of the things that we’ve learned and would certainly recommend is to continue to engage with the patient community early and often. When there’s a trusted relationship, they are very strong advocates again, with the ultimate goal of really trying to improve patient outcomes. But some of the lessons learned during the launch, there’s a few that I’ll highlight. I think the first one I’ll touch on is as it relates to diagnosis, and I alluded to this earlier around genetic testing, and even though we are at a positive inflection point in epilepsy genetic testing, I still think there remains an opportunity to educate about genetic testing, why it’s important to understand the etiology and how it potentially could influence treatment decisions aimed at improving patient outcomes. Another thing that I’ll bring up as a a learning lesson is the role that the caregiver plays in the treatment decision. Certainly, these families live very hectic and challenging lives. Caring for an individual with CDD and a treatment change is a very important decision and not one that the caregivers are always willing to make. And on our end, we respect that. And my goal on the scientific side is to really make sure that when a caregiver wants to inquire about a potential Ztalmy treatment change, that he or she is equipped with accurate, fair, balanced, easy to understand information that they can then speak to their provider about. The last thing that I’ll just quickly touch on, and I think we learned a lot during the Covid pandemic leading up to our ultimate launch is around the access to healthcare and the increased utilization of telehealth to improve access to physicians that are really skilled in these specific rare diseases. I certainly think that there are many opportunities to educate around the value of telehealth, how to embrace and leverage it, and ultimately to best manage these complex patients. There are some advocacy, medical society, and clinician activities that we’re considering at Marinus to really help people realize the benefits of telehealth and how it could help either their practice on the provider side or their loved one on the patient community side.

Daniel Levine: Alex Aimetti, Marinus chief scientific officer. Alex, thanks so much for your time today.

Alex Aimetti: I appreciate it. Thank you so much for the opportunity.

This transcript has been edited for clarity and readability.


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