Newborn Screening, mTOR Pathway May Offer New Hope for Tuberous Sclerosis

Darcy Krueger, MD, PhD

This is 3-part interview. To view part 2, click here.

TSC STEPS (NCT05104983), initiated in October 2021, is a phase 1/2 study that is the first of its kind to truly evaluate a targeted, disease-modifying therapy for preventing or delaying seizure onset in tuberous sclerosis complex (TSC) using a mechanism-based therapeutic approach. Led by Darcy Krueger, MD, PhD, the study will use TAVT-18 (Tavanta Therapeutics), a novel formulation of sirolimus (Ramapune; Pfizer), an FDA-approved medication for TSC that aims to regulate the mechanistic target of rapamycin (mTOR) signaling pathway.

Patients with TSC have genetic mutations in TSC1 and TSC2 genes, which cause dysregulation of this pathway. It has been shown that age at time of seizure onset among infants with the disease is linked to long-term neurodevelopmental outcome. In this new study, Krueger and his colleagues will treat infants with TAVT-18 the moment a clinical diagnosis is made, therefore treating the root disease itself, and not only the associated symptoms.

Krueger, director, Tuberous Sclerosis Clinic, Cincinnati Children’s, sees the immense weight a study like this holds for the clinical and patient community, if successful. In part 2 of an interview with NeurologyLive®, he discussed how newborn screening plays a role in the diagnosis of this genetic disorder, the need to improve diagnosis rates, and the origins of TSC STEPS. Additionally, Krueger stressed the questions that still need to be answered, along with how previous research has played a factor into the design of this new trial.

NeurologyLive®:Should newborn screening be more standardized? Is it something that should be done in every baby?

Darcy Krueger, MD, PhD: Yes, but we have to face the practical realities that of the cost involved if we were to do every individual in a country or worldwide. Even if it’s just a few cents per person, that adds up quickly. Secondly, it has to be a test that’s reliable such that I don’t go to a parent of a newborn and say, “Your child has this disorder,” and be totally wrong. We have to know that the tests are reliable and saying, “You have no worries, we’re 100% sure. Therefore, you don’t have to do anything else to look into this,” or that our test is pretty sure, 98% or 99% confident, such that we minimize how many people we put through unnecessary worry.

The flipside is that if we can get one of those 2 scenarios worked out, particularly for babies with tuberous sclerosis for example, we can save all sorts of subsequent worries because we started to do things now. For every 100 babies with tuberous sclerosis, for 99 of them, when we approach them on that first day or first week of life, we could say this is something we have to worry about and that we’re right.

How would you assess the current state of TSC diagnosis?

When they [clinicians] do make the diagnosis, yes, they’re fairly accurate. Every once in a while, we say well, this could be tuberous sclerosis and then down the road, weeks, months, or years, we say, well it just hasn’t panned out and there’s something different. We couldn’t tell when we first started talking about their diagnosis.

The harder challenge is when people have the diagnosis, but they either don’t get diagnosed, or that they get diagnosed, but they don’t get tracked into specialty centers, where the full evaluation and opportunity to have early interventions or clinical trial participation are not available. In those generic situations, TSC takes its march, seizures develop, and then, all of a sudden, you’re not eligible for a preventative strategy. That’s really our bigger challenge, it’s the missed cases, and less about when you have a case, people not recognizing it.

Can you discuss the timeline of events that led up to this point?

TSC Steps has been a long effort that builds on decades of scientific contribution, starting with the identification of the TSC genes by major collaborative groups in Europe and the United States. From there, the discovery that the mTOR pathway is not the only thing that drives what happens in TSC, but certainly a major player in the development of drugs that had already excited and bringing them into the TSC context. We started to evaluate them for shrinking tumors in the brain, shrinking tumors in the kidney, and preventing lung progression.

Now, most lately, showing that it works for epilepsy. Clinical trials have shown that it can reduce phase change and fibroma. We know that this pathway is key to many of the disease manifestations in TSC and targeting it has definite benefits. Building on all of that, we showed that it worked in epilepsy in later individuals. It didn’t work for everybody, but certainly in individuals for which other medications were not working. Then saying, can we safely do this in very young individuals? Can we take what we know about how safe it is in adults or older children and say it’s safe to treat babies?

We took the time to do that. We look for information across clinics around the world that specialize in TSC and what their experience was with treating babies this young. The second thing is, when we had this trial, it came with a lot of questions. What’s the ideal trial design that balances what we know from for example the EPISTOP or PREVENT trials, with what this trial would want to do? How do those interlink? We’ve designed the trial so that we can compare the data with these other studies and say, okay, what’s the benefit of targeting epilepsy alone vs targeting TSC by itself, and together? We’re excited about that. It’s taken us about 4 years to get to the point we are today, where it has funding from the Office of Orphan Products division of the FDA. We have federal funding to do this study over the next 4 years, we started on October 21 [2021], and already started enrollment.

We’re hoping to enroll 64 individuals over the next 2 years, and then follow them out till they’re 2 years of age. That’s why it’s a 4-year study. Enrollment has started and it’s going well, but we need to stay on this as a TSC community, both scientific and as families so that we can get this answered and know whether we need to be doing this for everybody who’s born with tuberous sclerosis.

Transcript has been edited for clarity.