Rare Community Profiles
Rare Community Profiles is a new Patient Worthy article series of long-form interviews featuring various stakeholders in the rare disease community, such as patients, their families, advocates, scientists, and more.
Takeda’s Mahnaz Asgharnejad Discusses Data on Soticlestat for LGS and Dravet Syndrome
In late April, the American Academy of Neurology (AAN) held its 75th Annual Meeting. Stakeholders from across the neurology sphere came together to discuss trends, guidelines, clinical practices, and new research regarding various neurology-centric topics.
Takeda Pharmaceuticals presented new data on soticlestat, an orally administered cholesterol 24-hydroxylase (CH24H) inhibitor. The Epilepsy Foundation explains that:
CH24H converts cholesterol to 24S-hydroxycholesterol (24HC) in the brain. Reduction of 24HC has been shown to reduce glutamatergic signaling and inflammation, which may have downstream effects on seizure susceptibility.
Currently, soticlestat is in development for developmental epileptic encephalopathies called Dravet syndrome and Lennox-Gastaut syndrome (LGS). Takeda’s presentations include preliminary data from the ENDYMION 1 trial, as well as data from the Phase 2 ELEKTRA trial.
Dr. Mahnaz Asgharnejad recently explained to Patient Worthy why the results of these trials are so impactful—and how soticlestat could potentially change the treatment landscape for Dravet syndrome and LGS.
JL: Thank you for taking the time to speak with us today. Can you tell me about yourself and your background?
MA: My name is Mahnaz Asgharnejad, PharmD, and I am the Vice President and Global Program Leader at Takeda Pharmaceuticals. I’ve worked in drug development within R&D for many years, including mostly compounds in neurosciences.
In your words, what is soticlestat?
Soticlestat (TAK-935) is a potential first-in-class treatment for Dravet syndrome and LGS being studied in Phase 3 clinical trials. It was discovered in our own research laboratories and uses a novel mechanism-of-action that may address the seizures and non-seizure symptoms by acting on pathways distinct from current antiepileptic drugs.
Soticlestat uses a novel mechanism-of-action (MoA) that may address the seizures and non-seizure symptoms of these conditions by acting on pathways distinct from current antiepileptic drugs. In clinical studies, soticlestat reduced seizure frequency and disease impact beyond seizures in children with DS and LGS. Data showed soticlestat was well-tolerated and can be used in combination with other medicines.
New data was presented on soticlestat at the AAN 75th Annual Meeting. Can you provide more insight into that data?
Interim data from the ENDYMION 1 study demonstrated that TAK-935 was associated with sustained seizure reductions in patients with DS and LGS over approximately 2 years.
Furthermore, post hoc analysis of the Phase 2 ELEKTRA study showed for both DS and LGS, a reduction in seizure frequency was observed with soticlestat for many seizure types that met the conditions for inclusion in these analyses, including generalized tonic-clonic seizures, focal seizures with motor signs, atonic seizures, and focal to bilateral tonic-clonic seizures. Therefore, further investigation of soticlestat into these seizures in other forms of epilepsy is warranted.
What do you feel is the most compelling data presented – from either the ENDYMION 1 study or the ELEKTRA study?
The ELEKTRA data showed that soticlestat is effective for the treatment of seizures in patients with DS and LEGS combined. Looking at the DS cohort, soticlestat also demonstrated strong efficacy in reducing convulsive seizures, though the sample size was small and not designed to show statistical significance. In the LGS cohort, there was directional efficacy in reducing seizures which we’re further investigating in a phase 3 study called SKYWAY to have a better understanding of the efficacy potential. The ENDYMION 1 data presented at AAN, though open-label, showed the long-term efficacy as well as safety and tolerability of soticlestat in both of these patient populations over two years.
What are the next steps in developing soticlestat?
The SKYLINE Phase 3 trial for DS and the SKYWAY Phase 3 trial for LGS are currently in progress, with data anticipated in 2024.
The main aim of SKYLINE Phase 3 trial for DS is to learn if soticlestat, when given as an add-on therapy, reduces the number of convulsive seizures in children and young adults with DS.
The main aim of the SKYWAY Phase 3 trial for LGS is to learn if soticlestat, when given as an add-on therapy, reduces the number of major motor drop seizures in children, teenagers, and adults with LGS and to assess the safety profile of soticlestat when given in combination with other therapies.
What made you want to focus on rare disease drug development in LGS and Dravet syndrome?
Dravet syndrome and LGS are rare and progressive developmental epileptic disorders that present early in a child’s life with severe, frequent and unpredictable seizures that can lead to delays in motor, cognitive, and behavioral development, as well as lifelong dependence on caregivers.
These disorders are often treatment-resistant, requiring the simultaneous use of several medications to address symptoms, an approach known as polypharmacy. Even then, most people do not achieve control of their seizures or other debilitating symptoms like impaired brain functioning and delayed language development. When uncontrolled, these can often get worse over time and result in tremendous long-term challenges for patients and their caregivers.
What are the challenges and rewards of rare disease drug development?
The rare disease community is negatively and disproportionately affected by a lack of disease awareness. People living with a rare disease and their support networks can experience challenges in accessing the expert support and care they need. We are determined to seek out and break down barriers faced by the rare disease community. With our continued focus on those with the greatest unmet needs facing health inequity, we are committed to identifying and bridging gaps in care, so that one day everyone may hopefully achieve optimal health, starting with access to a timely and accurate diagnosis.
How do you feel Takeda excels in aiding patients?
At Takeda, our mission is to develop innovative and potentially disease-modifying medicines for people impacted by neurological diseases, including rare neurological diseases with unmet needs. We are committed to improving patient care through support of scientific advances in medicine and increasing understanding of important neurological diseases such as neuromuscular and neurodegenerative diseases, narcolepsy and idiopathic hypersomnolence, and rare epilepsies such as Dravet syndrome and LGS.
Takeda’s dedication extends beyond our labs. We are committed to raising awareness for these conditions, educating patients and physicians, broadening access to therapies, and building strategic partnerships with industry, patients, patient organizations, caregivers and other key stakeholders. These collaborations make sure we are developing medicines and that our work is in partnership with patients, not simply for patients.
We are sincerely thankful to the hundreds of patients and caregivers for their participation in clinical trials, which is an additional burden to them. We can’t move science in rare diseases forward without their commitment and participation.
Are there any other exciting pipeline updates that you’d like to share?
As a company with a longstanding history and expertise in rare diseases, we have a range of potentially transformative medicine in development. For example, we are very excited that we have recently filed our recombinant ADAMTS-13 as a potential treatment of congenital thrombotic thrombocytopenic purpura (cTTP) with the FDA. The drug is called TAK-755 and is also being studied for immune mediated TTP.
I would like to add two other remarkable developments: fazirsiran as a potential first treatment for alpha-1 antitrypsin deficiency associated liver disease and TAK-861 as a totally new approach for the treatment of narcolepsy, replacing the effect of the missing orexin in narcolepsy type 1 patients.
