Developmental and epileptic encephalopathies (DEEs), or rare epilepsies, are somewhat of a newer topic. However, researchers are already making strides in creating treatments to address unmet patient needs. On September 30, 2020, biopharmaceutical company Ovid Therapeutics (“Ovid”) shared results from two studies on soticlesat. The therapy, also known as OV935 or TAK-935, is designed to treat patients with DEEs. According to study results, soticlestat is effective in reducing seizure frequency.
Both Ovid and Takeda Pharmaceutical Company co-developed soticlestat, an orally administered cholesterol 24-hydroxylase (CH24H) inhibitor. According to an article in the Annual Review of Biochemistry, CH24H:
is responsible for the majority of cholesterol turnover in the vertebrate central nervous system. The enzyme is expressed in neurons, including hippocampal and cortical neurons that are important for learning and memory formation.
In the brain, a neurotransmitter called glutamate stimulate epileptic activity. CH24H is believed to enhance and over-activate the glutamatergic pathway. As a result, researchers believe that inhibiting CH24H will reduce seizures, particularly in terms of frequency.
Studies on DEEs
The data shared came from the Phase 2 ARCADE study and its long-term extension study ENDYMION. Altogether, the studies explored the impact of soticlestat on patients with rare DEEs: CDKL5 deficiency disorder (CDD) and Dup15q syndrome. 12 patients with CDD, and 8 patients with Dup15q syndrome, enrolled in the studies. While some anti-epileptics stop being effective over long-term treatment, soticlestat was shown to have a sustained response period. 5 patients with CDD, and 4 patients with Dup15q syndrome, were continuously treated for 9 months. Of these, the patients with CDD experienced a 50% reduction in seizure frequency. Those with Dup15q syndrome saw a 74% reduction in seizure frequency. Additionally, soticlestat was safe and well-tolerated.
Researchers also saw improvements in communication, alertness, and overall quality of life. Side effects were mild and included rashes, constipation, and seizures.
Developmental and Epileptic Encephalopathies (DEEs)
According to an article in npj Genomic Medicines, developmental and epileptic encephalopathies (DEEs):
are a group of rare, severe neurodevelopmental disorders, where even the most thorough sequencing studies leave 60–65% of patients without a molecular diagnosis.
A separate article, published in Seminars in Pediatric Neurology, further explains:
In infants with KCNQ2 or STXBP1 encephalopathy, seizures may be controlled early after onset or cease spontaneously after a few years, but the developmental consequences tend to remain profound. The term “developmental and epileptic encephalopathy” expresses the concept that the genetic defect may be responsible for both the epilepsy and adverse development which is crucial to understanding the disease process for both families and clinicians.
DEEs typically occur in early life, perhaps early childhood. However, due to their rarity, onset, symptoms, and even overall prognosis all differ. Currently, there are no cures for DEEs. In fact, in many cases, there are not even approved treatments. Both CDKl5 deficiency disorder and Dup15q syndrome are forms of DEEs. As explained, neither have approved treatment options.
CDKL5 Deficiency Disorder (CDD)
Once considered a type of Rett syndrome, CDKL5 deficiency disorder (CDD) causes epilepsy and severe developmental delays. Around 90% of patients with CDD are female. There are slightly over 1,000 cases of CDD globally. Overall, CDKL5 gene mutations cause CDD. Normally, the CDLK5 protein plays a role in forming nerve cells in the brain. Patients only require one mutated gene to develop the disorder.
Symptoms often appear in infancy. Patients may experience symptoms within one week of birth or up to three months following birth. Often, seizures occur at least once daily, and do not respond to treatment. In nearly 2/3 of all cases, patients are unable to walk without assistance. Symptoms and characteristics include:
- A high, broad forehead
- Large, deep-set eyes
- Widely spaced teeth
- Inability to speak
- Intellectual and developmental delays
- Teeth grinding
- Irregular breathing
- Acid reflux
- Sleep issues
- Poor motor skills
- Feeding difficulties
- Repetitive hand movements
Learn more about CDD here.
Also known as chromosome 15q duplication, Dup15q syndrome is a rare chromosomal abnormality in which an extra copy of genetic material from 15q is present in each cell. Altogether, there are three main forms of Dup15q syndrome: micro duplications 11.2 and 13.3, interstitial duplication/triplication chromosome 15 (int dup15/trp15), and isodicentric chromosome 15 (idic15).
Symptoms vary, but may include:
- Failure to thrive
- Genital abnormalities
- Frequent seizures
- Developmental and intellectual delays
- Crossed eyes
- Behavioral difficulties
- Organ abnormalities
Learn more about Dup15q syndrome here.