CDKL5 Deficiency Disorder

Daiichi Sankyo’s quizartinib is indicated for use as a first-line treatment in adults with acute myeloid leukaemia. Credit: Nemes Laszlo / Shutterstock.com. The UK Medicines and Healthcare products Regulatory Agency (MHRA) has granted marketing authorisation to Daiichi Sankyo for quizartinib (Vanflyta) for use as a first-line treatment in adults with acute myeloid leukaemia (AML) with a FLT3-ITD mutation. The decision allows for the oral administration of quizartinib in combination with chemotherapy – a significant development in the treatment of AML. Taken once daily, quizartinib targets tyrosine kinases to hinder the growth of abnormal bone marrow cells. The treatment duration and dosage are determined by the prescribing physician and may continue post-chemotherapy. The approval is backed by a double-blind, randomised, placebo-controlled Phase III clinical trial in 539 adult subjects aged between 18 and 75 years with newly diagnosed FLT3-ITD positive AML. See Also: MHRA approves Marinus’ ganaxolone for CDKL5 deficiency disorder Innovent’s ROS1 TKI is one step closer to winning the Chinese NSCLC market The study demonstrated a statistically significant improvement in overall survival (time from randomisation to death from any cause) for patients who received quizartinib. Patients receiving quizartinib had a median overall survival of 31.9 months compared to 15.1 months for those receiving a placebo. Abnormal liver enzymes, low blood platelet and white blood cell levels, anaemia, diarrhoea, nausea, stomach pain and headache were the most common side effects linked to the trial. MHRA Healthcare Quality and Access interim executive director Julian Beach stated: “ Our key priorities are keeping patients safe and enabling their access to high quality, safe and effective medical products. “We’re assured that the appropriate regulatory standards for the approval of this medicine have been met. As with all medicines, we will keep its safety under close review.” In another development, the MHRA also gave marketing authorisation to Pfizer for etrasimod (Velsipity) for the treatment of moderately to severely active ulcerative colitis. Etrasimod is prescribed as a long-term treatment and should be initiated only under a doctor’s supervision. The approval is supported by two clinical studies, ELEVATE UC 52 and ELEVATE UC 12, indicating its efficacy for patients where standard treatments were inadequate. The UK National Institute for Health and Care Excellence (NICE) has also published a final guidance recommending etrasimod for ulcerative colitis. With the NICE recommendation, more than 25,000 people in England will be eligible to receive the treatment. The latest development comes after the MHRA approved Marinus Pharmaceuticals ’ ganaxolone, marketed as Ztalmy, an anti-seizure medication for cyclin-dependent kinase-like 5 (CDLK5) deficiency disorder .

The approval of ganaxolone is based on results from a Phase III clinical trial in subjects aged two to 19 years. Credit: LightField Studios / Shutterstock.com. The UK Medicines and Healthcare products Regulatory Agency (MHRA) has approved Marinus Pharmaceuticals Emerald’s ganaxolone, marketed as Ztalmy, an anti-seizure medication for cyclin-dependent kinase-like 5 (CDLK5) deficiency disorder (CDD). CDD is a rare genetic ailment characterised by early-onset seizures and severe developmental delays due to mutations in the CDLK5 gene, essential for normal brain development. Ganaxolone, administered orally via a dosing syringe, is a steroid that targets specific brain receptors to prevent epileptic seizures. The approval of ganaxolone is based on results from a Phase III clinical trial. The double-blind placebo-controlled study involved 101 subjects aged two to 19 years. See Also: BeiGene secures accelerated FDA approval for follicular lymphoma treatment FDA approves BMS’ Opdivo for urothelial carcinoma The subjects were randomised with 50 receiving ganaxolone and 51 a placebo over 17 weeks. Those treated with ganaxolone showed a significant reduction in 28-day seizure frequency, averaging almost 30%, versus a 6.5% reduction for those on the placebo at 13 weeks. Side effects linked to ganaxolone are drowsiness or sleepiness and fever. The MHRA will monitor the safety and efficacy of the drug. Individuals experiencing adverse effects are encouraged to consult their healthcare provider and report the incident through the MHRA Yellow Card scheme, accessible online or via mobile app stores. MHRA Healthcare Quality and Access interim executive director Julian Beach stated: “Keeping patients safe and enabling their access to high quality, safe and effective medical products are key priorities for us. “We’re assured that the appropriate regulatory standards for the approval of this medicine have been met. “As with all medicines, we will keep its safety under close review.” The latest development comes after the MHRA granted marketing authorisation for a new formulation of Amgen ’s XGEVA (denosumab) to prevent serious bone-related complications.

Scientists have found a new treatment target for CDKL5 deficiency disorder (CDD), one of the most common types of genetic epilepsy. Scientists at the Francis Crick Institute have found a new treatment target for CDKL5 deficiency disorder (CDD), one of the most common types of genetic epilepsy. CDD causes seizures and impaired development in children, and medications are limited to managing symptoms rather than tackling the root cause of the disease. The disorder involves losing the function of a gene producing the CDKL5 enzyme, which phosphorylates proteins, meaning it adds an extra phosphate molecule to alter their function. Following recent research from the same lab showing that a calcium channel could be a target for therapy for CDD, the team has now identified a new way to potentially treat CDD by boosting another enzyme's activity to compensate for the loss of CDKL5. In research published today in Molecular Psychiatry, the scientists studied mice that don't make the CDKL5 enzyme. These mice show similar symptoms to people with CDD like impaired learning or social interaction. The researchers first identified that CDKL5 is active in nerve cells in mice but not in another type of brain cell called an astrocyte. In the nerve cells, they measured the level of phosphorylation of EB2, a molecule known to be targeted by CDKL5, to understand what happens when CDKL5 isn't produced. Interestingly, even in mice that don't produce CDKL5, there was still some EB2 phosphorylation taking place, which suggested that another similar enzyme must also be able to phosphorylate it. By looking at enzymes similar to CDKL5, the researchers identified that one called CDKL2 also targets EB2 and is present in human neurons. In mice without both CDKL5 and CDKL2, the remaining EB2 phosphorylation almost fully dropped off. The researchers concluded that, although most activity comes from CDKL5, about 15% is from CDKL2, and the remaining <5% from another enzyme yet to be identified. Their research suggests that increasing the level of CDKL2 in people who are deficient in CDKL5 could potentially treat some of the effects on the brain in early development. Sila Ultanir, Group Leader of the Kinases and Brain Development Laboratory at the Crick, said, "CDD is a devastating condition that impacts young children from birth, and we don't know a huge amount about why losing this one enzyme is so disastrous for the developing brain. Through this research, we've identified a potential way to compensate for the loss of CDKL5. If we can increase levels of CDKL2, we might one day be able to stop symptoms from developing or getting worse." The researchers are now investigating if mice without CDKL5 can be treated by stimulating their brain cells to produce more CDKL2. The lab is also working with biotechnology companies to identify molecules that increase CDKL2 for potential new medicines for CDD. Margaux Silvestre, former PhD student at the Crick and now postdoctoral researcher at the Max Planck Institute for Brain Research in Frankfurt, said: "Our discoveries offer fresh insights into the expression and regulation of CDKL5 in the brain. Moreover, the identification of CDKL2 as a potential compensatory enzyme provides hope for uncovering better treatments that could truly make a difference in the lives of the children with this devastating condition. This research owes its success to all the authors involved in the publication but also the unwavering support we received from the technical teams at the Crick -- a big shoutout to them!" The research was funded by the Loulou Foundation, a private foundation dedicated to the development of therapeutics and eventual cures for CDD.