Craniodiaphyseal Dysplasia

Sarah Silbiger/Getty Images Ztalmy is Marinus’ oral suspension medication for patients ages two years and older who experience seizures linked with cyclin-dependent kinase-like 5 deficiency disorder. Sarah Silbiger/Getty Images Marinus Pharmaceutical’s proposed oral drug for seizures has received approval from the U.S. Food and Drug Administration , with projected market availability of July 2022. It was the first sole drug approval for the Radnor, Pennsylvania-based company. Ztalmy (ganaxolone) is Marinus’ oral suspension medication for patients ages two years and older who experience seizures linked with cyclin-dependent kinase-like 5 deficiency disorder (CDD). CDD is a rare type of genetic epilepsy caused by mutations in the CDKL5 gene that starts at a very early age, usually at around three months old, and is characterized by severe neurodevelopmental delay that impacts motor, cognitive, visual and speech functions. Ztalmy is a neuroactive steroid that acts as a positive allosteric modulator of the GABA A receptor and can control such seizures. “There has been a great unmet medical need for treatments that address seizures associated with CDKL5 deficiency disorder given their prominent role and profound impact on patients. To date, antiseizure treatment decisions have been based on very limited clinical evidence in this patient population and the resulting outcomes underscore the need for therapies that further improve seizure control,” noted Dr. Scott Demarest, clinical director of precision medicine at Children’s Hospital Colorado and principal investigator of the Marigold trial, which was the basis for the FDA’s decision. “Thanks to our research and this trial, we now have the first treatment specifically approved for seizures associated with CDKL5 deficiency disorder that was shown to have a positive benefit-risk profile,” Demarest added. The Phase III Marigold study involved 101 patients in a double-blind placebo-controlled evaluation process. At the end of the trial, patients who were given Ztalmy showed a median 30.7% reduction in 28-day major motor seizure frequency against the 6.9% who experienced the same in the placebo group. In the open-label extension, which lasted at least 12 months, 49.6% of the participants continued to experience the benefits, with the drug further demonstrating its safety, tolerability and efficacy. Common reactions, observed in less than 5%, included pyrexia, somnolence and sedation, seasonal allergy and salivary hypersecretion. Ztalmy, which is to be taken thrice a day, is expected to be commercially available by July 2022 in the U.S., depending on the U.S. Drug Enforcement Administration’s schedule. The FDA gave its go-ahead after looking into its merits under Priority Review. With this approval, Ztalmy now has a Rare Pediatric Disease Priority Review Voucher (PRV), which the company intends to monetize immediately. “This approval is monumental for the CDD community—bringing not only the first approved treatment option specifically for CDD patients, but renewed hope to those who have struggled to find medications that are effective in significantly reducing the number of seizures these patients experience on a daily basis,” commented Karen Utley, the president and co-founder of the International Foundation for CDKL5 Research. To make Ztalmy more readily available to many, Marinus is launching the Ztalmy One Program to provide assistance and services to patients as they obtain and use the drug. The program will also be offering financial support to patients who qualify for assistance.

Shares of Marinus Pharmaceuticals soared more than 60% in after-hours trading Monday following the company’s announcement that its experimental epilepsy treatment ganaxolone hit the mark in a Phase III study. Shares of Marinus Pharmaceuticals soared more than 60% in after-hours trading Monday following the company’s announcement that its experimental epilepsy treatment ganaxolone hit the mark in a Phase III study. The medication was aimed at treating children and young adults with CDKL5 deficiency disorder (CDD), a rare, genetic epilepsy with refractory seizures. Pediatric patients enrolled in the Phase III study who received ganaxolone demonstrated a 32.2% reduction of seizure burden. Patients who received a placebo only saw a 4% reduction, the company said. On average, patients enrolled had tried seven different AED medications prior to the study. Ganaxolone is a positive allosteric modulator of GABA A receptors. Ganaxolone exhibits antiseizure, antidepressant and anti-anxiety activity via its effects on synaptic and extrasynaptic GABA A receptors. The trial’s primary efficacy endpoint was the percentage change in 28-day frequency of major motor seizures during the double-blind phase relative to the six-week prospective baseline period. Ganaxolone was generally well tolerated with a safety pro with previous clinical studies. The most frequent adverse event was somnolence, Marinus said in its announcement. The trial showed numerical trends favoring ganaxolone across several predefined secondary endpoints, however, ganaxolone did not meet statistical significance. Ganaxolone did meet statistical significance in exploratory secondary endpoints. Based on the results from the study, Marinus said it will submit a New Drug Application for ganaxolone as a treatment of CDD to the U.S. Food and Drug Administration in mid-2021. The company will also seek regulatory approval by the European Medicines Agency later in 2021. Scott Braunstein, chief executive officer of Marinus, said the Phase III Marigold Study is the first double-blind and placebo-controlled study that proves efficacy specific to CDD. He said it’s also the first Phase III study to examine dosing pediatric patients three times per day with ganaxolone. “We believe we are one step closer to providing the first treatment indicated for CDD, and plan to continue our investments in the oral ganaxolone franchise,” Braunstein said in a statement. CDKL5 deficiency disorder is a rare genetic disorder caused by a mutation of the cyclin-dependent kinase-like 5 (CDKL5) gene, which is located on the X chromosome. CDD is characterized by early-onset, difficult-to-control seizures and severe neuro-developmental impairment. Most children affected by CDD cannot walk, talk, or feed themselves. Currently, there are no therapies approved specifically for CDD. Marinus received Rare Pediatric Disease Designation from the FDA in July. The victory for Marinus and ganaxolone has been a long time coming. Last year, the company saw two failures within two weeks for ganaxolone trials. The drug failed to hit endpoints in an epilepsy study and also failed in a Fragile X syndrome trial. The drug also failed to hit the mark in a postpartum depression study in 2019. “Today’s success with ganaxolone in CDD will pave the way for us to accelerate our clinical studies in tuberous sclerosis complex and possibly other rare pediatric epilepsies as well,” Chief Medical Officer Joe Hulihan said in a statement. “We will continue to explore the potential for ganaxolone’s unique mechanism of action to address other areas of unmet medical need.”

The deal broadens their work together from three to six programs for rare genetic diseases, as well as rights to collaborative R&D of novel gene therapies for lysosomal disorders and 12 additional rare diseases. Amicus Therapeutics , based in Cranbury, NJ, and the Perelman School of Medicine at the University of Pennsylvania (Penn) , are expanding their gene therapy collaboration . The deal broadens their work together from three to six programs for rare genetic diseases, as well as rights to collaborative R&D of novel gene therapies for lysosomal disorders (LDs) and 12 additional rare diseases. The collaboration ’ s rare genetic diseases now include Pompe disease, Fabry disease, CDKL5 deficiency disorder (CDD), Niemann-Pick Type C (NPC), Mycopolysaccharidosis Type IIIB (MPS IIIB), in addition to a next-generation program in Mycopolysaccharidosis Type IIIA (MPS IIIA), both known as part of Sanfillipo Syndrome. Also, the deal gives Amicus exclusive disease-specific access to collaborate with Penn’s Gene Therapy Program (GTP) to develop new gene therapy platform technologies for most lysosomal disorders and 12 more rare diseases. The ongoing Amicus-Penn collaboration has led to preclinical proof-of-concept in Pompe disease. The expansion combines Amicus’ protein engineering and glycobiology expertise with Penn’s gene transfer technologies. “This agreement is a significant step forward in creating a world-class industry-academia gene therapy partnership in rare diseases,” stated James M. Wilson, Professor of Medicine and Pediatrics at Perelman. “We have already seen highly encouraging preclinical results and proof-of-concept in Pompe disease through our existing collaboration and are excited by what we can further achieve together.” The deal is a Research, Collaboration and License Agreement. Amicus provides funding to Penn to advance the preclinical research programs in the Wilson Lab and to license specific technologies invented under the funded Research Collaboration. The initial collaboration focused on Pompe disease, Fabry disease, CDD and an undisclosed rare metabolic disorder. The new expansion adds NPC and MPS IIB in addition to a next-generation program for MPS IIA. The expanded deal is for five years. Amicus is investing $10 million per year for each of the five years. In return, Amicus will receive exclusive disease-specific rights to collaborate with GTP to research and develop therapies for lysosomal disorders. The Amicus rights also include additional rare diseases, such as Rett Syndrome, Angelman Syndrome, Myotonic Dystrophy and other muscular dystrophies. “The extension of our collaboration with Penn is a bold step forward in our commitment to create a potential cure that may alleviate an enormous amount of suffering for countless numbers of people in the world living with rare diseases, many of them children,” stated John F. Crowley, chairman and chief executive officer of Amicus. “Together with Penn we are now able to focus on additional lysosomal disorders, as well as several more prevalent rare diseases for which we can apply our understanding of underlying disease biology in rare metabolic disease, Amicus’ protein-engineering and development expertise and the world-renowned capabilities of Dr. Jim Wilson’s laboratory to develop novel gene therapy candidates.” On April 30, Amicus presented initial preclinical data from its adeno-associated viral (AAV) gene therapy program for Pompe disease in mice at the American Society of Gene & Cell Therapy in Washington, DC. Pompe disease is an inherited lysosomal storage disorder caused by deficiency of the enzyme acid alpha-glucosidase (GAA). Decreased or nonexistent levels of GAA cause accumulation of glycogen in cells, which results in Pompe disease symptoms. The preclinical data presented showed that the therapy resulted in more uniform cellular uptake and lysosomal targeting compared to natural hGAA AAV gene therapy, and showed robust glycogen reduction in all key tissues. At the time, Crowley stated, “As these data exceed our expectations, our preclinical studies are progressing well ahead of schedule and we now expect to select a clinical candidate in 2019 to move forward into IND-enabling studies.”