Interim Report January-June 2020
Primary mitochondrial diseases are metabolic diseases that affect the ability of cells to convert energy. The disorders can manifest differently depending on the organs affected by the genetic defects and are viewed as clinical syndromes. An estimated 125 in every 1,000,000 people suffer from a primary mitochondrial disease. Primary mitochondrial diseases often present in early childhood and lead to severe symptoms, such as mental retardation, myopathy, heart failure and rhythm disturbances, diabetes, movement disorders, stroke-like episodes, deafness, blindness, limited mobility of the eyes and seizures.
What is mitochondrial disease like? Listen to Roger suffering from MELAS:
KL1333 is a potent modulator of the cellular levels of NAD+, a central co-enzyme in the cell’s energy metabolism. KL1333 has in preclinical models been demonstrated to increase mitochondrial energy output, have long-term beneficial effects on energy metabolism, strengthen muscle function and improve biomarkers of mitochondrial disease. It is in clinical development stage intended to document the use for chronic oral treatment of primary mitochondrial disorders, in particular MELAS-MIDD spectrum disorders, mainly caused by the mutation m.3243A>G in the mitochondrial DNA (mtDNA) and affects about 35 in 1,000,000 people. An additional group is PEO-KSS spectrum disorders caused by a deletion of a large part of mtDNA which affects 15 in 1,000,000. KL1333 is currently being evaluated in clinical phase I studies and has been granted orphan drug designation in both the United States and Europe. KL1333 has been in-licensed from Yungjin Pharm, a Korean pharmaceutical company.
One of the most common causes of mitochondrial diseases relates to Complex I dysfunction, i.e. when energy conversion in the first of the five protein complexes in the mitochondrion that are essential for effective energy conversion does not function normally. This is apparent in disorders including Leigh syndrome and MELAS, both of which are very serious diseases with symptoms such as muscle weakness, epileptic fits and other severe neurological manifestations. The NVP015 project is based on an Abliva innovation in which the body’s own energy substrate, succinate, is made available in the cell via a prodrug technology. A prodrug is an inactive drug that is activated first when it enters the body by the transformation of its chemical structure. Within the project a lead compound, NV354, has been selected for further development in the program based on tolerability, oral bioavailability, plasma stability and organ delivery, specifically to the brain. In 2017 and 2018 Abliva received research grants from the Swedish innovation agency, Vinnova, for developing the succinate prodrugs as a new treatment for genetic mitochondrial diseases.
In 2018, Abliva out-licensed molecules from NVP015 for a targeted treatment of Leber’s Hereditary Optic Neuropathy (LHON) to BridgeBio Pharma’s new subsidiary Fortify Therapeutics. Fortify develops the in-licensed NVP015 chemistry further to establish a therapy for LHON.
Leber’s Hereditary Optic Neuropathy (LHON) is a disease caused by mitochondrial DNA mutations in subunits of NADH dehydrogenase (complex I), a component of the electron transport chain. This results in dysfunctional oxidative phosphorylation and ATP production, leading to degeneration of the retinal ganglion cells and loss of central vision. LHON most commonly affects males in their second or third decade of life. The prevalence of LHON in Europe is between 1:30,000-1:50,000.
In 2019, Abliva entered into an exclusive agreement to license and supply two of its first generation of succinate/malonate prodrugs as research tool compounds to Oroboros Instruments, a global supplier of mitochondrial research technologies.