New research supports Abliva’s KL1333 treatment strategy
Swedish biopharmaceutical Abliva develops treatments for primary mitochondrial diseases, rare and very severe diseases due to dysfunctional mitochondria leading to a reduction of patients’ longevity as well as quality of life. With its main candidate KL1333, the company aims to correct the NAD+/NADH ratio in primary mitochondrial disease patients to restore energy balance. Newly published research lends important support to the company’s treatment strategy.
Since last autumn, Abliva’s main focus is primary mitochondrial diseases, an area where the company has more than twenty years of experience and considerable internal expertise.
When an individual is affected by a primary mitochondrial disease, their mitochondria do not function as normal. This has serious consequences as the mitochondria is responsible for creating the energy humans need to function optimally, and a primary mitochondrial disease can lead to cell death and loss of organ function that in turn leads to difficulties in performing basic bodily functions such as moving, thinking, and breathing.
KL1333 – Abliva’s primary project
At the moment, Abliva has two projects against primary mitochondrial diseases in its pipeline, KL1333 against MELAS and similar syndromes and NV354 against Leigh syndrome. KL1333 is the company’s main candidate and is currently undergoing a clinical phase Ia/b study. Parallel to this clinical trial, material is being developed and the plan is for a phase II trial to start during the first half of 2021.
New research supports KL1333 strategy
Recently published research now lends support to Abliva’s chosen treatment strategy for MELAS. One of the most important targets for KL1333 is nicotinamide adenine dinucleotide (NAD), a cofactor central to metabolism and where the balance between its two forms, NAD+ and NADH, is critical for the cells’ energy production.
Lately, there has been a surge of interest in NAD+, the oxidised form of NAD, as the research community has gone from considering NAD+ as simply a metabolic cofactor to considering it a key cosubstrate for proteins regulating metabolism and longevity.
A recently published study by Goodman et al. examined how hepatic NADH reductive stress (i.e. an abnormally high NADH, the reduced form of NAD, and abnormally low NAD+) underlies common variation in metabolic traits. The study found that NADH reductive stress is important to the disease pathology of primary mitochondrial disease as well as to common metabolic disorders, and that the NAD+/NADH ratio is directly related to biomarkers which are elevated in mitochondrial disease.
Using advanced genetic tools to correct the NAD+/NADH ratio, the metabolic dysfunction and elevated biomarkers were reversed in the experimental model used. Such tools are presently not possible to use in a clinical setting.
Boosting NAD+ levels
This is of importance to Abliva and KL1333, as the pharmacological strategy of KL1333 is to similarly normalise the NAD+/NADH ratio and boost NAD+ levels in patients with primary mitochondrial disease.
The Goodman et al study and previous research by Vasmi Mootha at Harvard Medical School have pointed towards the dysfunctional ratio of NAD+ and NADH as a critical factor and one of the hallmarks of mitochondrial disease. Mitochondrial disease causes a decrease in NAD+ and a corresponding increase in NADH, i.e. a reduced NAD+/NADH ratio, as the dysfunctional mitochondria do not have the same capacity to convert NADH to NAD+ as healthy mitochondria. The cells and tissues misinterpret this lower ratio as a signal of having sufficient energy levels, when, in fact, the energy capacity is decreased.
A Finnish study published in Cell Metabolism in June of this year confirmed that NAD+ levels are reduced in patients with primary mitochondrial disease, both in muscle and in blood. The study further demonstrated promising signals that boosting NAD+ levels with B3 vitamin can be beneficial for mitochondrial disease patients.
Through KL1333, which is a potent NAD+ modulator, Abliva aims to do just that – boost the NAD+ levels to help patients with primary mitochondrial diseases. As Abliva is the first company with a precision therapy aiming to effectively correct the NAD+/NADH ratio in primary mitochondrial diseases, it seems fair to say that the Swedish company is at the forefront of the development in this area.
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