Mechanisms of Action
Abeta lowering
Our lead beta-amyloid (Abeta)-lowering compound for human use, ALP-496, is a cysteine protease inhibitor whose targets, cathepsin B and calpain-1, have been implicated in animal studies from a number of independent laboratories. Cathepsin B, which is significantly elevated in the brains of both Alzheimer's and TBI patients, has been shown to cleave the wild-type beta-secretase site of the amyloid precursor protein (APP) to produce Abeta in the activated pathway of neuronal secretion. Increased production of Abeta has been demonstrated to have a major role in Alzheimer's disease and TBI, and such increased production can be modulated by inhibition of cathepsin B activity by ALP-496.
The validation of cathepsin B as a viable target for treating Alzheimer’s disease and TBI has been demonstrated by gene knock-out studies. Mice without the cathepsin B gene are viable and indistinguishable from normal mice, but have substantially reduced Abeta in their brains. Moreover, in a transgenic mouse model of Alzheimer’s disease, mice that had the human APP gene with the wild-type beta-secretase site inserted into their genome responded to treatment with drug by exhibiting reduced Abeta levels and improved memory in a water maze test even when initial treatment was delayed until significant disease had developed. Similarly, cathepsin B deficient mice exhibited smaller lesion volume, less neuronal death, and significantly better functional outcomes in a model of TBI.
Increased cathepsin B activity, with resultant elevated Abeta levels, causes the activation of calpain-1 that is, in turn, subsequently auto-activating. Such increased calpain-1 activity causes breakdown of synapses and the initiation of the caspase cascade, a princple pathway leading to programmed cell death (apoptosis) of the neuron. Cathepsin B has also been implicated in the independent activation of caspases. Both enzymes have been well studied with respect to their contribution to tissue necrosis. Thus, ALP-496 inhibition of cathepsin B and calpain-1 brings about the reduction of Abeta and ultimately results in beneficial neuroprotection.
Neuroprotection
Beyond the neuroprotection mentioned above, when cleavage of the wild type beta-secretase site of APP is inhibited, APP is preferentially cleaved at the alpha-secretase site to produce sAPPalpha, a known neuroprotective molecule that has also been shown to stimulate neuroproliferation. ALSP has shown in animal studies that treatment with ALSP compounds reduces Abeta levels and increases sAPPalpha levels in the brain. Furthermore, in a reduced cathepsin B environment, Bcl-2 is increased which is also neuroprotective. Similarly, removing the suppression of brain-derived neurotrophic factor (BDNF) that is caused by soluble oligomers of amyloid beta would have a net neuroprotective effect. The subsequent lower Abeta levels support neuroprotection as calpain-1 is not activated under those conditions. Moreover, ALSP compounds are known to directly inhibit calpain-1 that is or has already become activated.
ALP-496
ALP-496 is a proprietary version of a drug, called EST (aka E64d) that was developed in Japan for a muscular dystrophy indication. Although EST did not reach the market for that indication, it was shown in Phase III trials to have an exceptionally wide safety margin. ALP-496 has deuterium replacing strategic hydrogens in the molecule, allowing for enhanced bioavailability and monitoring of the drug in the body.
Deuterium (D) is a non-radioactive form of hydrogen that is isolated from sea water. It is heavier than hydrogen (H) and thus a form of H2O that has the chemical structure D2O is called "heavy water." Deuterium forms a stronger chemical bond to the carbon atoms of a molecule than H does, and so selective deuterium modification in ALP-496 improves the drug’s metabolic properties allowing for a lower effective dose and potentially resulting in even better safety, tolerability and efficacy than the parent compound.
