Title : Early clinical development of modified P8 for the treatment of alzheimer’s disease
Abstract:
Alzheimer’s disease (AD) affects one in ten people over the age of 65, one in two over age 85. There are today 55 million people with AD worldwide. The largest increase in the number of people suffering with AD between now and 2050 will be in the developing world and any new therapeutic must be affordable and easy to administer for use everywhere. The pathological hallmarks of AD include the formation and accumulation in the brain of Aß, widely recognized to be the major neurotoxic agent in AD. Earlier therapeutic attempts at lowering total Aß production have failed due to off-target effects as they inhibited or modulated the catalytic activities of ß- or g-secretase, enzymes known to hydrolyze other substrates, many with critical cellular functions. After years of failures the first new drugs for AD in 20 years, monoclonal antibody (MAb) drugs Leqembi and now Kisunla, were approved by the FDA. Both target Aß and although they show modest (27% for Leqembi, 35% for Kisunla) cognitive improvement in patients, they provide the first definitive evidence that lowering Aß improves cognitive performance. These drugs represent promising first steps to developing new treatments to slow down and stop AD. There are many disadvantages to MAb drugs including high cost, mode of administration (by IV in the clinic once or twice a month) and safety since all MAbs are known to cause ARIAs (swelling and bleeding in the brain). MAb drugs would be out of the reach of most people in developing countries. We have a novel, differentiated technology that does not target the secretases and that addresses some of the disadvantages of the MAb drugs. Our peptide drug can inhibit the production of Aß in vitro and in a transgenic (Tg) mouse model of AD. Our best candidate, modified P8 (mP8), is 8-amino acids in length and can be delivered to the brain by subcutaneous injection. It reduces the production of Aß in Tg mouse brain and CSF by 50-70% following once-a-day subcutaneous administration. Importantly, these peptide-induced reductions of total Aß and Aß40 and 42, do not modify or inhibit either ß- or g-secretase activities. Our technology is also the earliest for intervention, as it stops the Aß from being produced, as opposed to dealing with its effects once it has accumulated. Our drug Nubytide will be affordable, easy to administer (once-a -day self-administered subcutaneous injection as opposed to IV once or twice a month) and safer than MAbs since peptides do not produce ARIAs, and will be potentially useful in all parts of the world. mP8 is being developed as a new, first-in-class, disease-modifying drug for the prevention and treatment of AD. IND-enabling GLP ADME, toxicology and safety pharmacology studies on mP8 in rats and monkeys have been completed and will be discussed. We are now poised to submit an IND to the FDA to carry out a first in human clinical study.
