Palomid 529 (P529), an experimental therapy to treat age-related macular degeneration, has been entered into the first-in-man studies, Paloma Pharmaceuticals, Inc. announced.
Palomid 529 is a non-steroidal, synthetic, small molecule drug created through computational design, synthetic and medicinal chemistry.
Palomid 529′s targets and inhibits the PI3K/Akt/mTOR signal transduction pathway as a dual TORC1/TORC2 inhibitor. It is a first-in-class PI3K/Akt/mTOR inhibitor causing the dissociation of both the TORC1 and TORC2 complexes.
The PI3K/Akt/mTOR pathway has been implicated in a wide variety of biological responses and is considered a major therapeutic target in an assortment of diseases.
Ocular diseases of neovasculature, age-related macular degeneration (AMD) and diabetic retinopathy (DR), create aberrant retinal vessels by secreting pro-angiogenic factors to induce the angiogenic cascade.
Aberrant vessels caused by pathological angiogenesis produce a variety of pathologies including edema and hemorrhage due in part by release of vascular endothelial growth factor (VEGF), inducing angiogenesis and vascular leakage.
As the PI3K/Akt/mTOR pathway is activated by a wide variety of pro-angiogenic cytokines, including but not limited to VEGF, agents capable of inhibiting the pathway is an attractive target for therapeutic intervention.
Central within the PI3K/Akt/mTOR signaling pathway are two distinct protein complexes, TORC1 and TORC2. TORC1 antagonists (rapamycin, also called Sirolimus) have shown activity in animal models of AMD and DR, and in human clinical trials.
As inhibition of both TORC1 and TORC2 should result in greater control of PI3K/Akt/mTOR signaling, dual inhibitors such as P529 would be expected to exert increased activity in back of the eye diseases of neovasculature.
The Phase I study, “A Phase I Open-Label Study to Investigate the Safety, Tolerability and Pharmacokinetic Profile of Single Intravitreal and Subconjunctival Doses of Palomid 529 in Patients with Advanced Neovascular Age-Related Macular Degeneration” will be a dose-ranging study aimed at safety but will also have objective measurement for efficacy.
“As P529 is an inhibitor of both the TORC1 and TORC2 arms ultimately controlling the PI3K/Akt/mTOR pathway it would be expected to have broad activity as an anti-angiogenic agent and further inhibit vascular permeability, two aspects that make a compelling story for clinical studies in AMD. We look forward to working with Paloma Pharmaceuticals on this interesting approach to wet AMD,” said Dr. Jeffrey Heier, M.D., principal investigator of the study with Ophthalmic Consultants of Boston.
“This external validation of P529 as a therapeutic agent to combat eye disease gives credence to not just our program for ocular disease but as P529 will be used formulated for other therapeutic areas, it also leads the way for acceptance of up-coming Phase I studies in cancer, epilepsy, dermatologic diseases and other indication areas in our pipeline,” stated Dr. David Sherris, Ph.D., president and CEO of Paloma Pharmaceuticals.
Acucela Inc’s ACU-4429 is another investigational oral treatment for dry age-related macular degeneration (dry AMD), currently undergoing clinical studies.
ACU-4429 utilizes Acucela’s visual cycle modulation (VCM) technology, and is designed to prevent or inhibit the generation of toxic by-products of the visual cycle that can lead to degenerative eye conditions like dry AMD.
Preclinical data indicate that ACU-4429 slows the rod visual cycle, resulting in decreased accumulation of a toxic by-product that is the precursor of lipofuscin, which are deposits of toxic substances.
Paloma Pharmaceuticals, Inc. is a drug development company with PI3K/Akt/mTOR inhibitors for cancer, ocular diseases (AMD and DR), CNS (epilepsy, Parkinson’s, Alzheimer’s, Huntington’s and Schizophrenia), fibrotic diseases (pulmonary and renal fibrosis), antiviral (HIV, HCV) and skin diseases (psoriasis and atopic dermatitis).