Paloma Pharmaceuticals, Inc. - Soaring Without Limits
Technology
The Core Technology of Paloma Pharmaceuticals
Paloma Pharmaceuticals, Inc. was formed to develop and commercialize drugs directed against diseases involving aberrant up-regulation of the PI3K/Akt/mTOR pathway including cancer, ocular diseases (macular degeneration and diabetic retinopathy), arthritis, fibrotic diseases (renal and pulmonary fibrosis), CNS (epilepsy and neurodegenerative diseases), antiviral (HIV/AIDS) and skin diseases (psoriasis and atopic dermatitis). Paloma has a series of novel, proprietary, small molecule drugs, "Palomids", created through an integrated design platform incorporating proprietary, customized and industry standard computational tools. The Company solely owns the intellectual property for the Palomids by both composition of matter and use (therapeutic indication).

The Company's small molecule program was initiated to make an "improved" small molecule anti-angiogenic agent showing broad activity, safety and the ability to work in a variety of pathological indications including, but not limited to, ocular diseases, oncology and skin diseases. To create such agents, the Company exploited a class of FDA approved drugs, antiestrogens. Antiestrogens are small molecule drugs previously shown to have both anti-angiogenic activity and the ability to inhibit aberrant cellular proliferation, i.e. "dual acting agents". The Palomids were created to "tease out" the anti-angiogenic and anti-proliferative activity of antiestrogens. This resulted in a new series of patentable non-steroidal small molecules drugs with enhanced anti-angiogenic activity without estrogen competitive binding activity and the possibility of estrogenic side-effects. Through an integrated series of chemical design and testing with both in vitro ("test tube") and in vivo (animal models) assays Palomids have shown promising activity as an anti-angiogenic agent and as a direct anti-proliferative agent through means outside of conventional antiestrogen action. This has resulted in a library of potent dual acting drugs (anti-angiogenic and anti-proliferative) capable of working on a wide variety of diseases without the limitation of those bearing estrogen receptors. The Company has chosen Palomid 529 (P529) as the lead for the clinic in multiple indications separated by administration formulation.

The Company "teased out" the Palomids from novel computationally designed "antiestrogens" lacking antiestrogen activity. For this reason the mechanism of action of the Palomids were not originally known. However after the completion of a series of in vitro and in vivo experiments, it was discovered that the P529 functioned by causing the dissociation of both the TORC1 and TORC2 complexes of the PI3K/Akt/mTOR pathway and hence resulted in a first-in-class small molecule drug PI3K/Akt/mTOR antagonist, see figure.

Since P529 was now identified to inhibit the PI3K/Akt/mTOR pathway, it was further shown to have activity in diseases outside of the Company's original aim. This resulted in the Company developing additional programs including CNS, antiviral and others. As the PI3K/Akt/mTOR pathway signals through both the TORC1 and TORC2 complexes, dual inhibitors could be expected to exert a more complete control of the pathway than other inhibitors which only inhibit the TORC1 arm such as rapamycin (Sirolimus) and other rapamycin analogs (rapalogs). Other dual TORC1/TORC2 inhibitors have been created by exploiting the observation that mTOR kinase is found in both complexes. These dual inhibitors were created by modifying tyrosine kinase inhibitors that could inhibit, to some degree, mTOR kinase. Although these inhibitors may be considered dual TORC1/TORC2 inhibitors, they would not be expected to cause the dissociation of the complexes unlike Palomid 529 which has been shown to cause the dissociation of both complexes. As it is very possible that the other proteins within the complexes have activity outside of mTOR kinase, it is conceivable that P529 would have increased activity over the mTOR kinase inhibitors or at least a different activity profile. To date, through a series of non-GLP and GLP toxicology studies, P529 has shown a positive toxicity profile giving P529 not just better control of the pathway but safety as well.



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