PF-4523655 (formerly RTP801i-14) is a synthetic, siRNA molecule designed to inhibit the expression of Quark’s proprietary target, RTP801. PF-4523655 is licensed to Pfizer on an exclusive worldwide basis. Results from a Phase I/II trial completed by Quark on Pfizer’s behalf showed that PF-4523655 was safe and well tolerated in patients with wet Age-related Macular Degeneration (wet-AMD) . Following successful completion of Phase I clinical studies, PF-4523655 is currently in two Phase II studies for Diabetic Macular Degeneration (DME) and AMD.
Quark discovered RTP801 using its BiFAR target discovery platform, which identifies clinically relevant critical genes and proteins that reverse the disease phenotype when inhibited. Discovery of RTP 801 gene was first reported by Quark in 2002. Since expression of RTP801 is rapidly upregulated in response to ischemia, hypoxia and/or oxidative stress, it represents a unique gene target that may regulate hypoxia-induced pathogenesis by a mechanism that is independent of growth factors such as VEGF. Both genetic inhibition (RTP801-knockout) and Intravitreal injection of PF-04523655) in preclinical animal models of laser-induced choroidal neovascularization (CNV) lead to inhibition of RTP801 expression, induction of expression of anti-angiogenic and neurotrophic factors and subsequent reduction of CNV volume, vessel leakage and choroid infiltration of inflammatory cells. Remarkably, PF-04523655 worked in cooperation or synergism with VEGF-based drugs. PF-04523655 was also shown to decrease retinal blood vessel leakage in the diabetic mice. Similar and additional effects (e.g., attenuation of apoptosis) were observed in RTP801 knockout mice subjected to the ttreatments of laser-induced CNV, STZ-induced diabetes, retinopathy of prematurity and some other non-ocular disease models.
Quark owns several families of patents covering the RTP801 gene, its RNA and protein product sequences, specific antibodies, gene inhibition and siRNA drug candidates for various indications. The Company has siRNA structure related technology licenses from Silence Therapeutics and from Alnylam Pharmaceuticals.
Despite recent medical advances, significant opportunities remain to improve outcomes for patients who suffer from DME and wet AMD. There are currently no approved pharmacological treatment options for patients with DME. Not all wet AMD patients respond to anti-VEGF therapy; the majority of patients treated in clinical trials did not regain significant vision and many that initially responded do not sustain this responsiveness in the longer term. Indeed, VEGF activity is just one of several disease mechanisms targeted by researchers studying wet AMD and other retinal diseases. Moreover, recent publications indicate that prolonged inhibition of VEGF signaling may have devastating effects on neural retina. Future treatment strategies may focus on other mechanisms and also on earlier intervention to prevent vision loss from occurring. PF-04523655 works by a unique mechanism of action and in preclinical studies has shown that it is potentially superior to anti-VEGF drugs. In addition it shows anti-inflammatory and anti-apoptotic properties and may offer a safer and more efficacious alternative to DME and AMD patients.
PF-4523655 is in Phase II clinical studies in DME and wet-AMD.