PF-655 (REDD14NP or RTP801i) is a synthetic siRNA designed to inhibit the expression of Quark’s proprietary target, RTP801. PF-655 has been studied in two Phase II clinical trials for the treatment of diabetic macular edema (DME) and for the treatment of wet age-related macular degeneration and is currently in Phase IIB for DME. PF-655 is licensed to Pfizer on an exclusive worldwide basis.
PF-655 was well tolerated in a Phase I/IIa study completed by Quark on Pfizer’s behalf in patients (NCT00725686) with Choroidal Neovascularization (CNV) saecondary to Age-Related Macular Degeneration (Wet AMD) and in Phase II studies for DME (Degas NCT01445899) and wet AMD (Monet NCT00713518).

The drug candidate

PF-655 is a stabilized, synthetic, chemically modified siRNA that inhibits Quark’s proprietary target RTP801, a stress-induced adaptor protein inhibiting mTOR function upstream to TSC1/TSC2 complex in response to a variety of stresses. Quark discovered the target gene, RTP801, using its BiFAR™ target discovery platform (PMID: 11884613). Expression of RTP801 is rapidly upregulated in response to ischemia, hypoxia and/or oxidative stress. Intravitreal injection of PF-655 in preclinical animal models of laser-induced choroidal neovascularization (CNV) led to inhibition of RTP801 expression via RNAi mechanism without TLR activation, induction of expression of anti-angiogenic and neurotrophic factors, and subsequent reduction of CNV volume, vessel leakage and infiltration of inflammatory cells into the choroid.

The mechanism of action of PF-655 is thought to be different from that of different types of VEGF inhibitors. In animal models, PF-655 when dosed with VEGF inhibitors in the CNV model, appears to improve results and also decreases retinal blood vessel leakage in diabetic mice. Attenuation of apoptosis in the inner nuclear layer of the retina and reduction of pathological retinal neovascularization were also observed in RTP801 knockout mice subjected to the model of oxygen-induced retinopathy (retinopathy of prematurity) (PMID: 15452091). Reduced pathology was also observed when RTP801 knockout mice were evaluated in a variety of non-ocular disease models, including cigarette smoke-induced lung injury and emphysema suggesting a more global function for RTP801 in pathological processes underlying acute and chronic stress-induced diseases.

Previous clinical studies

PF-655 (formally REDD14NP) has been studied in two Phase II clinical trials for the treatment of diabetic macular edema (DME) and a Phase I and one Phase II study for the treatment of wet age-related macular degeneration (AMD). A Phase I Open-Label, Dose Escalation Trial Of REDD14NP Delivered By A Single Intravitreal Injection To Patients With Choroidal Neovascularization (CNV) Secondary To Exudative Age-Related Macular Degeneration (“Wet AMD”).( NCT00725686), Phase II Open Label Multicenter, Prospective, Randomized, Age Related Macular Degeneration, Comparator Controlled Study Evaluating PF-04523655 Versus Ranibizumab In The Treatment Of Subjects With Choroidal Neovascularization (MONET Study).( NCT00713518) A Phase II Prospective, Randomized, Multi-Center, Diabetic Macular Edema Dose Ranging, Comparator Study Evaluating The Efficacy And Safety Of PF-04523655 Versus Laser Therapy (DEGAS)( NCT00701181). An Open-Label Dose Escalation Study of PF-04523655 (Stratum I) Combined With a Prospective, Randomized, Double-Masked, Multi-Center, Controlled Study (Stratum II) Evaluating the Efficacy and Safety of PF-04523655 Alone and in Combination With Ranibizumab Versus Ranibizumab Alone in Diabetic Macular Edema (MATISSE STUDY)( NCT01445899).
The Phase II MONET trial of PF-655 in wet AMD determined that PF-655 produced increasing improvements in mean visual acuity over the first 3-month period and that the combination with Ranibizumab (Lucentis™) was better in improving visual acuity than Lucentis alone. PF- 655 combination with ranibizumab (Lucentis®) in AMD patients demonstrated advantage in change in BCVA letters. In the Phase II DEGAS study for DME, following 12-months treatment with PF-655, a dose dependent improvement in visual acuity was observed in PF-655 treated patients, compared to patients treated with laser photocoagulation control. Based on the results of this study, and the demonstration of dose related effect on vision, a Phase IIb study (MATISSE NCT01445899) was conducted with PF-655 alone and in combination with Lucentisׂ in DME patients.

Diabetic Macular Edema

Diabetic macular edema (DME) is a complication of diabetic retinopathy, the result of retinal microvascular changes that occur in patients with diabetes and is the major cause of visual impairment in diabetic patients. Diabetes mellitus and its systemic and ophthalmic complications represent an enormous public health threat in the United States. The prevalence of diabetes in the United States is currently estimated at 9% or approximately 21 million, though only about 55% are estimated to be diagnosed. According to a disease review in the Digital Journal of Ophthalmology, diabetic macular edema affects up to 10% of all patients with diabetes with 75,000 new cases occurring every year. The standard of care is today anti VEGF therapy with Lucentis ™, Bevacizumab (Avastin®) or more recently Eyleaׂ.

Wet Age-Related Macular Degeneration

Age-related macular degeneration is a disease leading to the loss of central vision and is the leading cause of blindness in individuals 65 years and older. The clinical course of the disease is divided into two stages. The early stage is characterized by the development and accumulation of drusen (“dry” AMD). In the late stage, choroidal neovascularization (CNV) and leakage leads to disciform scarring (“wet” AMD), resulting in loss of vision. Current interventions include photodynamic therapy to eliminate abnormal blood vessels, and drug therapies in the form of VEGF blockade to inhibit abnormal angiogenesis that leads to choroidal neovascularization and eventual retinal neural apoptosis/death. Since they act exclusively on blood vessel formation, there is a need for additional therapies that directly protect the retinal neurons within existing lesions and enhance survival of damaged neurons, thus promoting the restoration of visual acuity. The incidence of the neovascular form of AMD is about 200,000 new cases per year in the US with an estimated prevalence of AMD resulting in visual impairment of approximately 1.7 million Americans over age 65.