An In-Depth Report on the Investigational Drug PF-04634817

I. Executive Summary

PF-04634817 is an investigational small molecule developed primarily by Pfizer Inc., designed as an orally administered dual antagonist of the C-C chemokine receptor type 2 (CCR2) and type 5 (CCR5). The therapeutic rationale underpinning its development was the critical role these chemokine receptors play in mediating inflammatory cell recruitment, a key pathological process in various chronic diseases, particularly diabetic complications such as diabetic nephropathy (DN) and diabetic macular edema (DME). Preclinical studies, notably in animal models of DN, demonstrated promising efficacy in reducing kidney inflammation, glomerulosclerosis, and improving renal function parameters.

The clinical development program for PF-04634817 encompassed several Phase 1 studies in healthy volunteers (including NCT01140672) and in subjects with renal impairment to establish its safety, tolerability, and pharmacokinetic profile. These studies indicated that PF-04634817 was generally well-tolerated, allowing progression to Phase 2 trials. Phase 2 studies subsequently evaluated the efficacy and safety of PF-04634817 in patients with DN (NCT01712061) and DME (NCT01994291).

In the diabetic nephropathy trial, PF-04634817 demonstrated only a modest reduction in albuminuria compared to placebo. In the diabetic macular edema trial, PF-04634817 was found to be inferior to the standard-of-care intravitreal ranibizumab in improving visual acuity, leading to the early termination of this study for business reasons. Across these trials, PF-04634817 maintained a generally favorable safety and tolerability profile. However, due to the demonstration of only modest clinical efficacy in both key indications, Pfizer ultimately discontinued the development of PF-04634817. The trajectory of PF-04634817, from encouraging preclinical data to clinical discontinuation, underscores the significant challenges in translating anti-inflammatory strategies for complex, multifactorial diseases into clinically meaningful benefits, even when initial safety and target engagement are achieved. This outcome reflects the complexities of modulating inflammatory pathways where redundancy and the high bar set by existing effective therapies present substantial hurdles.

II. Introduction to PF-04634817

A. Compound Overview and Identifiers

PF-04634817 is an investigational small molecule drug candidate that was the subject of extensive research and clinical evaluation.[1] It is cataloged under the DrugBank Accession Number DB14955 and the Chemical Abstracts Service (CAS) Number 1228111-63-4 for its free base form.[1] The compound was notably investigated in several clinical trials, including the Phase 1 study NCT01140672, which focused on its safety, tolerability, and pharmacokinetics in healthy adult subjects.[1]

B. Therapeutic Rationale: Targeting CCR2 and CCR5

The primary therapeutic strategy behind PF-04634817 was its function as an orally administered dual antagonist of two key chemokine receptors: C-C chemokine receptor type 2 (CCR2) and C-C chemokine receptor type 5 (CCR5).[2] Chemokine receptors, including CCR2 and CCR5, are pivotal in orchestrating the migration of leukocytes, such as monocytes, macrophages, and T-lymphocytes, to sites of inflammation and tissue injury.[6] Their ligands, including CCL2 (monocyte chemoattractant protein-1, MCP-1) for CCR2, and CCL3 (macrophage inflammatory protein-1 alpha, MIP-1$\alpha$), CCL4 (MIP-1$\beta$), and CCL5 (RANTES) for CCR5, are often upregulated in chronic inflammatory conditions.[6]

The rationale for developing a dual CCR2/CCR5 antagonist stems from the understanding that these receptors and their associated signaling pathways are significantly implicated in the pathogenesis of various inflammatory diseases, with a particular focus on diabetic complications. In conditions like diabetic nephropathy (DN) and diabetic macular edema (DME), the recruitment and activation of inflammatory cells contribute substantially to tissue damage, vascular leakage, and progressive organ dysfunction.[6] For instance, increased expression of these chemokines and their receptors has been observed in the kidneys and retinas of diabetic individuals, correlating with disease severity.[6] By simultaneously blocking both CCR2 and CCR5, PF-04634817 aimed to achieve a broader and potentially more effective anti-inflammatory effect than could be achieved by targeting a single receptor. This dual antagonism was hypothesized to reduce the influx of damaging inflammatory cells into affected tissues, thereby mitigating disease progression. The development of an oral formulation for indications like DME, where treatments often involve invasive intravitreal injections, also suggested an ambition to offer a more convenient and patient-friendly therapeutic option, provided comparable efficacy and safety could be demonstrated.

C. Developer(s) and Origin

PF-04634817 was primarily developed by Pfizer Inc., a major pharmaceutical company with extensive research and development programs.[4] Early in its development, specifically for the Phase 1 clinical trial NCT01247883, Incyte Corporation was listed as a collaborator alongside Pfizer.[4] The chemical structure of PF-04634817 is disclosed as "example 13" in U.S. Patent No. 8,293,903 B2, which forms a core piece of the intellectual property surrounding the compound.[14]

III. Physicochemical Properties and Formulation

A. Chemical Structure, Molecular Formula, and Weight

PF-04634817 is a synthetic organic small molecule. Its molecular formula is C25​H36​F3​N5​O3​.[1] The corresponding molecular weight is approximately 511.59 g/mol, with an exact mass of 511.27702451 Da.[1] The International Union of Pure and Applied Chemistry (IUPAC) name for PF-04634817 isamino]-1-propan-2-ylcyclopentyl]--2,5-diazabicyclo[2.2.1]heptan-2-yl]methanone.[1] Its structure is characterized by multiple chiral centers and heterocyclic ring systems. The SMILES (Simplified Molecular Input Line Entry System) string is CC(C)[C@@]1(CCC@HN[C@H]2CCOC[C@H]2OC)C(=O)N3C[C@@H]4C[C@H]3CN4C5=NC=NC(=C5)C(F)(F)F, and the InChIKey is MCRWZBYTLVCCJJ-DKALBXGISA-N.[1] Two-dimensional representations of its chemical structure are publicly available through databases such as DrugBank and PubChem.[1]

B. Synonyms and Salt Forms

PF-04634817 is known by several synonyms in scientific literature and databases, including PF 04634817, PF04634817, PF-4634817, PF 4634817, and PF4634817.2 It is also referenced as "example 13" in relation to its patent disclosure.14

A notable salt form developed during its investigation is PF-04634817 succinate, identified by CAS Number 2140301-98-8.2 The empirical formula for the succinate salt is C25​H36​F3​N5​O3​⋅C4​H6​O4​, with a corresponding molecular weight of 629.67 g/mol.18 The creation of a succinate salt is a common pharmaceutical practice aimed at optimizing characteristics such as solubility, stability, or ease of manufacturing compared to the free base, likely offering advantages for formulation or absorption that were beneficial for its clinical development.

C. Solubility and Other Relevant Properties

PF-04634817, in its free base form, is described as a white to off-white solid powder.2 It exhibits good solubility in dimethyl sulfoxide (DMSO), with concentrations around 50 mg/mL (approximately 97.74 mM) being achievable.2 Its predicted water solubility is considerably lower, at 0.0706 mg/mL (ALOGPS).1 The predicted octanol-water partition coefficient (logP) values are 2.22 (ALOGPS) and 2.91 (Chemaxon), suggesting moderate lipophilicity.1

The molecular weight of approximately 512 g/mol for the free base slightly exceeds the traditional Lipinski's Rule of Five guideline of 500 Da. However, other predicted physicochemical properties, such as the number of hydrogen bond donors (1) and acceptors (7-8, depending on source), and logP, generally fall within ranges considered acceptable for orally bioavailable drugs.1 While Chemaxon predictions indicate a violation of the Rule of Five ("Rule of Five: No"), they also suggest adherence to the MDDR-like Rule ("MDDR-like Rule: Yes"), implying that PF-04634817 possesses characteristics commonly found in successful drug molecules.1 These parameters are crucial determinants of a drug's absorption, distribution, metabolism, and excretion (ADME) profile, and the pursuit of an oral formulation indicates that these properties were initially deemed suitable for clinical progression.

IV. Mechanism of Action

A. Detailed Elucidation of CCR2 and CCR5 Antagonism

PF-04634817 functions as a dual antagonist of the C-C chemokine receptor type 2 (CCR2) and C-C chemokine receptor type 5 (CCR5).[2] These receptors are members of the G-protein coupled receptor (GPCR) superfamily.[7] Their primary physiological role is to mediate the chemotaxis, or directed migration, of various leukocyte populations, particularly monocytes/macrophages and T-lymphocytes, in response to gradients of their respective chemokine ligands.[6] Key ligands for CCR2 include CCL2 (MCP-1), while CCR5 binds to CCL3 (MIP-1$\alpha$), CCL4 (MIP-1$\beta$), and CCL5 (RANTES).[6]

Upon ligand binding, CCR2 and CCR5 initiate intracellular signaling cascades that promote cell migration, activation, and survival, contributing to inflammatory responses.[6] This signaling typically involves coupling to pertussis toxin-sensitive G$\alpha_i$ proteins, leading to the inhibition of adenylyl cyclase and a decrease in cyclic AMP (cAMP) levels. Simultaneously, the G$\beta\gamma$ subunits can activate downstream pathways including mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and phospholipase C, resulting in increased intracellular calcium concentrations and cytoskeletal rearrangements necessary for cell movement.[7] Prolonged agonist exposure leads to receptor phosphorylation by G-protein-coupled receptor kinases (GRKs) and protein kinase C (PKC), followed by β-arrestin recruitment, which mediates receptor desensitization and internalization, thereby attenuating signaling.[7]

As an antagonist, PF-04634817 is designed to bind to CCR2 and CCR5, thereby preventing the binding of their cognate chemokines. This blockade inhibits the downstream signaling events and, consequently, is intended to reduce the recruitment and activation of inflammatory cells at sites of pathology.

B. Role of CCR2/CCR5 Pathways in Target Pathologies

The therapeutic rationale for PF-04634817 was centered on the established involvement of CCR2 and CCR5 pathways in the pathogenesis of chronic inflammatory conditions, particularly complications arising from diabetes mellitus.

• Diabetic Nephropathy (DN): Inflammation is a recognized cardinal feature in the development and progression of DN.[5] The CCR2-CCL2 axis is prominently implicated in mediating renal injury through the recruitment of macrophages into the kidney. These infiltrating macrophages contribute to glomerular and tubulointerstitial damage via the production of pro-inflammatory cytokines, reactive oxygen species, and fibrotic mediators.[22] While the role of CCR5 in DN is less extensively characterized, it serves as a receptor for several pro-inflammatory chemokines whose levels are elevated in diabetic kidney disease.[5] Genetic polymorphisms leading to a loss of CCR5 function have been associated with better survival in individuals with type 2 diabetes, suggesting a detrimental role for CCR5 signaling in this context.[5] Therefore, the combined inhibition of CCR2 and CCR5 was hypothesized to offer a more comprehensive blockade of inflammatory cell influx and activation within the diabetic kidney, potentially leading to a reduction in albuminuria, preservation of glomerular structure, and slowing of renal function decline.[5]
• Diabetic Macular Edema (DME): DME is characterized by chronic intraretinal inflammation and breakdown of the blood-retinal barrier, leading to vascular leakage and macular thickening.[8] Elevated levels of chemokines, including CCL2 and CCL5, have been detected in the vitreous and aqueous humor of patients with diabetic retinopathy and DME.[8] The CCR2 pathway, in particular, has been linked preclinically to increased retinal vascular permeability and monocyte infiltration in experimental diabetes.[8] Furthermore, CCR2 signaling has been suggested to modulate the production of vascular endothelial growth factor (VEGF), a key driver of angiogenesis and vascular leakage in DME.[8] By antagonizing CCR2 and CCR5, PF-04634817 was intended to reduce retinal inflammation, decrease vascular permeability, and potentially improve visual acuity in patients with DME.[8]

C. Receptor Binding Affinity and Selectivity

PF-04634817 was characterized by its potency against both CCR2 and CCR5, although with some species-dependent and receptor-specific variations. For rat receptors, PF-04634817 demonstrated an IC50​ of 20.8 nM for CCR2 and an IC50​ of 470 nM for CCR5, indicating a roughly 20-fold higher potency for rat CCR2 over rat CCR5.2 Data from a broader table of CCR2 antagonists lists an IC50​ of 3.68 nM for PF-04634817 against human CCR2, though careful interpretation is needed to ensure this specific value pertains directly and exclusively to PF-04634817 from primary studies.25

This differential potency, particularly if mirrored in human receptors (i.e., significantly higher potency for CCR2 than CCR5), could imply that at clinically administered doses, the degree of CCR2 antagonism might be more profound than that of CCR5. Achieving robust blockade of CCR5 might necessitate higher drug concentrations, which could potentially increase the risk of off-target effects or may not be achievable within a safe therapeutic window. For a dual antagonist, ideally, potencies against both targets should be relatively balanced to ensure that both mechanisms contribute meaningfully to the therapeutic effect at a given dose. A substantial discrepancy in potency could lead to one target being effectively modulated while the other is only partially inhibited, potentially diminishing the overall efficacy if both targets are indeed critical for disease modification. The subsequent clinical findings of modest efficacy suggest that, despite the sound biological rationale, the inhibition of these two receptors by PF-04634817 was not sufficient to significantly alter the complex inflammatory milieu of diabetic complications in the broader patient populations studied.

V. Preclinical Evaluation

A. In Vitro Pharmacological Profile

PF-04634817 was identified as a potent, orally active dual antagonist of CCR2 and CCR5. In vitro assays established its inhibitory concentrations (IC50​ values) against rodent receptors: 20.8 nM for rat CCR2 and 470 nM for rat CCR5.[2] This indicates a higher in vitro potency for CCR2 compared to CCR5 in rats. The compound's discovery and chemical structure are detailed in U.S. Patent No. 8,293,903 B2, where it is referred to as "example 13".[14] While specific biological activity data from this patent are not fully detailed in the available summaries, it forms the basis of the compound's intellectual property.

B. In Vivo Efficacy in Animal Models

Diabetic Nephropathy (DN) Models

The most comprehensive preclinical efficacy data for PF-04634817 in DN comes from studies using hypertensive endothelial nitric oxide synthase (Nos3)-deficient mice with streptozotocin (STZ)-induced diabetes. This model is considered relevant as it exhibits features of progressive diabetic glomerulosclerosis.[4]

• Early Intervention: When PF-04634817 was administered at 30 mg/kg/day starting from week 2 after STZ induction (early intervention, continued until week 15), it significantly inhibited key pathological features of DN. These benefits included a reduction in kidney inflammation, attenuation of glomerulosclerosis, decreased albuminuria, preservation of podocyte numbers, and amelioration of renal function impairment. However, this early intervention did not affect hypertension in these mice.[22] An intriguing observation during early intervention was an additional increase in glycated hemoglobin (HbA1c​) levels in the PF-04634817-treated diabetic mice, despite no impact on fasting blood glucose levels.[4] The mechanism for this HbA1c​ elevation was not elucidated but represents an unusual finding.
• Late Intervention: When PF-04634817 (30 mg/kg/day) was administered later in the disease course (weeks 8-15 post-STZ), it still demonstrated efficacy in inhibiting kidney inflammation, reducing glomerulosclerosis, and mitigating renal dysfunction. However, in this late intervention setting, PF-04634817 alone did not significantly affect albuminuria.[22]
• Combination Therapy in Late Intervention: The combination of PF-04634817 with an angiotensin-converting enzyme inhibitor (ACEi; captopril) during late intervention yielded superior protection against kidney damage—specifically inflammation, glomerulosclerosis, and renal function impairment—compared to ACEi monotherapy. However, this combination did not offer additional benefits in reducing albuminuria beyond what was achieved with ACEi alone. Captopril monotherapy effectively suppressed hypertension and albuminuria in this model.[22]

These findings in the Nos3-deficient mouse model, showcasing PF-04634817's ability to mitigate multiple facets of diabetic kidney disease, particularly when combined with standard care like ACE inhibition for certain endpoints, provided a strong rationale for its clinical investigation in human DN.

Diabetic Macular Edema (DME) Models

Direct preclinical studies of PF-04634817 in animal models of DME are not extensively detailed in the available information. However, the rationale for its investigation in DME was supported by several lines of evidence:

1. The known upregulation of CCR2 and CCR5 pathway components (e.g., chemokines CCL2 and CCL5) in the retinas of diabetic animals and in the ocular fluids of human patients with diabetic retinopathy and DME.[8]
2. Preclinical studies linking the CCR2 pathway specifically to increased retinal vascular permeability and monocyte infiltration in experimental diabetes.[8]
3. Evidence suggesting that CCR2 antagonism might indirectly modulate VEGF levels, a key pathogenic factor in DME.[8]
4. Studies with other CCR2/CCR5 antagonists, such as TAK-779, demonstrated a reduction in retinal vascular permeability and decreased expression of CCR2 and CCR5 in the retinas of STZ-induced diabetic mice.[10] This provided proof-of-concept for the therapeutic potential of this class of compounds in DME.

Although an indirect justification, these points collectively supported the exploration of PF-04634817 for DME, leveraging the mechanistic understanding of CCR2/CCR5 roles in ocular inflammation and vascular dysfunction.

C. Preclinical Pharmacokinetics and Safety

PF-04634817 was characterized as an orally active and bioavailable compound in preclinical settings.[2] Preclinical safety assessments generally indicated that the compound was well-tolerated.[4]

D. Key Preclinical Publications/Presentations

The pivotal publication detailing the preclinical efficacy of PF-04634817 in diabetic nephropathy is:

• Tesch GH, et al. Combined inhibition of CCR2 and ACE provides added protection against progression of diabetic nephropathy in Nos3-deficient mice. Am J Physiol Renal Physiol. 2019 Dec 1;317(6):F1439-F1449.[4]

Early discovery work related to potent, orally bioavailable dual CCR2/CCR5 antagonists from Pfizer was presented in 2009, which may encompass the research lineage leading to PF-04634817, although the specific compound is not explicitly named as such in the available abstract.[27]

Table V.1: Summary of Key Preclinical Efficacy of PF-04634817 in Nos3-deficient Diabetic Mice (Adapted from Tesch GH et al., 2019)

Intervention Group	Kidney Inflammation	Glomerulosclerosis	Albuminuria	Podocyte Loss	Renal Function Impairment	Hypertension	HbA1c​ (vs Diabetic Control)
Diabetic Control	Increased	Increased	Increased	Increased	Impaired	Present	Baseline (Diabetic)
Early PF-04634817 (Wks 2-15)	Inhibited	Inhibited	Inhibited	Inhibited	Inhibited	No effect	Increased
Late PF-04634817 (Wks 8-15)	Inhibited	Inhibited	No effect	Partially Inhib.	Inhibited	No effect	Not Reported
Late ACEi (Wks 8-15)	Partially Inhib.	Partially Inhib.	Suppressed	Partially Inhib.	Partially Inhib.	Suppressed	Not Reported
Late PF-04634817 + ACEi (Wks 8-15)	Superior Inhibition	Superior Inhibition	No added benefit	Superior Inhib.	Superior Inhibition	Suppressed	Not Reported
Non-Diabetic Control	Normal	Normal	Normal	Normal	Normal	Absent	Normal

Note: "Inhibited" or "Suppressed" indicates a beneficial effect compared to Diabetic Control. "Superior Inhibition" for combination therapy is relative to ACEi monotherapy for those specific parameters. Podocyte loss and renal function impairment were generally inhibited/improved by interventions that reduced inflammation and glomerulosclerosis.

The anomalous increase in HbA1c​ with early PF-04634817 intervention in the Nos3−/− mice, despite no effect on fasting glucose, was a peculiar finding.[4] The underlying mechanism for this observation was not clarified in the provided materials and could have represented a species-specific effect, a model-specific artifact, or a subtle metabolic interaction warranting deeper investigation had development continued. Such unexpected preclinical signals can sometimes foreshadow complexities in human translation.

VI. Clinical Development Program

A. Overview of Clinical Trials

The clinical development of PF-04634817 advanced to Phase 2, focusing on its potential therapeutic utility in diabetic nephropathy (DN) and diabetic macular edema (DME).[12] This progression was based on the preclinical evidence suggesting a role for CCR2 and CCR5 antagonism in mitigating inflammatory processes central to these diabetic complications. However, despite demonstrating a generally acceptable safety profile, the clinical program for PF-04634817 was ultimately discontinued by Pfizer due to findings of modest efficacy in these patient populations.[5]

B. Phase 1 Clinical Studies

A series of Phase 1 clinical trials were conducted to assess the initial safety, tolerability, and pharmacokinetic (PK) profile of PF-04634817 in humans. These studies were foundational for dose selection and for understanding the drug's behavior in specific populations.

1. NCT01140672 (Healthy Volunteers)

This study, officially titled "A Multiple Dose Study To Determine Safety, Tolerability, and Pharmacokinetics Of PF-04634817 In Healthy Adult Subjects," was a key early-phase investigation sponsored by Pfizer.1 As a Phase 1 trial, its primary objectives were to evaluate the safety and tolerability of multiple ascending doses of PF-04634817 and to characterize its pharmacokinetic profile in healthy adult participants.1 While specific detailed results from NCT01140672 are not extensively provided in the available documentation beyond its contribution to the overall safety database and dose-finding for later trials 5, such studies typically involve intensive monitoring for adverse events and frequent blood sampling to determine parameters like Cmax​ (maximum concentration), Tmax​ (time to maximum concentration), AUC (area under the concentration-time curve), and elimination half-life. The findings from this and other Phase 1 studies supported the conclusion that PF-04634817 doses up to 300 mg once daily (QD) were generally safe and well-tolerated in healthy individuals, forming the basis for selecting the 200 mg QD dose for subsequent Phase 2 trials in patient populations.5

2. NCT01791855 (Renal Impairment)

Recognizing that PF-04634817 was being developed for diabetic nephropathy, a condition intrinsically linked to altered kidney function, Pfizer sponsored a Phase 1, single-dose, open-label study titled "A PHASE 1, SINGLE DOSE, OPEN-LABEL STUDY TO EVALUATE THE EFFECT OF RENAL IMPAIRMENT ON THE PHARMACOKINETICS OF PF-04634817".23 This trial, which has been completed, was crucial for understanding how varying degrees of renal insufficiency might affect the drug's exposure.5 The pharmacokinetic data obtained from NCT01791855, along with SimCYP modeling, directly informed dose adjustment strategies in later Phase 2 studies. Specifically, for the DN trial (NCT01712061), a lower dose of 150 mg PF-04634817 was implemented for subjects with moderate renal impairment (estimated glomerular filtration rate 20 to <30 mL/min/1.73 m2), compared to the 200 mg dose for those with milder impairment or normal renal function.5 This proactive approach to studying PK in a relevant special population demonstrates a rigorous development methodology.

3. NCT01247883 (Healthy Volunteers)

This Phase 1 study in healthy volunteers was sponsored by Pfizer in collaboration with Incyte Corporation.4 Like other Phase 1 trials, it contributed to the overall assessment of PF-04634817's safety, tolerability, and pharmacokinetics.5 Specific outcomes beyond this general contribution are not detailed in the provided sources.31

4. NCT01098870 / NCT01098877 (Healthy Volunteers)

Pfizer also sponsored these Phase 1 studies in healthy volunteers.13 NCT01098877 was noted to be placebo-controlled.13 These trials further expanded the early-phase safety and pharmacokinetic database for PF-04634817, supporting its progression.5

General Phase 1 Outcomes

Collectively, the Phase 1 program established that PF-04634817, when administered orally at doses up to 300 mg QD, was generally safe and well-tolerated by healthy volunteers.5 This body of data was critical for selecting the 200 mg QD dose used in the subsequent Phase 2 efficacy studies in patients with DN and DME.

Table VI.B.1: Summary of Known Phase 1 Clinical Trials for PF-04634817

NCT Identifier	Abbreviated Official Title	Sponsor(s)	Phase	Subject Population	Status	Key Objectives/Findings
NCT01140672	Multiple Dose Safety, Tolerability, PK in Healthy Adults	Pfizer	1	Healthy Volunteers	Completed	Assess safety, tolerability, PK; supported doses up to 300 mg QD as safe 1
NCT01791855	Effect of Renal Impairment on PK	Pfizer	1	Renal Impairment Subjects	Completed	Evaluated PK in renal impairment; informed dose adjustments for Phase 2 DN trial 5
NCT01247883	Safety, Tolerability, PK in Healthy Volunteers	Pfizer, Incyte Corp.	1	Healthy Volunteers	Completed	Contributed to safety/tolerability database and dose selection 4
NCT01098870/NCT01098877	Safety, Tolerability, PK in Healthy Volunteers (NCT01098877 placebo-controlled)	Pfizer	1	Healthy Volunteers	Completed	Contributed to safety/tolerability database and dose selection 5

This systematic early clinical evaluation, including studies in specific populations like those with renal impairment, reflects a standard and thorough approach to de-risking subsequent, more complex Phase 2 trials.

C. Phase 2 Clinical Studies

Following the Phase 1 program, PF-04634817 was advanced into Phase 2 trials to evaluate its efficacy and safety in its primary target patient populations.

1. NCT01712061 (Diabetic Nephropathy)

This Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group study was designed "To Evaluate The Efficacy And Safety Of A Chemokine CCR2/5 Receptor Antagonist In Adults With Type 2 Diabetes And Overt Nephropathy".5 Sponsored by Pfizer, the trial enrolled adult subjects with type 2 diabetes, overt nephropathy (defined by a urinary albumin-to-creatinine ratio of ≥300 mg/g), and an eGFR between 20 and 75 mL/min/1.73 m2, who were already receiving standard of care (SOC) with an ACE inhibitor or an angiotensin receptor blocker (ARB).5 Subjects were randomized (3:1) to receive either oral PF-04634817 (200 mg QD, or 150 mg QD if baseline eGFR was <30 mL/min/1.73 m2) or a matching placebo, in addition to their SOC, for 12 weeks.5

The primary efficacy endpoint was the change from baseline in UACR at week 12.[5] The study, which has been completed, found a placebo-adjusted reduction in UACR of 8.2% (ratio of geometric means PF-04634817/placebo: 0.918; 95% credible interval: 0.75–1.09) at week 12 in the PF-04634817 arm.[5] This effect was characterized as "modest efficacy".[5] Despite this limited efficacy, PF-04634817 appeared to be safe and well-tolerated in this patient population.[4] The results of this trial were published by Gale JD, et al. in Kidney Int Rep. 2018.[5]

2. NCT01994291 (Diabetic Macular Edema)

This Phase 2, multicenter, randomized, double-masked, parallel-group study was titled "A Phase 2, Multi-Center Study To Compare The Efficacy And Safety Of A Chemokine CCR2/5 Receptor Antagonist With Ranibizumab In Adults With Diabetic Macular Edema".8 Sponsored by Pfizer, the trial aimed to compare oral PF-04634817 (200 mg QD) plus monthly masked sham intravitreal injections against monthly intravitreal ranibizumab (0.3 mg or 0.5 mg) plus oral placebo in adult subjects with DME.8 The primary endpoint was the change from baseline in Best-Corrected Visual Acuity (BCVA) in the study eye at week 12, with a non-inferiority hypothesis for PF-04634817 compared to ranibizumab.8

The study enrolled 199 subjects but was terminated early by Pfizer for "business reasons".[8] The efficacy results at week 12 showed that PF-04634817 was inferior to ranibizumab. The least squares (LS) mean difference in BCVA change from baseline between the PF-04634817 group and the ranibizumab group was -2.41 letters (80% CI: -3.91, -0.91; P=0.0399), failing to meet the non-inferiority margin.[8] Furthermore, subjects treated with PF-04634817 experienced a small increase in central subfield retinal thickness, whereas those treated with ranibizumab had a notable decrease.[8] Pharmacodynamic assessments confirmed target engagement, as evidenced by increased serum MCP-1 concentrations in the PF-04634817 arm.[8] In terms of safety, PF-04634817 was generally well tolerated, with an adverse event profile similar to that of ranibizumab.[8] The findings of this trial were published by Gale JD, et al. in Invest Ophthalmol Vis Sci. 2018.[4]

The selection of ranibizumab, a highly effective anti-VEGF agent delivered locally, as a comparator for an oral systemic therapy in the DME trial (NCT01994291) established a particularly high efficacy threshold. The modest reduction in albuminuria observed in the DN trial (NCT01712061), while statistically noted, may not have been perceived as sufficiently robust to predict a meaningful impact on long-term renal outcomes, especially given the complexity of DN progression. This apparent disconnect between the promising preclinical efficacy, especially in the Nos3-deficient mouse model for DN, and the less compelling clinical outcomes in humans highlights the well-recognized translational gap in drug development. Animal models, while valuable, do not fully recapitulate the intricacies of human disease, including genetic heterogeneity, disease duration, comorbidities, and the influence of concomitant medications.

Table VI.C.1: Comparative Summary of Phase 2 Efficacy and Safety Outcomes for PF-04634817

Feature	NCT01712061 (Diabetic Nephropathy)	NCT01994291 (Diabetic Macular Edema)
Primary Efficacy Endpoint	Change from baseline in UACR at Week 12	Change from baseline in BCVA at Week 12 (Non-inferiority to Ranibizumab)
PF-04634817 Result	8.2% placebo-adjusted reduction in UACR (Ratio 0.918; 95% CI: 0.75-1.09) 5	Inferior to Ranibizumab; LS Mean difference -2.41 letters (80% CI: -3.91, -0.91) 8
Comparator Result	Placebo	Ranibizumab (0.3mg or 0.5mg intravitreal)
Key Secondary Efficacy Outcomes	Modest effects on other renal parameters	Small increase in central retinal thickness (vs decrease with Ranibizumab) 8
Pharmacodynamics	Not detailed in snippets	Increased serum MCP-1, indicating CCR2 target engagement 8
Overall Safety Summary	Appeared safe and well-tolerated 5	Generally well tolerated, AE profile similar to ranibizumab 8
Study Status	Completed 5	Terminated early for "business reasons" 8

VII. Integrated Safety and Tolerability Profile

A. Summary of Adverse Events (AEs) Across Clinical Program

PF-04634817 was generally reported as well-tolerated throughout its clinical development program. Phase 1 studies in healthy volunteers established that oral doses up to 300 mg once daily were acceptable from a safety perspective.[5]

In the Phase 2 trial for diabetic nephropathy (NCT01712061), PF-04634817 appeared safe and well-tolerated.[5] The proportion of subjects experiencing any adverse event was 25.9% in the PF-04634817 group compared to 17.9% in the placebo group. Serious adverse events (SAEs) were reported in 3.5% of PF-04634817-treated subjects versus 1.8% of placebo-treated subjects (one source indicated 0 SAEs for placebo).[5] Discontinuations due to AEs were similar between groups (5.9% for PF-04634817 vs. 5.4% for placebo).[5] Treatment-emergent AEs (TEAEs) reported in ≥1% of subjects in the PF-04634817 arm included gastrointestinal disorders (such as diarrhea and nausea), general disorders (fatigue), abnormal laboratory investigations (increased gamma-glutamyltransferase, decreased GFR, increased lipase), nervous system disorders (dizziness), and skin and subcutaneous tissue disorders (acne, rash).[5]

In the Phase 2 trial for diabetic macular edema (NCT01994291), PF-04634817 was also generally well tolerated, with an overall incidence of all-cause and treatment-related AEs, SAEs, and severe AEs being similar to the ranibizumab comparator arm.[8] Most AEs were of mild or moderate severity. Eye disorders were the most frequently reported AEs by system organ class in both treatment arms.[8] Four subjects in the PF-04634817 arm discontinued due to AEs, with two of these (diabetic retinal edema and cardiac failure) considered treatment-related. In comparison, four subjects in the ranibizumab arm discontinued due to AEs, none of which were deemed treatment-related.[8] SAEs reported in the PF-04634817 arm included aortic valve stenosis, ischemic stroke, and one case of cardiac failure that was considered treatment-related.[8]

B. Overall Assessment of Safety

Across its clinical development program, PF-04634817 was consistently described as having a "good safety profile" or being "safe and well-tolerated," particularly when contextualized with its modest efficacy outcomes.[5] The adverse event profile did not reveal any unexpected or overwhelmingly concerning safety signals that would independently necessitate program termination. The types of AEs observed, such as gastrointestinal issues or dizziness, are not uncommon in clinical trials. While cardiac AEs were noted in the DME trial, these occurred in a diabetic population already at an elevated baseline risk for cardiovascular events, requiring careful assessment of causality. Crucially, the narrative surrounding the drug's discontinuation consistently emphasizes the lack of compelling efficacy rather than significant safety concerns as the primary driver.

VIII. Pharmacokinetics in Humans

A. Absorption, Distribution, Metabolism, and Excretion (ADME) Profile

PF-04634817 was developed as an orally administered drug.[2] Human pharmacokinetic data from the Phase 2 DME trial (NCT01994291) indicated that steady-state plasma concentrations of PF-04634817 were achieved approximately one week after initiating daily oral dosing.[8] Specific details regarding the metabolic pathways, protein binding, volume of distribution, or primary routes of excretion for PF-04634817 in humans are not extensively provided in the available documentation.[38]

B. Impact of Renal Impairment

The influence of renal function on the pharmacokinetics of PF-04634817 was specifically investigated in a dedicated Phase 1 study (NCT01791855).[4] This study confirmed that kidney impairment could potentially affect the drug's pharmacokinetic profile. These findings, supported by SimCYP (a physiologically based pharmacokinetic modeling and simulation platform) predictions, led to the implementation of a dose-adjustment strategy in the Phase 2 diabetic nephropathy trial (NCT01712061). In that trial, subjects with an eGFR between 20 and <30 mL/min/1.73 m2 received a reduced dose of 150 mg QD, while those with an eGFR ≥30 mL/min/1.73 m2 received 200 mg QD.[5] This careful consideration of renal function demonstrates a responsible approach to developing a drug intended for a population where renal impairment is prevalent.

C. Pharmacodynamic Effects

Evidence of target engagement in humans was observed. In the Phase 2 DME trial (NCT01994291), administration of PF-04634817 resulted in increased mean percentage changes in serum concentrations of MCP-1 (CCL2), the primary ligand for CCR2.[8] An increase in the circulating levels of a chemokine ligand upon administration of its receptor antagonist is a recognized pharmacodynamic marker of receptor blockade; as the receptor is occupied by the antagonist, the ligand cannot bind and clear through receptor-mediated internalization, leading to its accumulation in the circulation. This finding confirmed that PF-04634817 was indeed engaging and antagonizing CCR2 in humans at the doses administered. This confirmation of target engagement is significant because it suggests that the subsequent lack of robust clinical efficacy was likely not due to a failure of the drug to reach and interact with its intended molecular target, but rather due to other factors such as the complexity of the disease biology or an insufficient magnitude of effect from modulating this specific pathway.

Table VIII.1: Summary of Human Pharmacokinetic and Pharmacodynamic Findings for PF-04634817

Feature	Healthy Volunteers (e.g., NCT01140672)	Renal Impairment Subjects (NCT01791855)	DME Patients (NCT01994291)	DN Patients (NCT01712061)
Administration Route	Oral	Oral	Oral (200 mg QD)	Oral (150 or 200 mg QD)
Time to Steady State	Not detailed	Not detailed	Approx. 1 week 8	Not detailed
Key PK Observations	Doses up to 300 mg QD well-tolerated 5	PK affected by renal impairment 5	-	Dose adjusted based on eGFR due to PK findings in renal impairment 5
Key PD Markers	Not detailed	Not detailed	Increased serum MCP-1 (CCL2) concentrations 8	Not detailed

IX. Development Discontinuation and Rationale

A. Official Status

The clinical development of PF-04634817 was officially discontinued by its primary developer, Pfizer Inc..[5] The compound had reached Phase 2 of clinical investigation for indications including diabetic nephropathy and diabetic macular edema.[12]

B. Analysis of Efficacy Shortcomings

The decision to halt the development program was driven by the efficacy results observed in the Phase 2 trials:

• Diabetic Nephropathy (NCT01712061): In this study, PF-04634817 demonstrated only a "modest effect" on the primary endpoint, which was the reduction of albuminuria. Specifically, a placebo-adjusted reduction in UACR of 8.2% (ratio 0.918; 95% credible interval: 0.75–1.09) was observed at week 12.[5] This level of improvement was evidently not considered sufficiently robust or clinically meaningful to warrant further development for this chronic and progressive condition.
• Diabetic Macular Edema (NCT01994291): The outcomes in this indication were more definitive in their lack of promise. PF-04634817 was found to be "inferior" to the active comparator, monthly intravitreal ranibizumab, in terms of improving Best-Corrected Visual Acuity (BCVA) at 12 weeks. The LS mean difference in BCVA change from baseline was -2.41 letters in favor of ranibizumab.[8] Given that ranibizumab is an established and effective therapy for DME, a new agent, particularly an oral systemic one, would need to demonstrate at least non-inferiority, if not superiority or benefits in specific patient subgroups or safety/convenience, to be considered a viable alternative. The study was subsequently terminated early, officially for "business reasons," a decision likely precipitated by these unfavorable interim efficacy data.[8]

C. Pfizer's Stated Reasons for Discontinuation

The consistently cited reason for the discontinuation of PF-04634817's development across various reports and publications is its "modest efficacy" or "insufficient efficacy".[5] This was emphasized despite the drug generally demonstrating a "good safety profile" or being "safe and well-tolerated".[5] This indicates that the risk-benefit assessment did not favor continued development primarily due to the low probability of achieving clinically significant therapeutic benefits that would justify its use over existing treatments or address unmet needs sufficiently.

D. Timeline and Context from Pfizer Pipeline Updates

Pfizer's public pipeline disclosures provide some context for the development timeline. As of February 28, 2013, PF-04634817 was listed in Phase 2 development for Diabetic Nephropathy.[41] By February 28, 2014, the pipeline update showed PF-04634817 in Phase 2 for both Diabetic Nephropathy and Diabetic Macular Edema, indicating an expansion or progression of the DME indication during that period.[12] The subsequent discontinuation would have occurred after these Phase 2 trials yielded their respective efficacy data. The failure to meet the efficacy threshold for DN (an 8.2% UACR reduction likely deemed insufficient for long-term impact) and the clear inferiority to ranibizumab for DME, an established standard of care, were critical factors. The term "business reasons" for the DME trial termination often serves as an encompassing term for a lack of competitive efficacy or a low probability of achieving market success based on emerging data.

X. Discussion and Conclusion

A. Comprehensive Summary of PF-04634817's Development Journey

PF-04634817 embarked on its development journey as an orally available small molecule dual antagonist of CCR2 and CCR5, underpinned by a strong biological rationale targeting key inflammatory pathways implicated in diabetic complications. Preclinical studies, particularly in animal models of diabetic nephropathy, yielded encouraging results, demonstrating reductions in kidney inflammation, structural damage (glomerulosclerosis), and improvements in markers of renal function. This preclinical promise supported a comprehensive Phase 1 program that established an acceptable safety and pharmacokinetic profile in healthy volunteers and in subjects with renal impairment, allowing for informed dose selection for Phase 2 trials.

The Phase 2 program focused on two primary indications: diabetic nephropathy (DN) and diabetic macular edema (DME). In DN, PF-04634817 showed only a modest effect on reducing albuminuria. In DME, it proved inferior to the existing standard-of-care, intravitreal ranibizumab, in improving visual acuity. Throughout these clinical investigations, PF-04634817 generally maintained a favorable safety and tolerability profile. However, the lack of compelling clinical efficacy in either indication ultimately led Pfizer to discontinue its development.

B. Critical Analysis of Preclinical to Clinical Translation

The trajectory of PF-04634817 from promising preclinical findings to modest clinical outcomes is a stark reminder of the challenges inherent in translating therapies from animal models to human patients, a phenomenon often termed the "valley of death" in drug development. Several factors may have contributed to this disconnect:

1. Limitations of Animal Models: While the Nos3-deficient mouse model used for DN studies exhibits features relevant to human disease, animal models seldom fully recapitulate the chronic, complex, and heterogeneous nature of human diabetic complications. Human diabetes involves decades of metabolic dysregulation, diverse genetic backgrounds, varied comorbidities, and lifestyle factors that are difficult to simulate preclinically.
2. Species Differences: Potential differences in the precise roles, expression levels, or pharmacology of CCR2 and CCR5 between rodents and humans could influence drug efficacy. While target engagement (CCR2 antagonism) was confirmed in humans via increased MCP-1 levels [8], the downstream biological consequences of this engagement may differ.
3. Complexity and Redundancy of Inflammatory Pathways: Diabetic complications are driven by a multitude of interacting pathological pathways, not solely CCR2/CCR5-mediated inflammation. The inflammatory milieu is complex, with numerous cytokines, chemokines, and cell types involved. It is plausible that blocking only these two receptors was insufficient to overcome the overall inflammatory burden or that compensatory inflammatory pathways were activated, thereby limiting the therapeutic benefit. This highlights a common difficulty in developing anti-inflammatory agents for chronic diseases where pathway redundancy is significant.
4. Clinical Endpoints and Comparators: In the DME trial, the choice of ranibizumab as a comparator set a very high bar for efficacy.[8] For an oral systemic drug to compete with a potent, locally administered anti-VEGF agent, it would need to show substantial benefit, which PF-04634817 did not achieve. In the DN trial, while albuminuria is a validated surrogate endpoint, its modest reduction might not have been deemed sufficient by the developers to predict a meaningful impact on hard renal outcomes like progression to end-stage renal disease or significant GFR preservation in the long term.
5. Unexplained Preclinical Findings: The observation in preclinical studies that early PF-04634817 intervention led to an increase in HbA1c​ levels in diabetic mice, despite no effect on fasting glucose, was an anomaly.[4] While the implications of this finding for human studies are unclear from the available data, such unexpected preclinical signals can sometimes hint at unforeseen complexities.

C. Implications for Future CCR2/CCR5 Antagonist Development

The discontinuation of PF-04634817, alongside challenges faced by other CCR2/CCR5 antagonists in various indications [7], offers valuable lessons for future drug development efforts targeting these chemokine receptors:

1. Need for Refined Patient Selection and Biomarkers: The broad anti-inflammatory approach may be less effective in heterogeneous patient populations. Future development could benefit from identifying patient subgroups most likely to respond, potentially through genetic markers, baseline inflammatory profiles, or specific chemokine expression levels. Beyond target engagement biomarkers (like MCP-1 elevation), biomarkers that predict clinical response or reflect significant modulation of the core disease-driving pathways are crucial.
2. Consideration of Combination Therapies: The preclinical data suggesting additive benefits when PF-04634817 was combined with an ACE inhibitor for some DN endpoints [22] hints at the potential utility of CCR2/CCR5 antagonists as part of multi-target therapeutic strategies. Addressing complex diseases often requires tackling multiple pathogenic mechanisms simultaneously.
3. Re-evaluation of Indications and Endpoints: While DN and DME were logical choices based on inflammatory involvement, the specific roles of CCR2/CCR5 might be more dominant or less redundant in other inflammatory or fibrotic conditions. Furthermore, clinical trial endpoints need to be carefully chosen to reflect clinically meaningful benefits that can differentiate a new therapy.
4. Challenges for Systemic vs. Local Therapies: For localized pathologies like DME, an oral systemic therapy faces a significant challenge in demonstrating comparable efficacy to highly effective local treatments (e.g., intravitreal anti-VEGFs) without introducing systemic side effects. The convenience of oral administration must be weighed against potentially lower target tissue concentrations and broader systemic exposure.

In conclusion, PF-04634817 represents a well-characterized investigational drug whose development was halted not due to safety concerns but because it failed to demonstrate sufficient clinical efficacy in its target indications of diabetic nephropathy and diabetic macular edema. Its story underscores the complexities of translating promising preclinical anti-inflammatory concepts into effective human therapies, particularly for chronic multifactorial diseases with established treatment paradigms. The lessons learned from its development can inform future strategies for targeting chemokine pathways and navigating the challenging path from bench to bedside.

XI. References

[User Query] User Query

30 Renal Insufficiency Completed Phase 1 Trials for PF-04634817 (DB14955) | DrugBank Online.

2 PF-04634817 | PF-4634817 | CAS#1228111-63-4 | chemokine antagonist | MedKoo.

20 PF-04634817 | CCR2/5 antagonist | CAS# 1228111-63-4 | InvivoChem.

16 Pf-04634817 | C25H36F3N5O3 | CID 46198579 - PubChem.

1 PF-04634817 | DrugBank Online.

6 Frontiers | The Emerging Role of Chemokine Receptor CCR5 in Endothelial Dysfunction (frontiersin.org)

7 Frontiers | Antagonist tolerance at chemokine receptors: Current standing and emerging concepts (frontiersin.org)

18 PF-04634817 succinate SML3583 | Sigma-Aldrich (sigmaaldrich.com)

4 PF-04634817 | Dual CCR2/CCR5 antagonist | MedChemExpress (medchemexpress.com)

14 PF-04634817 (PF04634817) | IUPHAR/BPS Guide to PHARMACOLOGY (guidetopharmacology.org)

3 PF-04634817 | DrugBank Online (go.drugbank.com)

42 PF-04634817 | DrugBank Online (go.drugbank.com)

17 PF-04634817 | CCR2 /CCR5 dual antagonist | Buy from Supplier AdooQ® (adooq.com)

29 PF-04634817 - Inxight Drugs - ncats.io (ncats.io)

8 A CCR2/5 Inhibitor, PF-04634817, Is Inferior to Monthly Ranibizumab in the Treatment of Diabetic Macular Edema (arvojournals.org)

7 Frontiers | Antagonist tolerance at chemokine receptors: Current standing and emerging concepts (frontiersin.org)

16 Pf-04634817 | C25H36F3N5O3 | CID 46198579 - PubChem (nih.gov)

37 A CCR2/5 Inhibitor, PF-04634817, Is Inferior to Monthly Ranibizumab in the Treatment of Diabetic Macular Edema | IOVS | ARVO Journals (arvojournals.org)

33 Diabetic Nephropathies Clinical Trials and Investigational Drugs - Drug Target Review (idrblab.net)

22 Combined inhibition of CCR2 and ACE provides added protection against progression of diabetic nephropathy in Nos3-deficient mice - PubMed (nih.gov)

30 Renal Insufficiency Completed Phase 1 Trials for PF-04634817 (DB14955) | DrugBank Online (go.drugbank.com)

36 Ranibizumab Terminated Phase 2 Trials for Diabetic Macular Edema (DME) Treatment | DrugBank Online (go.drugbank.com)

43 PF-04634817 Terminated Phase 2 Trials for Diabetic Macular Edema (DME) Treatment | DrugBank Online (go.drugbank.com)

5 Effect of PF-04634817, an Oral CCR2/5 Chemokine Receptor Antagonist, on Albuminuria in Adults with Overt Diabetic Nephropathy - PMC (nih.gov)

35 Effect of PF-04634817, an Oral CCR2/5 Chemokine Receptor Antagonist, on Albuminuria in Adults with Overt Diabetic Nephropathy - PubMed (nih.gov)

4 PF-04634817 | Dual CCR2/CCR5 antagonist | MedChemExpress (medchemexpress.com)

23 PF-04634817 - Drug Targets, Indications, Patents - Patsnap Synapse (patsnap.com)

44 Novel Therapies for Kidney Disease in People With Diabetes - PubMed (nih.gov)

26 Effect of late intervention with PF-04634817, angiotensin-converting... | Download Scientific Diagram (researchgate.net)

29 PF-04634817 - Inxight Drugs - ncats.io (ncats.io)

23 PF-04634817 - Drug Targets, Indications, Patents - Patsnap Synapse (patsnap.com)

5 Effect of PF-04634817, an Oral CCR2/5 Chemokine Receptor Antagonist, on Albuminuria in Adults with Overt Diabetic Nephropathy - PMC (nih.gov)

35 Effect of PF-04634817, an Oral CCR2/5 Chemokine Receptor Antagonist, on Albuminuria in Adults with Overt Diabetic Nephropathy - PubMed (nih.gov)

13 (PDF) G-Protein-Coupled Receptors in Rheumatoid Arthritis: Recent Insights into Mechanisms and Functional Roles (researchgate.net)

37 A CCR2/5 Inhibitor, PF-04634817, Is Inferior to Monthly Ranibizumab in the Treatment of Diabetic Macular Edema | IOVS | ARVO Journals (arvojournals.org)

45 Selected ongoing and recently completed clinical trials in diabetic... | Download Table (researchgate.net)

5 Effect of PF-04634817, an Oral CCR2/5 Chemokine Receptor Antagonist, on Albuminuria in Adults with Overt Diabetic Nephropathy - PMC (nih.gov)

31 (PDF) G-Protein-Coupled Receptors in Rheumatoid Arthritis: Recent Insights into Mechanisms and Functional Roles (researchgate.net)

8 A CCR2/5 Inhibitor, PF-04634817, Is Inferior to Monthly Ranibizumab in the Treatment of Diabetic Macular Edema (arvojournals.org)

32 (PDF) The CCL2/CCR2 Axis in the Pathogenesis of HIV-1 Infection: A New Cellular Target for Therapy (researchgate.net)

23 PF-04634817 - Drug Targets, Indications, Patents - Patsnap Synapse (patsnap.com)

25 Potentials of C‐C motif chemokine 2–C‐C chemokine receptor type 2 axis in cancer and inflammatory disease therapy - PMC (nih.gov)

4 PF-04634817 | Dual CCR2/CCR5 antagonist | MedChemExpress (medchemexpress.com)

46 CCR2/CCR5 inhibitor PF-04634817 for NASH and liver fibrosis - Taylor & Francis Online (tandfonline.com)

9 (PDF) Novel targets for the treatment of diabetic nephropathy: an update on pathophysiological Nocel targets for the treatment of diabetic nephropathy (researchgate.net)

21 (PDF) Pathogenic Pathways and Therapeutic Approaches Targeting Inflammation in Diabetic Nephropathy (researchgate.net)

47 (PDF) Novel Therapies in Development for Diabetic Macular Edema (researchgate.net)

23 PF-04634817 - Drug Targets, Indications, Patents - Patsnap Synapse (patsnap.com)

4 PF-04634817 | Dual CCR2/CCR5 antagonist | MedChemExpress (medchemexpress.com)

10 A Potential Novel Therapeutic Target in Diabetic Retinopathy: A Chemokine Receptor (CCR2/CCR5) Inhibitor Reduces Retinal Vascular Leakage in an Animal Model - PMC (nih.gov)

14 PF-04634817 (PF04634817) | IUPHAR/BPS Guide to PHARMACOLOGY (guidetopharmacology.org)

15 immuno_tagged_ligands.csv (guidetopharmacology.org)

15 immuno_tagged_ligands.csv (guidetopharmacology.org)

5 Effect of PF-04634817, an Oral CCR2/5 Chemokine Receptor Antagonist, on Albuminuria in Adults with Overt Diabetic Nephropathy - PMC (nih.gov)

27 (PDF) Discovery of a Potent and Orally Bioavailable CCR2 and CCR5 Dual Antagonist (researchgate.net)

40 (PDF) Discovery of BMS-753426: A Potent Orally Bioavailable Antagonist of CC Chemokine Receptor 2 (researchgate.net)

27 (PDF) Discovery of a Potent and Orally Bioavailable CCR2 and CCR5 Dual Antagonist (researchgate.net)

24 (PDF) Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities (researchgate.net)

48 Inflammation in Diabetic Nephropathy: Pathogenesis and Therapeutic Implications - PMC (nih.gov)

11 The Role of Chemokines and Chemokine Receptors in Diabetic Nephropathy - PMC (nih.gov)

49 (PDF) The Role of Chemokines and Chemokine Receptors in Diabetic Nephropathy (researchgate.net)

19 PF-04634817 succinate | CAS 2140301-98-8 | CCR2/CCR5 (glpbio.com)

49 (PDF) The Role of Chemokines and Chemokine Receptors in Diabetic Nephropathy (researchgate.net)

15 immuno_tagged_ligands.csv (guidetopharmacology.org)

12 Pfizer Pipeline Update February 28, 2014 (q4cdn.com)

41 pipeline_2013_0228.pdf (pfizer.com)

4 PF-04634817 | Dual CCR2/CCR5 antagonist | MedChemExpress (medchemexpress.com)

27 (PDF) Discovery of a Potent and Orally Bioavailable CCR2 and CCR5 Dual Antagonist (researchgate.net)

28 CCR2 and CCR5 Receptor Antagonists as New Potential Drugs in the Treatment of Inflammatory and Neuropathic Pain - PMC (nih.gov)

1 PF-04634817 | DrugBank Online.

18 PF-04634817 succinate SML3583 | Sigma-Aldrich.

8 A CCR2/5 Inhibitor, PF-04634817, Is Inferior to Monthly Ranibizumab in the Treatment of Diabetic Macular Edema.

34 Effect of PF-04634817, an Oral CCR2/5 Chemokine Receptor Antagonist, on Albuminuria in Adults with Overt Diabetic Nephropathy.

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