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Abstract Number: 1493

A Phase 1 Study of FPA008, an Anti-Colony Stimulating Factor 1 Receptor (anti-CSF1R) Antibody in Healthy Volunteers and Subjects with Rheumatoid Arthritis (RA): Preliminary Results

Julie Hambleton1, Lei Zhou1, Seema Rogers1, Sjoerd van Marle2, Thijs van Iersel2, James Zanghi1, Emma Masteller1, Kevin Baker1 and Brian Wong1, 1Five Prime Therapeutics, South San Francisco, CA, 2PRA Health Sciences, Groningen, Netherlands

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Macrophage, osteoclasts and rheumatoid arthritis, treatment

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Session Information

Title: Rheumatoid Arthritis - Small Molecules, Biologics and Gene Therapy: Novel therapies, Biosimilars, Strategies and Mechanisms in Rheumatoid Arthritis

Session Type: Abstract Submissions (ACR)

Background/Purpose

Activation of CSF1R via IL34 or CSF1 results in activation, differentiation, and survival of monocytes, macrophages and osteoclasts.  CSF1R activation produces inflammatory cytokines responsible for joint destruction, thus pathway inhibition may provide a therapeutic benefit to RA patients (pts). FPA008 is a humanized IgG4 anti-CSF1R antibody that blocks ligand binding and has preclinical activity in models of arthritis. This is a double-blind, randomized, placebo-controlled first-in-human trial designed in 3 parts to study safety, pharmacokinetics (PK) and pharmacodynamic (PD) biomarkers. In Parts 1 & 2, healthy volunteers received either one or two doses, respectively. Part 3 will be in RA pts, and clinical and radiographic efficacy parameters will also be explored.

Methods

In Part 1, 8 subjects were randomized (3:1) to receive a single intravenous infusion of FPA008 or placebo, per dose cohort of 0.2, 1, 3, or 10 mg/kg. In Part 2, 8 subjects were randomized (3:1) to receive 2 doses of FPA008 or placebo administered 14 days apart, at 1 or 3 mg/kg. Dose escalation decisions were based on the incidence of dose limiting toxicities (DLTs), plus attributed adverse events (AEs) beyond the DLT period. PK, bone turnover biomarkers, CSF1 and IL34 serum concentrations, and CD16+ monocytes were assessed. Part 3 consists of an open-label evaluation of 3 dose levels in RA pts whose disease is not responding to methotrexate. Three pts per dose level will receive 2 doses of FPA008 administered 14 days apart. Thereafter, 30 new pts will be randomized (2:2:1) to one of two dose levels of FPA008 or placebo, respectively.

Results

As of May 30, 2014, the first 5 cohorts in Parts 1 and 2 (up to 1 mg/kg, two doses) were completed through the DLT period. No DLTs were reported.

Frequently reported AEs were Grade 1 or 2 pruritus, headache and periorbital edema. Dosing in the 10 mg/kg cohort was associated with moderate periorbital edema, facial and finger swelling, and mild, transient blurred vision outside the DLT period.  Dose-dependent elevations of CK and LDH were noted at 1 mg/kg and above; AST elevation occurred at 3 mg/kg and above; and mild ALT elevation occurred at 10 mg/kg in one subject. These elevations were not associated with clinical signs/symptoms or abnormalities in total bilirubin, CK isoenzymes or troponin, were reversible, and were expected due to FPA008-mediated inhibition of Kupffer cells responsible for removing these enzymes.  

Non-linear PK was observed, with exposure increasing greater than dose proportionality from 0.2 to 3 mg/kg, suggesting target mediated clearance. Suppression of CD16+ monocytes, decreased bone turn-over biomarkers (CTx, Trap5), and dose-dependent increase in serum CSF1 and IL34 concentrations were observed. 

Conclusion

FPA008 is well tolerated up to 3 mg/kg.  Persistent AEs beyond the DLT period at 10 mg/kg coincide with the prolonged PK exposure. PD effects of full suppression of non-classical CD16+ monocytes and decrease of bone turnover biomarkers were noted at dose levels tested and may track with clinical benefit in RA pts. Updated data including preliminary data in RA pts will be presented. 


Disclosure:

J. Hambleton,

Five Prime Therapeutics,

3,

Five Prime Therapeutics,

1;

L. Zhou,

Five Prime Therapeutics,

5;

S. Rogers,

Five Prime Therapeutics,

3,

Five Prime Therapeutics,

1;

S. van Marle,
None;

T. van Iersel,

PRA Health Sciences,

3;

J. Zanghi,

Five Prime Therapeutics,

3,

Five Prime Therapeutics,

1;

E. Masteller,

Five Prime Therapeutics,

3,

Five Prime Therapeutics,

1;

K. Baker,

Five Prime Therapeutics,

3,

Five Prime Therapeutics,

1;

B. Wong,

Five Prime Therapeutics,

3,

Five Prime Therapeutics,

1.

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