ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2240

An Exploratory 4-Week Study of a P2X3 Antagonist AF-219 in the Treatment of Patients with Osteoarthritis (OA) of the Knee

Vibeke Strand1, Michael Kitt2, Alan Kivitz3, Anthony Ford2, Peter Butera2 and Bruce McCarthy2, 1Stanford University, Portola Valley, CA, 2Afferent Pharmaceuticals, Inc., San Mateo, CA, 3Altoona Center for Clinical Research, Duncansville, PA

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords:

Session Information

Title: Osteoarthritis - Clinical Aspects: Therapeutics

Session Type: Abstract Submissions (ACR)

Background/Purpose

Targeting P2X3 receptors that mediate the sensitizing effects of ATP released from inflamed and damaged tissues on the primary afferent neurons (PAN) of musculoskeletal structures may interrupt processes that drive hyperalgesia and allodynia. P2X3 blockade in a range of rodent hyperalgesia models has demonstrated efficacy. Recently, AF-219, a selective P2X3 antagonist, has shown efficacy in patients with refractory chronic cough. This was a multicenter phase 2 study to assess safety and efficacy of AF-219 versus placebo in patients with moderate to severe pain due to OA of the knee over 4 weeks. Secondary objectives assessed changes in physical function, stiffness, global assessment of OA, and health related quality of life.

Methods

Eligible patients, 40-80 years with Kellgren-Lawrence grade ≥2 and OA of ≥6 months duration required baseline average daily pain between 5 and 9 on the Numeric Pain Rating Scale (NPRS) following pain medication washout. Primary endpoint analysis of change from Baseline (Week 4) of weekly average daily NPRS used a mixed effects model with repeated measures yielding an overall 1-sided α=0.0225.  

Results The Full Analysis Population included 164 patients (AF-219 n=78, placebo n=86) who received ≥ one dose of study medication and completed ≥50% of week 1 daily NPRS scores. 134 patients completed 4 weeks treatment (AF-219 n=56, placebo n=78) due to early discontinuations for taste-related adverse events (AEs) with active treatment and lack of efficacy in placebo. Reduction in weekly average daily NPRS in AF-219 treated patients was numerically greater than placebo at each week. This difference was greatest in week 2 (p=0.0436).

Normalized pain, stiffness, physical function, and total  WOMAC scores revealed larger numeric mean reductions at all end of treatment analyses; the Week 1 normalized total WOMAC score was significantly better in AF-219 treated patients (p=0.0176). Patient (PGIC) and Clinician Global Impression of Change (CGIC) and Short Form-36 physical component summary and role physical and bodily pain domains at end of treatment were significantly improved compared with placebo. Placebo patients took significantly more rescue medication over all 4 weeks.

There were no deaths or SAEs during the treatment phase. AEs were generally mild. 88% AF-219 treated patients reported dysgeusia/hypogeusia and 19% discontinued treatment due to dysgeusia.

Conclusion

In patients with OA of the knee, treatment with the P2X3 antagonist AF-219 resulted in improvement in pain and symptoms compared with placebo.

References: Ford A., Purinergic Signalling, 2012, Abdulqawi R., Eur Respir J 2013, Jarvis M., Proc Natl Acad Sci USA, 2002

Disclosure:

V. Strand,

Afferent Pharmaceuticals, Inc.,

5;

M. Kitt,

Afferent Pharmaceuticals, Inc.,

3;

A. Kivitz,
None;

A. Ford,

Afferent Pharmaceuticals, Inc.,

3;

P. Butera,

Afferent Pharmaceuticals, Inc.,

3;

B. McCarthy,

Afferent Pharmaceuticals, Inc.,

3.

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