Tanezumab-Related Adverse Events Adjudicated

Alice Goodman

November 13, 2012

WASHINGTON, DC — Although tanezumab appeared to be highly effective in treating pain and functional impairment in patients with hip and knee osteoarthritis, clinical trials of the drug were temporarily halted by the US Food and Drug Administration (FDA) in 2010 after 87 cases of osteonecrosis were reported in nearly 7000 patients treated with different dose levels of the drug. An independent adjudication committee (IAC) has since determined that only 2 of those 87 cases represented treatment-induced osteonecrosis. However, the drug did cause rapid worsening of osteoarthritis (OA) in 68 patients treated at higher doses and in combination with nonsteroidal antiinflammatory drugs (NSAIDs), according to the IAC findings, presented here for the first time at ACR 2012.

The IAC was chaired by David Hungerford, MD, a retired orthopedic surgeon from Johns Hopkins University School of Medicine and former head of orthopedic surgery, the Good Samaritan Hospital, Baltimore, Maryland, who is an expert on osteonecrosis. The committee also included 3 rheumatologists and 1 bone pathologist.

"We found that despite initial reports from study investigators, tanezumab treatment was not associated with an increase in osteonecrosis, but was associated with an increase in rapid progression of osteoarthritis in 68 patients. These patients were administered higher doses of tanezumab, and were administered tanezumab in combination with NSAIDs," said lead author of the report, IAC member, Marc Hochberg, MD, head of Rheumatology and Clinical Immunology, University of Maryland School of Medicine in Baltimore.

The phase 3 studies reviewed by the IAC included 1029 placebo recipients; 604 patients treated with tanezumab, 2.5 mg; 1771 treated with tanezumab, 5 mg; 1898 receiving tanezumab, 10 mg; 587 receiving tanezumab, 2.5 mg, plus an NSAID; and 1249 treated with tanezumab, 5 mg, plus an NSAID; and 1192 receiving tanezumab, 10 mg, plus NSAID. A total of 1266 patients were treated with an active comparator.

Tanezumab monotherapy was associated with rates of rapidly progressive OA, ranging from 0 events per 1000 patient-years at the lowest dose of 2.5 mg to 11 events per 1000 patient-years at the 10-mg dose (P < .0124 for the difference between the dosing groups). The rate of rapidly progressive OA was higher when tanezumab was combined with NSAIDs, and there was an additional increase with higher doses of tanezumab in combination with NSAID.

The IAC also found that 9 adjudicated events of rapidly progressive OA occurred before these patients received study medication as participants in a phase 3 OA study.

Tanezumab Testing Resumes, With Certain Caveats

Leslie Tive, PhD, senior director of Medical Affairs at Pfizer (the manufacturer of tanezumab), said, "The FDA has lifted the hold on the development program, and Pfizer plans to incorporate the AC advice into our clinical trials of tanezumab."

"In my 33 years of rheumatology practice, I've never seen anything like this drug in terms of its efficacy in alleviating pain and functional disability. We want to get it to market. We need to figure out how to prevent worsening osteoarthritis using lower doses of the drug and as monotherapy. We want to revive this program," stated Stanley Cohen, MD, from Rheumatology Associates, Dallas, Texas, who served as past president of the ACR.

"The take-home message of this study is that if the sponsor wants to develop this compound for OA pain at the knee and hip, they will need to study it at doses of 2.5 or 5 mg infusion every 8 weeks and not in combination with NSAIDs," stated Lee Simon, MD, a rheumatologist and consultant with SDG, LLC in Cambridge, Massachusetts.

"Probably the most important factor moving forward is to identify when and in whom to use this drug. We need to understand who is at risk for serious adverse events and should not be exposed to this drug," Dr. Simon stated.

Dr. Hochberg has received funding from Abbott Laboratories, Astra Zeneca, Bioiberica S.A., Eli Lilly Inc, Genentech/Roche, Merck Inc, Novartis Pharma A.G., Pfizer Inc, Stryker LLC, and Xoma. Dr. Cohen has served as a clinical investigator and/or research consultant for Amgen Inc, Biogen Idec, Bristol-Myers Squibb, Centocor Ortho Biotech Inc, Genentech Inc, Hoffmann-La Roche Inc, Pfizer Inc, and sanofi-aventis. Dr. Simon reports financial relationships with more than 190 pharmaceutical companies, including Pfizer, and other institutions.

ACR 2012. Abstract 260. Presented November 11, 2012.