The FDA released briefing documents Monday in which agency reviewers found only "modest" benefit for Pfizer and Eli Lilly's experimental osteoarthritis (OA) drug tanezumab in clinical trials, while the NGF inhibitor has been associated with risks of joint destruction and neuropathy. The assessment was released in advance of an advisory panel meeting scheduled for March 24 and March 25 that will discuss a filing seeking approval of tanezumab to treat moderate-to-severe OA in adults unable to get pain relief from other analgesics.
According to the companies, the regulatory submission for tanezumab contains data that span 39 trials totalling more than 18,000 patients, including the Phase III A4091056, A4091057 and A4091058 studies evaluating the drug in patients with moderate-to-severe OA of the hip or knee. The first two assessed tanezumab against placebo, while the third used nonsteroidal anti-inflammatory drugs (NSAIDs) as the comparator. Staff reviewers concluded that while tanezumab has shown effectiveness against placebo, "the treatment effect size is modest," and there is "no convincing evidence of superior efficacy…over NSAIDs."
The companies are looking to have tanezumab approved at the 2.5-mg dose, administered subcutaneously every eight weeks by a health professional in a healthcare setting, in accordance with a risk evaluation and mitigation strategy (REMS) they have proposed. However, FDA staffers suggested the REMS programme is "not sufficient" to balance the risk of rapidly progressing osteoarthritis (RPOA) that has been seen with tanezumab.
They noted that the incidence of RPOA type 1 was two- to four-fold higher in patients treated with tanezumab compared to those treated with NSAIDs, while processes that present with bone destruction/collapse, such as osteonecrosis and RPOA type 2, occurred exclusively in those given tanezumab. The drug also presents a higher risk of patients requiring total joint replacement (TJR). Specifically, its was associated with a two- to three-fold risk of TJR surgery in both the A4091056 and A4091058 trials, although FDA staffers said it was "unclear" why there was no such imbalance seen in A4091057, the second trial that tested tanezumab versus placebo.
Meanwhile, FDA reviewers said tanezumab also carries a risk of abnormal peripheral sensation characterised as mild mononeuropathy, with the most common manifestation being carpal tunnel syndrome. Still, data suggest it has some advantage compared to NSAIDs in terms of fewer gastrointestinal bleeds, although these cases were infrequent overall. There was also no difference noted for cardiovascular and renal safety outcomes.
"We disagree with [Pfizer and Eli Lilly's] conclusion that patients would view severe joint problems as much less important and [that they would be] willing to accept increases in the annual risk of severe rapidly progressive joint problems requiring total joint replacement," the FDA staff report said. They also suggested there is "no clear evidence" that the companies' REMS programme, which contains elements to assure safe use (ETASU) that would include restricted distribution, "will have an impact on preventing or the progression of RPOA." Further, while the mitigation strategies may have worked when used during clinical testing, "it is unclear that those strategies could be replicated in clinical practice," FDA staff said.
Pfizer and Eli Lilly formed a partnership in 2013 to jointly develop and market tanezumab. The drug later received a fast-track designation by the FDA for the treatment of chronic pain associated with OA and chronic low back pain.
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