Lilly, Pfizer's phase 3 pain data show mixed efficacy, clear safety issues

The safety issues are in keeping with earlier studies of NGF inhibitors. (Bruce Blaus/CC BY-SA 4.0)

A phase 3 trial has painted a mixed picture of the safety and efficacy of Eli Lilly and Pfizer’s painkiller tanezumab. Neither dose of the nerve growth factor (NGF) inhibitor hit all the co-primary efficacy goals, and both fared worse than placebo on the safety assessments.

Tanezumab has come through a series of late-phase tests over the past year, with at least one of the tested doses hitting the primary endpoints across three clinical trials in osteoarthritis and chronic lower back pain. However, the studies also failed to quash long-standing safety concerns, which laid waste to the once-hyped NGF inhibitor field around a decade ago.

Now, Lilly and Pfizer have reported a set of data that clarify the safety concerns and add to questions about efficacy, prompting Wolfe Research analyst Tim Anderson to sound the death knell for the drug. 

"To us, the product is likely dead, if not from a regulatory standpoint (i.e., is it even approvable?) then from a commercial one (i.e., will it ever sell?)," Anderson wrote in a note to investors. 

In the trial of 3,000 people with moderate-to-severe osteoarthritis of the hip or knee, the higher, subcutaneous dose of tanezumab beat the control—an oral nonsteroidal anti-inflammatory—against two of the three co-primary endpoints. The lower dose of tanezumab failed to beat the control against any of the endpoints. Lower doses of tanezumab failed to move the needle in some of the previous studies, too.

Lilly and Pfizer captured the efficacy data, which looked at pain, physical function and patients’ views of their osteoarthritis, at 16 weeks but continued monitoring them long after that to gather safety results, most notably through an 80-week assessment of a primary composite joint safety endpoint.

In the high-dose cohort, the incidence of the safety endpoint was 7.1%, as compared to 1.5% in the control group. The divergent performance was driven by the rate of rapidly progressive osteoarthritis (RPOA) in the treatment arm. More than 6% of people in the high-dose arm developed RPOA, against around 1% in the control group.  

The one case of osteonecrosis—a bone disease—seen in the trial occurred in the high-dose arm. And 8% of patients in the high-dose cohort required total joint replacement, as compared to 2.6% in the control group. Nine of the 10 deaths in the trial occurred in the tanezumab arms, but Lilly and Pfizer think they were all unrelated to the study drug.

The safety issues illustrated by clinical data are in keeping with earlier studies of NGF inhibitors, a class of drugs that was derailed around a decade ago by reports of higher rates of joint replacement in patients receiving the experimental molecules. Since then, rising alarm about the harm caused by opioids has created a pressing need for non-addictive painkillers, meaning adverse events once deemed intolerable by regulators, physicians and patients may now be acceptable.

Even in light of that favorable environment for tanezumab, Lilly and Pfizer gave a muted response to the latest data and the implications for the prospects of the NGF inhibitor. 

“We are analyzing these findings in the context of the recent phase 3 results as we assess potential next steps for tanezumab. We plan to review the totality of data from our clinical development program for tanezumab with regulatory authorities,” Ken Verburg, tanezumab development team leader at Pfizer, said in a statement. 

Regeneron and Teva Pharmaceutical also have an NGF inhibitor, fasinumab, in late-phase development.