Pfizer Inc. and Eli Lilly and Co. reported top-line results from a phase III trial of tanezumab, prompting concerns about the nerve growth factor (NGF) inhibitor's safety and efficacy, another step in the epic process of trying to get the drug approved.

The long-term safety and efficacy study of tanezumab in subjects with osteoarthritis (OA) of the hip or knee compared the joint safety and 16-week efficacy of tanezumab relative to nonsteroidal anti-inflammatory drugs (NSAIDs). The 5-mg treatment arm met two of three co-primary efficacy endpoints, while patients' assessment of their OA was not statistically different than the NSAIDs. That showed, the companies said, "a statistically significant improvement in pain and physical function compared to NSAIDs at the 16-week analysis."

Patients receiving the lower 2.5-mg dose did not experience a statistically significant improvement in their pain, physician function or overall assessment of their OA at 16 weeks compared to NSAIDs. In the safety analysis, there was a higher rate of joint safety events in the tanezumab arms compared to NSAIDs at 80 weeks. The difference was "statistically significant," the companies noted.

Tanezumab 2.5 mg or 5 mg was administered subcutaneously every eight weeks for 56 weeks. Preliminary safety data showed that the overall adverse event profile was generally consistent with previous studies of tanezumab in OA, though in this study, discontinuations due to adverse events were higher among those receiving tanezumab compared to NSAIDs during the 56-week treatment period.

There was a 24-week safety follow-up in which there were 10 deaths, nine of which occurred in the tanezumab treatment arms and one was in the NSAID treatment arm. The companies said none were considered treatment related.

The incidence of the primary composite joint safety endpoint was 7.1% in the tanezumab 5-mg arm, 3.8% in the tanezumab 2.5-mg arm and 1.5% in the NSAIDs arm. Rapidly progressive osteoarthritis (RPOA) accounted for the majority of events observed in the composite joint safety endpoint. The incidence of RPOA overall was 6.3% in the tanezumab 5-mg arm, 3.2% in the tanezumab 2.5-mg arm and 1.2% in the NSAIDs arm. The incidence of total joint replacement was 8% in the tanezumab 5-mg arm, 5.3% in the tanezumab 2.5-mg arm and 2.6% in the NSAIDs arm.

Overall, those results cast a dark shadow over the drug's future, according to SVB Leerink analysts.

"The significant safety imbalances in the study, and the marginal efficacy of the drug, effectively signaled the end of this program, in our view, and probably puts the outlook for the entire class in (more) jeopardy," SBV Leerink analysts noted. "It is hard for us to imagine how these results could have been much worse."

The safety liabilities "effectively kills this program in our view," they noted.

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

Teva, Regeneron drug still in mix

In January and February, Pfizer and Lilly had positive news for tanezumab. First, they reported that 5 mg of tanezumab met all three co-primary endpoints – pain, physical function and global osteoarthritis assessment – of a second phase III trial in patients with moderate to severe osteoarthritis, while a 2.5-mg dose met just two of the three endpoints, namely pain and physical function. In that study, 2.1% of patients on drug developed RPOA, while none in the control arm did. They then reported a second positive phase III readout three weeks later: The higher dose of the drug (10 mg) used in the study attained the primary endpoint of a statistically significant improvement in pain at 16 weeks, as compared with placebo. A lower dose (5 mg) did not attain statistical significance at the same time point. (See BioWorld, Feb. 20, 2019.)

Pfizer acquired tanezumab in 2006 through its purchase of Rinat Neuroscience Corp. It was then called RN-624 and it was in phase II trials for osteoarthritis. (See BioWorld Today, April 10, 2006.)

A few years later, the conditions of some patients on the drug worsened. The preclinical data indicated the drug had caused adverse changes to the sympathetic nervous system of mature animals, prompting the FDA to put a partial hold on development of all NGF inhibitors, aside from those being developed for bone metastases. Lilly bought into the program in 2013, and in 2015 an FDA advisory committee lifted the partial hold. (See BioWorld Today, March 24, 2015.)

Teva Pharmaceutical Industries Ltd., of Petach Tikva, Israel, and Regeneron Pharmaceuticals Inc., of Tarrytown, N.Y., are also in the mix with another NGF inhibitor, fasinumab, which has also demonstrated signs of efficacy in a phase III trial in OA, although the two companies had to drop two of the study's highest doses following an efficacy analysis 16 weeks into a 56-week study. (See BioWorld, Aug. 17, 2018.)

The Teva/Regeneron phase III study of fasinumab is a randomized, double-blind, multidose, placebo- and NSAID-controlled study to evaluate its safety and efficacy in patients with pain due to osteoarthritis of the knee or hip. It began in October 2017 and is slated for completion by June 15, 2020. It includes 1,620 participants in 68 locations across the U.S.