Anti-NGF Analgesic Tanezumab Faces Bleak Prospects as Pfizer/Eli Lilly Report Phase 3 Osteoarthritis Trial Results

PfizerWith PartnersEli LillyTop-line results from the Phase III clinical trial (A4091058) of tanezumab, a novel non-opioid analgesic, for the treatment of osteoarthritis (OA) were recently announced. The study aimed to compare the efficacy of two doses of tanezumab (2.5 mg and 5 mg) with nonsteroidal anti-inflammatory drugs (NSAIDs) over 56 weeks, as well as long-term safety (80 weeks), in patients with moderate-to-severe OA of the hip or knee. The results showed that only the high dose of tanezumab demonstrated significant efficacy, but it was also associated with a markedly increased incidence of joint-related adverse events.

Study A4091058 was a randomized, double-blind, active-controlled, multicenter, parallel-group study conducted in patients with moderate-to-severe osteoarthritis (OA) to evaluate the safety and efficacy of subcutaneous tanezumab compared with oral nonsteroidal anti-inflammatory drug (NSAID) therapy over 56 weeks. The study was conducted globally (including in the United States, Europe, Asia, and Latin America) and enrolled a total of 3,021 patients who had inadequate pain relief with or were intolerant to acetaminophen and tramadol or opioids (or were unwilling to take opioids), and who had been receiving stable-dose NSAID therapy prior to screening and had derived at least some therapeutic benefit from such treatment before randomization. Patients had a mean OA duration of approximately 8 years, a baseline Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score of 7 (on a scale of 0–10), and reported at study initiation that pain significantly impacted their functional ability in daily life.

Patients were randomized in a 1:1:1 ratio to receive either of two doses of tanezumab (2.5 mg or 5 mg, administered subcutaneously every 8 weeks) or oral NSAIDs (naproxen 500 mg, celecoxib 100 mg, or diclofenac sustained-release 75 mg, administered orally twice daily) during the 56-week treatment period; the study also included a 24-week safety follow-up period. The primary safety endpoint was the assessment of joint safety over the 80-week period (56-week treatment period + 24-week safety follow-up period), including a composite measure of adjudicated outcomes for rapidly progressive osteoarthritis (RPOA) type 1 or type 2, subchondral insufficiency fractures, primary osteonecrosis, or pathological fractures. The co-primary efficacy endpoints evaluated the changes from baseline to Week 16 in the WOMAC pain subscale, the WOMAC physical function subscale, and the Patient’s Global Assessment of OA (PGA).

The results showed that at the Week 16 efficacy analysis, the high-dose (5 mg) tanezumab group met two of the three co-primary endpoints compared with the NSAID treatment group: pain and physical function demonstrated statistically significant improvements, whereas the change in patients’ global assessment of OA did not reach statistical significance. In contrast, the low-dose (2.5 mg) tanezumab group did not achieve statistically significant improvements over the NSAID treatment group in pain, physical function, or patients’ global assessment of OA.

Ten patients died during the study: nine in the tanezumab group and one in the NSAID group. None of these deaths were considered treatment-related; five occurred during the treatment period and five occurred after the treatment period. The safety analysis conducted at Week 80 showed that the incidence of joint safety events was significantly higher in the tanezumab group than in the NSAID group, with the difference being statistically significant.

The specific data for the incidence of the primary composite joint safety endpoint were as follows: 7.1% in the tanezumab 5 mg group, 3.8% in the tanezumab 2.5 mg group, and 1.5% in the NSAID group. Rapidly progressive osteoarthritis (RPOA) accounted for the majority of events observed in the composite joint safety endpoint, with incidence rates of 6.3%, 3.2%, and 1.2% in the tanezumab 5 mg, 2.5 mg, and NSAID groups, respectively. The majority of RPOA events observed in the tanezumab treatment groups (81%) were classified as Type 1 RPOA. One case of osteonecrosis occurred in the tanezumab 5 mg group, while no cases were reported in the 2.5 mg or NSAID groups. Subchondral insufficiency fractures occurred in 7, 6, and 4 patients in the tanezumab 5 mg, 2.5 mg, and NSAID groups, respectively; no pathological fractures were reported in any group. Regarding joint replacement rates, the figures were 8.0% for the tanezumab 5 mg group, 5.3% for the 2.5 mg group, and 2.6% for the NSAID group.

Ken Verburg, Head of the tanezumab Development Team within Pfizer’s Global Product Development organization, stated, “We are evaluating these safety findings in light of the recent Phase III results to determine the potential next steps for tanezumab. We plan to review the complete dataset from our tanezumab clinical development program with regulatory authorities.”

Christi Shaw, President of Eli Lilly Biopharmaceuticals, stated, “Eli Lilly and CompanyRecognizing the significant unmet medical needs in the patient population with osteoarthritis, we are committed to understanding the results from these studies.”

NGF Inhibitor Analgesics: Safety Concerns Resurface After a Decade—Where Do We Go from Here?

Tanezumab is a humanized monoclonal antibody that selectively targets, binds to, and inhibitsNeurite Outgrowthfactor (NGF) exerts its effects. NGF levels in the body increase during injury, inflammation, or chronic pain. By selectively inhibiting NGF, this medication can help prevent pain signals generated in muscles, skin, and organs from reaching the spinal cord and brain. Tanezumab has a novel mechanism of action, distinct from opioids and other analgesics (including NSAIDs). In studies conducted to date, no risk of addiction, misuse, or dependence has been observed with tanezumab.

Tanezumab was developed by Pfizer in 2013Eli LillySigned an agreement worth $1.8 billion for co-development and commercialization. In June 2017, the United StatesFDAGranted Fast Track designation for the treatment of OA and chronic low back pain (CLBP).

It is worth noting that over the past year, tanezumab has passed a series of Phase III clinical trials, with at least one dose achieving the primary endpoint in three studies on OA and CLAP. However, these studies have not eliminated long-standing safety concerns. These issues first emerged in the field of NGF inhibitors approximately 10 years ago.

Pfizer andEli LillyThe newly released data further highlight the safety concerns associated with NGF inhibitors, while also intensifying industry skepticism regarding the efficacy of tanezumab. This has prompted Tim Anderson, an analyst at Wolfe Research, to sound the alarm on the drug’s prospects: “For us, the fate of this drug is likely sealed—first from a regulatory standpoint, and second from a commercial perspective.”

The safety issues observed in this clinical trial are consistent with earlier studies on NGF inhibitors, a class of drugs that fell out of favor a decade ago due to high rates of joint replacement among patients receiving the investigational medication. Since then, growing alarms over the harms caused by opioid analgesics have created an urgent need for non-addictive pain relievers, meaning that adverse events previously deemed unacceptable by regulators, physicians, and patients may now be considered tolerable.

However, even considering this favorable landscape for tanezumab,Eli LillyPfizer’s response to the latest data and its impact on the prospects of this NGF inhibitor was also subdued. Currently, Regeneron and Teva have another NGF inhibitor, fasinumab, in late-stage clinical development. The recurrence of joint-related safety events with tanezumab will undoubtedly affect the drug’s prospects. (BioonBioon.com）