Pfizer and Eli Lilly said they will study the mixed Phase III results generated by their non-opioid chronic pain candidate tanezumab before deciding whether to continue developing the nerve growth factor (NGF) inhibitor.

The phama giants have released topline results from the Phase III trial, designed to compare the long-term safety and efficacy of two tanezumab dosages, 2.5 mg and 5 mg, to nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with moderate-to-severe osteoarthritis (OA) of the hip or knee.

The topline results for Study A4091058 (NCT02528188) showed the tanezumab 5 mg treatment arm meeting two of the three co-primary efficacy endpoints—by showing a statistically significant improvement in pain and physical function compared to NSAIDs after 16 weeks, as well as no statistical difference between OA self-assessment by tanezumab patients compared with NSAID patients.

However, patients who received tanezumab 2.5 mg showed no statistically significant improvement in pain, physical function, or patients’ overall assessment of their OA at 16 weeks compared to NSAIDs.

The co-primary efficacy endpoints evaluated changes from baseline to week 16 in the WOMAC Pain subscale, the WOMAC Physical Function subscale, and the Patient’s Global Assessment of OA.

The trial’s safety analysis showed a higher rate of joint safety events in the tanezumab arms compared to NSAIDs at 80 weeks: Incidence of the primary composite joint safety endpoint was 7.1%in the tanezumab 5 mg arm, compared with 3.8% in the tanezumab 2.5 mg arm and 1.5% in the NSAIDs arm.

Joint safety was a composite measure consisting of adjudicated outcomes of rapidly progressive osteoarthritis (RPOA) type 1 or type 2, subchondral insufficiency fracture, osteonecrosis, or pathological fracture.

The primary safety endpoint evaluated a composite measure of adjudicated outcomes of RPOA type 1 or type 2, subchondral insufficiency fracture, primary osteonecrosis, or pathological fracture through 80 weeks—56 weeks of treatment plus a 24-week safety follow-up period.

RPOA type 1 was defined as a significant loss of joint space width ≥2 mm (predicated on optimal joint positioning) within approximately one year, without gross structural failure. RPOA type 2 was defined as abnormal bone loss or destruction, including limited or total collapse of at least one subchondral surface that is not normally present in conventional end-stage OA.

RPOA accounted for most events observed in the composite joint safety endpoint, Lilly and Pfizer acknowledged. 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% percent in the NSAIDs arm.

More than three-quarters (81%) of RPOA events observed with tanezumab were RPOA type 1, Pfizer and Lilly said.

‘Analyzing these findings’

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

Tanezumab is a humanized monoclonal antibody designed to selectively target NGF, a regulator of pain processing and sensitivity. Tanezumab selectively binds to NGF, inhibiting it from activating pain-signaling neurons.

Among other NGF inhibitors in development are fasinumab, co-developed by Regeneron Pharmaceuticals and Teva Pharmaceutical Industries. Last year those companies announced positive topline Phase III results for fasinumab in patients with chronic pain from OA of the knee or hip.

In 2015, the FDA lifted a partial clinical hold had been in effect for tanezumab and all other anti-NGF antibodies since December 2012, following adverse changes in the sympathetic nervous system of mature animals. As a result, Lilly paid Pfizer the $200 million upfront payment agreed upon two years earlier.

During the hold in 2013, Pfizer and Lilly agreed to co-develop and co-commercialize tanezumab, with the companies agreeing to equally share product development expenses as well as potential revenues and certain product-related costs. In return, Lilly agreed to pay Pfizer the upfront money once the FDA addressed the clinical hold, plus $1.58 billion tied to achieving regulatory and sales milestones.

In June 2017, Pfizer and Lilly received the FDA’s Fast Track designation for tanezumab for the treatment of OA and chronic low back pain.

In Study A4091058, a total 3,021 patients were randomized 1:1:1 to NSAIDs or tanezumab 2.5 mg or 5 mg administered subcutaneously every eight weeks, for a total of 56 weeks. The oral NSAIDs studied were either naproxen 500 mg, celecoxib 100 mg, or diclofenac extended release 75 mg.

Preliminary safety data showed that discontinuations due to adverse events were higher among those receiving tanezumab compared to NSAIDs during the 56-week treatment period—though the overall adverse event profile with tanezumab was generally consistent with previous studies of tanezumab in OA, Pfizer and Lilly said.

Ten patients died in the study—of which nine occurred in the tanezumab treatment arms and the other, in the NSAID treatment arm. None were considered related to treatment; five occurred during the treatment period and five, after the treatment period.

No pathological fractures were seen in patients treated with tanezumab or NSAIDs. Among other safety events, however:

  • Osteonecrosis—One patient in the tanezumab 5 mg arm; none in the tanezumab 2.5 mg or NSAIDs arms.
  • Subchondral insufficiency fracture—Seven tanezumab 5 mg patients; six tanezumab 2.5 mg patients; and four NSAIDs patients.
  • Total joint replacement—8.0% in the tanezumab 5 mg arm; 5.3% in the tanezumab 2.5 mg arm; and 2.6% in the NSAIDs arm.

Full results from Study A4091058 will be submitted for future scientific publication or presentation, Pfizer and Lilly added.

“Lilly and Pfizer recognize the significant unmet needs for patients living with osteoarthritis,” added Christi Shaw, president, Lilly Bio-Medicines. “We are committed to understanding these results for people who suffer from chronic pain.”

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