番茄社区

CHICAGO -- The monoclonal antibody tanezumab, which blocks nerve growth factor, showed significant benefits in pain and function among patients with osteoarthritis (OA) of the knee or hip, and rates of severe adverse joint events such as rapidly progressive OA that had plagued earlier studies were low, a researcher reported at the here.

In a that included almost 700 patients, changes in pain scores on the Western Ontario and McMaster Universities (WOMAC) scale at week 16 were -2.64 among patients who were randomized to placebo compared with -3.23 for patients receiving two doses of 2.5 mg of subcutaneous tanezumab and -3.37 for those whose initial dose was 2.5 mg followed by titration to 5 mg for the second dose. The difference in least squares means from baseline were -0.60 (P=0.0129) and -0.73 (P=0.0023), for the two dose regimens, respectively, according to Thomas J. Schnitzer, MD, of Northwestern University in Chicago.

"It's been a long hard road as to whether this drug could be approved," said Lee Simon, MD, of SDG LLC, a drug development consulting firm in Cambridge, Mass., who was not involved in the study. "The pain relief [with tanezumab] is so substantial depending on the dose, that there have been very bad side effects such as rapidly progressive OA," said Simon, who formerly was division director of the FDA's Center for Drug Evaluation and Research.

In 2010, the FDA imposed a partial clinical hold on the development program for tanezumab because of numerous reports of suspected osteonecrosis that necessitated total joint replacement. Only two of the 87 suspected cases turned out to be osteonecrosis, and in 2012 the FDA lifted the clinical hold. However, later that year it imposed a new partial clinical hold because of peripheral nervous system adverse effects observed with nerve growth factors in animal models. That hold was lifted in 2015, and sponsors Pfizer/Lilly planned further studies using lower doses given subcutaneously rather than the higher intravenous doses used previously.

There also were multiple cases of rapidly progressive OA in an earlier study that was halted because of the clinical hold. In the FDA's Arthritis Advisory Committee's briefing document concerning adjudication of the clinical hold, the agency stated, "The mechanisms responsible for rapidly progressive OA associated with tanezumab treatment are uncertain but may result in part from reduced joint pain leading to increased joint loading and overuse and further damage to a susceptible joint."

The current study consisted of a 16-week treatment period and a 24-week safety follow-up phase. Patients had not responded to or tolerated standard pain treatments including acetaminophen, nonsteroidal anti-inflammatory drugs, and tramadol. The treatment was given at baseline and at week 8, with efficacy being assessed at week 16.

Among the 696 patients enrolled in the study, two thirds were female, mean age was 61, and mean disease duration was 9.5 years. WOMAC pain scores at baseline ranged from 7.1 to 7.4, and most patients had Kellgren-Lawrence radiographic scores of 3 or 4.

Co-primary endpoints along with WOMAC pain scores were changes in WOMAC physical function and patient's global assessment. For physical function, the changes from baseline in the placebo, 2.5 mg, and 2.5/5 mg groups were -2.56, -3.22 (P=0.0065) and -3.45 (P=0.0002), while changes in patient global scores were -0.65, -0.87 (P=0.0109) and -0.90 (P=0.0038), respectively.

A key secondary endpoint of a 50% improvement over baseline was achieved by 38% of the placebo group and 55% to 57% of the tanezumab-treated patients (P<0.001), Schnitzer reported in a late-breaker session at the meeting.

With regard to safety, about half of patients in all groups experienced any adverse event, but very few discontinued because of adverse events (0-0.9%).

Joint safety was assessed by a blinded adjudication committee of cases requiring total joint replacement as well as any investigator or central reader reports of suspected rapidly progressive OA.

Joint replacements were seen more often in the tanezumab-treated patients, with eight cases in the 2.5 mg arm and 16 in the 2.5/5 mg arm compared with four cases in the placebo arm. All joints that required surgery had been Kellgren-Lawrence grades 3 or 4 at baseline.

"Obviously, there is an imbalance in the joint replacement events. The reason for this is not known but is not consistent with prior data," Schnitzer said.

"In 26 of the 28 joints replaced, the blinded adjudication committee felt that the x-ray findings were consistent with normal progression of OA," he said.

The incidence rate of rapidly progressive OA was 1.3%, and all patients experiencing this serious complication were Kellgren-Lawrence grade 4 at baseline.

Paresthesias were reported in 3.5% and 1.3% of the 2.5 mg and 2.5/5 mg groups compared with 0.4% of the placebo group.

Two larger, longer studies underway will provide more data to better characterize safety, he said.

"We are beginning to identify a dose that may be acceptable for pain relief in the gigantic arena of OA, which is very exciting because we have not had many new drugs in this particular field," Simon told 番茄社区.

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