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A phase III study of the nerve growth factor and monoclonal antibody tanezumab showed positive results in a refractory patient population with knee or hip osteoarthritis (OA) -- good enough that this agent may finally be approved after a long and rocky development road.

Among 849 patients enrolled from 104 sites from 2016 to 2018 who had not responded to other oral or injectable treatments, those randomized to 5-mg tanezumab had a change on the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) pain subscale of -2.85 at week 24 compared with -2.24 for those receiving placebo, for a mean difference of -0.62 (P=0.0006), according to Francis Berenbaum, MD, PhD, of the Sorbonne Université in Paris, and colleagues.

Patients receiving tanezumab 2.5 mg also had significantly greater reductions in pain compared with placebo, with a mean difference of -0.46 (P=0.0088), the researchers reported online in .

"This study demonstrates subcutaneous tanezumab at a dose of 5 mg every 8 weeks statistically significantly improves pain, physical function, and patient global assessment of OA at 24 weeks in patients with moderate-to-severe OA who have not responded to or could not tolerate standard-of-care analgesics," wrote Berenbaum and colleagues.

The FDA decided last month to given subcutaneously in doses of 2.5 for moderate-to-severe OA that has not responded to conventional treatments, according to developers Pfizer and Eli Lilly.

"I think that from a regulatory point of view that it's highly likely that this will be approved for a very specific patient population," said Lee Simon, MD, director of SDG LLC, a drug development consulting firm in Boston, and previously the division director of the FDA's Analgesic, Anti-inflammatory and Ophthalmologic Drug Products.

The History

Osteoarthritis is a major cause of disability worldwide, with current treatment recommendations focusing on nonpharmacologic strategies and analgesics such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids. Many patients ultimately require costly total joint replacements. Concerns about inadequate efficacy and potential adverse effects have spurred efforts to develop new treatments for this common condition.

is a protein that is involved in the generation and modulation of pain and hyperalgesia in various pain conditions, including osteoarthritis.

Initial with tanezumab administered the medication intravenously in fixed doses up to 10 mg. However, some of those studies found cases of that was suspected to be osteonecrosis necessitating total joint replacements, and preclinical studies had also detected changes in the sympathetic nervous system. Because of those concerns, in 2010 and 2012 the FDA placed partial clinical holds on studies of nerve growth factor antibodies.

After further safety investigations, the FDA holds were lifted by 2015, and additional studies were planned using lower doses administered subcutaneously.

"The phase III OA program conducted after the clinical holds were removed (post-2015) used only lower doses of tanezumab administered subcutaneously in difficult-to-treat patients, incorporated extensive risk mitigation and surveillance, excluded patients with evidence of or risk factors for rapidly progressive OA, or who were unsuitable for joint replacement and restricted chronic concomitant use of NSAIDs while in the study," Berenbaum and colleagues explained.

In one of those subsequent studies, which was conducted from 2016 to 2018 and included 698 patients, WOMAC pain scores declined from 7.1 to 3.6 at week 16 among patients receiving 2.5-mg tanezumab, from 7.3 to 3.6 in patients who started on 2.5 mg and increased to 5 mg at week 8, and from 7.3 to 4.4 in those who received placebo. However, "the improvements were modest and tanezumab-treated patients had more joint safety events and total joint replacements," wrote Thomas J. Schnitzer, MD, PhD, of Northwestern University Feinberg School of Medicine in Chicago, and co-authors in a 2019 study in .

In accompanying that study, Jeffrey N. Katz, MD, of Brigham and Women's Hospital in Boston, wrote: "It could be argued that the risks of rapidly progressive OA and total joint replacement are too high for policymakers to permit entry of tanezumab into the market for advanced, symptomatic OA. However, given the prevalence and disability burden of OA, and the paucity of effective alternatives, it would be reasonable to allow patients and physicians to make these decisions together."

The Current Study

The new study also was conducted from 2016 to 2018 in Europe and Japan, and included a 24-week double-blind phase followed by a 24-week safety follow-up. The treatments of placebo, 2.5-mg tanezumab, or the 5-mg dose were given subcutaneously at baseline and weeks 8 and 16.

For inclusion in the study, patients were required to have radiographically confirmed OA and inadequate responses or intolerance to acetaminophen, oral NSAIDs, and opioids. That was an important difference compared with earlier trials, Simon told 名媛直播. "The patient population included people who could not take opioids or who failed opioids, which was not necessarily clearly delineated in previous trials. That's very important from a regulatory point of view. This population is a group of patients who have no alternative. What else is there other than joint replacement?"

Patients also had to have baseline WOMAC scores for pain and physical function of 5 or higher in the index joint, and to have ratings of fair, poor, or very poor on the baseline patient global assessment. Patients with risk factors for rapidly progressive OA such as a history of that event, subchondral insufficiency fractures, or spontaneous osteonecrosis of the knee were excluded.

Most of the participants were women whose mean age was 65 and whose disease duration averaged 7 years.

The three co-primary endpoints were changes on the WOMAC pain score, WOMAC physical function subscale, and patient global assessment.

With the 5-mg dose, significant improvements were seen on all three of those endpoints. As with the WOMAC pain scores, the mean difference compared with placebo on the WOMAC physical function score was -0.71 (P<0.0001), and the difference was -0.19 on the patient global assessment (P=0.0051).

For the 2.5-mg group, the researchers reported, the mean difference on the WOMAC physical function score was significant, with a mean difference of -0.59 (P=0.0008). But the 2.5-mg dose did not meet the full three-part primary endpoint, with a nonstatistically significant change on the patient global assessment of -0.11 (P=0.1092) compared with placebo.

On a secondary endpoint of reduction of 50% or more on the WOMAC pain score, responses were seen in 33.8% of patients on placebo, 45.4% on tanezumab 2.5 mg, and 47.9% on tanezumab 5 mg.

Rapidly progressive OA was seen in 1.4% and 2.8% of the 2.5-mg and 5-mg groups, respectively, and in none of the placebo group. Total joint replacements were reported in similar numbers across the groups, at 6.7% to 7.8%, and in most cases were considered to be elective.

Additional adverse events observed throughout the 48-week study included paresthesia, reported by 2.1% of the 2.5-mg group, 4.2% of the 5-mg group, and 2.1% of the placebo group, and hypoesthesia, reported by 2.5%, 2.5%, and 0.7%, respectively.

What's Next?

It's important to recognize that the effect size with tanezumab is modest, Simon said. "Is it what we had seen at the beginning of these development programs 14 years ago? No. We're not seeing the 80% benefit lasting for 8 to 10 weeks that we saw earlier. We're seeing a mild-to-moderate benefit similar to what we see with everything we have available orally or injectable -- but in a group of patients who can't take anything else."

The effect size seen with tanezumab has been estimated at 0.2 to 0.24. With , an injection of hyaluronic acid, the effect size was found to be 0.23, and depending on the study, NSAIDs have an effect size of 0.23 to 0.54.

"Acetaminophen barely has an effect size in truly well-done and adequately controlled trials, and glucocorticoids have a better effect size but don't last very long," Simon said. "So in the end this is a modest effect size at the 5 mg dose. I don't know that they could approve the 2.5 mg dose, because the patients didn't notice improvements, although the measurements did."

He added that it's possible that if tanezumab is FDA approved for OA, the labeling could have a boxed warning about the potential for joint problems and destruction and the paresthesia and hypoesthesia. "That's the only worry I would have from a labeling point of view," Simon said.

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