FDA panel rejects Pfizer's tanezumab for osteoarthritis pain over risk-benefit doubts
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A pair of FDA advisory committees has rejected a risk mitigation proposal from Pfizer for its NGF-blocker tanezumab, stating it would fail to ensure the drug’s benefits outweigh its risks for patients with osteoarthritis.
In a 19-1 vote, members of the FDA’s Arthritis Advisory Committee (AAC) and the Drug Safety and Risk Management Advisory Committee (DSaRM) ruled that while clinical data suggest tanezumab (Pfizer, Eli Lilly & Co.) can benefit patients with OA, the associated risk for joint destruction, or rapidly progressing osteoarthritis (RPOA), and other safety outcomes was too great, even with the proposed mitigation efforts.
“I concur with the sponsor’s contention, that there is an unmet need for efficacious treatment of osteoarthritis, and more so, in both my own practice and in the testimonies presented that we heard yesterday, I really hear the plea from patients with chronic arthritis pain looking for relief,” DSaRM member Edward Y. Cheng, MD, of the University of Minnesota Medical School, said prior to the vote. “Unfortunately, however, this drug, tanezumab does not fulfill this need.”
Going further, Cheng argued that tanezumab’s risk for RPOA, combined with its reported failure to prevent total joint replacement, negates any benefits it may have, which he characterized as “minimally better than placebo.”
“It has a similar clinical efficacy and is clinically comparable to existing therapies — it’s really no better than taking aspirin or ibuprofen,” he said. “And it does not avoid or delay total joint arthroplasty. As imperfect a metric as that is, it is not better than an anti-inflammatory, and in some ways might be worse, as some of the data has shown.”
Cheng added: “So, why would we approve a drug treatment for osteoarthritis that’s minimally better than placebo, no better than existing therapies like aspirin and anti-inflammatories, has a worse risk profile than placebo and existing therapies, and poses a risk to non-target joints with irreversible damage — to the point that we are tussling with this Risk Evaluation and Mitigation Strategy program, which in my opinion is more accurately a post-marketing surveillance program?”
The risk mitigation strategy
Pfizer is seeking tanezumab’s approval for relief of signs and symptoms of moderate-to-severe OA in adults for whom other analgesics were ineffective or are not appropriate. The company’s biologics license application is specifically for the drug’s 2.5 mg dose, the lowest studied in patients with OA, administered subcutaneously every 8 weeks, according to a Risk Evaluation and Mitigation Strategy (REMS) program proposed by the company.
The intent of that REMS program was to mitigate the risk for RPOA, which was reported in patients with OA treated with tanezumab in studies.
Pfizer’s REMS proposal included limiting the dose to 2.5 mg, baseline and annual X-rays of knees and hips, prescriber education, excluding patients with other types of preexisting joint disease, and limiting the drug to those with more severe OA that is unresponsive to other analgesics.
However, an FDA review team deemed these measures insufficient to mitigate the risk for RPOA. Their concerns included data suggesting that tanezumab is associated with RPOA in healthy joints, as well as the substantial disagreements regarding X-ray interpretation between experts during clinical trials.
They also had their doubts about the real-world feasibility of using specially trained radiologists to detect RPOA.
“Unfortunately, affective risk mitigations to prevent tanezumab-related joint destruction are few,” said Robert Shibuya, MD, medical officer for the Division of Anesthesiology, Addiction Medicine, and Pain Medicine at the FDA Center for Drug Evaluation and Research, as he addressed the joint meeting. “Minimizing concurrent NSAID use may be feasible, and labeling could limit the dose of tanezumab. However, the applicant has not been able to identify the early signs and symptoms of tanezumab-associated arthropathy and has not been able to elucidate the mechanism for this adverse reaction.”
“The applicant has proposed a REMS with active imaging surveillance,” he added. “The initial scheme required accurate measurement of joint space width, which showed poor concordance in clinical trial, and is likely unfeasible in the real world. The proposal now is to use Kellgren-Lawrence grade change to guide when to stop treatment. We have not had the opportunity to discuss this internally. However, on its face, given how the KL grades are written, I would be concerned about subjectivity and consistency, particularly when this is applied by community radiologists.”
Ultimately, a near-unanimous majority of committee members were inclined to agree. In particular, several members of both committees said the proposed REMS measures could screen for adverse effects but would not be able to mitigate them.
Meanwhile, Suzanne B. Robotti, a consumer representative on the DSaRM, president of the MedShadow Foundation and executive director for DES Action USA, expressed concern over unanswered questions about tanezumab’s long-term use, particularly the lack of any data showing a drop in adverse events.
“The risks are just not clear yet,” she said. “Importantly the patient has multiple other options that are equal in efficacy. A new drug with risks must have better efficacy. And if it isn’t understood why this drug is working, I don’t know how you’re going to mitigate its effects.”
Concerning history
Tanezumab’s long road to yet another setback began more than 15 years ago. When its new drug application was initially submitted in April 2004, it had been structured to demonstrate efficacy in a variety of pain conditions. According to an FDA briefing document released days before the joint committee hearing, Pfizer conducted a total of 41 clinical studies, 38 interventional trials and three observational studies, enrolling and analyzing nearly 18,000 patients with approximately 13,000 exposed to at least one dose of tanezumab. During this time, the FDA held at least 43 formal meetings with Pfizer regarding the drug’s development.
However, an FDA review team at the time concluded there was no convincing evidence that tanezumab was superior to NSAIDs.
Then, in April 2010, the FDA became aware of potential safety risks for joint destruction — characterized as RPOA — and neuropathy, based on reports of joint-related adverse events in patients with OA treated with tanezumab in ongoing and completed phase 2 and 3 trials.
The ongoing OA studies were placed on hold pending a March 2012 FDA advisory committee meeting, and were only allowed to resume with the introduction of risk mitigation measures.
Pfizer conducted three studies of tanezumab following the introduction of these measures after 2015. According to the FDA briefing documents, these are the most relevant in evaluating the drug’s effectiveness and risk-benefit profile.
The safety data
For those post-2015 studies, Pfizer defined five radiographic diagnoses that represented a composite joint safety endpoint. These included ROPA type 1 — defined as a decrease in joint space width of 2 mm or more in 1 year with no structural changes — and ROPA type 2 — or a loss, destruction or collapse of bone — as well as subchondral insufficiency fracture, osteonecrosis, and pathologic fracture.
According to the FDA briefing document, data from the post-2015 studies suggest the risk for developing a composite joint safety endpoint with tanezumab 2.5 mg was 2.4 (95% CI, 1-3.8) excessive events per 100 patient years, compared with NSAIDs. Compared with placebo, the risk was 2.4 (95% CI, 1-4.4) excessive events per 100 patient years with tanezumab 2.5 mg.
In addition, among the 33 composite joint safety endpoints that occurred in joints that were radiographically healthy at baseline, 31 were in patients who received tanezumab. Meanwhile, all six instances of advanced destruction that developed in health joints were found in patients treated with tanezumab.
The data also suggest that the risk for joint destruction is two- to three-fold higher if tanezumab is used concomitantly with NSAIDs.
Tanezumab was also associated with an increased risk for total joint replacement in two of the three post-2015 studies, with evidence of dose response, according to the briefing document. FDA analyses show hazard ratios for total joint replacement of approximately two for the 2.5 mg tanezumab dose, and hazard ratios surpassing three for doses above 2.5 mg.
“Tanezumab carries the risk of joint destruction,” Shibuya told the joint meeting. “Because cases of joint destruction and total joint replacement continue to rise after 1 year of treatment, we consider the trajectory of this risk, when extrapolated to years of therapy, to be uncertain. Whether or not patients can appreciate the fact that tanezumab can damage healthy joints is unknown.”
Pfizer argues in favor of approval
According to Shibuya, Pfizer was able to provide “substantial evidence” of tanezumab’s efficacy, albeit with what he called a “modest treatment effect size.”
Presenters from Pfizer who addressed the joint hearing argued that the drug, in both its 2.5 and 5 mg doses, provides clinically important improvements in pain and physical function in knee and hip OA. They added that the efficacy of the 2.5-mg dose has been shown to be maintained over long-term treatment.
According to Ken Verburg, PhD, senior vice president and medicine team lead for global product development and internal medicine at Pfizer Inc., tanezumab offers a distinct alternative to opioids, and as such addresses a significant unmet need in OA pain management.
“Tanezumab is not intended for all patients with OA pain, nor as a replacement for NSAIDs,” Verburg told the committee members. “Given societal risks and the wellbeing of patients, however, we want to avoid putting patients on opioids whenever possible.
“Tanezumab is associated with one serious risk — rapidly progressive osteoarthritis that may necessitate a total joint replacement,” he added. “We conclude that the risk for drug safety events with tanezumab is outweighed by the risk of NSAIDs and opioids, and is acceptable in the context of the unmet medical need of the target population and the benefit of tanezumab therapy.”
Additionally, Verburg argued that RPOA is not unique to tanezumab or nerve growth factor inhibitors in general. Published studies describing idiopathic rapidly progressive OA date back more than 50 years, he said.
“Beginning at about the same time frame, that parallel investigations identified analgesic hip with NSAIDs, which the reported radiologic and clinical profile was reminiscent of idiopathic rapidly progressive OA,” Verburg said.
“If approved, tanezumab will be the first in a new pharmacologic class of pain therapy,” he added. “It has a mechanism of action that is distinct from that of NSAIDs and opioids, and is devoid of risks of abuse, addiction or overdose, or other serious safety concerns associated with opioid or NSAID use. The benefit-risk balance of tanezumab 2.5 mg subcutaneously is positive in the context of the unmet medical need, the efficacy and safety profile, the intended patient population and the proposed risk management plan.”
Hetlena J. Johnson, EdS, a consumer representative on the AAC, lodged the lone “yes” vote in favor of the REMS proposal’s ability to ensure the drug’s benefits outweigh the risks.
Explaining her vote, she said she wanted to give REMS process more time.
“With many drugs that are introduced, they are not given enough time in terms of findings that solution for patients who are suffering right now,” Johnson said. “With the REMS, I felt that the patients were advised what was going on, and that they were getting a benefit, but it cannot be completed, and cannot get past the risk, without getting enough time. There is more that can be studied. Although I see some things that can be improved, I thought it could be a ‘yes’.”
Perspective
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Nancy E. Lane, MD
There is an unmet need for nonopioid, nonsteroidal long-acting analgesics — no question. And while the lower dose of tanezumab that Pfizer is proposing does reduce the risk for adverse events, especially the rapidly progressing OA, there appears to be concern that the post-marketing surveillance program will not be able to determine the actual risk in the general public. It sounds to me that the committee is recommending that Pfizer produce another type of post-marketing plan to determine the safety of tanezumab.
The FDA is not killing tanezumab; it is just asking Pfizer and Lilly to go back and design a more complete post-marketing surveillance program.
I am still optimistic. It’s clear that the lower dose of tanezumab — the 2.5 mg subcutaneously every 8 weeks — is quite effective and patients will benefit from it, but we need to know who is more at risk for these adverse events so we can properly identify the right patients who should receive the medication.
The big issue is that we know two injections 8 weeks apart are effective and safe with very few safety issues, but with continuous injections, we just don’t know. That is, I think, what the FDA is most concerned about — continuous use, every 8 weeks, forever.
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