Pfizer’s Tanezumab REMS Faces US FDA Doubts Heading Into Panel Review
Executive Summary
Measures aimed at mitigating risk of progressive joint damage with the first-in-class nerve growth factor inhibitor may not be clinically feasible to implement or prevent rapid progression of osteoarthritis, FDA reviewers say; agency briefing document describes efficacy as 'modest' and says the sponsor's patient preference study was flawed and 'uninformative.'
Pfizer Inc.’s proposed Risk Evaluation and Mitigation Strategy for the osteoarthritis drug tanezumab may be neither clinically feasible to implement nor useful in preventing the risk of progressive joint damage from the nerve growth factor inhibitor, the US Food and Drug Administration said.
In advisory committee briefing documents released 22 March, agency reviewers said although the proposed REMS is consistent with mitigation measures implemented during the drug’s clinical development program, “there is no clear evidence to support that requiring and implementing the proposed elements will have an impact on preventing or the progression of” rapidly progressing osteoarthritis (RPOA).
Advisory Committee Voting Question
- Will the REMS proposed by the applicant ensure that the benefits of tanezumab outweigh its risks?
“Furthermore, even if the mitigation strategies employed in the clinical trial demonstrated effectiveness, it is unclear if those strategies could be replicated in clinical practice,” the agency said.
The FDA’s Arthritis Advisory Committee and Drug Safety and Risk Management Advisory Committee will meet on 24-25 March to consider the approvability of tanezumab for relief of signs and symptoms of moderate to severe osteoarthritis in adult patients for whom use of other analgesics is ineffective or not appropriate.
The agency’s 213-page briefing document reads like a long piece of bad news for Pfizer and partner Eli Lilly and Company in their efforts to bring to market the first anti-NGF, a drug class that has been positioned as an alternative to opioid analgesics but has had a troubled safety history.
Little Enthusiasm
The briefing document suggests FDA reviewers find little to be enthusiastic about with tanezumab.
They take issue with the proposed indication statement, which is novel with regard to both the qualifier “moderate to severe” and the exact wording of the allusion to treatment failure with prior analgesics. In addition, the agency states that, at this time, the “signs and symptoms” portion of the proposed indication will not be entertained.
The FDA’s review found substantial evidence of efficacy, albeit modest, relative to placebo, with no convincing evidence of superior efficacy against nonsteroidal anti-inflammatories (NSAIDs).
The agency also cites a host of methodological issues with a Pfizer-sponsored patient preference study that render it “uninformative for regulatory decision-making.”
On the safety side, the review cites the increased risk of RPOA and total joint replacement with tanezumab. The heightened risk of joint destruction when tanezumab is used concomitantly with NSAIDs raises labeling implications, FDA reviewers said, and there is evidence that the drug can adversely target healthy joints
As for the proposed REMS, which includes a requirement for bilateral X-rays of the knees and hips two months before the first dose and annually thereafter, the review team has concerns that the plan “is not sufficient to mitigate the risk of RPOA and would not ensure that the benefits of tanezumab outweigh the risks of the RPOA.”
The agency presents the advisory committee with two discussion questions on characterization of the risks of joint-related adverse reactions and mitigation strategies, followed by one voting question. (See box.)
Clinical Hold Leads To Mitigation Measures
Pfizer submitted the tanezumab biologics license application in December 2019, but the review has continued past its user fee goal date. Pfizer announced in July 2020 the application was not expected to go to an advisory committee, but three months later the company said the agency planned to convene a panel review in March 2021.
In April 2010, FDA learned of a potential safety signal based on reports of unusual and unexpected joint-related adverse events in tanezumab-treated patients with osteoarthritis in ongoing and completed Phase II and III trials. Anti-NGF studies were place on clinical hold and an advisory committee meeting was convened in March 2012 to discuss the joint-related safety signals with the class. (Also see "Anti-NGF Studies Face Major Redesign After Arthritis Advisory Cmte. Urges Resumed Testing" - Pink Sheet, 12 Mar, 2012.) Studies in osteoarthritis patients eventually were allowed to resume with measures designed to minimize the adverse effect of tanezumab on joints.
Although the tanezumab development program spans 15 years and 41 clinical studies, the FDA’s risk/benefit assessment for the current BLA focuses primarily on three trials: studies 1056 and 1057 (both placebo-controlled) and study 1058 (NSAID active-controlled). These studies, referred to as the post-2015 studies, were conducted with the proposed dosing regimen (2.5mg subcutaneous every eight weeks) in an osteoarthritis population purported to have exhausted other treatment options, and they included risk mitigation measures implemented after the FDA allowed studies to resume.
In study 1056, tanezumab 2.5mg was statistically superior to placebo for all three co-primary endpoints: change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, WOMAC function and Patient Global Assessment of Osteoarthritis. In study 1057, statistical superiority was demonstrated for tanezumab only on the two WOMAC endpoints.
“The treatment effect size for WOMAC pain was 0.60 and 0.46 for Studies 1056 and 1057, respectively. Compared to most systemic analgesics in OA studies, this represents a modest effect size versus placebo,” the FDA’s briefing document states.
Study 1058 was designed as a superiority study against NSAIDs, and treatment with tanezumab 2.5mg failed to meet any of the coprimary endpoints at week 16.
Increased Risks Of Safety Endpoint, Joint Replacement
The post-2015 studies included a composite joint safety endpoint (CJSE) encompassing:
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RPOA Type 1: Defined as a decrease in joint space width ≥ 2mm in one year with no structural changes (but not applied to joints with baseline joint space of less than 2mm);
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RPOA Type 2: Defined as loss/destruction/collapse of bone;
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Subchondral Insufficiency Fracture: Defined as focal bone defect/radiolucency/subchondral cortex;
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Osteonecrosis; and
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Pathologic fracture.
Study measures aimed at mitigating the risk of joint damage included plain radiograhs of knee, hip and shoulder at screening and end of study in the placebo-controlled trials. In the active-controlled trial, participants underwent plain radiographs of knee, hip and shoulder and MRI of hip and knees at screening, with additional radiographs and surveillance MRI at subsequent timepoints.
Radiographs were to be taken using standardized technique, and imaging studies were read by a blinded, central radiologist. Study drug was stopped for RPOA1 or a more severe change. NSAID use was limited, and in study 1058 patients who failed to respond to the first two doses of study drug were discontinued.
The FDA found tanezumab 2.5mg was associated with a 2.6-fold increased relative risk of CJSE relative to NSAIDs. “Time-to-event curves are equivocal with regard to whether risk plateaus or continues to rise following one year of treatment. The most common form of CJSE observed was RPOA1,” the agency said.
Subgroup analyses did not identify any factors that appeared to predict patients more likely to develop a CJSE. “We found no strong evidence to suggest that patients with less advanced disease at baseline may be at lower risk of treatment-related CJSE,” the agency said. “Furthermore, it is important to note that 33 of the adjudicated CJSE occurred in radiographically healthy joints.”
For the most part, RPOA1 is asymptomatic, and good data do not currently exist to make a definitive prediction regarding outcomes, the agency acknowledged. However, if a patient on tanezumab is at higher risk of total joint replacement than a patient who is not, “that represents an unequivocally bad outcome because it indicates that the joint destruction has progressed, and patients become exposed to the morbidity and risks of major surgery,” the FDA said.
Tanezumab 2.5mg was associated with approximately a two-fold increase in the risk of total joint replacement surgery relative to placebo in study 1056 and NSAIDs in study 1058, although this signal was not replicated in study 1057, the agency said.
REMS Includes Annual X-rays
Pfizer has proposed a REMS with elements to assure safe use. The proposed clinical risk mitigation measures include:
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Patient counseling on the risk of joint destruction and to avoid the use of NSAIDs;
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Bilateral X-rays of knees and hips within two months of the first dose and annually thereafter;
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Monitoring the patient for pain of RPOA; and
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Unenrolling the patient from the REMS if they develop RPOA.
The REMS is based on a premise that the proposed mitigation measures would be able to affect the development and progression of RPOA in patients taking tanezumab, the FDA said. However, the available data do not inform whether the risk mitigation measures used in the post-2015 studies and included in the proposed REMS reduce the risk of joint destruction, the briefing document states.
“While discontinuing drug after RPOA1 might arrest the destructive process, there are inadequate data to inform whether that assumption is true. The entire risk management scheme assumes that detection of RPOA1 and discontinuing drug substantially affects outcome.”
“While discontinuing drug after RPOA1 might arrest the destructive process, there are inadequate data to inform whether that assumption is true. The entire risk management scheme assumes that detection of RPOA1 and discontinuing drug substantially affects outcome.” – FDA briefing document
In the post-2015 studies that included risk mitigation measures, 15% of patient progressed to total joint replacement following RPOA1, and 60% of patients with RPOA2 progressed to joint replacement. “Stopping drug after patients develop RPOA2 does not appear to be effective in preventing further damage to the joints,” the FDA review states.
Agency reviewers also suggest the plan for radiography surveillance in a real-world clinical setting is unlikely to be feasible. In the clinical trials, there were a substantial number of disagreements between experts recruited by Pfizer to assess surveillance radiographs. “Those radiographs were performed and interpreted under optimal conditions. Under real-world conditions, measuring [joint space width] and comparing to the prior study and detecting changes in the range of fractions of millimeters does not appear feasible.”
Furthermore, MRI likely represents a superior imaging modality but may not be feasible to use regularly in clinical practice as a surveillance tool, the FDA said.
Patient Preference Study
In its briefing document, Pfizer asserted the benefit of tanezumab 2.5mg has been demonstrated in a population of osteoarthritis patients for whom current treatments are ineffective or are clinically not appropriate because of contraindications, co‑morbidities, lack of tolerability or patient choice/unwillingness to take opioids. “These difficult-to-treat patients are not served by current therapies and there remains unmet medical need.”
The risk of joint safety with tanezumab 2.5mg “is not life-threatening, occurs at a low incidence and is manageable” through labeling (including a boxed warning for RPOA and total joint replacement), REMS and a postmarketing safety surveillance study to further characterize the drug’s risks, the company said.
“The key finding from this study was that patients were more willing to accept risk of serious joint problems than risk of physical dependence with opioids, indicating patients prefer the attributes of tanezumab over those of opioids.” – Pfizer briefing document
The sponsor also points to results from a US patient preference study, which found that achieving pain and symptom relief was most important to osteoarthritis patients, following by avoiding physical dependence and avoiding risks of myocardial infarction and severe joint problems. “The key finding from this study was that patients were more willing to accept risk of serious joint problems than risk of physical dependence with opioids, indicating patients prefer the attributes of tanezumab over those of opioids.”
Pfizer did not seek the FDA’s input on the design of the patient preference study, the agency said, concluding that the research suffers from various methodological flaws.
The study sample was not appropriate for regulatory decision-making, there was an inadequate description of severe joint problems requiring total joint replacement and several key attributes were missing, the agency said. In addition, the study used a “forced choice” format that was less than ideal, and there were unexplained anomalies in the results, according to the agency.