Anti-NGF Drugs Clinical Holds Could Depend On What FDA Panel Thinks Of Standard Of Care

FDA’s Arthritis Advisory Committee will review troubling reports that the drugs, meant to relieve chronic pain from osteoarthritis and other diseases, may also destroy patients’ joints.

The Arthritis Advisory Committee will be in the unusual position of having to advise FDA March 12 on whether it should lift the clinical holds it has placed on ongoing clinical trials of anti-nerve growth factor agents, perhaps using risk mitigation proposals advanced by sponsors Pfizer, Regeneron and J&J.

The panel will be asked to vote on two questions:

1. Whether the anti-NGF agents, including Pfizer Inc.’s tanezumab, Regeneron Pharmaceuticals Inc.’s REGN475, and fulranumab, which is being studied by Johnson & Johnsonunit Janssen Research & Development LLC, should be studied in conditions like osteoarthritis, for which there are treatments (and, for additional discussion, whether the studies should be restricted to patients refractory to the current standard of care); and
2. Whether anti-NGF agents should be studied for the management of pain associated with conditions for which nothing seems to work, such as interstitial cystitis or chronic pancreatitis (and again, for additional discussion, whether the studies should be restricted to patients refractory to the current standard of care).

The advisory committee meeting “is unusual in that these products are still in the Investigational New Drug (IND) phase of development and are not already approved or under review as New Drug Applications,” DAAAP Director Bob Rappaport noted in a background document posted on FDA’s website.

In April 2010 FDA’s Division of Anesthesia, Analgesia and Addiction Products became aware of a potential safety signal – unusual and unexpected joint-related adverse events, namely osteonecrosis and avascular necrosis – among osteoarthritis patients participating in Pfizer’s ongoing and completed Phase II and III trials of tanezumab. FDA quickly imposed clinical holds (Also see "No Relief For Pfizer As It Shuts Down Additional Tanezumab Trials" - Pink Sheet, 20 Jul, 2010.).

In December of that year, J&J reported a pathologically verified case of AVN of the hip in a patient with no known history of osteoarthritis exposed to fulranumab in a study of chronic low back pain. Thus, in December 2010 and January 2011 the agency placed the three active investigational new drug applications for the anti-NGF agents on clinical hold, while AstraZeneca PLC announced it had voluntarily ceased its work on MEDI578, a nerve inhibitor in early-stage development at its subsidiary, MedImmune LLC (Also see "Regeneron, J&J, AstraZeneca Pull Plug On NGF Inhibitors In Development For Pain Indications" - Pink Sheet, 30 Dec, 2010.).

“However, studies were allowed to proceed in terminal cancer patients with intractable severe pain due to bone metastases, where the benefit of the treatment might outweigh the risks,” Rappaport noted.

The committee will now be asked if the agents are even safe enough to study, and the outcome may depend to a large extent on how well panels think current products on the market are doing the job. Sponsors will also make the case that the adverse events are not as concerning as they appear at first, and that sufficient safeguards can be put in place for the trials.

Will Limiting NSAIDs Be Enough?

As summarized by FDA, the sponsors’ position is that rapidly progressing osteoarthritis (RPOA) was detected as a safety signal in the tanezumab and fulranumab clinical trials, with type 2 RPOA “a relatively distinct finding in the tanezumab studies”; osteonecrosis was not a safety signal; many of the adverse events were pre-existing or associated with a subchondral insufficiency fracture of the knee or atrophic osteoarthritis of the hip; use of nonsteroidal anti-inflammatory drugs up to 90 days did not increase risk; and a possible explanation for the safety signal is that patients who felt pain relief put increased load on susceptible joints.

In addition, the sponsors argued that anti-NGF agents may be better than other analgesics in treating osteoarthritis and other painful conditions; the risk-benefit profile of tanezumab monotherapy to treat osteoarthritis is favorable compared to placebo, NSAIDs or extended-release oxycodone; but the risk-benefit profile of tanezumab/NSAID combination therapy is unfavorable compared to NSAID treatment alone and to tanezumab monotherapy.

Janssen and Pfizer submitted complete responses to the clinical holds in June and July of 2011, respectively, including adjudication of all reports of joint replacements. Regeneron also submitted additional information regarding reports of joint replacements during its trials. FDA’s need to study the additional data led to postponement of the Arthritis Advisory Committee meeting, which was originally supposed to be held in September (Also see "Anti-NGFs Advisory Committee Postponed As FDA Reviews New Information" - Pink Sheet, 19 Aug, 2011.).

FDA did its own two adjudications of the adverse events, one by Nona Colburn of the agency’s Center for Devices and Radiological Health and one by an outside expert, Joan Bathon of Columbia University Medical Center. They broadly agreed with the sponsors’ findings, FDA noted in an addendum to its background package. “Overall, both sets of adjudications are in general agreement with the adjudications conducted by the sponsors. Differences in the adjudications may be due to differences in the adjudication processes and definitions used to determine the diagnoses, in addition to differences in the interpretation of the data by the adjudicators.”

“There appears to be a safety signal of rapid joint destruction,” FDA said, noting that this may be labeled osteonecrosis, RPOA, a non-osteoarthritis process or some combination of these, and this is “associated with both anti-NGF agent monotherapy and anti-NGF agent plus NSAID therapy.” Combination therapy increases the risk, but taking an anti-NGF therapy by itself still presents a risk. “In fact, some cases occurred in patients without a history of OA, which further supports this conclusion. There is some evidence that the joint destruction seen in some cases may be a unique clinical form of rapidly destructive arthropathy.”

A Clinical Trial REMS?

The committee will be asked to discuss the sponsors’ specific recommendations for alleviating the risk of adverse events if the trials continue. Pfizer, for example, would exclude chronic concomitant NSAID use; drop the 10 mg dose of tanezumab in osteoarthritis and adopt a more cautious approach to escalated doses in other non-osteoarthritic chronic pain conditions; exclude patients with pre-existing rapidly progressive osteoarthritis from treatment with tanezumab; discontinue patients who do not respond adequately to initial doses of tanezumab; treat only those patients who do not respond to, are intolerant of or contraindicated for the existing standard of care; do increased monitoring; flag and review patients with increased, severe, and persistent joint pain during the study, and submit their adverse events to an adjudication committee; and have a data safety monitoring board conduct unblinded interim analyses according to pre-specified stopping rules.

Janssen would screen potential subjects for a number of risk factors for osteoarthritis progression, monitor subjects on an ongoing basis for the trial to watch for the development of RPOA, limit their NSAID use and do extended follow-up after the study or joint replacement surgery to detect safety signals. Investigators will be able to suspend or stop treatment if they see subjects have joint-related adverse events. Like Pfizer, Janssen will use adjudication committees and independent DMCs.

Regeneron would beef up informed consent and appropriate communication of the data and potential risks to investigators, IRBs, and national health authorities; exclude high-risk patients such as those with a history of RPOA, subchondral fractures, or joint dysplasia; minimize the dose of anti-NGF treatment and exclude concomitant chronic NSAIDs. In non-OA indications, because of the apparent need for higher doses of anti-NGF, the company would also exclude patients with evidence of mechanical/structural joint diseases. Use would be restricted to “high unmet need populations” and patients who develop such warning signs as subchondral fractures or accelerated joint space narrowing would stop receiving the study drug, and an independent DMC would assess the emerging data.

FDA also is asking the panel to discuss whether the painful, rapid joint destruction seen in the trials so far is occurring at an unusually high rate or is unusually severe; whether the committee agrees with the sponsors’ interpretation of the data and suggestions for how to proceed; whether there are additional populations for which further clinical trials would be acceptable; and, if clinical trials are allowed to proceed, what screening procedures, safety monitoring and follow-up assessments should be included, as well as whether concurrent NSAID use should be allowed (and/or limited after approval) and whether additional nonclinical studies might shed some light.