How Safe will be Safe Enough for Regulators and Payers?
In August 2018, FDA Commissioner Scott Gottlieb provided an update to the ongoing efforts to address the opioid crisis, one part of which is an innovation challenge to find alternatives to oral opioids for use in chronic pain. Among pharmacological alternatives to existing analgesic classes, including opioid analgesics, the late-phase anti-nerve growth factor (NGF) class (Pfizer/Eli Lilly’s tanezumab and Regeneron/Teva’s fasinumab) is the furthest along in development and the most promising to provide pain relief without the risk of addiction.
The most commonly prescribed analgesics are opioid analgesic-based drugs for most chronic pain types; nonsteroidal anti-inflammatory drugs (NSAIDs) for inflammatory pain types (e.g., osteoarthritic pain); and antidepressants, antiepileptic drugs, and local anesthetics for neuropathic pain types (e.g., postherpetic neuralgia). Opioid analgesics have long been a key drug class to treat pain conditions and work by binding to opioid receptors in the central nervous system (CNS) to block the transmission of pain signals to the brain. However, their ability to block pain signals has also led to an increased risk of abuse or addiction with these therapies and have contributed to the growing opioid epidemic in the United States.
Anti-NGF agents work by binding to NGF directly and inhibiting the NGF signaling pathway. This pathway is responsible for the modulation of pain and normal responses to painful stimuli. Overstimulation of the pathway can lead to peripheral sensitization and pain hypersensitivity, hallmarks of chronic pain. However, NGF also plays a role in the maintenance of bone homeostasis by modulating differentiation of osteoblasts and osteoclasts, cells that secrete matrices for bone formation or absorb tissue during growth and healing, respectively1. By blocking the NGF cascade, which has yielded truly impressive efficacy outcomes in clinical trials, anti-NGF agents have also been associated with osteonecrosis and rapidly progressing osteoarthritis (RPOA) which, back in 2010, led to an FDA-imposed hold on the development of the class. An adjudication committee found that the majority of cases of osteonecrosis were not anti-NGF agent dependent and, by eliminating investigation of the highest dose of the drugs and reducing concomitant NSAID prescribing, Pfizer/Lilly and Regeneron/Teva received permission from the FDA in 2015 to continue Phase III trials2. The companies have since launched large Phase III trials to evaluate the safety of their drugs, and the first high-level results were released in the summer of 2018.
Pfizer/Lilly’s preliminary safety data from the first of their latest set of Phase III trials of tanezumab in OA pain (clinicaltrials.gov NCT02697773) yielded a rate of RPOA of 1.5% in tanezumab-treated patients, while Regeneron/Teva report a placebo-adjusted rate of 2% in fasinumab-treated patients in their Phase III trial in this population (clinicaltrials.gov NCT02683239). Neither study identified cases of osteonecrosis, which is great news for the class; however, the questions remain if 1.5-2% rates of RPOA will be considered “safe,” first by the FDA to gain marketing approval and then by prescribers and payers, and if these rates will be preferable—by all stakeholders including patients—to the risks associated with long-term use of opioid analgesics.
A literature search yields differing definitions of RPOA and, with these, differing rates in the OA pain population. The Osteoarthritis Initiative found rates of 3.4% in their patient population with a definition of progressing from no knee OA (Kellgren-Lawrence grade 0 or 1) to advanced-stage OA in that joint (KL grade 3 or 4) within four years, while other researchers based their definition of RPOA on measurement of joint space width (JSW) changes3. Using this definition, researchers found that 2% of OA patients experience more than 1.05 mm/year changes in their medial JSW. The anti-NGF adjudication committee used a more stringent criteria of a change in JSW of 2mm in one year or the presence of chondrolysis and bone destruction not normally seen in end-stage OA2; however, it is important to note that they were evaluating patients with reported osteonecrosis from anti-NGF clinical trials and the incidence rate in this cohort is not representative of the overall OA population. Nevertheless, using the adjudication committee’s definition of arthropathy, the rates reported thus far in the topline data for the Phase III trials of tanezumab and fasinumab are on par with those seen in the general population, but we eagerly await more detailed information on the findings in these studies.
Prior to the occurrences of osteonecrosis in 2010, RPOA was not a commonly seen or tracked adverse event in analgesic trials. One of the most prescribed analgesics for the treatment of inflammatory pain, Pfizer’s Celebrex (generically available), reports musculoskeletal adverse reactions including arthrosis in less than 1.9% of patients, with GI, CNS, respiratory, and skin reactions occurring in a higher percentage of patients. But now that the focus is on RPOA and osteonecrosis associated with the anti-NGF drugs, the burden falls to Pfizer/Lilly and Regeneron/Teva to prove that tanezumab and fasinumab are safe and will not lead to worse outcomes in real world patients. Managed care organization pharmacy and medical directors surveyed by DRG for our 2018 Osteoarthritic Pain U.S. Access and Reimbursement content were fairly split if the risk of RPOA is more or less acceptable than the risk of addiction with opioid analgesics, especially when considering the anticipated price differences between the anti-NGF agents and generic oral opioid analgesics. Surveyed prescribers are more sanguine about the value of anti-NGF agents given their impressive efficacy results to date and prescribers’ desire to avoid the risk and negative aspects of prescribing opioid analgesics to chronic pain patients.
Assuming the anti-NGF agents are able to provide equivalent (or better) safety as currently available analgesics, they would likely still be prescribed as a third-line or later therapy due to restrictive utilization controls imposed by U.S. payers and the widespread availability of generic oral analgesics. However, even if they capture extremely modest patient share, their high prices compared with the generic oral analgesics currently available will drive blockbuster sales by the second year after launch (see DRG’s 2017 Osteoarthritic Pain Disease Landscape and Forecast). As the general population continues to age, the prevalence of OA will continue to grow, and with the opioid epidemic continuing to be a driving force for policy and prescribing changes in the United States, Pfizer/Lilly and Teva/Regeneron have the potential to alter the chronic pain treatment paradigm and offer an efficacious and non-addictive analgesic for chronic pain patients – provided the FDA and insurers agree on how safe is safe enough.
- Mediero et al. Abstract: Pro-Nerve Growth Factor (ProNGF) Stimulates Bone Growth By Stimulating Osteoblasts and Inhibiting Osteoclast Differentiation, an Explanation for Anti-NGF-Mediated Osteonecrosis. ACR/ARHP Annual Meeting. 2014.
- Hochberg M.C. Serious Joint-Related Adverse Events in Randomized Controlled Trials of Anti-Nerve Growth Factor Monoclonal Antibodies. Osteoarthritis and Cartilage. 2015;23(1):S18-S21.
- Driban et al. Best Performing Definition of Accelerated Knee Osteoarthritis: Data From the Osteoarthritis Initiative. Therapeutic Advances in Musculoskeletal Disease. 2016;8(5):165-171.