Biotech Tracker News - Lymphoma Risk for TNF Inhibitors
March 03, 2003 The FDA’s Arthritis Advisory Committee is scheduled to meet tomorrow, March 4, 2003, from 9 a.m. to 4 p.m EST to hear a safety update on the TNFa inhibitors Humira (adalimumab), Remicade (infliximab), and Enbrel (etanercept). The meeting will specifically focus on the agents’ contribution to lymphoma risk. Lymphoproliferation (the uncontrolled growth of specific immune cells often resulting in lymphoma or other “lymphoid malignancies”) is a known biological consequence of TNF upregulation, TNF downregulation, TNF inhibition by drugs, RA and some of its treatments, and other autoimmune diseases and some of their treatments. The degree to which these influences interact remains to be clarified. The rank order of benefit and harm attributable to these scenarios also requires investigative clarification.  It is likely that inhibiting TNFa contributes to an attributable risk of lymphoma above the level associated with rheumatoid arthritis (RA). The degree to which this is true remains uncertain, and the committee is likely to demand both more rigorous retrospective analyses of relevant available data, as well as new, prospective surveillance studies designed to better characterize the drug-associated risk. These studies also can be designed to better clarify the maximum amount of drug exposure (time on drug) individuals and profiled subpopulations should be permitted in order to maintain a favorable benefit to risk (therapeutic to adversity) ratio.  Based upon available attributable lymphoma risk data, the committee is unlikely to immediately recommend the placement of a use ceiling on the drugs, unless it does so on the basis of data unavailable to the public or as a temporizing measure prior to generation of more substantive information. We do not anticipate significant changes to our revenue models for Enbrel, Remicade, or Humira, at least until the relevant risks are better clarified through further investigation. Modeling adjustments, perhaps severe, based on appropriate use ceilings are likely to be needed when such data are available.  Distinction Between Enbrel, Remicade, and Humira An important question likely to be addressed at tomorrow’s meeting is whether any differences in lymphoma risk can be attributed to each drugs’ use. It is unlikely that the committee will conclude that definitive data exists that conclusively distinguishes a comparative attributable risk difference between Enbrel versus Remicade versus Humira. The committee may recommend that the drugs be prospectively studied by a uniform set of criteria designed to better characterize differential risk.  In Humira clinical trials, the ratio of the observed rate of lymphoma occurrence to the age-adjusted expected rate of lymphoma occurrence has been approximately 5.4 (almost five an a half times more so observed than expected). The literature regarding Enbrel and Remicade is somewhat less clear, but Brown, Greene, et al published a study (Arthritis Rheum 2002 Dec; 46(12):3151-8) designed to investigate the occurrence of lymphoproliferative disorders in patients treated with these agents. MedWatch and postmarketing adverse event surveillance system data identified 26 cases of lymphoproliferative disorders following treatment with Enbrel (18 cases) or Remicade (8 cases). 81% were non-Hodgkin lymphomas. Most significant was that the interval between drug use initiation and the development of lymphoma was only a median of 8 weeks. In 2 cases (1 with each drug), lymphoma regression was observed following discontinuation of the drug without specific chemo- or biotherapy. Both labels warn that lymphoma can be associated with drug administration, and that the magnitude of risk remains unclear. Some evidence exists indicating that the degree of risk at least approximates that of Humira.  These data must be considered against a medical literature backdrop that suggests that the overall rate of lymphoid malignancies in patients with RA is somewhere between 1.5 to 8.7 times that of the general population. The bulk of investigation, however, is focused on lifetime risk and includes certain specific factors that are unlikely relevant to the current dilemma. Extracting more relevant investigations, the pertinent RA-associated risk is likely on the order of 1.5 to 4 times that of the general population. Other Adversities Although other malignancies have been related to the use of these agents, no other malignancies have been demonstrated with any degree of certainty to merit special attention based upon a significantly increased incidence over the general population. Conditions that also merit special attention with regard to Enbrel, Remicade, and Humira safety profiles are congestive heart failure; tuberculosis; and specific neurological events, such as multiple sclerosis, characterized by the demyelination (loss of the insulating, conduction-promoting sheath of myelin protein) of central nervous system neurons. The committee may provide counsel to the FDA regarding these risks as well.  It would not be unreasonable to expect that Humira and, especially, Enbrel, labels would, at least eventually, require the same degree of contraindicative attention given to Remicade in at least NYSA class III/IV cases. The Remicade label also suggests cautious use in less severely affected individuals. Both Enbrel and Remicade clearly exacerbate class III/IV CHF. The current contraindication and surveillance profiles related to both active and latent tuberculosis, as well as other infectious processes, are well characterized on the products’ label, and are unlikely to merit significantly increased attention in the absence of new data demonstrating a greater acceleration of risk than already outlined. The current contraindication and surveillance profiles related to demyelinating neurological disease, including MS, have been well-outlined by information disseminated to physicians and patients, but the labels could merit stronger contraindication profiles based upon recent data. In any case, clarification of these issues should go a long way to providing enhanced patient safety without significantly affecting the appropriate continued use profiles of the drugs at this time.
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