Thank you very much. Actually, that title is about a decade old and out of date, in terms of my title at FDA. I'm in the Division of Hematology in the Clinical Review Branch. I would like to first of all thank Dr. Senior for inviting me here today.
Disclaimer
The findings and conclusions in this presentation have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy. Any views or opinions expressed during this presentation represent those of the presenter and not necessarily those of the Center for Biologics Evaluation and Research or FDA.
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I'd like to mention that I'm required to mention the disclaimer, and that the findings and conclusions of this presentation have not formally been disseminated by the FDA, and should not be construed as agency determination or policy.
Acknowledgment
• Bruce Schneider, M.D., CBER • Patrick Swann, Ph.D., CDER • Douglas Pratt, M.D., OVRR/CBER
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I'd like also to give thanks to Doctors Bruce Schneider in CBER, Patrick Swann in CDER and Douglas Pratt in the Office of Vaccines, who helped provide some of the background information for this broad overview of what our experience has been in seeing hepatotoxic types of reactions with biologic compounds.
Hepatotoxicity from Biologics is Rare
Examples of overt hepatotoxicity with a reduction in actual hepatic function resulting from administration of biologics has been rare:
• Administration of a viscerotropic virus – Yellow Fever Vaccine – Adenovirus vector in Gene Therapy
If we talk about the examples of hepatotoxicity from biologics, we're really talking about a handful of types of examples. On the one hand, we have examples of severe hepatic injury from viscerotropic viruses such as yellow fever vaccine, where we're getting a live virus that can target the liver. Also we've had unfortunate experience with adenovirus vector in gene therapy, leading to death. The class of approved products in the U.S. for TNF alpha inhibitors, the package inserts of all of them talk about the risk of drug-induced autoimmune hepatitis, and then we also have autoimmune hepatitis and liver injury resulting from flares with treatment with alpha interferon.
Infliximab-Induced Autoimmune Hepatitis
• Infliximab – IgG1 murine-human chimeric monoclonal antibody which binds and neutralizes TNF
• Indicated for active RA, ankylosing spondylitis and psoriatic arthritis
• Serious hepatotoxicity estimated incidence: ~1:16,500 users per year
• 5-fold increased risk over methotrexate
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So I'll just give you a little bit more detail with respect to one of the TNF alpha inhibitors that's been associated with autoimmune hepatitis. Infliximab is a chimeric neurine human monoclonal antibody, which binds and neutralizes tumor necrosis factor. It's indicated in the U.S. for active rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. The serious hepatotoxicity with this particular biologic has been estimated to be about 1 in 16,500 users per year, but that may be more of a reporting rate than a true incidence rate. One study found, epidemiologic study found a five-fold increased risk of hepatic injury in comparison to methotrexate, another known small molecule with hepatotoxic potential.
Infliximab-Induced Autoimmune Hepatitis
• Onset from 2 weeks to > 1 year after start of treatment
• Liver injury predominantly hepatocellular • Acute liver failure with need for transplant
or death reported
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So the onset of autoimmune hepatitis following infliximab therapy can be after as short a period of two weeks, or it can begin after a year from the start of treatment. The liver injury is predominantly hepatocellular, and there have been cases of acute liver failure with need for a transplant or death.
Infliximab-Induced Autoimmune Hepatitis
• Positive anti-nuclear, anti-DS DNA, and anti-smooth muscle antibodies positive in 2/3 affected patients.
• Binding of infliximab to transmembrane
TNF induces apoptosis, leading to release of nucleosomes which may trigger autoimmunity.
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In two-thirds of affected patients where this has been looked at, they've seen positive anti-nuclear, anti-double stranded DNA and anti-smooth muscle antibodies, and it's been noted that the product binds to transmembrane TNF, inducing apoptosis, leading to release of nucleosomes which may trigger autoimmunity.
Biologic-induced flare of chronic hepatitis B
• In addition to being associated with rare cases of autoimmune hepatitis, Alpha interferon treatment for chronic hepatitis B is often associated with transient “flares” of chronic hepatitis B with marked further elevation of ALT.
• Interferon induces T cell cytolytic activity and natural killer cell function
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However, it's also been postulated that the body may produce antibodies against the biologic chimeric protein, and that these antigen antibody complexes will be cleared, to some extent, by the sinusoids of the liver. This may activate Kupffer cells, which may in turn lead to production of reactive oxygen species, among a cascade of other mechanisms.
Interferon-induced flare of chronic hepatitis
• Flares during interferon alpha 2b treatment of chronic hepatitis B can lead to hepatic dysfunction if a sufficient number of hepatocytes are lost during the “flare” in patients with marginal hepatic reserve.
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With respect to chronic hepatitis B treatment, we know that alpha interferon treatment has been associated with transient flares, not uncommonly of chronic hepatitis B with marked further elevation of ALT, and that the product induces T cell cytolytic activity and natural killer cell function. But we should also recognize that the flares during interferon alpha 2B treatment of chronic hepatitis B can lead to hepatic dysfunction, if a sufficient number of hepatocytes are lost during the flare in patients with marginal hepatic reserve, leading to true liver dysfunction, not just the further elevation of the ALT and AST markers.
Even mild hepatic effects from biologics rarely seen
• In a 1 year RCT involving 2 formulations of IGIV, 1 formulation was associated with statistically significant asymptomatic increases in both AST and ALT > 3x the ULN. AST and ALT remained normal in a short-term study of the same formulation.
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So even mild hepatic effects seem to be rather uncommon with biologics, and in our particular division, our clinical trials are much smaller typically than what's seen in the Center for Drugs. In the ten years, more than ten years I've been in CBER, I don't think I've ever seen a clinical trial with more than 200 subjects, for example. But in a one year study of about 160 or so subjects, comparing head to head two formulations of an immunoglobulin intravenous product, one formulation was associated with statistically significant asymptomatic increases of both AST and ALT, greater than three times the upper limit of normal, in comparison to the other formulation. That was a one year study. Now a shorter term study with just a few administrations over a period of a week or so did not show that finding, and we haven't seen that finding with about eight or so other immunoglobulin intravenous products that have been studied over the last several years, in somewhat smaller sized trials.
Mild hepatic effects
• Mild reversible aminotransferases elevations during gene therapy using an adenovirus-associated virus vector.
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We've also seen mild reversible immunotransferase elevations during gene therapy, using an adenovirus associated virus vector,
Hepatotoxic Novel Vaccine Adjuvants?
• CBER is actively monitoring vaccine trials involving novel, non aluminum oxide based adjuvants for any occurrence of autoimmune disease, including autoimmune hepatitis.
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Vaccines is looking very actively as to whether with any of the newer, non-aluminum oxide-based adjuvants, whether we will see any examples of autoimmune disease, including autoimmune hepatitis with those newer investigational vaccines, but it's too early to say anything about tha.
Why is DILI Rare with Biologics?
• Number of approved drugs is much greater than the number of licensed biologics.
• Most biologics not truly xenobiotics. Although particular amino and/or RNA/DNA sequences may be unique, the building blocks occur naturally in the recipient of these products.
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So why is DILI rare with the biologics, which I think is the question that prompted John Senior to put this section on the program today. Well first of all, we can say that the impression certainly is the number of approved products that are drugs and small molecules is much greater to date than the number of licensed biologics. So that's partly a numbers game. Most biologics, though, are not true xenobiotics. Although particular amino acid and/or RNA/DNA sequences may be unique in some products, the building blocks occur naturally in the recipients of these products.
Degradative pathways for biologics follow rapid, largely first-order protease and nuclease enzymatic digestion, unlike the situation for drugs, which interact with oxidative and other intracellular systems.
Hepatotoxicity encountered with biologics may be explainable by some biological reaction of the protein or nucleic acid and may not resemble "idiosyncratic“ DILI as seen with some small molecules.
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The degradative pathways for biologics follow rapid large free first order protease and nuclease, enzymatic digestion, unlike the situation for many drugs that interact with oxidative and other intracellular systems. So hepatotoxicity encountered with biologics may be explainable by some specific biological reactions of the protein or nucleic acid, and may not resemble the idiosyncratic DILI as seen with some small molecules, and in some cases may be related to neoantigenicity formation of immune complexes and the mechanism that I postulated, that was postulated earlier through sinusoidal clearance, activation of Kupffer cells, reactive oxygen, species generation, et cetera.
Selected References • Aithal G.P. Hepatotoxicity related to
• Raper SE et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol. Genet. Metab. 80:148-158 (2003)
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Here are just a few references for the various examples that I touch on, of liver injury ---
References (cont.)
• Findlay G.M., Martin N.H. Jaundice following yellow-fever immunization. Brit. Med. Bull. 1:115-116 (1943)
• Flink H.J. et al. Flares in chronic hepatitis B patients induced by the host or the virus? Relation to treatment response during Peg-interferon alpha-2b therapy. Gut 54:1604-1609 (2005)
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--- and hepatic abnormalities seen with various classes of biologics. Thank you.
