Res update final
- 1. Therapeutic monoclonal antibodies -Why they are becoming so common -Some perspectives for internal medicine BRIAN SKAUG RESIDENT UPDATE TALK MARCH 2ND-3RD 2015
- 2. Most internal medicine specialties have monoclonal antibodies at their disposal Hematology/Oncology: rituximab (Rituxan), bevacizumab (Avastin), many more Rheumatology: infliximab (Remicade), adalimumab (Humira), many more Gastroenterology: Remicade, Humira Endocrinology: denosumab (Prolia) Cardiology: abciximab (ReoPro), PCSK9 inhibitors soon Allergy/Pulmonary: Omalizumab (Xolair) Nephrology: basilixumab for certain transplant recipients Also Dermatology (Humira, others), Ophthalmology (Avastin), Neurology (natalizumab/Tysabri)
- 3. Production of therapeutic monoclonal antibodies is rapidly increasing Year: 1986 2000 2015 2025 Number of FDA-approved mAb’s 1 6 ?36 39 mAb’s currently in Phase 3 clinical trials Muromonab (OKT3) for renal transplant patients http://www.antibodysociety.org/news/approved_mabs.php http://www.antibodysociety.org/news/news_mnth.php
- 4. Clinical and basic science advances that led to therapeutic mAb production 1890’s: von Behring: serum therapy to treat diphtheria. First demonstration of therapeutic passive immunity Passive immunity 1890’s In vitro mAb’s 1975 -Structure/function of DNA -Genetic code -Structure of Ab’s 1940’s-60’s -recombinant DNA technology -Transgenic and knockout mice -genetics of Ab diversity 1980’s 1990’s -Genomics -Proteomics -better understanding of disease pathophysiology -identification of numerous drug “targets” -understanding of antibody structure/function -use of non-human vectors (mice, bacteria) to mass produce pre-specified proteins or antibodies
- 5. 1975: Isolation of monoclonal antibodies using hybridoma technology 1975: Kohler and Milstein--fused mouse lymphocytes with immortalized cells to produce monoclonal antibodies in vitro
- 6. 1986: Muromonab/OKT3—the first therapeutic monoclonal antibody The good: some benefit in patients with acute transplant rejection The bad: vast majority of patients develop antibodies against muromonab—reduced half-life and diminished response on repeat injections N Engl J Med. 1992 Sep 3;327(10):736. Anaphylactic shock after retreatment with OKT3 monoclonal antibody. Abramowicz D, Crusiaux A, Goldman M. The ugly: Reviewed in Weiner, J Immunther. 2006
- 7. Conversion of mAb’s from mouse to partially or fully human was the final step to effective and safe therapeutic mAb’s Rituximab (Rituxan) Infliximab (Remicade) Human constant domain + rodent variable domain Trastuzumab (Herceptin) Bevacizumab (Avastin) Rodent complimentarity- determining region -Human immunoglobulin genes in mouse -Phage display (in vitro) Adalimumab (Humira) Denosumab (Prolia) Images adapted from Foltz et al. Circulation. 2013
- 8. Phage display and transgenic mice: Two different methods to produce human mAb’s Nelson et al., Nat Rev Drug Disc. 2010 Brekke et al., Nat Rev Drug Disc. 2003
- 9. 2003: PCSK9 mutations identified as a cause of autosomal dominant hypercholesterolemia. Abifadel et al., Nat Gen. 2003 PCSK9 inhibitors—from target identification to therapy in a decade 2003-2006: identification and characterization of target 2009: mAb produced and studied in animals 2011-2014: Human trials applications for FDA approval 2004: Mouse studies show PCSK9 downregulates LDL receptor, raising serum LDL Maxwell et al., Proc. Natl. Acad. Sci., 2004 Park et al., J. Biol. Chem. 2004 Benjannet et al., J. Biol. Chem. 2004 Image adapted from Mullard., Nat Rev Drug Disc. 2012 2005: loss of function mutations in PCSK9 are associated with low LDL Cohen et al., Nat Gen. 2005 And… 2006: reduced risk of coronary heart disease Cohen et al., NEJM. 2006 2014: 3 different mAbs against PCSK9 being tested in phase 3 clinical trials Dadu et al., Nat Rev Cardiol. 2014 2009: Animal study using monoclonal antibody targeting PCSK9 Result: reduced LDL levels Chan et al., Proc Natl Acad Sci. 2004 2012: Numerous phase 2 trials show LDL reduction by anti-PCSK9 mAb’s Dias et al. J Am Coll Cardiol. 2012 Koren et al. Lancet. 2012 Guigliano et al. Lancet. 2012 Raal et al., Circulation. 2012 Sullivan et al., JAMA. 2012 McKenney et al., J Am Coll Cardiol. 2012 Stein et al., NEJM. 2012 Stein et al., Lancet. 2012 Roth et al., NEJM. 2012 Image from Stein et al., NEJM. 2012
- 10. Therapeutic monoclonal antibodies are costly Annual cost, Medicaid population Bonafede et al., Clinicoecon Outcomes Res. 2014 Estimated costs based on Uptodate.com Herceptin $4460 $70,000 Avastin $3,000 variable Remicade $2,200 $20,000 Prolia $1,100 $2,200 Single dose Annual
- 11. Several commercial factors favor reliance on mAb’s for future therapies -mAb’s are profitable -numerous companies now have “infrastructure” for mAb development ◦ >15 companies with FDA-approved mAb’s -mAb’s are more likely to “succeed” ◦ 14% likelihood of mAbs in phase 1 getting FDA approval ◦ 7% likelihood of small molecules -No such thing as a “generic” mAb 2011 US sales data (in billions) Aggarwal. Nat Biotechnol. 2012 http://www.actip.org/pages/monoclonal_antibodiestable.html Hey et al., Nat Biotechnol. 2014
- 12. Lessons from TNFa inhibitors: proven benefits, diminishing responses, and unanticipated adverse effects 1997: Infliximab effective in refractory Crohn’s Disease Targan et al., NEJM. 1997 TNFa inhibitors are currently FDA approved for: -Crohn's disease, ulcerative colitis -Rheumatoid arthritis -Ankylosing spondylitis -Psoriatic arthritis -Plaque psoriasis http://www.drugs.com 2003: Anti-infliximab antibodies, infusion reactions, and loss of treatment response Baert et al., NEJM. 2003 2009: Adalimumab (human) has lower but still large percentage of anti-mAb Ab formation and treatment failure compared to infliximab in RA patients Radstake et al., Ann Rheum Dis. 2009 Increased risk of TB reactivation in RA patients treated with infliximab (24 per 100,000 vs 6 per 100,000) Keane et al., NEJM. 2001 Worsening of CHF by infliximab Chung et al., Circulation. 2003 Alternative therapy regimen without biologic has similar longterm efficacy for RA. van Vollenhoven et al. Lancet. 2012 Roughly 17,000 euro difference in cost at 21 month follow up. Eriksson et al., Ann Rheum Dis. 2014 Large percentage of Crohn’s Disease patients have diminishing response to TNFa inhibitors. Ben-Horin et al., Ailment Pharmacol Ther. 2011
- 13. Some perspectives for Internal Medicine -Lots of mAb’s already available, many more on the way -Potential for meeting some unmet medical needs -Universally expensive -Diminishing therapeutic response is a problem even with human mAbs -Require same stringency for safety, efficacy, and cost-effectiveness as “traditional” drugs
- 14. Coming soon to a clinic near you… Monoclonal antibodies approved by the FDA in 2014 Name of mAb Molecular target Disease it is approved for Siltuximab Interleukin-6 Castleman Disease Vedolizumab a4b7 integrin inflammatory bowel disease Ramucirumab VEGFR2 gastric cancer Pembrolizumab PD1 melanoma Blinatumomab CD19,CD3 acute lymphoblastic leukemia Nivolumab PD1 melanoma http://www.antibodysociety.org/news/approved_mabs.php