Therapeutic monoclonal antibodies -Why they are becoming so common-Some perspectives for internal medicine

BRIAN SKAUG

RESIDENT UPDATE TALK

MARCH 2N D-3R D 2015

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)

Production of therapeutic monoclonal antibodies is rapidly increasing

Year: 1986 20002015 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.phphttp://www.antibodysociety.org/news/news_mnth.php

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

1975: Isolation of monoclonal antibodies using hybridoma technology

1975: Kohler and Milstein--fused mouse lymphocytes with immortalized cells to produce monoclonal antibodies in vitro

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

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

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

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 approval2004: Mouse studies show PCSK9 downregulates LDL receptor, raising serum LDL

Maxwell et al., Proc. Natl. Acad. Sci., 2004Park et al., J. Biol. Chem. 2004Benjannet 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 LDLCohen et al., Nat Gen. 2005

And…2006: reduced risk of coronary heart diseaseCohen et al., NEJM. 2006

2014: 3 different mAbs against PCSK9 being tested in phase 3 clinical trialsDadu et al., Nat Rev Cardiol. 2014

2009: Animal study using monoclonal antibody targeting PCSK9Result: reduced LDL levelsChan et al., Proc Natl Acad Sci. 2004

2012: Numerous phase 2 trials show LDL reduction by anti-PCSK9 mAb’sDias et al. J Am Coll Cardiol. 2012Koren et al. Lancet. 2012Guigliano et al. Lancet. 2012Raal et al., Circulation. 2012Sullivan et al., JAMA. 2012McKenney et al., J Am Coll Cardiol. 2012Stein et al., NEJM. 2012Stein et al., Lancet. 2012Roth et al., NEJM. 2012

Image from Stein et al., NEJM. 2012

Therapeutic monoclonal antibodies are costly

Annual cost, Medicaid populationBonafede et al., Clinicoecon Outcomes Res. 2014

Estimated costs based onUptodate.com

Herceptin $4460 $70,000

Avastin $3,000 variable

Remicade $2,200 $20,000

Prolia $1,100 $2,200

Single dose Annual

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. 2012http://www.actip.org/pages/monoclonal_antibodiestable.htmlHey et al., Nat Biotechnol. 2014

Lessons from TNFa inhibitors: proven benefits, diminishing responses, and unanticipated adverse effects

1997: Infliximab effective in refractory Crohn’s DiseaseTargan 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 responseBaert 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 patientsRadstake 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 infliximabChung 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

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

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