Micardis Sign-on Letter to Boehringer Ingelheim
3 December 2012
Peter Piliero, M.D.
Clinical Development and Medical Affairs
General Medicine and Scientific Affairs
Boehringer Ingelheim Pharmaceuticals
900 Ridgebury Road
Ridgefield, CT 06877
Dear Dr. Piliero:
We, the undersigned organizations and individuals, urge Boehringer Ingelheim Pharmaceuticals to reconsider its negative decision to provide free telmisartan (Micardis) and matching placebo to the AIDS Clinical Trials Group so that it may move forward with Study A5317, a multicenter trial evaluating the effects of telmisartan on fibrotic and inflammatory contributors to end-organ disease in HIV-infected patients well controlled on antiretroviral therapy.
Understanding the pathogenesis of, and discovering therapies for, end-organ diseases associated with immune activation and inflammation have become critical fields of HIV research. The incidence and prevalence of such health complications, including cardiovascular disease (CVD), diabetes mellitus, various neoplasms, and liver disease, surpass those of AIDS-related manifestations, are considerably higher compared with age-matched HIV-negative populations, and are a leading cause of morbidity and mortality among those living with HIV.
Telmisartan’s angiotensin II receptor antagonism and peroxisome proliferator–activated receptor-γ (PPAR-γ) agonism, compounded by its unique structure among the angiotensin receptor blocker (ARB) class of agents, has numerous potential benefits and safety advantages for people living with HIV.
As described in the A5317 protocol, in addition to its documented efficacy as a treatment for hypertension, telmisartan has been shown to decrease visceral adipose tissue (VAT) and CVD mortality in HIV-negative patients. Other therapeutic effects documented in HIV-negative study populations include improved surrogate markers of atherosclerosis, improved lipid and glucose metabolism, reversal of vascular inflammation, and improved endothelial and renal function parameters.
Small studies also suggest benefits in people living with HIV, including improved insulin sensitivity and lipid profiles, inflammatory markers (e.g., cystatin C and IL-18), and VAT and subcutaneous adipose tissue (SAT) volumes. Additionally, considering telmisartan is not excreted renally and neither inhibits nor induces the cytochrome P450 isoenzyme system, telmisartan shows potential for use in HIV-positive patients living with, or at risk for, renal impairment, while also avoiding the potential for numerous clinically significant drug-drug interactions.
Though A5317 focuses primarily on the effects of telmisartan on lymphoid- and adipose tissue fibrosis, it will provide key insight into the anti-inflammatory potential of angiotensin blockade and PPAR-γagonism, along with the potential clinical utility of telmisartan to prevent or reverse various end-organ and metabolic diseases.
We understand that the A5317 protocol team has made multiple attempts to secure free- or low-cost telmisartan from Boehringer Ingelheim, but to no avail. Whatever the reason—lack of market interest, telmisartan's pending patent expiration and/or the company's lack of an investiagor-initiated study program for this drug—it sours Boehringer Ingelheim's long history of cooperation with the HIV/AIDS community and collaboration with researchers.
Unlike antiretroviral development, the advancement of pathogenesis and therapeutic research pertaining to immune activation, inflammation, aging, non-AIDS-related health complications, end-organ disease, and a cure for HIV is highly dependent on exploration of agents that have been approved for other indications, including branded products registered to single pharmaceutical companies. Advancing this science, which may ultimately have a profound effect on morbidity and mortality rates for HIV-positive people, should remain a Boehringer Ingelheim imperative.
Given A5317’s small sample
s size (N=54), 2:1 randomization to active drug, and limited duration (48 weeks), we implore Boehringer Ingelheim to provide free Micardis to the protocol team for evaluation. We also request that Boehringer Ingelheim provide matching placebo.
Requiring the ACTG to purchase the drug at market prices will prove unnecessarily expensive, in light of the National Institute of Allergy and Infectious Diseases (NIAID)-funded HIV clinical research network’s ever-shrinking budget. Depending on where Micardis is purchased, the ACTG may be forced to pay up to $6,300 for 30-day supplies of the 80 mg tablets—with total spending for telmisartan alone likely to exceed $70,000 over the duration of the study—for its 36 trial subjects expected to be randomized to active drug.
Additionally, the procurement of matching placebo through compounding pharmacies or academic institutions is already proving both cost- and time-prohibitive, ultimately forcing the A5317 protocol team to explore a randomized, open-label evaluation of telmisartan. Such a study would be very difficult to accrue, in light of the need for serial lymphoid- and adipose tissue biopsies.
The advancement of inflammation, immune activation, and end-organ research depends heavily on collaboration and leadership by all stakeholders, particularly by those with a long history in therapeutic development. We hope that that Boehringer Ingelheim’s long-standing reputation as a key partner working toward the goal of disease-free survival for people living with HIV will remain evident with support of A5317.
Paul Bellman, MD
Jeanne Bergman, AIDStruth.org
Jeff Berry, Test Positive Aware Network
Paul Broker, University of Minnesota Medical School
Alasdair Burton, UCLA CAB -ACTG
Polly Clayden, HIV i-Base
Graig Cote, ACTU-Columbus, The Ohio State University
Lynda Dee, AIDS Action Baltimore
Michael Dorosh, AIDS Treatment Activists Coalition
Firas El Chaer
David Evans, Project Inform
Richard Ferri, PhD, NP, ACRN, FAAN
Gregory Fisher, University of Washington ACTU
Laurency Gaston, GATG
Howard Grossman, MD, AlphaBetterCare
Tim Horn, Treatment Action Group
H. Irving Hunter, Community Service Network, Inc
John James, AIDS Treatment News
Richard Jefferys, Treatment Action Group
Chad Kenney, PWA Coalition Colorado
Bobby Khumanthem, Indian Harm Reduction Network (IHRN)
Jim Konetsky, God's Love We Deliver
Tapiwanashe Kujinga, Pan-African Treatment Access Movement
Stephen LeBlanc, AIDS Policy Project
Michael Luciano, MUSC/Lowcountry AIDS Services Consumer Advisory Board
Dr. Joshua Matacotta
Steven Muchnick, PhD
NorthWestern University ACTG CAB
Sandra M. Palleja, MD
Laura Pinsky, Columbia University
Earl Plante, Treatment Action Group
Robert Riester, Treatment Action Group
Denisse Rivera, ACTU
David Scondras, Search For A Cure
Sista Yaa Simpson, TACTS-The Association of Clinical Trial Services
Tracy Swan, Treatment Action Group
Jeff Taylor, Positive Life Palm Springs
Jacob Tenai, GCAB Chair-Eldoret CRS
David Thomas, ACTG Clinical Trials Board, Northwestern Memorial Hospital
Paul Van Steenwyk
Jennifer Van Landingham
Ricardo Vargas, University of Puerto Rico
Carlos Velez, ACTU Project, University of Puerto Rico, CAB Chair
Vicki Weeks, Shelter Resources, Inc. D.b.a. Belle Reve New Orleans
Jeannie Wraight, HIV Haven
Gary Paul Wright, African American Office of Gay Concerns