LOVELACE RESPIRATORY RESEARCH INSTITUTE(LRRI)An independent, nonprofit, research institute serving humanity through research on the prevention, treatment, and cure of respiratory disease.LRRI is the only private, basic-science biomedical research organization totally dedicated to the study of respiratory diseases and reduction of their public health burden

IT ALL STARTED WITH A BOY BORN IN A LOG CABIN, TUBERCULOSIS, AND A RAILROADBelle, MOSt. Louis, MOStrong City, KS,Stone quarries,Lantry Construction& the AmarilloCut-offSunnyside, NM,And the Belen cut-offAlbuquerque,NMBNSF Route Map

WHO WAS LOVELACE (William Randolph Lovelace I) ? William Randolph Lovelace born in log cabin in Belle, MO WRL goes to medical school in St. Louis1905WRL graduates from St. Louis University Med. School & begins internship at St. Marys Hospital (Sisters of Charity) Fatigue & Pulmonary hemorrhage reveal tuberculosis. WRL contacts Lantry & Sharp Co. about a job as company surgeon on the new Santa Fe RR construction in NM1906WRL arrives in Sunnyside (Ft. Sumner) in late April 1908Entire family moved to NM (including brother Edgar, his wife, and 6 month old son WRLII)1913Moved to Albuquerque, opened office above Kistler Collister on Central, got contract for Santa Fe RR health operations, became heavily involved with St. Joseph Hospital1915Began visits to Mayo Clinic & friendship with Will & Charlie1919Dr. Edgar Lassiter marries WRLs sister Lora (& became partner)1922 Lovelace Clinic began1946Uncle Doc recruits nephew Randy to head organization

YOUNG DOC LOVELACES FIRST CLINIC

WHO WAS LOVELACE (William Randolph Lovelace I) ? William Randolph Lovelace born in log cabin in Belle, MO WRL goes to medical school in St. Louis1905WRL graduates from St. Louis University Med. School & begins internship at St. Marys Hospital (Sisters of Charity) Fatigue & Pulmonary hemorrhage reveal tuberculosis. WRL contacts Lantry & Sharp Co. about a job as company surgeon on the new Santa Fe RR construction in NM1906WRL arrives in Sunnyside (Ft. Sumner) in late April 1908Entire family moved to NM (including brother Edgar, his wife, and 6 month old son WRLII)1913Moved to Albuquerque, opened office above Kistler Collister on Central, got contract for Santa Fe RR health operations, became heavily involved with St. Joseph Hospital1915Began visits to Mayo Clinic & friendship with Will & Charlie1919Dr. Edgar Lassiter marries WRLs sister Lora (& became partner)1922 Lovelace Clinic began1946Uncle Doc recruits nephew Randy to head organization

DOC LOVELACES SPORTY TRANSPORTATION FOR MAKING HOUSE CALLS

WHO WAS LOVELACE (William Randolph Lovelace I) ? William Randolph Lovelace born in log cabin in Belle, MO WRL goes to medical school in St. Louis1905WRL graduates from St. Louis University Med. School & begins internship at St. Marys Hospital (Sisters of Charity) Fatigue & Pulmonary hemorrhage reveal tuberculosis. WRL contacts Lantry & Sharp Co. about a job as company surgeon on the new Santa Fe RR construction in NM1906WRL arrives in Sunnyside (Ft. Sumner) in late April 1908Entire family moved to NM (including brother Edgar, his wife, and 6 month old son WRLII)1913Moved to Albuquerque, opened office above Kistler Collister on Central, got contract for Santa Fe RR health operations, became heavily involved with St. Joseph Hospital1915Began visits to Mayo Clinic & friendship with Will & Charlie1919Dr. Edgar Lassiter marries WRLs sister Lora (& became partner)1922 Lovelace Clinic began1946Uncle Doc recruits nephew Randy to head organization

THE ORIGINAL LOVELACE FAMILY HOME

WHO WAS LOVELACE (William Randolph Lovelace II) ?1908Randy came to NM as 6 mo child of WRL Is brother Edgar, raised on fathers ranch and in Uncle Docs home1925Graduated Albuquerque HS (voted least likely to succeed!)1928Became pilot in Navy ROTC1930BS from Washington Univ. , St. Louis1934MD from Harvard1936Fellowship in surgery at Mayo, member of Mayo Aero Medical Unit, Surgical Chief in 19411940Collier Trophy for BLB oxygen mask1943Chief of military Aero Medical Laboratory, Wright Field, OH1943Distinguished Flying Cross for parachute jump from 40,200 ft. to test oxygen equipment (his first jump!)1946Lost two sons to polio, returned to NM1947Joined Uncle Doc in organizing and managing Lovelace Foundation for Medical Education & Research1965Died in airplane accident returning from Aspen, CO

Col. Randy et. al. invented the oxygen masks and G-suits that became standard for military pilots.

He believed his science to the extent that he laid his life on the line by making his first parachute jump (against Uncle Docs strong advice).

Jumping at 40,000 ft, and sky-diving to a lower altitude, he lost a glove and nearly froze a hand but the mask worked fine!

WHO WAS LOVELACE (William Randolph Lovelace II) ?1908Randy came to NM as 6 mo child of WRL Is brother Edgar, raised on fathers ranch and in Uncle Docs home1925Graduated Albuquerque HS (voted least likely to succeed!)1928Became pilot in Navy ROTC1930BS from Washington Univ. , St. Louis1934MD from Harvard1936Fellowship in surgery at Mayo, member of Mayo Aero Medical Unit, Surgical Chief in 19411940Collier Trophy for BLB oxygen mask1943Chief of military Aero Medical Laboratory, Wright Field, OH1943Distinguished Flying Cross for parachute jump from 40,200 ft. to test oxygen equipment (his first jump!)1946Lost two sons to polio, returned to NM1947Joined Uncle Doc in organizing and managing Lovelace Foundation for Medical Education & Research1965Died in airplane accident returning from Aspen, CO

UNCLE DOC AND RANDYAT THE BIRTH OF THE FOUNDATION

WHO WAS LOVELACE (William Randolph Lovelace II) ?1908Randy came to NM as 6 mo child of WRL Is brother Edgar, raised on fathers ranch and in Uncle Docs home1925Graduated Albuquerque HS (voted least likely to succeed!)1928Became pilot in Navy ROTC1930BS from Washington Univ. , St. Louis1934MD from Harvard1936Fellowship in surgery at Mayo, member of Mayo Aero Medical Unit, Surgical Chief in 19411940Collier Trophy for BLB oxygen mask1943Chief of military Aero Medical Laboratory, Wright Field, OH1943Distinguished Flying Cross for parachute jump from 40,200 ft. to test oxygen equipment (his first jump!)1946Lost two sons to polio, returned to NM1947Joined Uncle Doc in organizing and managing Lovelace Foundation for Medical Education & Research1965Died in airplane accident returning from Aspen, CO

FROM UNCLE DOC TO PRESIDENT BOBUncle Docs dream comestrue!Randys dreamTakes shapeWork on radiationand blast injurybeginsA contract is received from AEC to build a program on inhaled aircontaminantsResearch on altitude physiology, airline pilots and astronauts

THE FPIL FACILITY IN 1969

FROM UNCLE DOC TO PRESIDENT BOBUncle Docs dream comestrue!Randys dreamTakes shapeWork on radiationand blast injurybeginsA contract is received from AEC to build a program on inhaled aircontaminantsLBERI is createdto operate ITRIseparately from the parent corporationResearch on altitude physiology, airline pilots and astronauts

LBERI/ITRI EXECUTIVE MANAGEMENT

FROM UNCLE DOC TO PRESIDENT BOBUncle Docs dream comestrue!Randys dreamTakes shapeWork on radiationand blast injurybeginsA contract is received from AEC to build a program on inhaled aircontaminantsThe Board of DirectorsDecides that it doesnt want to be in the HMO business (and the endowment is born)After a 7-year effort,DOE agrees to privatizethe ITRI facilityLBERI is createdto operate ITRIseparately from the parent corporationResearch on altitude physiology, airline pilots and astronauts

LSR is created to conduct clinical trialsBob Rubin rides into town and operations are merged into a single entity structured around a lung health mission

FROM UNCLE DOC TO PRESIDENT BOBUncle Docs dream comestrue!Randys dreamTakes shapeWork on radiationand blast injurybeginsA contract is received from AEC to build a program on inhaled aircontaminantsThe Board of DirectorsDecides that it doesnt want to be in the HMO business (and the endowment is born)After a 7-year effort,DOE agrees to privatizethe ITRI facilityLBERI is createdto operate ITRIseparately from the parent corporationResearch on altitude physiology, airline pilots and astronauts

LSR is created to conduct clinical trialsBob Rubin rides into town and operations are merged into a single entity structured around a lung health mission

HOW IS LRRI ORGANIZED TODAY?

Lovelace Respiratory Research Institute (LRRI):Parent corporationNot-for-profit 501(c)(3)Non-federal research, philanthropy, endowment

Lovelace Biomedical and Environmental Research Institute (LBERI):Wholly-owned not-for-profit subsidiaryFederally-funded research

Lovelace Scientific Resources (LSR):Wholly-owned for-profit subsidiaryClinical trials, other for-profit research

LRRI EXECUTIVE STRUCTURE

Bob RubinPresident & Chief Executive Officer

Jacqueline Lovelace-JohnsonChairman, Board of Directors

Pat MarxVice President, LRRIChief Operating Officer, LRRI

Joe MauderlyVice President, LRRIPresident, LBERI

Chuck HobbsVice President, LBERI

Tess BurlesonPresident, LSRChief Financial Officer, LRRI

LRRI ORGANIZATION CHART

LRRI SCIENTIFIC ORGANIZATIONAL CHART

LSR ORGANIZATION

LRRI Headquarters and Research Facility North (125,000 sq. ft.)Inhalation Toxicology Research Institute Facility South (325,000 sq. ft.)

LRRI FACILITIES

WHAT DOES LRRI DO?

Research on Causes, Mechanisms, Prevention & Treatment of Respiratory Diseases

WHO PAYS FOR IT?Sources of FY-2003 Non-LSR Research Funding

HOW IS LRRI DOING?

$M Total FederalWeve grown slightly despite the close-out of major DOE fundingWeve been investing heavily in people, working structure, facilities, and new major programs since the 1996 privatization

NIH REVENUE IS GROWING STEADILY

$M(est.)This was one of Dr. Rubins major goals for the past several years

OUR FUNDING SUCCESS RATE IS GREAT!FY-03 Non-Clinical Research Proposals(As of 2/20/04, Does Not Include LSR or NERC)Funded Not Funded PendingTotal

FederalNo.25 (39%)39 (61%)16 80$M 10.9 (27%) 29.5 (73%)24.1 64.5

Non-FederalNo.39 (53%)35 (47%)11 85$M 4.1 (34%) 7.8 (66%) 3.2 15.1

TotalNo.64 (46%)74 (54%)27 165*$M15.0 (29%)37.3 (71%)27.3 79.6______________* A proposal was sent out every 1.5 working days!

WHAT ARE OUR PRINCIPAL RESEARCH ACTIVITIES? MECHANISMS, DETECTION, AND TREATMENT OF DISEASEInflammation (triggers, mediators, cell damage & repair, control of mucous cells)Lung Cancer (responsible genes, early detection)Asthma and immunology (determinants of allergic asthma, immunosuppresion)Infectious disease (defenses, impairment of resistance to viruses & bacteria)Emphysema (mechanisms, animal models, tobacco and environmental causes)Preclinical studies of new drugs (efficacy, safety, FDA compliance)Inhalation drug delivery (aerosolization, regional deposition, pharmacokinetics)Clinical trials (phases II IV, multiple centers)Pharmacoeconomics (burden of illness, costs, medication compliance, outcomes)

Principal Research Activities Contd. RESPIRATORY HEALTH RISKSInhalation toxicology (toxic mechanisms, dosimetry & metabolism, dose-response, interspecies comparisons)Inhalation hazard assessment (commercial and defense-related chemical and biological agents, product safety testing, Regulatory compliance, workplace hazards)Environmental air pollution (source emissions, particles, multi-pollutant mixtures, bio-toxins)Radiation (inhaled radionuclides, external radiation, risk modeling)AEROSOL TECHNOLOGY Instrumentation (development, testing, & demonstration, chambers & wind tunnels, field studies, verification of detection efficiency)Aerosol generation & dispersion (generation technologies, surrogate & tracer aerosols, room & site dispersion, on-site measurements)

WHAT DOES LSR DO?Clinical Trials contracting with pharmaceutical companies to test new drugs and therapies in humans Primarily phase II-IV trialsI Initial in-bed toxicity testsII Efficacy/toxicity trials in small groupsIII Efficacy trials in larger populationsIV New uses for approved drugs Expecting $4 million in revenues this yearLSR has done over 750 trials and now has multiple centersAlbuquerque1987Phoenix1994Las Vegas1997Miami2002Santa Anna/Beverly Hills2003Santa Fe2003Austin2004Sarasota2004

OUR NON-RESEARCH ACTIVITIES SUPPORT THE RESEARCH MISSIONPhilanthropic fundraisingDonations solicited from individuals, companies, and foundationsTax deductable gifts (money, goods)Facilities rentalLeasing/subleasing office, laboratory, and storage spaceEndowmentInvestment income from principal created by sale of healthcare systemLovelace-Anderson Endowment FoundationLovelace endowmentNon-respiratory research activities capitalizing on facilities & capabilitiesPrimate housingResearch on non-respiratory issuesEducational activities

WHAT ARE OUR DISTINGUISHING RESEARCH ASSETS?Core capabilities (not the only ones of course, but the ones we are best known for)Aerosol science Animal models of human responses & diseaseInhalation exposuresRespiratory molecular & cellular biologyHazardous materialsCore facilitatorsFlexible, entrepreneurial, management structureCollaborative, cross-disciplinary teamworkTranslational, gene-to-disease expression perspectiveExtensive, specialized facilitiesMulti-species animal resourcesDedicated grants, quality assurance, and communications support

HOW ARE WE DOING WITH PUBLICATIONS OUR PRIMARY PRODUCT?In CY 2003, LRRI scientists authored or co-authored 79 submitted articles, chapters, books, and published reports

In addition to several published and unpublished technical reports to sponsors

The publications reflect a high level of collaboration within LRRI and with external scientists

Only 3 submissions had only one author

LRRI staff were the lead authors of 54 publications (research done entirely or primarily at LRRI)

External scientists were lead authors of 25 publications

HOW DOES THIS BUSINESS WORK? Example: Dr. Ted Barrett et al. - Progress on Asthma PreventionEvolved from longstanding research on pulmonary immunityLRRI internal funds invested in venture science 1. Proved that allergic parents produce allergy-prone babiesMated dogs sensitized to ragweed (& non-sensitized dogs)Exposed all pups to airborne ragweed pollen beginning at 6 daysResults: Pups from allergic parents developed ragweed allergy by 6 mo! Pups from non-allergic parents did not Pups from allergic parents + ragweed

Pups from allergic parents ragweed Pups from non-allergic parents + ragweed

Example Contd Outcomes Published the study in a top journalE.G. Barrett, K. Rudolph, L.E. Bowen & D. E. Bice, Prenatal Allergic Status Influences the Risk of Developing Allergic Sensitization and an Asthmatic-Like Phenotype in Canine Offspring, Immunology 110: 493-500, 2003

Journal commissioned a special commentary on the studyB. Zemann & A. Rot, What Dogs may Teach Humans About the Vertical Transmission of Allergy Predisposition, Immunology, 110: 427-429, 2003Well-controlled mechanistic experimental models, such as the canine model established by Barrett et al. may provide invaluable clues to the molecular mechanisms of vertical transfer of allergy predisposition -----. In the long term, to asthmatic parents and children, the dog may truly turn out to be mans best friend.

Began capitalizing on the model to explore prevention by immune priming

Example Contd the Second Study2. Proved that single treatment with a certain bacterial DNA sequence (CpG) prevented allergyRepeated first experiment with allergic parentsGave some pups single inhalation dose of CpG at 6 daysResult: Pups receiving CpG did not develop ragweed allergy! Pups not receiving CpG didRagweed without CpG

No Ragweed or CpG Ragweed with CpG

Example Contd Current Status Ted & colleagues have an NIH grant pendingMaternal Influence in the Development of Asthma5 years for total of $3.1M ($592K first year) Currently under review

We propose to test the hypothesis that elevated levels of maternal allergen-specific factors and/or a skewed cytokine environment during pregnancy and/or early childhood are risk factors for the development of allergic sensitization and asthma in offspring from allergic mothers.

Ted & colleagues are working with a pharmaceutical company to develop the preventive therapy (aka asthma vaccine)Yield on investment:Substantial scientific and public health return Substantial likely financial return

IT TAKES QUITE A TEAM TO MAKE LRRI WORK!

This is a small, dedicated, personal organization where everyone can, and should, feel like part of a teamI think Uncle Doc and Randy would like what we are doing today!et. al. is ourmost valuableemployee!

MOTHERS SMOKING DURING PREGNANCY MAY CAUSE ASTHMA IN ADOLESCENTSMice exposed to cigarette smoke or clean air during pregnancyYoung exposed to either cigarette smoke or clean air after birthAirway reactivity to Aspergillus protein tested at 8 weeks of age 4 groups: no smoke, smoke before, both before and after, or only after birthResult:Exposure before birth or both before and after birth nearly doubled airway reactivity in adolescent rats, but exposure only after birth had little effect Implication:Mothers smoking during pregnancy may contribute to airway reactivity of adolescents, but exposure to second-hand smoke after birth may not.Dr. Mohan Sopori, et. al.New Study Points Finger Toward Smoking Before Birth! Of course, exposure of children to tobacco smoke is known to increase other respiratory illnesses

% of Normal AirwayReactivity

None After Before Before Birth + After Birth Birth Exposure to Tobacco Smoke

TREATMENT IMPROVES SURVIVAL OF PATIENTS WITH CRONIC LUNG DISEASENew Evidence Overturns Conventional Wisdom! Question: Do inhaled corticosteroids (ICS) and/or long-acting beta agonists (LABA) prolong survival of patients with serious chronic obstructive pulmonary disease (COPD)? (Most clinicians thought not) Data from Lovelace Health Plan (Albuquerque) and Kaiser Health Plan (Atlanta) Groups: ICS only = 786, LABA only = 170, ICS + LABA = 332, Other treatments = 397Dr. Floyd Frost, et. al.Results:Both ICS and LABA increased survival during 1100-day follow-upCombination even more beneficialImplications:These findings refute the conventional wisdom that inhaled corticosteroids have little benefit for survival, and indicate that the 2-drug combination yields benefits that outweigh side effectsGathering more data to confirm results and better define treatment-survival relationships

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Other Treatments

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LABA

ICS + LABA

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NEW MEXICO LAB EMERGES AS NEW PLAYER ON THE PHARMACEUTICAL RESEARCH SCENE Group Shifts Efforts Toward Preclinical Drug Research Beginning in 1996, LRRI began turning its respiratory research expertise and the newly-privatized Inhalation Toxicology Research Institute facility into a center for preclinical studies of new pharmaceuticalsDr. Chuck Hobbs, et. al. By FY-1999, annual revenue had surpassed $1 million By 2002, the preclinical business was boomingAnipryl (L-deprenylHCl): on the market because of LRRI research Targets cognitive function and behavioral problems in aged dogs (e.g.,Alzheimers) Deprenyl Animal Health Inc. came to LRRI because of old dogs in colony Partnered with U. California, Irvine to study learning and memory function FDA approved claims of efficacy based on our results Promotion and distribution now managed by Pfizer LRRI will be a silent partner behind new respiratory drugs appearing on the shelf in coming years

Fiscal Year

Revenue in $ M

NEW EVIDENCE INCREASES URGENCY OF GETTING SMOKING VEHICLES OFF THE ROADHigh Polluters Even More Dangerous than Expected! Samples collected from normal and smoking gasoline and diesel cars & pickups Lung inflammation measured in rats 24 hrs after dosing into lung Five different measures of inflammation gave consistent potency ranking Result:At same dose, emissions from smokers were more toxic than emissions from normal vehiclesImplication:High polluters not only emit more pollution, but their emissions are also more toxic all the more reason to get them off the road!It was known that 20% of vehicles cause 80% of pollutionThese results show that high polluters cause an even greater portion of the lung irritation from vehicle emissionsDr. JeanClare Seagrave. et. al.

RelativeInflammatoryPotency (Average of 5 different measures of inflammation)

White Black Smoking Normal NormalSmoker Smoker Diesel Diesel GasolineGasoline Gasoline

2-DRUG COMBINATION MAY BE KNOCK-OUT PUNCH FOR REPEAT LUNG TUMORS IN SMOKERSAnti-cancer genes are silenced two ways: Changing gene structure (methylation) Cloaking with protein (histone formation)Drug combo targets both effects : deoxyazacytidine (DAC) sodium phenyl butyrate (SPB) Mice given tobacco carcinogen known to cause multiple lung tumors Treated with 2-drug combination for 4 weeksResult:Treatment for only 4 weeks reduced the tumor response by two-thirdsImplication:Proof of concept for preventing recurrence using 2-drug combination Toxic DAC can only be used for chemotherapy, not prevention Now testing selenium, which has same action (selenium/SPB combo would be safe) Human chemoprevention trial with selenium is underwayDr. Steve Belinsky, et. al.Breakthrough in Preventing Second Tumors After Surgery?

Tumor Response

Average Number of TumorsPer Mouse

Untreated Treated

LRRI MODEL POINTS TOWARD PROTECTIVE EFFECT OF LOW DOSES OF RADIATIONThe Hormesis Crowd May Have it Right After All!Dr. Bobby Scot, et. al.tRegulations assume even the smallest doses cause excess cancer risk Termed linear, no-threshold (LNT) assumptionEvidence from humans, animals, and cells suggesting that very low doses may actually reduce risk has not been incorporated into predictive modelsLRRI developed revolutionary mathematical model showing protective effect, using recent data from animal and human cells in other labsResult:Model fitting the recent data shows the magnitude of protective effect at doses below those causing adverse effectsImplications:Reduces estimates of health impact from low dosesSupports using low-dose anti-cancer therapy

No. of TransformedCells per 105

Gamma Radiation Dose (millisievert)

Model For Low-Dose Protection From Neoplastic Transformation

CLINICAL TRIALS LAB HELPS BRING NEW DRUGS TO MARKET Lovelace Scientific Resources (LSR) operates clinical trials in multiple centers Over 100 studies in Albuquerque, 30 in Phoenix, and 30 in Las Vegas last year Many drugs now on the market were tested by LSRActos Detrol-LA NeurontinAdvair inhaler Diovan SingularAvandia Fosamax ViagraCelebrex Lantus VioxxCozaar Lipitor Zocor

Darlene Harbour, RN, CCRC, et. al.