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|Item 7.01||Regulation FD Disclosure.|
On December 6, 2022, Eagle Pharmaceuticals, Inc., or the Company, released an investor presentation relating to the Company’s hospital-based products and product candidates, including BARHEMSYS, BYFAVO, Landiolol, and CAL02 and Enalare Therapeutics Inc.’s ENA-001. The Company will refer to the presentation during its previously announced Investor Day taking place on December 6, 2022, at 8:00am ET.
A copy of the above-referenced presentation is furnished as Exhibit 99.1 to this Current Report on Form 8-K and is incorporated herein by reference. The information furnished pursuant to Item 7.01 of this current report, including Exhibit 99.1, shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended, or the Exchange Act, or otherwise subject to the liabilities of that section, and shall not be deemed incorporated by reference into any of the Company’s filings under the Securities Act of 1933, as amended, or the Exchange Act, whether made before or after the date hereof, regardless of any general incorporation language in such filing, except as shall be expressly set forth by specific reference in such filing. The furnishing of the information in this Current Report on Form 8-K is not intended to, and does not, constitute a determination or admission by the Company that the information in this Current Report on Form 8-K is material or complete, or that investors should consider this information before making an investment decision with respect to any security of the Company.
|Item 9.01||Financial Statements and Exhibits.|
|99.1||Presentation of the Company, dated December 6, 2022.|
|104||Cover Page Interactive Data File (embedded within the Inline XBRL document).|
Pursuant to the requirements of the Securities Exchange Act of 1934, the Registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
|Dated: December 6, 2022||EAGLE PHARMACEUTICALS, INC.|
|By:||/s/ Scott Tarriff|
|Chief Executive Officer|
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 1 2022 Eagle Pharmaceuticals, Inc. All rights reserved. December 6, 2022Investor Day
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 2 Forward-Looking StatementsThis presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, and other securities law. Forward-looking statements are statements that are not historical facts. Words and phrases such as anticipated, forward, will, would, could, should, may, remain, potential, prepare, expected, believe, plan, near future, belief, guidance, estimate, and similar expressions are intended to identify forward-looking statements. These statements include, but are not limited to, statements with respect to: the Companys development programs, products and pipeline; any further investments in Enalare and Enalares development programs; the potential exercise of the Companys option to acquire all of Enalares outstanding shares; the ability of the Companys products to address challenges faced by healthcare providers and hospitals today; the Companys ability to achieve revenue growth; the potential for the Company to transition into a diversified pharmaceutical company with a portfolio of branded, first-in-class assets; the Companys and Enalares ability to obtain and maintain regulatory approval of its products and product candidates; the Company's clinical development plan for its product candidates, including the number and timing of development initiatives or new indications for the Companys product candidates; the ability of the Companys and Enalares products and product candidates; the development of, potential benefits of and expected regulatory activities and matters with respect to the product candidates of the Company and Enalare; the potential therapeutic and economicbenefits of the Companys and Enalares products and product candidates; potential commercial opportunities, addressable markets, patient populations and settings for the Companys and Enalares products and product candidates; the achievement of milestones and deliverables; the potential use of ENA-001 to help preterm infants with respiratory conditions; the ability of ENA-001 and other products and product candidates to address unmet clinical needs, including for patients with post-operative respiratory depression and in combatting community drug overdose; CAL02s ability to neutralize virulence factors produced by bacteria that are commonly associated severe pneumonia; the potential of CAL02 to be a medical breakthrough and offer unique therapeutic benefits to seriously ill patients, potentially improving the treatment regimen for patients with severe community-acquired pneumonia, shortening the duration of illness and improving patient outcomes; the Companys expectations for the design and timing of the planned CAL02Phase 2 study, including with respect to enrollment and site selection and the timing thereof; potential regulatory exclusivity, CAL02s potential eligibility for fast track and breakthrough therapy designations and the potential for a CAL02 new drug applicationfor the treatment of SCABP to qualify for priority review; the ability of hospital environmental trends to bolster the value proposition of the Companys acute care portfolio, including of Barhemsys and Byfavo; the ability of Barhemsys to reduce overall hospital stays;the strategic fit of Barhemsys and Byfavo with the Companys specialized hospital-based salesforce; the Companys marketing, product development, partnering and growth strategy, including relating to the commercialization of Barhemsys and Byfavo, and the ability of Acacias technology and know-how to help the Company achieve its strategy; the ability of Barhemsys, Byfavo and Landiolol to address unmet clinical needs; the ability of Barhemsys to offer significant economic savings to hospitals and ambulatory centers; the ability of Byfavo to offer potential health economic benefits and enable shorter procedure times and greater patient throughput; the potential market opportunity for the Companys products or product candidates, including for Barhemsys, Byfavo or Landiolol; expected patient volumes; the progress and success of the Companys launch of any products; the period of marketing exclusivity forproducts or product candidates, including CAL02; the timing, scope or likelihood and timing of regulatory filings and approvals from the FDA for the Companys product candidates and the Companys ability to maintain regulatory approval of its products and product candidates; the Company's clinical development plan for the product candidates; the implementation of certain healthcare reform measures; the ability of the Company to obtain and maintain coverage and adequate reimbursement for its products; the successofthe Company's collaborations with its strategic partners and the timing and results of these partners preclinical studies and clinical trials, and the Companys potential earnings potential through such collaborations; the Company's plans and ability to advance the product candidate in its pipeline; potential opportunities for, and the Companys ability to complete, business development transactions, in a timely manner, on favorable terms to the Company, or at all; the sufficiency of the Companys cash flows and capital resources and expectations with respect to deployment of cash resources; and the Companys ability to achieve expected future financial performance and results. All of such statements are subject to certain risks and uncertainties, many of which are difficult to predictand generally beyond the Companys control, that could cause actual results to differ materially from those expressed in, or impliedor projected by, the forward-looking information and statements. Such risks and uncertainties include, but are not limited to: the risk that the anticipated benefits of the Companys recently completed transaction with Acacia are not realized; the ability of Enalaretoachieve milestones and deliverables under the BARDA agreement and otherwise accelerate and achieve successful results in the development of ENA-001; the impacts of the COVID-19 pandemic and geopolitical events such as the conflict in Ukraine, including disruption or impact in the sales of the Company's marketed products, interruptions or other adverse effects to clinical trials,delays in regulatory review, manufacturing and supply chain interruptions, adverse effects on healthcare systems, disruption in the operations of the Company's third party partners and disruption of the global economy, and the overall impact of the COVID-19 pandemicor other events on the Company's business, financial condition and results of operations; macroeconomic conditions, including rising inflation and uncertain credit and financial markets; whether the Company will incur unforeseen expenses or liabilities or other market factors; whether the Company will successfully implement its development plan for its product candidates; delay in or failuretoobtain regulatory approval of the Company's or its partners product candidates; whether the Company can successfully market and commercialize its product candidates; the success of the Company's relationships with its partners; the availability and pricingof third party sourced products and materials; the outcome of litigation involving any of its products or that may have an impact on any of our products; successful compliance with the FDA and other governmental regulations applicable to product approvals, manufacturing facilities, products and/or businesses; general economic conditions, including the potential adverse effects of public healthissues, including the COVID-19 pandemic and geopolitical events, on economic activity and the performance of the financial markets generally; the strength and enforceability of the Company's intellectual property rights or the rights of third parties; competition from other pharmaceutical and biotechnology companies and the potential for competition from generic entrants into the market; the risksinherent in the early stages of drug development and in conducting clinical trials; factors in addition to the foregoing that may impact the Companys financial projects and guidance, including among other things, any potential business development transactions, acquisitions, restructurings or legal settlements, in addition to any unanticipated factors, that may cause the Companys actual results and outcomes to materially differ from its projections and guidance; and those risks and uncertainties identified in the Risk Factors sections of the Company's Annual Report on Form 10-K for the year ended December 31, 2021, filed with the Securities and Exchange Commission (the SEC) on March 8, 2022, the Companys Quarterly Report on Form 10-Q for the quarter ended March 31, 2022, filedwith the SEC on May 9, 2022, the Companys Quarterly Report on Form 10-Q for the quarter ended June 30, 2022, filed with the SEC on August 9, 2022, the Companys Quarterly Report on Form 10-Q for the quarter ended September 30, 2022, filed with the SEC on November 9, 2022 and its other subsequent filings with the SEC. Readers are cautioned not to place undue reliance on theseforward-looking statements. All forward-looking statements contained in this press release speak only as of the date on which they were made. Except to the extent required by law, the Company undertakes no obligation to update such statements to reflectevents that occur or circumstances that exist after the date on which they were made.This presentation includes statistical and other industry and market data that the Company obtained from industry publications and research, surveys and studies conducted by third parties or us. Industry publications and third-party research, surveys and studies generally indicate that their information has been obtained from sources believed to be reliable, although they do not guaranteethe accuracy or completeness of such information. All of the market data used in this presentation involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such estimates. While the Company believes these industry publications and third-party research, surveys and studies are reliable, the Company has not independently verified such data. The industry in which the Company operates is subject to a high degree of uncertainty, change and risk due to a variety of factors, which could cause results to differ materially from those expressed in the estimates made by the independent parties and by the Company.This presentation includes statements and commentary of independent third parties, including key opinion leaders and Enalare,which are strictly the views, opinions and expectations of such third parties and are not the responsibility of the Company.
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 33 7:30 AMRegistration and Breakfast 8:00 AMOverview of the Day 8:10AMIntroduction of the SpeakersHerm CukierDr. Joe Pergolizzi & Dr. TJ Gan −Postoperative Respiratory DepressionDr. Eugene Vortsman −Community OverdoseDr. Prem Fort −Apnea of Prematurity Midmorning Break (15 minutes) 10:05AMDeb Hussain −Hospital LandscapeDr. TJ Gan −Barhemsys Dr. Rick Dutton−Byfavo 11:05AMQ&A/Panel Discussion 8:20AMENA-001Barhemsysand ByfavoScott TarriffEagle Investor Day Agenda 9:50AM 10:55AMLandiololDr. Mike Greenberg 11:50 AMLunch 9:15AMCAL02Dr. Andre Kalil −Disease State Overview−Therapeutic PotentialDr. Valentin Curt −CAL02 Overview and Development Plan Dr. Mike Greenberg
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 4 Eagle Hospital Business Overview RYANODEX Vasopressin Barhemsys Byfavo Landiolol1 CAL022Acute Care Hospital Commercially Available Pipeline & Potential Pipeline ENA-0013 Hospital business currently being commercialized by 50 field resources For treatment of malignant hyperthermiaApproved to increase blood pressure in adults with vasodilatory shock1Eagle Pharmaceuticals. Press Release, January 31, 2022. https://investor.eagleus.com/press-releases/news-details/2022/Eagle-Pharmaceuticals-on-Track-to-Support-Submission-of-New-Drug-Application-in-Second-Quarter-2022-for-Landiolol-a-Beta-1-Adrenergic-Blocker/default.aspx. 2Eagle Pharmaceuticals. Press Release, November 14, 2021. https://investor.eagleus.com/news-releases/news-release-details/eagle-pharmaceuticals- announces-fda-acceptance-investigational .. 3 On 8/9/22 Eagle took an equity stake in, with option to acquire, EnalareNDA Filing StagePhase II Study StagePhase II Study Stage
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 5 Seek additional strategic transactions Build pipelineinternally Leverage Acaciainfrastructure Move from 505(b)2To longer life NCEs Reinvest cash flow The Evolution of Eagle PharmaceuticalsLegacyBusinessAcaciaPharmaExpandingPipeline RYANODEX Vasopressin BENDEKA BELRAPZO PEMFEXY TREAKISYM Japan Barhemsys Byfavo Landiolol1 CAL022 ENA-0013Acquiredin June 2022Expansion ofhospital businessPotential Future Strategic TransactionsAim to Keep Moving Up the Value Chain BrandedGenericOncology NDAs 505(b)2PotentialPipeline 1Eagle Pharmaceuticals. Press Release, January 31, 2022. https://investor.eagleus.com/press-releases/news-details/2022/Eagle-Pharmaceuticals-on-Track-to-Support-Submission-of-New-Drug-Application-in-Second-Quarter-2022-for-Landiolol-a-Beta-1-Adrenergic-Blocker/default.aspx. 2Eagle Pharmaceuticals. Press Release, November 14, 2021. https://investor.eagleus.com/news-releases/news-release-details/eagle-pharmaceuticals- announces-fda-acceptance-investigational .. 3 On 8/9/22 Eagle took an equity stake in, with option to acquire, Enalare
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 6 6 Introduction of the Speakers
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 7 Patients Served by Acute Care/Hospital Portfolio ByfavoRyanodexLandiololENA-001CAL02ByfavoVasopressinLandiololENA-001CAL02BarhemsysByfavoRyanodexVasopressinLandiololENA-001ByfavoVasopressinENA-001BarhemsysRyanodexVasopressinLandiololENA-001Emergency DepartmentPACUOperating Room Procedural SuiteCritical Care Pre-operative
8 8 Eagle SpeakersValentin Curt, MDInterim Chief Medical Officer, SVP Clinical Drug Development, at Eagle Pharmaceuticals, Inc.25+ years of experience in clinical drug development and managing global clinical development plansPrior executive positions held at Imbrium Therapeutics, Purdue Pharma, Daiichi Sankyo, and NovartisMichael Greenberg, MDVice President of Medical Affairs at Eagle PharmaceuticalsEmergency medicine physician with expertise in medical affairsPrior experience consulting with the FDA Center for Drug Evaluation and Research (CDER)Deb HussainSenior Vice President, Head of Commercial, at Eagle Pharmaceuticals25 years of pharmaceutical industry experience leading commercial launches in the hospital and critical care spaceJoined Eagle from Acacia Pharma, with prior experience at Eli Lilly and CompanyScott TarriffFounder, Chief Executive Officer, President, Director of Eagle PharmaceuticalsHeld executive-level positions at Par Pharmaceutical Companies, Inc. and Bristol-Myers SquibbReceived prestigious Ernst and Young Entrepreneur Of The Year Award in the Specialty Pharmaceutical category, NJ
9 9 KOL BiographiesHerm CukierExecutive Chairman, President, and CEO of Enalare TherapeuticsSuccessful executive with commercial and operational expertise across several global, blockbuster products30+ years industry experience in senior leadership roles with preeminent organizations, including Bayer, Bristol Myers Squibb, and PfizerDr. Richard DuttonChief Quality Officer for US Anesthesia Partners (USAP) Responsible for data analysis and performance measurement using the collective data and evaluations of all USAP practices to improve patient safety and clinical outcomesServed in clinical leadership positions with the American Society of Anesthesiologists, including Chief Quality Officer and Medical Director of the Anesthesia Quality InstituteDr. Prem FortAttending Neonatologist, Johns Hopkins All Childrens Maternal, Fetal & Neonatal Institute Co-chair of the MFN research councilResearch focus includes respiratory management of premature infants, control of breathing, and apnea of premature, specifically as it relates to its management with caffeine Dr. TJ GanProfessor and Head, Division of Anesthesiology, Critical Care and Pain Medicine, UT Texas MD Anderson Cancer Center, Houston,TexasPerioperative Medicine Executive Section Editor of Anesthesia and Analgesia and on the Editorial Board of Perioperative MedicineOver 300 manuscripts in peer-reviewed journals and numerous books and book chapters
10 10 KOL BiographiesDr. Joseph PergolizziChief Research and Development Officer, Board Member and Co-founder of Enalare Therapeutics Internationally recognized thought leader in areas of perioperative and pain medicines, drug development, and regulatory affairsHighly published in top-tier journals and a frequent scientific advisor for public and private companies. He is a serial entrepreneur who has started more than 20 companiesDr. Andre KalilProfessor of Medicine at the University of Nebraska Medical Center Division of Infectious DiseasesNamed the 2021 Scientist Laureate, the highest honor UNMC bestows upon researchersPracticing physician and clinical researcher working on many challenging infections, including transplant-related infections, pneumonia, sepsis, Ebola and COVID-19 Dr. Eugene VortsmanEmergency Medicine Attending Physician and Clinical Director of Addiction Medicine and Disease Management for the Emergency Department at Long Island Jewish Medical CenterChair of Pain Committee of Long Island Jewish Medical CenterCo-chair of the Northwell System Substance Abuse and Pain Advisory CommitteeAssociate Professor of Emergency Medicine for Hofstra Medical School
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 11 11 ENA-001
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 12 ENA-001 -Potential to Improve Clinical Outcomes for Patients Post-operativeCommunity Drug OverdoseApnea of Prematurity Agnostic Respiratory StimulantRapid ActingMultiple FormulationsNovel MoleculeSignificant Medical NeedRespiratory Depression Affects Millions of PatientsPotential Novel SolutionData ConfidenceStrong Foundation of Data Five Phase 1 Human StudiesNo SAEsMore than 100 animal studiesExternal SupportSupport and Partnership with Major Government Entities BARDA PartnershipNIH FundingCommercial OpportunityCould Lead to Significant Value Creation Strong IPGlobal RightsBlockbuster AnalogsPathway to Approval Fast-Track StatusOrphan Drug DesignationRare Pediatric Disease DesignationHHS ASPR BARDA support EnalareTherapeutics Inc. All rights reserved..
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 13 Respiratory Depression: A Global Health Emergency Normal Respiration12-20 breaths/minMinute ventilation of 5 to 8 liter/min (resting)Harmonized balance of O2and CO2 levels in the blood Respiratory Depression<10 breaths/minInadequate minute ventilation (hypoventilation)Low oxygen saturation (Hypoxemia)High blood CO2levels (Hypercapnia)Breathing rate & qualityMedications and health conditions can impact the bodys natural ability to maintain appropriate levels of blood gasesIllustrative Insufficient respirationMedicationsSedatives and anestheticsNarcotics (Opioids)AlcoholOther substances that depress brain functionSynergistic effect from drug combinationsHealth ConditionsObesity and agingViral or bacterial infectionsNeuromuscular diseasesSleep apneaChronic lung diseasesUnder-developed respiratory control system Common Causes of Respiratory Depression EnalareTherapeutics Inc. All rights reserved..
CONFIDENTIAL AND INTERNAL 2022 Eagle Pharmaceuticals, Inc. All rights reserved. 14 Partnership with BARDA on Development of ENA-001 as a Rescue Medicine for Drug-induced Respiratory DepressionEnalare/BARDA ENA-001 PartnershipSupports development of an intramuscular (IM) formulation of ENA-001 for use as a threat-agnostic therapeutic agent in the community settingPartnership includes funding, scientific guidance, and active engagement with FDA interactionsContract for up to $50 million over six years supports development program through an NDA filing EnalareTherapeutics Inc. All rights reserved..
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 15 ENA-001 -Multiple Product Candidates Under Development with Potential to Benefit Patients Across the Hospital and Community Settings Setting of UseHospital & Ambulatory (outpatient) clinicsCommunity, First Responders, ERHospital Neonatal Intensive Care UnitsAddressable Market300+ million annual global surgical proceduresWorsening drug overdose epidemic, >100K US deaths annually10% of infants born premature globallyProfileStrong health economics, Global blockbuster opportunityGovernment support via partnerships with NIH & BARDAFDA Orphan Drug & Rare Pediatric Disease Designations Shallow or stopped breathing in premature infants Opioids, non-opioids, and polypharmacy overdoses Treatment and prevention for at-risk surgical patients.Post-operative respiratory depressionCommunity drug overdose & MCM*Apnea of prematurity* MCM = Medical Countermeasure EnalareTherapeutics Inc. All rights reserved..
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 16 ENA-001 = A One-of-a-Kind Molecule with a Novel Mechanism of Action TASK 1 TASK 3 BKCa↓O2, ↓pH↑ENA-001 Depolarization of carotid body glomus cells drives breathingChannel agonists decrease potassium conductanceLow oxygen, pH (and doxapram) act on TASK channelsENA-001 acts on BK channelsBK channels = greater inherent conductance vs TASKMore sensitive transduction pathwayAction occurs at relatively low plasma levels of ENA-001Low risk of untoward effects EnalareTherapeutics Inc. All rights reserved..
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 17 ENA-001 = A Unique Product Profile with Potentially Broad Applications to Stimulate Breathing ENA-001hydrogensulphatesalt2-N,O-dimethylhydroxylamino-4,6-bispropylamino-s-triazineAgnostic:Potential to stimulate breathing irrespective of the cause of respiratory depression; potential to be used across multiple patient populationsNatural:Utilizesthebodysventilationcontrol systemtobeneficiallyinfluencebreathingPeripheral:Affectsventilationviatheperipheral chemoreceptorpathwaysinthecarotidbodyMay rapidly stimulate ventilation in patients with acute respiratory insufficiencyIntended not to interfere with pain suppression or sedation May avoid the withdrawal effect experienced with opioid antagonists EnalareTherapeutics Inc. All rights reserved..
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 18 ENA-001 = Well Tolerated Across Five Clinical Studies Totaling >110 Subjects StudyDescription# of SubjectsGAL-021-101Single, ascending dose study in healthy subjects.30GAL-021-102Extended the dose range -established the maximum respiratory stimulatory dose in the healthy subjects without concomitant use of opioids or anesthetic agents.18GAL-021-104Assessed the potential therapeutic utility under conditions that simulate the post-operative state. Alfentanil was used to suppress ventilation.23GAL-021-106Designed to evaluate the safety and tolerability in healthy subjects during 5 days of 12-hour continuous infusion of 0.125, 0.25, and 0.5 mg/kg.28ENA-001-108Assessed the potential therapeutic utility under conditions that simulate the post-operative state. Propofol was used to suppress ventilation.12Well ToleratedAgnostic EfficacyTherapeutic DoseConsistent Results The Emergence of an Exciting Product Profile EnalareTherapeutics Inc. All rights reserved..
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 19 Clinical Study 104: Respiratory Stimulatory Effects in Subjects with Impaired Respiratory Drive due to an Opioid Study Design:Healthy volunteersAdministered low and high levels of alfentanil, a potent opioid, to induce moderate to severe respiratory depressionObservations:Well toleratedClinical trial data indicated:Improvements across multiple respiratory metricsNo impact on pain analgesiaConclusion: ENA-001 continuous infusion IV produced respiratory stimulatory effects during opioid-induced respiratory depression -Study was a Phase 1b trial in healthy volunteers targeted at a post operative respiratory depression indication-Conducted at Center for Human Drug Research, (CHDR), Zernikedreef 8, 2333 CL Leiden, The Netherlands-Registered with the EnduraCT database, No: 2012-004363-50 EnalareTherapeutics Inc. All rights reserved..
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 20 Clinical Study 106: Rising Multiple Dose 5-day Study of ENA-001Objectives: Safety, Tolerability, Pharmacokinetics (PK) Standard Double Blinded, Placebo Controlled Study Infusions: 12 hours x 5 daysThree Dose Levels (0.125, 0.25, 0.5 mg/kg/h) Safety Profile & TolerabilityWell tolerated except for infusion site burning sensation and local phlebitis after several days of the infusions CV parameters similar (corrected for baseline)⎯Blood pressure transient post-infusion increase⎯Cardiac intervals unchanged Endocrine-metabolic parameters similar to placebo Pharmacokinetics (PK)Similar Days 1 and 5 Well-behaved PK Study 106 Results EnalareTherapeutics Inc. All rights reserved..
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 21 Clinical Study 108: Respiratory Stimulatory Effects in Subjects with Impaired Respiratory Drive due to an Anesthetic To determine the safety, tolerability, and ventilatory response of low and high doses of ENA-001 under both hypoxic and hypercapnic conditions in conjunction with low and high doses of propofolPrimary Safety Endpoint: treatment emergent adverse eventsPrimary Ventilatory Endpoint: Hypoxic Sensitivity (Δ ventilation/Δ SaO2)Objective:Model:Results:Healthy volunteers with ventilatory depression (desensitization) via propofol administration in the presence of no, low, or high doses of ENA-001Hypoxic sensitivity determined by hypoxic challenge, with and without hypercapnic challengeWell tolerated with no serious adverse events (SAEs)Hypoxic sensitivity increased with high dose of ENA-001 (p<0.0001) under all conditions of no, low, and high dose of propofolHypoxic sensitivity restored to above baseline levels during high dose propofol exposure EnalareTherapeutics Inc. All rights reserved..
CONFIDENTIAL AND INTERNAL 2022 Eagle Pharmaceuticals, Inc. All rights reserved. 22 Post-op (Fast-track)Start fentanyl tox study ~ in early 2023Expect to start Phase 2 enrollment ~ as early as 3Q23Potential for Phase 2 topline data ~ in 2Q24Community Drug Overdose (BARDA and NIH funding)Currently executing toxicology studies with intramuscular formulation (IM)Expect to start Phase 1 enrollment as soon as mid-year 2023Apnea of Prematurity (Rare Pediatric Disease and Orphan Drug designations)Recently completed animal proof of conceptDesigning next set of animal studies and clinical pathwayENA-001 Timeline**Expected for planning purposes EnalareTherapeutics Inc. All rights reserved..
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 23 Real World Experience Respiratory DepressionDr. TJ GanDivision Head of Anesthesiology, Critical Care and Pain Medicine MD AndersonEmergency Medicine PhysicianClinical Director of Addiction Medicine and Disease Management Northwell HealthNeonatologist Johns Hopkins All Childrens Maternal, Fetal & Neonatal InstituteDr. Eugene VortsmanDr. Prem FortPost-operative respiratory depressionCommunity drug overdoseApnea of prematurity EnalareTherapeutics Inc. All rights reserved..
24 The Burden of Respiratory Depression T. J. Gan, M.D., M.B.A., F.R.C.A., M.H.S. Professor and Division Head Anesthesiology, Critical Cre and Pain Medicine UT Texas MD Anderson Cancer Center Founding President, American Society for Enhanced Recovery (ASER) aserhq.org | enhancedrecovery.org President, Perioperative Quality Initiative (POQI.org) 24
25 Postoperative Pulmonary Complications (PPC) PPC is any event that occurs in the postoperative period that produces physiologic dysfunction or clinical diseaseIncidence 2 -40%2.73.4% of patients undergoing non-cardiac surgery (NSQIP database)9.6% in elective abdominalsurgeries in VApatientsLawrence VA et al. J Gen Intern Med 1995;10(12):671-678Dimick JB et al. J Am Coll Surg 2004;199(4):531-537
26 Prediction and Monitoring for PORD are Poor Unable to accurately predict which patient will have an episode of PORD PACU Staff routinely miss low oxygen, <90% of episodes1Incidence of post-operative hypoxemia underestimated1Up to 62% transferred from floor to ICU had serious abnormalities 8-48 hours prior to transfer2,3Not recognized or acted onAlarm-fatiguePatients experiencing PORD utilize greater resources, have an increased length of stay and increased healthcare costsEducation, monitoring, other procedures have not significantly reduced these events4Need for a comprehensive and reliable approach to assessment and recognition of PORDPORD = Postoperative Respiratory DepressionPACU = Post Anesthesia Care UnitICU = Intensive Care Unit1. Sun Z et al. Anesth Analg. 2015;121:709-7152. Hillman KM et al. Inten Care Med. 2002;28:1629-16343. Gong MN et al. BMJ Open. 2016;6::e0113474. Ayad S et al. Br J Anaesth. 2019;123(3):378-391
27 Manifestations of PPC Respiratory failurePneumoniaAtelectasisDyspneaProlonged mechanical ventilationUnexpected reintubationHypoxemia (blood gas or SpO2)Administration of naloxoneBranson Rd et al. Respir Care 2013;58(11):1974 1984
28 Postoperative Pulmonary Complications (PPC) Risk Factors Miskovic A and Lumb AB. British Journal of Anaesthesia, 118 (3): 31734 (2017)
29 NSQIP database >220,000 patientsIncidence of unanticipated early postoperative intubation (UEPI) 0.9%Ramachandran SK et al. Anesthesiology 2011; 115:4453
30 Out of 9,799 claims, 92 were due to RD88% occurred within 24 h of surgery97% were judged as preventable with better monitoring and responseMedian payment -$216,750 Lee L et al. Anesthesiology 2015; 122:659-65
Average cost of a complication > $10,000J AmColl Surg2004;199:531537 31
32 Postoperative Opioid - induced Respiratory Depression Patients with ≥1 respiratory depression episode had a longer length of stay (6.4 vs 5.0 days) and higher hospital cost ($21,892 vs $18,206) Respiratory depression episodes includeRespiratory rate ≤ 5 bpm,Oxygen saturation ≤ 85%,End-tidal carbon dioxide ≤15 or ≥ 60mmHg for ≥3 minApnea episode lasting > 30 seconds; orAny respiratory event requiring interventionKhanna et al. BMC Anesthesiology (2021) 21:88
33 The Future of Postoperative Respiratory Care Cannot prevent all PORDOpioids are not the sole culprit of PORDAnesthetics, paralyzing agents, and sedatives that do not respond to naloxoneProlonged apnea at the end of surgery delays wakeupGoal: Improved respiratory and ventilatory function Proactive ApproachConduct risk assessmentDoes not identify a specific patientTake a universal approachHelps keep everyone below the line of moderate riskConsider respiratory stimulant prior to transfer to PACUPORD = Postoperative Respiratory DepressionPACU = Post Anesthesia Care Unit
34 Summary Postoperative respiratory complications are common and preventable1% of postoperative patients require unexpected reintubationPostoperative respiratory complications increase length of stay and substantially increase costApnea and respiratory depression delay wakeup following surgery and increase cost
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 35 Clinical Director of Addiction Medicine and Disease Management: Every day, Emergency Departments around the country struggle managing overdoses with only ONE tool availableleading to dangerous situations for staff and patients.Chair of Pain Advisory Committee: Every month, hospitals manage iatrogenic overdoses with only ONE tool leading to regulatory scrutiny and worse outcomes for patients.Co-Chair of the Substance Use and Pain Advisory Committee: Every day, pre-and post-hospital environment have ONE tool to manage difficult patients leading to dangerous situations for EMS and ambulatory outpatient procedures.Dr. Eugene Vortsman Potential New Tool for Emergency Setting Unique, Proprietary, and Confidential Information of Enalare Therapeutics Inc. 2021 ENA-001 has the potential to be a new effective tool needed in the emergency setting to improve patient outcomes
36 36 Apnea of Prematurity andENA-001 Prem Fort, MDChair-MFNI Research CouncilAssistant Professor of PediatricsJohns Hopkins School of MedicineJohns Hopkins All Childrens Hospital, FLhttps://commons.wikimedia.org/wiki/File:Premature_infant_with_ventilator https://commons.wikimedia.org/wiki/File:Premature_birth_Alberta,_Canada
37 37 Premature Infants 15 MILLION 500,000 US 1 in 10 US <37 weeks
38 38 Apnea: Obstructive vs. Centralhttps://www.nhlbi.nih.gov/health/sleep-apnea/causesObstructiveCentral https://slidetodoc.com/patterns-of-respiration-by-ahmad-younes-professor-of/
39 39 Apnea of prematurity is defined as cessation of breathing for ≥ 20 seconds or < 20 seconds if accompanied by bradycardia (<100 BPM) and/or cyanosis and pallor in infants < 37 weeks gestational age (GA)AAP COFN. Pediatrics 137: 2016Apnea of Prematurity
40 40 APNEACessation of Breath 12 million a yearwithAPNEA ofPrematurity https://www.whattoexpect.com/first-year/caring-for-a-premature-baby.aspx
41 41 Eichenwald et al. Pediatrics 108:928-33, 2001Gestational Age inWeeks30 (n=25)31 (n=40)32 (n=95)33 (n=122)%with apnea92905948Background: Percentage of Moderate Preterm Infants with Apnea
42 42 APNEA OF PREMATURITYHow is it treated?neotechproducts.com respiratory-care-sleep-medicine.advanceweb.com
43 43 APNEA OF PREMATURITYHow is it treated? Apnea/Day 443026221612840PreCaffeineWithCaffeineAranda et al. J Pediatr 90:467, 1977 canva.com
44 44 APNEA OF PREMATURITYMany left untreatedApnea/Day 443026221612840PreCaffeineWithCaffeineAranda et al. J Pediatr 90:467, 1977
45 45 Chavez-Valdez R, Ahlawat R, Wills-Karp M, Gauda EB. Mechanisms of modulation of cytokine release by human cord blood monocytes exposed to high concentrations of caffeine. Pediatric research. 2016;80(1):101-109Elevated Markers of InflammationIs Caffeine Safe?
46 46 Valdez RC, Ahlawat R, Wills-Karp M, Nathan A, Ezell T, Gauda EB. Correlation between Serum Caffeine Levels and Changes in Cytokine Profile in a Cohort of Preterm Infants. The Journal of pediatrics. 2011;158(1):57-64.e1.The Sweet SpotCaffeine’s Limits
47 47 Meta-Analysis and Systematic Review
48 48 Meta-Analysis and Systematic Review
49 49 12345 The Effect of Apnea on Hospitalization https://commons.wikimedia.org/wiki/File:Yegorov-Simeon_the_Righteous https://slidetodoc.com/patterns-of-respiration-by-ahmad-younes-professor-of/
50 50 Alternate Treatments Pergolizzi Jr, Joseph V., et al. "The limited management options for apnoea of prematurity."Journal of Clinical Pharmacy and Therapeutics47.3 (2022): 396-401.
51 51 AAP. Hospital discharge of the high-risk neonate. Pediatrics 2008;122:1119-26Altman M, Vanpee M, Bendito A, Norman M. Shorter hospital stay for moderately preterm infants. Acta Paediatrica (Oslo, Norway: 1992) 2006;95:1228-33Eichenwald EC, Blackwell M, Lloyd JS, Tran T, Wilker RE, Richardson DK. Inter-neonatal intensive care unit variation in discharge timing: influence of apnea and feeding management. Pediatrics 2001;108:928-33Eichenwald EC, Aina A, Stark AR. Apnea frequently persists beyond term gestation in infants delivered at 24 to 28 weeks. Pediatrics 1997;100:354-9Erenberg A, Leff RD, Haack DG, Mosdell KW, Hicks GM, Wynne BA. Caffeine citrate for the treatment of apnea of prematurity: a double-blind, placebo-controlled study. Pharmacotherapy 2000;20:644-52Hunt CE, Brouillette RT. Methylxanthine treatment in infants at risk for sudden infant death syndrome. Annals of the New York Academy of Sciences 1988;533:119-26Lorch SA, Srinivasan L, Escobar GJ. Epidemiology of apnea and bradycardia resolution in premature infants. Pediatrics 2011;128:e366-73Mohammed, Sameh, et al. "High versus low-dose caffeine for apnea of prematurity: a randomized controlled trial." European journal of pediatrics174.7 (2015): 949-956.Schmidt B, Roberts RS, Davis P, et al. Caffeine therapy for apnea of prematurity. The New England Journal of Medicine 2006;354:2112-21Subhani M, Katz S, DeCristofaro JD. Prediction of post-discharge complications by pre-discharge event recordings in infants with apnea of prematurity. Journal of Perinatology: Official Journal of the California Perinatal Association 2000;20:92-5REFERENCES
52 52 Endesfelder, Stefanie, et al. "Caffeine Protects Against Anticonvulsant-Induced Neurotoxicity in the Developing Rat Brain." Neurotoxicity Research(2017): 1-13Köroğlu, Özge A., et al. "Anti-inflammatory effect of caffeine is associated with improved lung function after lipopolysaccharide-induced amnionitis." Neonatology106.3 (2014): 235-240.Chavez-Valdez R, Ahlawat R, Wills-Karp M, Gauda EB. Mechanisms of modulation of cytokine release by human cord blood monocytes exposed to high concentrations of caffeine. Pediatric research. 2016;80(1):101-109. Valdez RC, Ahlawat R, Wills-Karp M, Nathan A, Ezell T, Gauda EB. Correlation between Serum Caffeine Levels and Changes in Cytokine Profile in a Cohort of Preterm Infants. The Journal of pediatrics. 2011;158(1):57-64.e1. doi:10.1016/j.jpeds.2010.06.051.
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 53 53 CAL02
54 54 Disease State OverviewAndre Kalil, MD, MPHProfessor of MedicineUniversity of Nebraska Medical Center
55 55 Chest X-ray: Normal LungsChest X-ray: Lungs with pneumoniaComputerized tomography (CT) scan: Lungs with pneumonia
56 Tilghman Arch Intern Med 1937;59:602–19. Pneumonia before Antibiotics
57© 2022 Eagle Pharmaceuticals, Inc. All rights reserved. Pneumonia OverviewPneumonia is defined as "new lung infiltrates plus clinical evidence that the infiltrate is of an infectious origin, which include the new onset of fever, purulent sputum, leukocytosis, and decline in oxygenation”. –The Infectious Disease Society & American Thoracic SocietyPneumonia that is contracted outside of the health care setting is considered community-acquired pneumonia (CAP).Hospital-acquired pneumonia (HAP), or nosocomial pneumonia, is a lower respiratory infection that was not incubating at the time of hospital admission and that presents clinically 2 or more days after hospitalization.Ventilator-associated pneumonia (VAP) is defined as pneumonia that presents more than 48 hours after endotracheal intubation. CAP HAP VAP
58© 2022 Eagle Pharmaceuticals, Inc. All rights reserved. CAP Poses a Significant Public Health Burden In the US, the annual incidence of CAP was 2.4 cases per 1,000 adults with the highest rates among adults ≥651 Globally mortality with CAP is up to 50% in the ICU.2-7 CAP is the second most common cause of hospitalization and the third leading cause of hospital readmission causing direct hospitalization costs of ~17 billion USD.8 -9 1.Jain S, Self WH, Wunderink RG, Fakhran S, Balk R, Bramley AM, Reed C, Grijalva CG, Anderson EJ, Courtney DM, Chappell JD, Qi C, Hart EM, Carroll F, Trabue C, Donnelly HK, Williams DJ, Zhu Y, Arnold SR, Ampofo K, Waterer GW, Levine M, Lindstrom S, Winchell JM, Katz JM, Erdman D, Schneider E, Hicks LA, McCullers JA, Pavia AT, Edwards KM, Finelli L; CDC EPIC Study Team. Community-Acquired Pneumonia Requiring Hospitalization among U.S. Adults. N Engl J Med. 2015 Jul 30;373(5):415-27.2.Arnold FW, Wiemken TL, Peyrani P, Ramirez JA, Brock GN; CAPO authors. Mortality differences among hospitalized patients with community-acquired pneumonia in three world regions: results from the Community-Acquired Pneumonia Organization (CAPO) International Cohort Study. Respir Med. 2013 Jul;107(7):1101-11. doi: 10.1016/j.rmed.2013.04.003. 3.Heo JY, Song JY. Disease Burden and Etiologic Distribution of Community-Acquired Pneumonia in Adults: Evolving Epidemiology in the Era of Pneumococcal Conjugate Vaccines. Infect Chemother. 2018 Dec;50(4):287-300. doi: 10.3947/ic.2018.50.4.287. 4.Cillniz C, Ewig S, Polverino E, Marcos MA, Prina E, Sellares J, Ferrer M, Ortega M, Gabarrs A, Mensa J, Torres A. Community-acquired pneumonia in outpatients: aetiology and outcomes. Eur Respir J. 2012 Oct;40(4):931-8. doi: 10.1183/09031936.00168811.5.Lawrence H, Lim WS, McKeever TM. Variation in clinical outcomes and process of care measures in community acquired pneumonia:a systematic review. Pneumonia (Nathan). 2020 Sep 25;12:10. doi: 10.1186/s41479-020-00073-4.6.AlOtair HA, Hussein MA, Elhoseny MA, Alzeer AH, Khan MF. Severe pneumonia requiring ICU admission: Revisited. Journal of Taibah University Medical Sciences. 2015;10(3):293-299.7.Joya-Montosa C, Delgado-Amaya MD, Molina-Diaz H, Curiel Balsera E. Analysis of the mortality rate in patients admitted to the ICU for severe community-acquired pneumonia. Crit Care. 2015;19(Suppl 1):S7.8.Fingar K, Washington R. Trends in Hospital Readmissions for Four High-Volume Conditions, 20092013. Healthcare Cost and Utilization Project Statistical Brief #196. Agency for Healthcare Research and Quality. November 2015. Available at: https://hcup-us.ahrq.gov/reports/statbriefs/sb196-Readmissions-Trends-High-Volume-Conditions.jsp. 9.File TM, Marrie TJ. Burden of Community-Acquired Pneumonia in North American Adults. Postgraduate Medicine. 2010;122(2):130-141.
59 Mortality of Hospitalized CAP German, 2006-2007N=388,406 hospitalized CAPCRB-65 hospital mortality: 14.1% 1.8% 14.9% EwigThorax2009;64:1062-1069 class 1: 16.55% class 2: 71.55% class 3: 11.91% Mechanical ventilation: 5.1%
60 Severe CAP P<0.001 Retrospective study of prospective data, N=844 severe bacteremic pneumococcal pneumoniaPitt bacteremic score ≤/>4 Combination 23.4% Monotherapy 55.3%Critically ill pts (30d mortality) Baddour AJRCCM 2004;170:440
61 Severe CAP (HR, 1.45; 95% CI, 0.96–2.18; p=.07)(HR, 1.69; 95% CI, 1.09–2.60; p=.01) Retrospective study of prospective data, N=529 ICU admitted CAPShock Y/N β-lactam plus fluoroquinolones(HR, 1.77; 95% CI, 1.01–3.15; p=.05)Monotherapy vs. combination β-lactam plus macrolide(HR, 1.73; 95% CI, 1.08 –2.76; p=.02) Rodriguez CCM 2007;35:1493
62 Severe CAP HR 0.48, 95% CI 0.23–0.97, p=.04 Martin-Loeches ICM 2010;36:612 Prospective observational studyN=217 SCAP requiring MVSevere sepsis/septic shock 75.5%Therapy according to ATS/IDSA 2007 guidelines, N=100 (45.9%)Combination with fluoroquinolone (N=46) or macrolide (N=56)
63 Hospitalized CAP Treatment Failure 2 open, prospective multicenter studies (moxifloxacin; standard)n = 1236Treatment failure (15.9%) CURB65≥2 (20.3%, p=.004) LOS (15.4 vs 9.8d, p<.001) Costs (2206 vs 1284€, p<.001) Mortality (17.3 vs 5.2%, p<.001)89.1% of group standard received therapy in accordance with guidelines Initial therapy with β β Ott ERJ 2012;39:611
64 Pneumonia and Stroke/Acute MI 11.522.533.544.555.560-3031-9091-365Time post discharge (days)OR for new onset IHD or stroke Corales-Medina et al JAMA 2015 CHS (n=5888) ARIC (n=15792)
65 Pneumonia and New Onset Heart Failure 13579111331-9091-180181-3651-5 yearsTime post discharge (days)OR for new onset heart failure Corales-Medina et al Am Heart J 2015
66 Risks (hazard ratios) of first readmission to hospital and death for one year after hospitalization for heart failure, acute myocardial infarction, or pneumonia Dharmarajan K et al. BMJ 2015;350:bmj.h411
67 Mortality Due to CAP Mortality in thesubsequent2 yearsInpatient mortality
68 Lakbar I et al. Sci Report 2021 Aug 13;11(1):164 Mortality and Highly Antimicrobial-Resistant Bacteria
69 Suarez-de-laRica et al. Rev Esp Quimiot 2021 Aug;34(4):330-336. doi: 10.37201/req/031.2021Secondary Infections in Mechanically Ventilated Patients with COVID-19
70© 2022 Eagle Pharmaceuticals, Inc. All rights reserved. Pneumonia Management HAP, VAP, CAP suspected Obtain lower respiratory tract sample (and blood if VAP)for culture and microscopy if patient is clinically stable Begin empiric antimicrobial therapy using local antibiogram unless there islow clinical suspicion for pneumonia and a negative lower respiratory tract culture Days 2 & 3: Check cultures & assess clinical response Clinical improvement at 48-72 hours No Cultures - Cultures + Search for other pathogens, complications, other diagnoses or other sites of infections Adjust antibiotic therapy. Search for other pathogens, complications, other diagnoses or other sites of infection Yes Cultures - Cultures + Consider stopping antibiotics De-escalate antibiotics if possible. Treat selected patients for 7-8 days and reassess Revised: Trevor Van Schooneveld, MD and Kiri Rolek, PharmaD (July 2015)
71© 2022 Eagle Pharmaceuticals, Inc. All rights reserved. Pneumonia Treatment CAP In-Patient Therapy Medical Ward NoRecent Antibiotics RecentAntibiotics ClarithromycinAzithromycinPLUSCefotaxime, Cetriaxone,Ampicillin-sulbactam, orErtapenemORMoxifloxacin,Levofloxacin,Gemifloxacin*,or Gatifloxacin(regimen selected will depend on nature of recent antibiotic therapy) No PseudomonasRisk PseudomonasRisk Intensive Care Unit No β-lactamAllergy β-lactamAllergy ClarithromycinAzithromycinPLUSCefotaxime,Ceftriaxone,Ampicillin-Sulbactam, orErtapenemORMoxifloxacin,Levofloxacin,Gemifloxacin*,or Gatifloxacin Moxifloxacin,Levofloxacin,Gemifloxacin*,or Gatifloxacin+/-Clindamycin No β-lactamAllergy β-lactamAllergy Anti-pseudomonalAgent(piperracillin,Piperacillin-Tazobactam,Cefepime,Imipenem, orMeropenem)PLUSCiprofloxacinORAnti-pseudomonalAgent PLUSAminoglycosidePLUSClarithromycin,or azithromycinORMoxifloxacin,Levofloxacin,Gemifloxacin*,or gatifloxacin AztreonamPLUSMoxifloxacin,Levofloxacin,Gemifloxacin*,or gatifloxacin+/-aminoglycoside
72© 2022 Eagle Pharmaceuticals, Inc. All rights reserved. Complications Associated with PneumoniaA Significant Unmet Medical Need Pneumonia is the most common infection requiring hospitalization and admission to ICU* 3rd most common cause of death globally (2.5million deaths/year)** Admission to ICU and length of hospitalization tightly linked to development of pneumonia complications* Adequate empirical antibacterial therapy shows no reduction in risk of death for pneumoniapatients admitted to ICU* Pneumonia complications place considerable burden on healthcare resources through increasesin rates of hospitalization, lengthy in-patient care, cost of care and readmission rates* In the US about 1 million adults seek care for pneumonia yearly and 50,000 die from this disease* 35% -58% mortality rate due to pneumonia complications such as acute respiratory distress,kidney, liver and heart damage and sepsis*** *American Thoracic Society Top 20 Pneumonia Facts--2019 **Pneumonia & Deaths 2020 American Thoracic Society ***Ibn Saled et al, Crit.Care Med 47, 445-352 2019
73 Unmet Need in Severe CABP Unknown bacterial speciation upon admission and antibiotic resistance can complicate clinical management Current CABP treatments have limitations and do not address the propagation of the inflammatory response Treatment failure and high mortality rates remain problematic for severe CAP patients There is a current unmet need for new treatment modalities that are effective in decreasing morbidity and mortality in severe CAP
74 Unknown Bacterial Speciation Upon Admission and Antibiotic Resistance Can Complicate Clinical Management The microbial etiology of CAP may not be characterized in ~50% of patients.1 Cases of resistant pneumococcal pneumonia in the US result in ~32,000 additional doctor visits and 19,000 additional hospitalizations each year.2 Methicillin-resistant Staphylococcus aureus (MRSA) is now considered to be an important pathogen in CABP.3 Antibiotic resistant Pseudomonas aeruginosa and Klebsiella pneumoniae can cause CAP in a small proportion of patients.1 Antibiotic Selection 1.Shoar S, Musher DM. Etiology of community-acquired pneumonia in adults: a systematic review. Pneumonia (Nathan). 2020 Oct 5;12:11. doi: 10.1186/s41479-020-00074-3.2.Centers for Disease Control & Prevention. Antibiotic Resistance Threats in the United States, 2013. US Department of Health and Human Services. Available at: https://www.cdc.gov/drugresistance/threat-report-2013/index.html. 3.Mandell ALW, R. Methicillin-resistant staphylococcus aureus and community-acquired pneumonia: An evolving relationship. Clin Infect Dis. 2012;54(8):1134-1136
75 75 CAL02 Overview & Development PlanValentin Curt, M.D.
76© 2022 Eagle Pharmaceuticals, Inc. All rights reserved. Severe Pneumonia -Key Targets TRIGGERMEDIATORSIMPACTOUTCOMEPERIPHERAL VASCULATUREMYOCARDIUMCYTOKINES /CHEMOKINESSEPSISSEPTICSHOCKDEATHSENSORSPLASMAPROTEINSYSTEMSBLOOD ANDLYMPHATICCELLSVASCULAR AND TISSUECELLSENDOTHELIAL STRESSRESPONSECELLDYSFUNCTIONINSULT BACTERIA VIRULENCEFACTORS ORGANFAILURE BACTERAEMIA HARMED IMMUNEINFLAMMATORYDEFENSEBURSTHEMODYNAMICINSTABILITY A COMMON DENOMINATOR IN SEVERE, COMPLICATED, AND RESISTANT INFECTIONS: An underserved patientpopulation:Mortality rates for ICU pneumonia patients remain as high as40%, worldwide,due to complications which most often occur even when tissues are alreadypathogen-free,and the pulmonary process isclearingCAL02, a novel first-in-class broad-spectrum anti-virulence agent being developed for the treatment of severe community-acquired bacterial pneumonia, could potentially neutralize the most relevant virulence factors in severe pneumonia“Capture” of bacterial toxinCAL02Electron micrograph Virulence effectorshave a key role in promoting severe disease:play a critical role in the development ofsevere complicationsreinforce mechanisms of resistancefacilitate and exacerbate co-infections
77© 2022 Eagle Pharmaceuticals, Inc. All rights reserved. Bacterial Virulence Factors (VFs)VFs play a decisive role in the development of long-term, severe, and fatal pneumonia complicationsCurrently not targeted by established antibioticsVFs are a part of the pathogens armory that triggers multiple pathogenic processes: Promote bacterial colonization and growthDisrupt tissue barriersFacilitate tissue penetration and infections invasivenessAct synergistically to help bacteria evade the innate and adaptive immune response of the hostUltimately VFs contribute to edema, inflammation, and organ failure
78© 2022 Eagle Pharmaceuticals, Inc. All rights reserved. Bacterial Virulence Factors (VFs) ClassificationSingle largest category (25-30% of cytotoxic bacterial proteins)Function to perforate membranes of host cellsClassified as α-PFTs and β-PFTs based on the pore-forming mechanismβ-PFTs and most α-PFTs preferentially target cholesterol and sphingomyelin Pore-forming Toxins (PFTs) Toxins with hemolytic activityToxins with destructive enzymatic activities (proteases, lipases, DNase)Secreted vesicular or appended virulence effectors Other Virulence Factors
79© 2022 Eagle Pharmaceuticals, Inc. All rights reserved. Bacterial Causes of Pneumonia HAP H. influenzae-early onset HAPP. aeruginosaS. aureus (including MSSA and MRSA)GNEB(K. pneumoniae, E. coli)Acinetobacter*species-ICU patientsS. pneumoniae-early onset HAP VAP P. aeruginosaS. aureus (including MSSA and MRSA)S. maltophiliaAcinobacter species Severe CAP S. pneumoniae: 50-60% of SCAP cases worldwideLeading cause of lower respiratory infection morbidity and mortality globally (1.2 million deaths/year)*Legionella pneumophila*: 8-12%*S. aureus (including MSSA and MRSA): 2-12%Mortality rates of 50% in SCAP*H. influenzae: 5-10%*P. aeruginosa: (3-6%)Significant mortality rates*Gram-negative enteric bacilli (GNEB) such as E. coli and K. pneumoniae: <2%*Significant mortality rates 100%*Cilloniz C, et al Thorax 66 340-346 2011
80© 2022 Eagle Pharmaceuticals, Inc. All rights reserved. We believe CAL02, a novel first-in-class broad-spectrum anti-virulence agent being developed for the treatment of severe community-acquired bacterial pneumonia, could potentially overcome the limitations faced by current approachestargeting virulenceVirulence Factors: Pore-Forming Toxins Inactive soluble PFT LipidplatformsHost cell cytosolExtracellular spaceBinding to lipid platforms OligomerizationPore formation Tissue and organ damage Pro-inflammatory responseCell death Membrane insertion
81© 2022 Eagle Pharmaceuticals, Inc. All rights reserved. CAL02 Mechanism of Action Against Virulence Factors CAL02 is a novel first-in-class broad-spectrum anti-virulence agent being developed for the treatment of severe community-acquired bacterial pneumonia. It is being developed to neutralize virulence factors produced by bacteria that are commonly associated with severe pneumonia and potentially add to standard of care to help improve clinical outcomes.
82© 2022 Eagle Pharmaceuticals, Inc. All rights reserved. CAL02Product Overview ▪Patented composition ofmatter▪Sterile liquid solution ready forinjection▪Stable for 36 months when refrigerated (6 months when stored atroom temperature)▪Route of administration: IV Infusion2 doses separated 24 hours apart CAL02 (drug product) Specific mixture of re-engineered empty liposomes solely composed of sphingomyelin and cholesterol capable of capturing and neutralizing a broad spectrum of virulence effectors ►Novel, first in class►Being developed for treatmentfor patients with severe pneumonia►Phase 2 adaptive design study underway►Potential for Qualified Infectious Disease Product (QIDP) Designation under the Generating Antibiotic Incentives Now (GAIN) Act►Potentially eligible for 10 years marketing exclusivity
83© 2022 Eagle Pharmaceuticals, Inc. All rights reserved. CAL02 Novel, First-in-Class Virulence Neutralizer AgentMechanismof ActionAddress the downstream effects of bacterial VFs/PFTs through competitive inhibitionBinds to virulence factor molecules secreted by infecting bacteria, prohibiting host tissue cell bindingActs as an extracellular sink for these toxinsPotential to attenuate pore forming toxin related effects including host tissue damage, immune dysregulation, and inflammation that contribute to increase disease severityLead IndicationSevere Community Acquired PneumoniaSignificant morbidity and mortality despite advances in direct acting antibacterialsSignificant medical need and burden on health care systemsDifferentiated AdvantagesPotential to be used as adjuvant therapy with any traditional antibacterial [therapy agnostic]Potential to be used against any bacteria that produces pore forming toxins [bacteria agnostic]Potential to carry less risk of antibacterial resistance developmentDevelopment Program ProgressFirst-in-Human (FIH) proof of concept study showed tolerability as well as encouraging trendsRegulatory interactions with FDA and EMA may be eligible for special designations and review processesGlobal Phase 2 study underwayScalable manufacturing process
84© 2022 Eagle Pharmaceuticals, Inc. All rights reserved. CAL02 Non-Clinical Program Proof-of-Concept2022CombioxinSA.Allrights reserved. Improvedsurvival Decreasedpro-inflammatoryresponses Shielded immunedefense Organprotection(lung,heartinjury,tissuenecrosis)
85© 2022 Eagle Pharmaceuticals, Inc. All rights reserved. Safety pharmacology studies in rats (respiratory, CNS) and dogs: no safety signals even at the maximum feasible dose, i.e., a maximum tolerated dose (MTD)could not be determinedCAL02 Non-Clinical Safety Pharmacology and Toxicology CAL02 is taken up by macrophages and eliminated via the liver, its half-life in human is estimated to be 24-30 hours CAL02toxin complex degradation and elimination do not cause any toxicity, even in critically ill patients with liver failure Promising biological safety profile (no impact on flora, non-immunogenic, biologically neutral)
86© 2022 Eagle Pharmaceuticals, Inc. All rights reserved. CAL02 Clinical Data in Humans: Safety Outcomes First-In-Human Study ResultsRandomized, double-blind, placebo-controlled3 arms / 19 patients:CAL02 Low dose (4 mg/kg) + Standard of CareCAL02 High dose (16 mg/kg) + Standard of CarePlacebo (saline) + Standard of Care2 IV administration 24h apartSevere CAPP: At least 1 major criteria (mechanical ventilation/ vasopressors) or 3 minor criteriaPrimary objective: Safety & TolerabilitySecondary objective : Efficacy & PharmacodynamicsDisease severity of the study population corresponded to that expected from the inclusion/ exclusion criteriaSeverity at baseline:Mean APACHE II Score: 21.5 (95% CI 19.3-23.7)58% in Septic Shock>40% under Invasive Mechanical VentilationNo differences between treatment groups considered to have a substantial effect on safety and efficacy outcomesCAL02 showed the same safetyprofile as placebo (saline)Adverse Event (AE) occurred in 12 (85%) of 14 patients in the CAL02 groups combined and in all 5 (100%) patients in the placebo group.Serious Adverse Event (SAE) occurred in 4 (29%) of 14 patients in the CAL02 groups combined and 2 (40%) of 5 patients in the placebo group1 AE (mild increase in the triglycerides) in a patient in the CAL02 High dose group was reported as related to study drug. However, the analysis of the changes in triglyceride in the CAL02 groups compared with the placebo group revealed no correction with CAL02.No AEs were liked to local tolerability events. Baseline Characteristics Safety Outcomes
87© 2022 Eagle Pharmaceuticals, Inc. All rights reserved. CAL02 Clinical Data in Humans: Efficacy Outcomes Low-dose CAL02(n=3)High-dose CAL02(n=10)Placebo(n=5)Curedatearlytestofcure(day8)05(56%)*1(20%)Curedattestofcure(betweendays15–22)2(100%)*10(100%)5(100%)Mediantimetocure(days)15·0(14to16)†8·0(6to16)10·0(7to14)All-causemortality1(33%)1(10%)1(20%)Relative change inSequential Organ Failure Assessment score frombaseline today 8–65·9%(–34·7to–97·1)–64·7% (–46·3 to–83·1)–29·2% (–12·8 to–45·5)Relative change inAcute Physiology and Chronic Health EvaluationIIscorefrombaselinetoday8–59·9% (–34·0 to–85·8)–60·4% (–45·3 to–75·5)–22·1% (–15·5 to–28·7)Relative change in PaO2/FiO2 from baseline to day8153·1 %(116·2 to189·9)78·4%(7·4to149·3)58·5%(–27·5to137·9)Mediandurationofinvasivemechanicalventilation(days)†12·0(5to19)†4·5(4to14)12·0(11to56)28-day ventilation-free days(days)16·5(1·8to31·2)†25·1 (22·0 to28·2)†17·8 (7·7 to27·9)Mediandurationofintensivecareunitstay(days)15·0(9to21)†5·0(2to15)12·0(6to56)Mediandurationofstayinhospital(days)33·0(12to54)†13·0(4to28)†21·0(6to56)Dataaren(%),median(range),ormean(95%CI).PaO2/FiO2=partialpressureofoxygenintheblood/fractionofinspiredoxygen.*Onepatientwasmissingfortheassessment(because of death). †One patient censored because ofdeath.OverviewofprimaryandsecondaryefficacyendpointsinCAL02andplacebotreatmentgroups(as-treatedpopulation)
88© 2022 Eagle Pharmaceuticals, Inc. All rights reserved. CAL02 Phase 2 Study Design DesignAn adaptive, randomized, multicenter, double-blind, placebo-controlled study to assess the efficacy and safety of CAL02 administered intravenously in addition to standard of care in subjects with severe community acquired bacterial pneumonia (SCABP)Study populationPatients hospitalized with SCABP, with protocol-defined severity criteriaPrimary objective(s)Time to clinical recoverySafety and tolerabilitySecondary objectivesLength of ICU and hospital stay; Evolution of SOFA score; All-cause mortality; Need for ventilation/oxygen therapy/vasopressorsExploratory objectivesEvolution of inflammatory biomarkersTreatment administrationIV infusion, two administrations 24 hours apartTreatment regimensCAL02PlaceboSample sizeApproximately 276 subjectsStudy sitesApproximately 120 centers across 22 countriesInterim analysesAt 33% of subjects completed and at 50% of subjects completed approximately 1 year after 1stpatient in
89© 2022 Eagle Pharmaceuticals, Inc. All rights reserved. CAL02 Potential CompetitiveAdvantagesLimited useRestrictions imposed by stewardship measures and purchasers, as antibiotics are inevitably linked to the emergence of new resistancesSlow and laborious market penetrationBased on non-inferiority resultsLast-resort treatmentsIncreasingly competitive spaceLimited scope of applicationAction dedicated against resistant mechanismNew mechanisms ultimately facing resistance issuesMonoclonal antibodies targeting a single toxinAgents targeting a downstream specific pathway or cytokine dedicated to target patients already in shock Limitations of current approaches(approved / in development) CAL02Potentially will not drive resistance; would fill a significant medical gapIf approved, may offer physicians a new treatment; potential to dramatically improve outcomesPotentially combines with any treatment (antibacterial agnostic)May lead to a tremendous economy on cost of care; broad-spectrum (used irrespective of pathogen identification or hemoculture or resistance to antibacterials)Potential for expedited regulatory pathway to approval
90 90 CAL02: Potential Unique Therapeutic BenefitAndre Kalil, MD, MPHProfessor of MedicineUniversity of Nebraska Medical Center
91© 2022 Eagle Pharmaceuticals, Inc. All rights reserved. CAL02: Potential Unique Therapeutic BenefitPositive trends over placebo in efficacyparameters*+▪Reduction of mortality risk+▪Potentially faster and complete recovery of organ function+▪Shorter duration of mechanicalventilation▪Immediate decrease in inflammatory biomarkers (e.g.IL-6)▪Shorter ICU length of stay++statisticallysignificant▪Compellingsafetyprofile▪Didnot prompt any newresistance▪Unique broad-spectrumactivity▪No impact onflora▪Non-immunogenic▪Biologicallyneutral May offer a unique therapeutic benefit to critically ill patients Potential to become first line empirical therapy*, if approved Potential to address a significant unmet medical need A straightforward and innovative approach A potentially unique therapeutic benefit to critically ill patients *Laterre et al. Lancet Infect Dis 2019 19(6):629-630
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 92 92 Barhemsysand Byfavo
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 93 Hospital Environmental Trends Bolster the Value Proposition of Eagles Acute Care Portfolio Rising costs of supplies, wages, and operationsNegative reimbursement trendsContinued staffing shortages Shifting of surgical and procedural volume to outpatient sites of careFocus on cost containmentIncrease focus on quality, safety, and efficiencySafety and efficacy of both Barhemsys and Byfavo provide new options, contributing to the focus on quality and safetyBoth Barhemsys and Byfavo can help improve patient throughput, potentially contributing to the efficiency of the health systems Profiles of Barhemsys & Byfavo enable them to be a part of the solution Hospitals taking initiatives to address environmental trends Profitability within hospitals continues to be a significant challenge https://www.aha.org/costsofcaring , https://www.aha.org/fact-sheets/2022-09-13-fact-sheet-advocacy-priorities-fall-2022
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 94 BarhemsysCompelling Clinical and Commercial Proposition O Post Operative Nausea and Vomiting (PONV) is associated with increased length of Post Anesthesia Care Unit (PACU) stay and greater resource utilization PONV contributes to patient dissatisfactionBreakthrough PONV is not being addressed promptly and aggressively Is non-sedating a common complaint of standard antiemetic agentsOpportunity to reduce PACU and overall hospital staysPotential to offer significant economic savings to hospital vs. current standard of care Throughput and health economic benefits Only FDA-approvedproduct for PONV rescue2 Significant unmet need1 First and only FDA-approved antiemetic for rescue treatment of PONV despite prophylaxis3Excellent safety profile demonstrated in clinical studiesAlso demonstrated to be effective for prevention1. Fourth Consensus Guidelines for the Management of Postoperative Nausea and Vomiting; 2 FDA labels for other recommended treatments do not include treatment after failed prophylaxis. Treatment agents recommended by Society for Ambulatory Anesthesiology Consensus Guidelines (2014). Habib et al (2019): no agent has previously been shown in a prospective trial to be more effective than a placebo for treating PONV for patients who have failed prophylaxis. 3 FDA labels for other recommended treatments do not include treatment after failed prophylaxis.
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 95 ByfavoCompelling Clinical and Commercial Proposition O No new approved drugs in the sedation space for over 20+ yearsCustomers seeking fast and predictable effect with rapid recovery for quick dischargeShort recovery time enabling efficiency and enhanced patient throughputBenzodiazepine intentionally designed for rapid onset and rapid offset, in dosages independent of patient weight, to offer clinicians a predicable level of sedation and procedural efficiency for procedures lasting 30 minutes or less maximizing patient comfort and satisfaction Strong value proposition Broad label with health economic benefits Clear unmet need Indicated for procedural sedation in adults in procedures lasting 30 minutes or lessSubstantial clinical data package shows compelling efficacy and safety in colonoscopies and bronchoscopies, including least fit patientsCommercial use across broad range of procedure and patient types *Important Safety Information (ISI) can be found at: https://bynder.acaciapharma.com/m/403e8c343b2922de/original/Byfavo-PI.pdf
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 96 96 Barhemsys:Management of Postoperative Nausea and Vomiting
97 Management of PostoperativeNausea and Vomiting.The Role of Amisupride.T.J. Gan, M.D., M.B.A., F.R.C.A., M.H.S.Division Head of Anesthesiology, Critical Care and Pain Medicine, The University of Texas MD Anderson Cancer Center Founding President, American Society for Enhanced Recovery (ASER) aserhq.org | enhancedrecovery.org President, Perioperative Quality Initiative (POQI) poqi.org 97
98 PONV Is Common and Complex A common complication of surgery and anesthesia Despite prophylaxis, 30% of patients still experience PONV in the PACUUnpleasant and associated with patient discomfort and dissatisfaction with perioperative careA greater concern for patients than avoiding postoperative painAssociated with delayed discharge from the recovery room andunanticipatedor extended inpatient hospital stay ($2,607/day); therefore, a cause of potentially avoidable healthcare costs1. Pierre S, et al. BJA Education. 2013;13(1):28-32. 2. Rahman MH, et al. Pharm J. 2004;273:786-793. 3. White PF, et al. Anesth Analg. 2008;107:452-458. 4. Habib AS, et al. Anesthesiology. 2019;130(2):203-212. 5.Eberhart LH, et al. Anesthesiology. 2002;89(5):760-761. 6. Kaiser Family Foundation.http://kff.org/other/state-indicator/expenses-per-inpatient-day. AccessedSeptember 22, 2021. 7.Gan TJ, et al. Anesth Analg. 2020;131(2):411-448
99 Patients Perceive PONV to Be Worse than Pain1. Eberhart LH, et al. Anesthesiology. 2002;89(5):760-761. 2. Hill RP, et al. Anesthesiology. 2000;92:958-967. 3. Gan TJ, et al. Br J Anaesth.2004;92(5):681-688. 11%13%27%49%Relative Importance of Patient Postoperative Recovery Concerns (%) (N=220)1PONVPainAlertnessAdditional cost PONVThe most common reason for poor patient satisfaction during the perioperative period2A greater concern for some patients than pain, alertness, or additional cost1,3 99
100 Shifting Towards Patient-Centered Care1Provider Satisfaction Volume-Based CareValue-Based Care1Triple Aim of CarePatient ExperienceOAS CAHPS2Fourth AimHealthcare EfficiencyHealthcare QualityMIPS Measure 4303Provider SatisfactionQuality of PONV Management Is Measured by National Performance MetricsOAS CAHPS=Outpatient and Ambulatory Surgery Consumer Assessment of Healthcare Providers and Systems. MIPS=Merit-based Incentive Payment System. 1. Bodenheimer T, Sinsky C. Ann Fam Med. 2014;12(6):573-576. 2. Outpatient and ambulatory surgery CAHPS (OAS CAHPS). https://www.cms.gov/Research-Statistics-Data-and-Systems/Research/CAHPS/OAS-CAHPS.html. Accessed September 22, 2021.3. Merit-Based Incentive System Overview. https://qpp.cms.gov/mips/overview. Accessed September 22, 2021.
101 Number of Publications on PONV 0200040006000800010000120001st (2003)2nd (2007)3rd (2014)4th (2020)PONV Consensus Guidelines PubMed Search: Postoperative Nausea, Vomiting
102 PONV Risk Factors -Adults Risk FactorsPointsFemale Gender1Non-Smoker1History of PONV1Postoperative Opioids1Sum of points1-4 123450%20%40%60%80%100%Number of Risk FactorsGan TJ et al. Anesth Analg 2020;131:41148Apfel C, et al. Acta Anaesthesiol Scand 1998;42:495-501
103 Etiology and Pathophysiology of Nausea and Vomiting Are Complex Peripheral MechanismsCentral Mechanisms Peripheral1 Vomiting center Vomiting reflex In GI tract2: 5-HT3 receptorsMechanoreceptors Chemoreceptors Higher cortical centers1,2 Vestibular system1,2 CTZ1 5-HT3=5-hydroxytrytamine type 3. CTZ=chemoreceptor trigger zone. GI=gastrointestinal. 1. Rahman MH, et al. Pharm J. 2004;273:786-793. 2. Singh P, et al. Therap Adv Gastroenterol. 2016;9(1):98-112.
104 ReceptorAntagonistNeurotransmitterCholinergic muscarinicM3/M5receptorD2/D3receptorH1receptor5-HT3receptorNK-1 receptor AcetylcholineDopamine Histamine Substance P/NK-1 Serotonin CTZNausea and Vomiting Are Mediated by Multiple Neurotransmitters and Their Receptors1-4D=dopamine. H=histamine. M=muscarinic. NK=neurokinin. 1. Watcha MF, et al. Anesthesiology. 1992;77(1):162-184. 2. Shaikh SI, et al. Anesth Essays Res. 2016;10(3):388-396. 3. Kovac AL. In: Gan TJ, Habib A. eds. Postoperative Nausea and Vomiting: A Practical Guide. Cambridge, UK: Cambridge University Press; 2016:13-22. 4. Darmani NA, et al. J Neural Transm. 1999;106:1045-1061.
105 Anticholinergics(transdermal scopolamine) Antihistamines(dimenhydrinate, promethazine) Dopamine antagonists(droperidol, haloperidol) 5-HT3antagonists(ondansetron, granisetron, palonosetron) NK-1 antagonists(aprepitant, rolapitant) Corticosteroids(dexamethasone, methylprednisolone)They are classified on the basis of their action over various receptors1-3Main Drug Classes Manage PONV1. Whelan R, Apfel CC. Pharmacology and Physiology for Anesthesia. 2013;503-522. 2. Shaikh SI, et al. Anesth Essays Res. 2016;10(3):388-396.3. Gan TJ, et al. Anesth Analg. 2020;131(2):411-448.
106 Monotherapy Combination therapy with 3 antiemetics PONV Incidence 52 Combination therapy with 2 antiemetics No antiemetic0123Number of AntiemeticsPONV Incidence (%) 372822Combination Therapy in Patients at Moderate or High Risk May Reduce Incidence of PONV Therapy TypeApfel CC. N Engl J Med. 2004;350(24):2441-2451.
107 can experiencePONV despite prophylaxis3,4can experiencePONV1,2 can experiencevomiting4can experiencenausea4,5 In high-risk patients In patients who failed prophylaxis NEARLY80%MORE THAN30%MORE THAN95%MORE THAN20%Breakthrough PONV Occurs Despite Prophylaxis1. Gan TJ, et al. Anesth Analg. 2014;118(1):85-113. 2. Apfel CC, et al. Anesthesiology. 1999;91(3):693-700. 3. White PF, et al. Anesth Analg. 2008;107:452-458. 4. Habib AS, et al. Anesthesiology. 2019;130(2):203-212. 5. Habib AS, et al. Curr Med Res Opin. 2006;22(6):1039-1099.
108 For patients failing typical pre-or perioperative prophylaxis with 5-HT3 antagonist, rescue treatment choices are limited.1Limited Treatment Options Exist for Patients Failing Prophylaxis Rescue Treatment ChoiceChallenges5-HT3 antagonistsNo benefits if reused within 6 hours2MetoclopramideInadequate efficacy2, Boxed Warning3Dexamethasone Slow to act2Promethazine Received Boxed Warning for tissue necrosis concerns4Droperidol Received Boxed Warning for QTc interval prolongation concerns5DimenhydrinateLimited evidence available for use2AprepitantIndicated for prophylaxis only6 Current guidelines recommend use of an antiemetic from a different class than that used for prophylaxis11. Habib, et al. Anesthesiology. 2019 Feb;130(2):203-212 2. Gan TJ, et al. Anesth Analg. 2014;118(1):85-113. 3. Reglan (metoclopramide injection) [Package Information]. Deerfield, IL. Baxter Healthcare Corporation; 2010. 4. Phenergan (promethazine HCL). [Package Information]. Eatontown, NJ. West-Ward Pharmaceuticals; 2012. 5. Inapsine (droperidol injection). [Package Information]. Decatur, IL. Taylor Pharmaceuticals; 2006. 6. EMEND (aprepitant) [Package Information]. Whitehouse Station, NJ.Merck & Co., Inc; 2017.
109 Barhemsys CharacteristicsAmisulpride (active ingredient of Barhemsys)1 Substituted benzamide (C17H27N3O4S)1,2Dopamine antagonist with high affinity for D2/D3receptors1,2 ‒Regional preference for D2and D3receptors in limbic, but not striatal structures2-4‒No appreciable affinity for any other receptors1,2Low blood-brain barrier (BBB) penetration at low doses used for PONV3Elimination half-life is 4-5 hours1Not metabolized by major CYP450 enzymes1Plasma protein binding is 25-30%1CYP450=cytochrome P450. 1. Barhemsys [Prescribing Information], Indianapolis, IN. Acacia Pharma; 2021. 2. Schoemaker H, et al. J Pharmacol Exp Ther. 1997;280(1):83-97. 3. Mller H-J. Prog in Neuro-Psychopharmacology & Biol Psych. 2003;27:1101-1111. 4. Xiberas X, et al. J Clinical Psychopharmacology. 2001;21(2):207-214.
110 Barhemsys: Evaluated in ~2000 Patients Over 4 Pivotal Clinical Trials11. Barhemsys [Prescribing Information], Indianapolis, IN. Acacia Pharma; 2021.2. Candiotti KA, et al. AnesthAnalg. 2018. 3. Habib AS, et al. Anesthesiology. 2019;130(2):203-212. 4. Gan TJ, et al. Anesthesiology. 2017;126(2):268-275. 5. Kranke P, et al. Anesthesiology. 2018;128(6)1099-1106
111 Barhemsys for Rescue TreatmentThe First and Only Antiemetic Indicatedto Treat PONV After FailedProphylaxis
112 PONV prophylaxis (N=2285)* SurgeryElective ambulatory or in-patient surgery under general anesthesia PONV in 0-24 hours? Qualifying Event Nausea ~98% Emesis ~20%YesNo Barhemsys 5 mg(n=237) Placebo(n=235) Barhemsys 10 mg(n=230)RANDOMIZED (N=702) Exit trial Assessment period for 24 hours postdosingPrimary EndpointComplete response Defined as no emesis (retching or vomiting) 30 minutes to 24 hours after dosing or use of rescue medication in 24 hours after dosingRescue Treatment Clinical Trial DesignBarhemsys 5 mg is not approved for the treatment or rescue treatment of PONV. *Total IV anesthesia with propofol was not permitted, though a single dose at induction was allowed. One or more nondopamine antagonist antiemetics were allowed as prophylaxis. Patients were excluded if they had received a D2antagonist antiemetic. As judged by investigator. Habib AS, et al. Anesthesiology. 2019;130(2):203-212. 112
113 Barhemsys 10 mg (n=230)Placebo (n=235)Age, median (range)47 (18-85)45 (18-81)Sex, female90.4%90.2%5-HT3antagonist76.5%77.4%Dexamethasone67.8%61.7%Other12.2%8.9%1 antiemetic52.6%51.1%≥2 antiemetics47.4%46.0%Patients with emesis17.4%24.3%Patients with nausea99.1%97.0%PONV in PACU 73.5%73.2%PONV 0-2 hours after surgery67.8%71.9%Patient Baseline Characteristics>90% of patients had 3-4 risk factorsMost were female, with a median age >45 Barhemsys 10 mg (n=230) Placebo (n=235)Rescue Treatment Trial:Patient Baseline Characteristics at RandomizationPONV Prophylactic TreatmentMajority of patients received a 5-HT3antagonist or dexamethasone~50% received ≥2 antiemetics Qualifying PONV EventMajority of patients experienced nausea in the PACU or within 2 hours of surgery PACU = Post Anesthesia Care UnitHabib AS, et al. Anesthesiology. 2019;130(2):203-212. 113
114 Patients with Complete Response at 24 Hours*Defined as: No Emesis or Use of Rescue Medication 42% of patients who received Barhemsys 10 mg after failing prophylaxis had complete response at 24 hours 13%(5%, 22%)Difference (95% CI) Barhemsys 10 mg(n=230)42%P=0.003Placebo(n=235)29% Barhemsys Was More Effective than Placebo at Treating PONV in Patients Who Failed ProphylaxisBarhemsys 5 mg is not approved for the treatment or rescue treatment of PONV. *The primary efficacy analysis was a comparison of the proportion of complete response between Barhemsys 10 mg and placebo inthe modified ITT population. Pearsons chi-squared test with a 1-sided 2.5% significance threshold was used to assess the difference between treatment groups. The modified ITT population was composed of randomized patients who received study medication.CI=confidence interval. ITT=intention-to-treat.Habib AS, et al. Anesthesiology. 2019;130(2):203-212. 114
115 The secondary endpoints listed were prespecified. These endpoints were not adequately powered, nor error controlled, and observed treatment differences cannot be regarded as statistically significant.Kaplan-Meier Curves of Complete Response Over Time* 01.0 0.8 0.6 0.4 0.2 0 24 14 15 16 17 18 19 20 21 22 23 3 4 5 6 7 8 9 10 11 12 13 1 2 Probability of Patient Continuing to Meet Criteria for Complete Response Time After Study Drug Administration (Hours)*HR (95% CI): 0.63 (0.50, 0.80); P<0.001Barhemsys 10 mg (n=230)Placebo(n=235) Patients with complete response at 24 hoursP=0.003 29%42% Patients with complete response at 2 hours 70% 49%Barhemsys Was More Effective than Placebo atTreating PONV in Patients Who Failed Prophylaxis (cont.)HR=hazard ratio. CI=confidence interval.Habib AS, et al. Anesthesiology. 2019;130(2):203-212. 115
116 050100150200250PACU length of stay, minutes 176(218) 141(174) Barhemsys 10 mg-treated patients had35 minutes shorter mean PACU length of stay than placebo-treated patientsMinutes (SD) 404550556065Hospital length of stay, hours 56(73) 50(80) Hours (SD)Barhemsys 10mg (n=230) Placebo(n=235) Secondary Endpoints: PACU and Hospital Length of StaySD=standard deviation.Habib AS, et al. Anesthesiology. 2019;130(2):203-212. The secondary endpoints listed were prespecified. These endpoints were not adequately powered, nor error controlled, and observed treatment differences cannot be regarded as statistically significant.Barhemsys 10 mg-treated patients had 6 hours shorter mean hospital length of stay than placebo-treated patients 116
117© 2022 Eagle Pharmaceuticals, Inc. All rights reserved. Patients characteristicsTreatment Success (N=82)Treatment Failure(N=30)p-valueAge years, mean (SD)A48.7 (18.0)47.4 (16.2)0.73BMI-Kg/m2, median (IQR)B28.6(24.4,35.5)34.1(29.9,41.00.003RaceCCaucasianBlackAsianOther/Not Reported62(75.6%)5(6.1%)1(1.2%)14(17.1%) 23(76.7%)3(10%)1(3.3%)3(10%)0.49Number of PONV risk factorsC12≥33(3.7%)23(28.1%)56(68.3%)1(3.3%)4(13.3%)25(83.3%)0.20PONV risksFemale sexDHistory of PONVDHistory of motion sicknessDNon-smokerc57(69.5%)20(26%)24(30.8%)72(90%)25(83.3%)6(23.1%)9(30%)27(90%)0.140.520.941.0Number of PONV ProphylaxisC012≥31(1.2%)17(20.7%)48(58.5%)16(19.5%)1(3.3%)3(10%)20(66.7%)6(20%)0.45Anethetic AgentsInhalation agentsCPropofol ( total intravenous anesthesia) D64(78.1%)17(20.7%)27(90%)3(10%)0.180.27Surgical Procedure (minutes)Surgery duration, median(IQR)BPACU duration, median(IQR)B94(64,143)120(90,145)108(73,131)120(104,145)0.910.25Opioid administration (IV morphine eq)Intraoperative opioids, median (IQR)BPACU opioids, median (IQR)B50(40,70)15(0.45)50(49.5,60)15(0.40)0.480.96AStudents T-Test; BWilcoxon Rank Sun; CFishers Exact Test; DChi-Square Efficacy of Amisulpride for Treatment of Postoperative Nausea and Vomiting in Post Anesthesia Care UnitAna Mavarez-Martinez, MD1, Kerri Stafford, B2, Jason Rosenfield 3, Jamie Romeiser, PhD1, Sergio D, Bergese, MD1, and Tong J. Gan, MD11Stony Brook University Hospital, Department of Anesthesiology. Stony Brook, NY. 2NYIT College of Osteopathic Medicine. Old Westbury, NY. 3University of Michigan. Ann Arbor, MI INTRODUCTIONWe assessed the efficacy of amisulpride when Used for rescue treatment of PONV in the Postanesthesia care unit (PACU)This review was approved by the Stony Brook University QA/QI committee.Data was retrospectively collected from Consecutive patients who:1.Underwent elective surgery at Stony Brook University Hospital from October 2020 to April 20212.Had a PONV episode, and requested for an antiemetic during the PACU stay.3.Received Amisulpride as the first antiemetic For PONV rescue treatment.We collected the following variables: Demographic, PONV risk factors, prophylactic PONV medications, intraoperative anesthetics, Surgical characteristics, and opioid administration (in total IV morphine equivalents).Postoperative nausea and vomiting (PONV) is a common complication following surgery, adversely affecting up to 80% of high-risk patients. Patients-specific risk factors for PONV include female sex, nonsmoking status, previous history of PONV or motion sickness, and use of opioids postoperatively.Amisulpride is a new selective dopamine-2 (D2) and dopamine-3 (D3) receptor antagonist recently approved by the Food and Drug Administration (FDA) for the prevention and treatment of PONV OBJECTIVE METHODS RESULTSOut of 112 patients who received Amisulpride for PONV rescue, 82 (73.2%) had a successful response (defined as no need for additional antiemetic Medication) and 30 (26.8%) failed treatment. Patients failing treatment required an additional antiemetic 50.3 (SD 63.9) minutes after Amisulpride dose.Age and race were similar between success and failure groups. BMI was significantly higher in the failure group (p=0.003)The number of PONV risk factors were numerically higher in the failure group (83.3% with ≥3 risk Factors) compared to the success group (68.3% with ≥3 risk factors); but differences did not reachSignificance (p= 0.20). This may be mostly attributable to the numerical differences in female sex between the failure group and success group (83.3% vs 68.3%)Proportion given inhaled agents was numerically higher in the failure group, but differences did not reach significance (90% vs. 78.1%, p=0.18) CONCLUSIONAmisulpride is associated with a 75% success rate when used as first line rescue therapy in the PACU.Failure from PONV prophylaxis is common despite risk-adjusted multimodal antiemetic therapy.
118© 2022 Eagle Pharmaceuticals, Inc. All rights reserved. Patients characteristicsTreatment Success (N=82)Treatment Failure(N=30)p-valueAge years, mean (SD)A48.7 (18.0)47.4 (16.2)0.73BMI-Kg/m2, median (IQR)B28.6(24.4,35.5)34.1(29.9,41.00.003RaceCCaucasianBlackAsianOther/Not Reported62(75.6%)5(6.1%)1(1.2%)14(17.1%) 23(76.7%)3(10%)1(3.3%)3(10%)0.49Number of PONV risk factorsC12≥33(3.7%)23(28.1%)56(68.3%)1(3.3%)4(13.3%)25(83.3%)0.20PONV risksFemale sexDHistory of PONVDHistory of motion sicknessDNon-smokerc57(69.5%)20(26%)24(30.8%)72(90%)25(83.3%)6(23.1%)9(30%)27(90%)0.140.520.941.0Number of PONV ProphylaxisC012≥31(1.2%)17(20.7%)48(58.5%)16(19.5%)1(3.3%)3(10%)20(66.7%)6(20%)0.45Anethetic AgentsInhalation agentsCPropofol ( total intravenous anesthesia) D64(78.1%)17(20.7%)27(90%)3(10%)0.180.27Surgical Procedure (minutes)Surgery duration, median(IQR)BPACU duration, median(IQR)B94(64,143)120(90,145)108(73,131)120(104,145)0.910.25Opioid administration (IV morphine eq)Intraoperative opioids, median (IQR)BPACU opioids, median (IQR)B50(40,70)15(0.45)50(49.5,60)15(0.40)0.480.96AStudents T-Test; BWilcoxon Rank Sun; CFishers Exact Test; DChi-Square Efficacy of Amisulpride for Treatment of Postoperative Nausea and Vomiting in Post Anesthesia Care UnitAna Mavarez-Martinez, MD1, Kerri Stafford, B2, Jason Rosenfield 3, Jamie Romeiser, PhD1, Sergio D, Bergese, MD1, and Tong J. Gan, MD11Stony Brook University Hospital, Department of Anesthesiology. Stony Brook, NY. 2NYIT College of Osteopathic Medicine. Old Westbury, NY. 3University of Michigan. Ann Arbor, MI INTRODUCTIONWe assessed the efficacy of amisulpride when Used for rescue treatment of PONV in the Postanesthesia care unit (PACU)This review was approved by the Stony Brook University QA/QI committee.Data was retrospectively collected from Consecutive patients who:1.Underwent elective surgery at Stony Brook University Hospital from October 2020 to April 20212.Had a PONV episode, and requested for an antiemetic during the PACU stay.3.Received Amisulpride as the first antiemetic For PONV rescue treatment.We collected the following variables: Demographic, PONV risk factors, prophylactic PONV medications, intraoperative anesthetics, Surgical characteristics, and opioid administration (in total IV morphine equivalents).Postoperative nausea and vomiting (PONV) is a common complication following surgery, adversely affecting up to 80% of high-risk patients. Patients-specific risk factors for PONV include female sex, nonsmoking status, previous history of PONV or motion sickness, and use of opioids postoperatively.Amisulpride is a new selective dopamine-2 (D2) and dopamine-3 (D3) receptor antagonist recently approved by the Food and Drug Administration (FDA) for the prevention and treatment of PONV OBJECTIVE METHODS RESULTSOut of 112 patients who received Amisulpride for PONV rescue, 82 (73.2%) had a successful response (defined as no need for additional antiemetic Medication) and 30 (26.8%) failed treatment. Patients failing treatment required an additional antiemetic 50.3 (SD 63.9) minutes after Amisulpride dose.Age and race were similar between success and failure groups. BMI was significantly higher in the failure group (p=0.003)The number of PONV risk factors were numerically higher in the failure group (83.3% with ≥3 risk Factors) compared to the success group (68.3% with ≥3 risk factors); but differences did not reachSignificance (p= 0.20). This may be mostly attributable to the numerical differences in female sex between the failure group and success group (83.3% vs 68.3%)Proportion given inhaled agents was numerically higher in the failure group, but differences did not reach significance (90% vs. 78.1%, p=0.18) CONCLUSIONAmisulpride is associated with a 75% success rate when used as first line rescue therapy in the PACU.Failure from PONV prophylaxis is common despite risk-adjusted multimodal antiemetic therapy.
119 Summary*PONV is common and causes patient distress and significant patient dissatisfactionPONV is multifactorial and mediated by multiple receptor systemsThe risks of PONV are predictableMultimodal prevention strategy is considered the standard of careAmisulpride is a new dopamine antagonistAlmisulpride has demonstrated efficacy in prevention and treatment of PONVAmisulpride is the only antiemetic proven safe and effective at the indicated dose for Rescue Treatment *Important Safety Information (ISI) can be found at: https://bynder.acaciapharma.com/m/5d7c2cd0d58865f7/original/Barhemsys-Prescribing-Information.pdf
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 120 120 Byfavo: Clinical PerspectiveRichard P. Dutton, MD MBA
CONFIDENTIAL AND INTERNAL 2022 Eagle Pharmaceuticals, Inc. All rights reserved. 121 My Credentials Adjunct Professor, Texas A&MAnesthesiologist, Baylor University Medical CenterChief Quality Officer, US Anesthesia Partners2009-2015: Executive Director, ASA Anesthesia Quality Institute 1994-2011: Professor, Chief of Trauma Anesthesia, Chief of Clinical Operations, R Adams Cowley Shock Trauma Center, University of Maryland
CONFIDENTIAL AND INTERNAL 2022 Eagle Pharmaceuticals, Inc. All rights reserved. 122 USAP in 2022 13 states, 16 platforms (cities), 60+ practices5,000 clinicians:–1,600 physician partners majority owners of the practice–800 employed physicians–2,600 CRNAs and AAs700 facilities served:–200 hospitals–250 ASCs25 healthcare systems2,500,000 cases3 equity investors: WCAS, Berkshire, GIC
CONFIDENTIAL AND INTERNAL 2022 Eagle Pharmaceuticals, Inc. All rights reserved. 123 Major Issues Confronting Anesthesiology Workforce: Too much demand, not enough supplyDriven by Non-Operating Room Anesthesia casesExacerbated by fragmentation, retirement, burnoutHospitals generally want more anesthesia coveragePayment: Increasing downward pressure from payers, including CMSStipends needed to fill gap between cost and revenueUniversal at hospitals, increasingly at ASCsIncreasing focus on anesthesia costsScope of practice: Interface with CRNAs and other medical specialties
CONFIDENTIAL AND INTERNAL 2022 Eagle Pharmaceuticals, Inc. All rights reserved. 124 Value Proposition: Hospitals Increased access OR timeCoverage for NORAIncreased efficiencyDecreased cancellationsReduced adverse eventsReduced transfusionsIncreased patient satisfactionReduced use of expensive medsDecreased length of stay
CONFIDENTIAL AND INTERNAL 2022 Eagle Pharmaceuticals, Inc. All rights reserved. 125 Value Proposition: Payers Increased outpatient surgeryDecreased:margin:10pt 0pt 10pt 0ptLength of staymargin:10pt 0pt 10pt 0ptCost of post-acute caremargin:10pt 0pt 10pt 0ptPreoperative testingmargin:10pt 0pt 10pt 0ptOpioid consumptionmargin:10pt 0pt 10pt 0ptReadmissionsmargin:10pt 0pt 10pt 0ptAdministrative burden
CONFIDENTIAL AND INTERNAL 2022 Eagle Pharmaceuticals, Inc. All rights reserved. 126 Workforce Solutions: New Models of Care Extended care team coverage ratiosAutonomous CRNA practiceNon-anesthesia physician coverageFire and forget regional anesthesia blocksExpansion of non-anesthesia nursing sedation services
CONFIDENTIAL AND INTERNAL 2022 Eagle Pharmaceuticals, Inc. All rights reserved. 127 Unmet Need in Procedural Sedation: An Ideal Sedative Characteristics1-5Pharmacokinetics1-5Pharmacodynamics1-3,6Short time to onsetLinear kineticsA predictable dose-response relationAbility to titrate to the desired range of sedationNo accumulationA balanced safety/risk profileRapid and consistent recovery leading to a quick dischargeRapid clearance through CYP450-independent metabolism Non-weightbased dosingPredictable amnestic effectContext insensitive half-time (half-time is independent of infusion duration)7,8High efficacy rate1.Practice Guidelines for Moderate Procedural Sedation and Analgesia 2018: A Report by the American Society of Anesthesiologists Task Force on Moderate Procedural Sedation and Analgesia, the American Association of Oral and Maxillofacial Surgeons, American College of Radiology, American Dental Association, AmericanSociety of Dentist Anesthesiologists, and Society of Interventional Radiology. Anesthesiology. 2018;128:437-479.2.Sheta SA. Procedural sedation analgesia. Saudi J Anaesth. 2010;4(1):11-16.3.Colao J, Rodriguez-Correa D. Rapidly metabolized anesthetics: novel alternative agents for procedural sedation. J Anesth Clin Res. 2016;7(11):1-6.4.Pambianco D, Cash B. New horizons for sedation: the ultrashort acting benzodiazepine remimazolam. Tech Gastrointest Endosc. 2016;18:22-28.5.Barends CRM, Absalom AR, Struys MMRF. Drug selection for ambulatory procedural sedation. Curr Opin Anaesthesiol. 2018;31(6):673-678.6.Cohen LB, Delegge MH, Aisenberg J, et al. AGA institute review of endoscopic sedation. Gastroenterology. 2007;133:675-701.7.Egan TD. Is anesthesiology going soft?: Trends in fragile pharmacology. Anesthesiology. 2009;111:229-30.8.Gepts E. Pharmacokinetic concepts for TCI anaesthesia. Anaesthesia. 1998;53:4-12.127
CONFIDENTIAL AND INTERNAL 2022 Eagle Pharmaceuticals, Inc. All rights reserved. 128 Current Select Standards of Care Have Limitations Rapid onset and offset anesthetic with narrow therapeutic index1Dose-related cardiorespiratory depression, pain at injection site1Non-linear dosing effects due to individual variability4Needs continuous monitoring by anesthesiologist, no reversal agent2Lipid formulation susceptible to bacterial contamination4better safety profile but longer onset and recovery1,2fastacting but significantsafetyissues1,2Benzodiazepine sedative, reversible by flumazenil1Slower onset and offset2,3Metabolized by cytochrome system; individual variability affects sedation1Active metabolite can accumulate and cause prolonged sedation2Risk of respiratory depression1PropofolMidazolam 1 Colao J, et al. J Anesth Clin Res. 2016; 7:690. 2 Whizar-Lugo V, et al. J Anesth Crit Care. 2016; 4(6): 00166. 3 Rex DK et al. Gastrointest Endosc. 2018 Sep;88(3):427-437. 4 Prescribing label for Propofol. 5 Prescribing label for Byfavo.128
CONFIDENTIAL AND INTERNAL 2022 Eagle Pharmaceuticals, Inc. All rights reserved. 129 Soft, Ester-Based Drug Design Due to the addition of a carboxylic ester linkage, Byfavo is rapidly hydrolyzed by tissue esterases to an inactive metabolite, with no meaningful contribution by CYP450 enzymes.3,4 Midazolam undergoes CYP450 metabolism to active metabolites.21. Reves JG, et al. Anesthesiology. 1985;62:310-324. 2. Midazolam Injection [package insert]. Lake Forest, IL: Hospira; 2018. 3. Byfavo [package insert]. Indianapolis, IN: Acacia Pharma Inc. 4. Pambianco D, Cash B. Tech Gastrointest Endosc. 2016;18:22-28. CYP450 metabolism 1,2 3,4
CONFIDENTIAL AND INTERNAL 2022 Eagle Pharmaceuticals, Inc. All rights reserved. 130 ByfavoRapid Onset/Offset Benzodiazepine *A sedative effect was defined as a MOAA/S score of ≤4. At 1 and 1.5 minutes, 40% and 62% of patients had a MOAA/S score of ≤4, respectively.1. Byfavo [package insert]. Indianapolis, IN: Acacia Pharma Inc. 2. Acacia Pharma. Data on File.Distribution half-life: 0.5-2.0 minutes1Onset of sedative effects: 1.0-1.5 minutes2,*Median time to peak sedation: 3.0-3.5 minutes following initial 5 mg (2mL) bolus IV dose1Rapid OffsetMedian time to fully alert: 11.0-14.0 minutes1Terminal half-life: 37-53 minutes1Volume of distribution: 0.76-0.98 L/kg1Clearance: 54-75 L/hr1 Rapid Onset
CONFIDENTIAL AND INTERNAL 2022 Eagle Pharmaceuticals, Inc. All rights reserved. 131 Patients Rapidly Achieved an Adequate Level of Sedation for Procedure Start with a Quick Recovery Bronchoscopy, ASA I-III543210MOAA/S Score, Mean (95% CI)01020304050607080Minutes After Start of Study Medication (0=First Dose) Colonoscopy, ASA I-III543210MOAA/S Score, Mean (95% CI)01020304050607080Minutes After Start of Study Medication (0=First Dose) ByfavoPlacebo with midazolamrescueOpen-label midazolam ByfavoPlacebo with midazolamrescueOpen-label midazolam The target level of sedation (MOAA/S=2-4) was maintained for a median 96.7% of the total procedure time in the Byfavo arm.1The target level of sedation (MOAA/S=2-4) was maintained for a median 92.9% of the total procedure time in the Byfavo arm.11. Acacia Pharma. Data on File.
CONFIDENTIAL AND INTERNAL 2022 Eagle Pharmaceuticals, Inc. All rights reserved. 132 So What..Why Byfavo? –Predictable effect reducing hemodynamic compromise–Reliable safetySedation without post-procedure neurologic dysfunction in at-risk patients–Safely administered by non-anesthesia clinicians–Potential for improved throughput in procedural units
CONFIDENTIAL AND INTERNAL 2022 Eagle Pharmaceuticals, Inc. All rights reserved. 133 Byfavo Candidate Populations –Short CV procedures: cardioversion, TEE, pacemaker battery change, etc. in fragile patients–GI, Pulmonary, Radiology sedation in at-risk patients (older, frail)–Bedside sedation (ED, PACU, ICU) for short painful procedures: dressing changes, fracture reduction
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 134 134 Landiolol
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 135 135 Overviewof Landiolol: An Ultra-Short-Acting Intravenous β-adrenergic Blocker
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 136 Landiolol Overview: NDA Under Review by FDA Ultra-short acting cardioselective beta1-blockerRapid rate control Supraventricular tachycardiaVentricular rateSimple intravenous dosingMultiple use settingsCritical/Intensive CarePerioperativeEmergency DepartmentSafety and efficacy qualified by approved marketing authorizations in the EU and Japan* *FDA has not determined the safety or efficacy of landiolol and landiolol is not approved for use in the United States. The safety and efficacy of landiolol have been established in Japan and the European Union.
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 137 Proposed Indications of Use*Landiolol is an ultra-short-acting β1-antagonist with limited effect on blood pressure and inotropy1,2Proposed Indication3Short-term reduction of ventricular rate in patients with supraventricular tachycardia, including atrial fibrillation and atrial flutter*FDA has not determined the safety or efficacy of landiolol and landiolol is not approved for use in the United States. The safety and efficacy of landiolol have been established in Japan and the European Union.1. Shibata S, et al. J Pharmacol Sci. 2012;118(2):255-265. 2. Wada Y, et al. J Arrhythm. 2016;32(2):82-88. 3. Eagle Pharmaceuticals. Press Release, January 31, 2022. https://investor.eagleus.com/press-releases/news-details/2022/Eagle-Pharmaceuticals-on-Track-to-Support-Submission-of-New-Drug-Application-in-Second-Quarter-2022-for-Landiolol-a-Beta-1-Adrenergic-Blocker/default.aspx.
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 138 Landiolol Potentially Addresses an Important Unmet Clinical NeedDesigned for potential use in acute-care patients in whom it is necessary to safely and rapidly reduce heart rate with limited effect in blood pressure and inotropy (e.g. patients in sepsis, patients with heart failure)Current therapeutic options for these patients are limitedComorbidities are common in this population: HEARTFAILURERENALIMPAIRMENTHEPATICDYSFUNCTIONRESPIRATORYINSUFFICIENCYReference Borianni G., et al. European Heart Rhythm Association (EHRA) consensus document on management of arrhythmias and cardiac electronic devices in the critically ill and post-surgery patient, endorsed by Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), Cardiac Arrhythmia Society of Southern Africa (CASSA), and Latin American Heart Rhythm Society (LAHRS)
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 139 Landiolol Features Minimal negative inotropic action due to limited effect on the refractory period of the action potential in cardiomyocytes2 Limited effect on blood pressure due to pure S-enantiomer molecular structure2,3 Rapid onset of action (≤1 min) and short duration of action (10-15 min)1 1. Krumpl G, et al. Eur J Clin Pharmacol. 2017;73(4):417-428. 2. Shibata S, et al. J Pharmacol Sci. 2012;118(2):255-265. 3. McKee JS, et al. Anesthesiology. 2014;121(6):1184-1193.
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 140 Landiolol Features Compatible in patients with respiratory disease (eg, asthma, COPD) due to high cardioselectivity (β1/β2-selectivity = 255:1) among β1 blockers1,4 Low volume of distribution (0.3-0.4 L/kg) leading to less distribution to tissues and fewer possible toxicities1,2 COPD, chronic obstructive pulmonary disease. CYP450, cytochrome P450.1. Landiolol. Summary of Product Characteristics, current version. 2. Krumpl G, et al. J Cardiovasc Pharmacol. 2018;71(3):137-146. 3. Nasrollahi-Shirazi S, et al. J Pharmacol Exp Ther. 2016;359(1):73-81. 4. Balik M, et al. Eur Heart J Suppl. 2018;20(A):A10-A14. Metabolized in the plasma (CYP450 is not involved) and eliminated primarily in urine3,4No dose adjustment is necessary in renal impairment and careful dosing is recommended in patients with hepatic impairment due to limited data3,4
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 141 Comparison of Landiolol and Other Rate/Rhythm Control Agents MedicationOnset of ActionElimination Half-LifeDuration of Effectβ1:β2 RatioEffect on HR and BPBeta BlockersLandiolol1-31 min4 min15 min255HR ↓↓ BP →Esmolol1,4,52 min9 min10-20 min33HR ↓ BP ↓ Atenolol6,75 min6-7 hours12 hours4.7HR ↓ BP ↓ Metoprolol7-1020 min3-7 hours5-8 hours2.3HR ↓ BP ↓ Other Rate/Rhythm Control AgentsAmiodarone11,121-30 min9-36 days1-3 hours----Digoxin135-30 min1.5-2 days1-4 hours----Diltiazem143 min3.4 hours0.5-10 hours----BP, blood pressure; HR, heart rate.1. Krumpl G, et al. Eur J Clin Pharmacol. 2017;73(4):417-428. 2. Landiolol. Summary of Product Characteristics, current version. 3. Nagai R, et al. Circ J. 2013;77(4):908-916. 4. Esmolol [prescribing information]. Paramus, NJ: WG Critical Care, LLC; 2016. 5. Domanovits H, et al. Eur Heart J Suppl. 2018;20(A):A1-A3. 6. Rehman B, et al. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020. 7. Baker JG. Br J Pharmacol. 2005;144(3):317-322. 8. Metoprolol [prescribing information]. Lake Forest, IL: Hospira, Inc.; 2020. 9. Frishman WH, et al. Am J Ther. 2008;15(6):565-76. 10. Kelly D, et al. Intern Med J. 2015;45(9):934-938. 11. Latini R, et al. Clin Pharmacokinet. 1984;9(2):136-156. 12. Amiodarone [prescribing information]. Deerfield, IL: Baxter Healthcare Corporation; 2011. 13. Digoxin [prescribing information].Kirkland, Canada: Jubilant HollisterStier General Partnership; 2016. 14. Diltiazem [prescribing information]. Bedford, OH: Ben Venue Laboratories, Inc.; 2007. Landiolol has a rapid onset of action and short duration of action with limited effect on BP1-3
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 142 Landiolol Conclusions Landiolol is intended to be a differentiated, ultra-short acting cardio-selective beta blocker that results in rapid control of ventricular rate Landiolol potentially addresses important unmet clinical needs If approved, landiolol has the potential to provide clinicians with a unique therapeutic option
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 143 143 Question & Answer Panel
2022 Eagle Pharmaceuticals, Inc. All rights reserved. 144 144 144 2022 Eagle Pharmaceuticals, Inc. All rights reserved. Thank You!