Measuring Clinical and Virologic Outcomes in Different Age and Risk Groups

Prabha Viswanathan, MD Senior Medical Officer Division of Antiviral Products Center for Drug Evaluation and Research, FDA ESCMID eLibrary © by author Overview • Common respiratory viruses and factors impacting the illness they cause • Endpoints in clinical trials – general concepts • Clinical and virologic outcomes in clinical trials of respiratory antivirals • Case Examples in antiviral drug development – Influenza – RSV

ESCMID eLibrary 2 © by author Adenovirus (ADV) Coronavirus (CoV) Common Enterovirus (EV) Respiratory Human Metapneumovirus (hMPV) Viruses Influenza Parainfluenza (PIV) Respiratory Syncytial Virus (RSV) Rhinovirus (HRV)

ESCMID eLibrary 3 © by author Virus + Host Factors = Clinical Disease

ESCMID eLibrary 4 4 © by author Anatomy Environment

Health Status

Comorbidity Immune Function ESCMID eLibrary 5 5 © by author Impact of Host Factors

• The same virus causes a different clinical illness in various population subgroups • The virus causes a similar disease across groups, but host factors affect the severity of the clinical illness

ESCMID eLibrary 6 © by author Examples: Virus Causes Different Disease Manifestation

RSV Bronchiolitis URI LRTI

PIV Croup URI ESCMIDURI = Upper Respiratory Infection; LRTI = LowereLibrary Respiratory Tract Infection 7 © by author Example: Virus Causes Similar Disease

Influenza

Common signs and symptoms: fever, headache, myalgia, malaise, URI symptoms, cough Populations at risk for more severe disease – respiratory failure

ESCMID eLibrary 8 © by author Relevance to Clinical Trials • Understanding when diseases are similar and different is important when designing trials for new antivirals, particularly for endpoint selection

• Different endpoints may be needed for trials evaluating the same drug and same virus in different populations (e.g. RSV)

• Similar endpoints could be utilized for different drugs and viruses that cause similar clinical illness (e.g. many respiratory viruses cause clinically indistinguishable URI symptoms in healthy adults)

ESCMID eLibrary 9 © by author Purpose: to determine whether a drug provides clinical benefit to patients Clinical Trial - Clinical benefit: A positive, clinically meaningful effect on how an individual Endpoints: feels, functions, or survives Overview One of the most important aspects of drug development is how that benefit is measured

ESCMID eLibrary 10 © by author Measuring “feels, functions, or survives”

Clinical Outcome Assessments • Direct measures of clinical benefit (COAs)

Surrogates • Measures that predict how a patient feels, functions, or survives

*Biomarker: a physiologic, pathologic, or anatomic characteristic that is objectively measured and evaluated as an indicator of some normal or 11 ESCMIDabnormal biologic function, process or response to a therapeutic intervention eLibrary © by author Clinical Outcome vs Surrogate Clinical Outcomes (Examples) Surrogate Measures • Objective measures: • Laboratory studies, biomarkers, – Survival other measurements that predict – Changes in vital signs the direct clinical benefit – Disease exacerbation/progression • Examples: – Clinical event (e.g. hospitalization, – HIV: viral load used for HIV cardiovascular event) complications • Subjective measures: – Glaucoma: intraocular pressure – Symptom score (includes Patient used for loss of vision Reported Outcome [PRO], Observer Reported Outcome [ObsRO]*) – Diabetes Mellitus: blood glucose/ hemoglobin A1c used for – Quality of life metrics complications * http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071975.pdfESCMID eLibrary 12 © by author Endpoints for Trials of Respiratory Antivirals

• Clinical Outcomes should be used to support approval of novel antiviral drugs – Treatment trials: endpoint measures how well the drug improves signs and symptoms of respiratory viral illness – Prevention trials: endpoint measures how well the drug prevents/mitigates respiratory viral illness • Objective or subjective measures can be used, or a combination of both – When COA instruments are used (e.g. PROs), validation is needed to ensure they are well-defined, reliable, interpretable, and able to detect changes • Optimal endpoints are still being established for many respiratory viruses

ESCMID eLibrary 13 © by author Surrogate Endpoints: Virologic Measures • Clinical trials of direct acting antiviral drugs should assess the impact of the drug on the virus – However, changes in virologic measures alone are not sufficient to demonstrate clinical benefit

• Virologic endpoints provide valuable information to guide development – Trends in viral load from dose-ranging studies can be used to optimize the dose and duration studied in pivotal trials – Reduction in viral load can help establish proof of concept, particularly when a correlation can be shown between virologic and clinical outcomes

• No surrogate markers, including viral load, have been identified that consistently correlate with clinical benefit for respiratory viruses ESCMID eLibrary 14 © by author Endpoints that have supported Case marketing approval of antiviral Examples: products Influenza and RSV Trials that did not demonstrate clinical benefit

ESCMID eLibrary 15 © by author Examples of FDA Approved Respiratory Antiviral Drugs

Drug 1 Virus Indication Endpoint Benefit Oseltamivir Influenza Treatment of TTAS 2 Symptoms Zanamivir acute resolve ~ 1 day Peramivir uncomplicated sooner than Baloxavir Influenza control Palivizumab RSV Prevention of Hospitalization 45-55% severe RSV LRTI reduction in in high risk hospitalization infants compared to control 1 This table does not include all drugs approved for influenza and RSV 2 Time To Alleviation of Symptoms ESCMID eLibrary 16 © by author TTAS for Uncomplicated Influenza: Baloxavir • Uncomplicated Influenza: abrupt onset of constitutional and upper respiratory tract signs and symptoms (e.g., fever, chills, myalgia, headache, malaise, nonproductive cough, sore throat, and rhinitis)* • In the registrational clinical trials, eligible subjects had: – Axillary temperature of at least 38˚C – At least one moderate or severe respiratory symptom (cough, nasal congestion, or sore throat) – At least one moderate or severe systemic symptom (headache, feverishness or chills, muscle or joint pain, or fatigue) – Symptoms present for no more than 48 hours • TTAS defined as the time when all seven symptoms (cough, sore throat, nasal congestion, headache, feverishness, myalgia, and fatigue) had been assessed by the subject as none or mild for a duration of at least 21.5 hours

*Centers for Disease Control and Prevention: https://www.cdc.gov/flu/professionals/acip/clinical.htm ESCMID eLibrary 17 © by author Baloxavir vs Placebo: CAPSTONE-1

Time to Alleviation of Symptoms Change in Viral Titer

Median TTAS was 26.5 hours shorter in the baloxavir Asterisks indicate a p value of < 0.05 as compared to group (53.7 hours; 95% CI, 49.5 to 58.5) vs. placebo placebo group (80.2 Hours; 95% CI, 72.6 to 87.1) (p<0.001).

Source: Hayden FG, et al. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. N Engl J Med 2018; 379: 913- 923.ESCMID eLibrary 18 © by author Baloxavir vs Oseltamivir Time to Alleviation of Symptoms Change in Viral Titer

Asterisks indicate a p value of < 0.05 as compared to placebo

ESCMID eLibrary 19 © by author Severe Influenza – Going Beyond Acute Uncomplicated

Population • Hospitalized patients

Examples of • Continuous measures • Time to clinical resolution (TTCR) or stability Endpoints • Time to achievement of protocol-specified hospital discharge Used in Prior criteria Severe • Binary Influenza Trials • Incidence of influenza-related complications • Incidence of ICU admission

Median TTCR: 42.5 (34-57.9) vs. 49.5 (40- 61.9) hours peramivir vs. placebo (p=0.97) in ITTI non-NAI population

FDA does not have a single “best endpoint” for this indication -Unlike acute uncomplicated influenza, data are lacking to support any particular endpoint in this population

Consider clinical signs & symptoms, hospital duration, time to normalization of vital signs and oxygenation, need for supplemental oxygen/assisted ventilation, mortality

Sponsors are encouraged to submit development proposals in advance, providing evidence for the ability of their proposed endpoint to directly measure how a patient feels, functions, or survives ESCMID eLibrary 22 © by author Endpoints in Current Severe Influenza Trials

Baloxavir marboxil1 Pimodivir2

• Randomized, double blind trial of • Randomized, double blind trial of baloxavir+SOC vs. placebo+SOC in 240 pimodivir+SOC vs. placebo+SOC in 600 hospitalized patients ages 12 and older hospitalized patients 13-85 years of age • Primary Endpoint: Time to Clinical • Primary Endpoint: Hospital Recovery Scale, Improvement up to day 35 Day 6 – Time to Hospital Discharge OR 1. Not hospitalized – Time to NEWS2* score ≤ 2 maintained 2. Non-ICU hospitalization, not requiring for 24 hours supplemental O2 3. Non-ICU hospitalization, requiring * Source: supplemental O2 https://www.rcplondon.ac.uk/projects/outputs/national-early- warning-score-news-2 4. ICU hospitalization, not requiring supplemental O2 5. Requiring invasive mechanical ventilation 6. Death 1. Clinical trials.gov identifier: NCT03684044 2. ClinicalESCMID trials.gov identifier: NCT03376321 eLibrary 23 © by author Presatovir for RSV • Presatovir (GS-5806) is an RSV entry inhibitor • Phase 1 Challenge Study – Healthy adults experimentally inoculated with a clinical challenge strain of RSV, delivered intranasally – Randomized to receive various doses/durations of presatovir vs. placebo – Primary end point: area under the curve (AUC) for RSV viral load – Secondary end points: • Mucus weight • Symptom scores ClinicalTrials.govESCMID number, NCT01756482 eLibrary 24 © by author Presatovir Challenge Study

• Compared to placebo, treatment with presatovir resulted in – Lower RSV viral load AUC – Lower mucus weights – Greater improvement in symptom scores

• Treatment with presatovir was well-tolerated

Source: DeVincenzo et al. NEJM 2014 Aug 21;371(8):711-22 ESCMID eLibrary 25 © by author Different Results with Natural RSV Infection

Adults hospitalized with Lung transplant Stem cell transplant RSV Infection: recipients: recipients: Presatovir did not Treatment with Trend to clinical benefit for significantly reduce viral presatovir did not patients treated with load or improve clinical result in improved viral presatovir but prespecified outcomes in hospitalized or clinical outcomes2 thresholds were not met for adults with RSV1 the coprimary and secondary endpoints 3

1Abstract presented at 2018 ATS conference. Hanfelt-Goade et al. American Journal of Respiratory and Critical Care Medicine 2018;197:A4457 2 Gottlieb et al. Journal of Heart and Lung Transplantation, Volume 37, Issue 4, Supplement, April 2018, Page S155 3Abstract presented at 2018 BMT Tandem Meeting. Chemaly et al LBA7 ESCMID eLibrary 26 © by author There continues to be uncertainty about which endpoints are optimal for clinical trials of respiratory Lessons antivirals There are still gaps in our understanding of the Learned interaction between virus and host factors and how From these contribute to disease manifestations - Timing of treatment relative to symptom onset Influenza may be a factor affecting outcomes and RSV - Mechanism of action of the antiviral drugs may also need to be considered in trial design and endpoint selection (e.g. viral entry inhibitors may not be optimal once infection is established and disease has progressed) ESCMID eLibrary 27 © by author Conclusions • There are many respiratory viruses that cause an overlapping constellation of symptoms in some populations, but distinct diseases in others • The interplay between the virus and host factors determine the course of clinical illness • Clinical trials for antiviral drugs should employ outcomes that demonstrate evidence of clinical benefit (something that matters to the patient) – Clinical severity scores (including PRO instruments and related tools) may be used to establish a benefit that matters – Surrogate markers, including virologic measures, are important supportive evidence of efficacy • The field is learning from successes and challenges in drug development for influenza and RSV ESCMID eLibrary 28 © by author Acknowledgments • John Farley • Michael • Debbie Thomson Birnkrant • Will Ince • Jeff Murray • Peter Miele • Wendy Carter • Mary Singer • Jules O’Rear • Adam Sherwat