Learn best practices for utilizing cardiac biomarkers across various components of a clinical trial from Dr. James Januzzi, a leading expert in cardiovascular biomarkers.

1. M A K I N G T H E C O M P L E X S E A M L E S S
AGENDA
• Rationale for application of cardiac biomarkers in clinical trials
• Gaining efficiencies in clinical trials with biomarkers
• Lessons learned in HF trials utilizing biomarkers and strategies to
mitigate operational challenges
• Q&A
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James Januzzi, MD Kelly Millhaem, MHA
Richard Lee, MD Liz Moore, DNP, MSN,
CPNP-AC, CPN

2. RATIONALE FOR
BIOMARKERS
IN CV TRIALS

3. M A K I N G T H E C O M P L E X S E A M L E S S
AIM OF BIOMARKERS IN CV TRIALS
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Efficacy Endpoints – identify
quantitative response to study
treatment
Diagnostic Tool
Eligibility Criteria –
establish baseline
characteristics
Safety Endpoints – markers of
myocardial injury & toxicity
Prognostic Indicators
Match IMP with mechanism-based
biological effect

4. M A K I N G T H E C O M P L E X S E A M L E S S
THE DOUBLE-EDGED SWORD OF BIOMARKERS
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Predictive population enrichment
Risk-based Stratification
Efficacy Endpoints Early POC
Safety Monitoring
Higher screen fails
Alternative biological sources
Biomarker assay availability & variability
Limitations of current biomarkers – NP, cTn

5. M A K I N G T H E C O M P L E X S E A M L E S S
HYPOTHETICAL TRIAL
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Biomarkers
In CV Trial
Inclusion
• Men or women 18-85 years with documented HFrEF
• NT-proBNP >300 pg/mL at SCR
• On Guideline-Directed Medical Treatment
• Afib allowable if adequately anti-coagulated
“ToughREF” Trial
• Phase IIa, open-label, POC exploratory trial
• 40 Subjects with HFrEF in 12 sites
• Hypothetical IP: “IM-007”
Primary Objective
• To evaluate effect of a 16-week treatment with IP on cardiac PD, as determined by TTE assessments and cardiac
biomarkers in stable chronic HFrEF subjects.
Primary Endpoint
• Change from baseline to Week 16 in LVEF and NT-proBNP

6. M A K I N G T H E C O M P L E X S E A M L E S S
HYPOTHETICAL TRIAL
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“ToughREF”
Trial
Challenges
• SFR of 65% with 2/3 of SF due to inadequate NT-proBNP at SCR
• Only 4 sites had reliable databases
• 30% enrolled patients on sacubitril/valsartan
• 25% enrolled patients on chronic Afib
• Large splay in NT-proBP levels from 320 pg/mL to 2,200 pg/mL
Interim Analysis
• 50% of patients finished treated with evaluable data
• Inconsistent changes in NT-proBNP at Week 16 compared to baseline
• Trend to improvement in mean LVEF of 3.5% at Week 16 compared to baseline, not statistically significant

7. GAINING EFFICIENCIES
IN CLINICAL TRIALS
WITH BIOMARKERS

8. M A K I N G T H E C O M P L E X S E A M L E S S
WHAT ARE THE CURRENT STRENGTHS OF
CARDIAC MARKERS IN TRIALS?
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Januzzi et al, JACC 2021;77:1922-33

9. M A K I N G T H E C O M P L E X S E A M L E S S
WHAT IS THE CURRENT STATE OF MARKER
USE IN HF TRIALS?
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Use of biomarkers has grown
exponentially in clinical trials
of HF, for example
Januzzi et al, JACC 2021;77:1922-33

10. M A K I N G T H E C O M P L E X S E A M L E S S
WHEN MIGHT BIOMARKERS BE USED?
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Markers may have a broad
range of applications, however
significant caveats apply…
Januzzi et al, JACC 2021;77:1922-33

11. M A K I N G T H E C O M P L E X S E A M L E S S
WHAT IS NEEDED IN ORDER TO USE
BIOMARKERS IN TRIALS?
• It is striking how often
biomarkers are used with
tenuous links to the things
being monitored…
• Examples:
‒ change in NPs x benefit
in HF
‒ Change in troponin x
toxicity
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Januzzi et al, JACC 2021;77:1922-33

12. M A K I N G T H E C O M P L E X S E A M L E S S
CHALLENGES FACED WHEN BIOMARKERS
ARE USED IN TRIALS
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Januzzi et al, JACC 2021;77:1922-33
Variable sampling strategies
Variable storage strategies
“Save samples and we’ll figure it out retrospectively”
Ambiguity regarding link between biomarker and pathology
The “Usual Suspect” syndrome

13. M A K I N G T H E C O M P L E X S E A M L E S S
THE USUAL SUSPECTS
The same 2 biomarkers can
NOT inform everything we
do in clinical trials!
Where is the imagination
and inductive science?
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troponin
troponin NT-proBNP troponin NT-proBNP

14. M A K I N G T H E C O M P L E X S E A M L E S S
WHAT IS NEEDED TO FACILITATE A MORE
FUNCTIONAL FUTURE STATE
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Januzzi et al, JACC 2021;77:1922-33
Earlier consideration of the place a
biomarker plays in compound
development—the “biomarker Phase 2”
Close Industry/Regulatory relationship
Routine sample acquisition and storage
protocols
Optimization of assay performance and
standardization of cut-offs
Global collaboration and establishment
of biobanks

15. M A K I N G T H E C O M P L E X S E A M L E S S
RATHER THAN FOCUS ON THE USUAL SUSPECTS,
THINK ABOUT MARKERS EARLIER
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Recent data using inductive
statistical methods applied to
omics databases have identified
unique drug-marker pairs and
potential druggable targets
Michelhaugh and Januzzi, JACC BTS, 2020;5:1043-53

16. M A K I N G T H E C O M P L E X S E A M L E S S
ULTIMATELY, THE FUTURE STATE COULD
LOOK LIKE THIS:
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The future state could be a
broad ranging combination
of new or discovered
proteomic-based markers
with other omics and
clinical data for superior
prediction of response and
improved prognosis
Januzzi et al, JACC 2021;77:1922-33

17. STRATEGIES TO
MITIGATE OPERATIONAL
CHALLENGES

18. M A K I N G T H E C O M P L E X S E A M L E S S
CARDIAC BIOMARKERS & TRIAL EXECUTION
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Target Patient
Population
cTnT
BNP
cTnI
How do we balance the scientific needs of
clinical trials with study execution?

19. M A K I N G T H E C O M P L E X S E A M L E S S
CASE STUDY: ENROLLMENT IMPACT
# Screened # Enrolled
Indication: Heart Failure
Challenge: Lack of enrollment
due to strict entry criteria
Strategy: Proactive collaboration
between medical and operational
teams to revise criteria while
preserving scientific integrity of trial
Outcome: Successful and on-time
enrollment of trial

20. M A K I N G T H E C O M P L E X S E A M L E S S
CARDIAC BIOMARKERS: ENROLLMENT
• “Tier” screening procedures to reduce invasive procedures & cost
• Pre-screen testing for specific biomarkers
• Use of historical values as guide
• Permit repeat testing during screening phase, within reason
• Provide guidance for time of day, fasting conditions
• Discuss potential challenges during site feasibility and selection
process
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LAB DRAWS IMAGING FUNCTIONAL TESTING

21. M A K I N G T H E C O M P L E X S E A M L E S S
SITE ENGAGEMENT - ENROLLMENT
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Target sites that utilize CV
biomarker testing in SOC practice
Site education materials,
Identification of the ‘right’ patient
Database mining

22. M A K I N G T H E C O M P L E X S E A M L E S S
MONITORING AND ASSESSING SAFETY RISK
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PROTOCOL DESIGN
• Specify assay types
• High sensitivity vs.
standard assays
• BNP versus NT-
proBNP
• Streamline testing
• Serial collections at
baseline or during trial
• Include additional
safety assessments
where possible (PE,
Vitals, ECG, etc)
SITE TRAINING
• Laboratory collection
best practices
• Split sample shipping
• Sample collection
timing
• Timely data entry of
medical history, AE
and medications
EVALUATION
• Interpretation of results
• Not every biomarker
predicts risk
• Confounding variables
• Consideration of
factors that
increase/decrease
circulating
concentrations
QUALITY
OVERSIGHT & RISK
MANAGEMENT
•Cumulative trend review
•Routine Clinical Data
Reviews
•Identify missing or
inadequate collections

23. M A K I N G T H E C O M P L E X S E A M L E S S
SHARPENING THE EDGE OF CV BIOMARKERS
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Balancing the “pros”
& “cons” of
biomarkers in drug
development
Understanding the
strengths and
weaknesses of
current biomarkers
Adapting the
application of
biomarkers during
study and avoidance
of common pitfalls
“Building a better
biomarker.”
Development of
better biomarker(s)
to predict response
to therapy and to
target the right study
population

24. DISCUSSION AND Q/A

25. THANK YOU