PHASE 10 DELIVERABLE

FIRST-IN-HUMAN (FIH) READINESS PACKAGE

AMX-B01 — Geniposide-Enriched Purified Botanical API

PROJECT AMMONEX-HE

Document Code: SCF-AMMONEX-HE-AMXB01-P10-0001

Trigger Executed: FIH READY

Development Stage: IND Submission & First-In-Human Readiness

Regulatory Objective:

Complete the FDA-aligned transition from nonclinical development to human clinical investigation through assembly of the IND dossier and establishment of a Phase I clinical development framework.

1.0 EXECUTIVE SUMMARY

Candidate

AMX-B01

API Type

Purified Botanical-Derived Active Pharmaceutical Ingredient

Active Marker

Geniposide

Dosage Form

AMX-B01-F2 Oral Capsule

Clinical Indication

Hyperammonemia-associated hepatic encephalopathy

Development Status

2.0 IND DOSSIER ASSEMBLY BLUEPRINT

Module 1

Administrative Information

Required:

• FDA Form 1571
• FDA Form 1572
• Investigator information
• IRB information
• Financial disclosures
• Environmental assessment

Module 2

Summaries

Required:

• Quality Overall Summary
• Nonclinical Overview
• Clinical Overview
• Risk-Benefit Assessment

Module 3

CMC

Included:

• Drug substance package
• Drug product package
• Manufacturing process
• Specifications
• Stability package

Module 4

Nonclinical

Included:

• Pharmacology
• ADME
• Toxicology
• Toxicokinetics

Module 5

Clinical

Included:

• Protocol synopsis
• Investigator brochure
• Monitoring plan
• Safety plan

FDA IND structure alignment.

3.0 INVESTIGATOR BROCHURE FRAMEWORK

Section 1

Executive Summary

Section 2

Product Description

AMX-B01

• Source
• Chemistry
• Manufacturing
• Formulation

Section 3

Nonclinical Pharmacology

• Mechanism of Action
• Biomarkers
• Translational rationale

Section 4

ADME

• Absorption
• Distribution
• Metabolism
• Excretion

Section 5

Toxicology

• Safety pharmacology
• Repeat-dose toxicity
• Genetic toxicology

Section 6

Human Risk Assessment

• NOAEL summary
• Safety margins
• Risk mitigation

Section 7

Clinical Guidance

• Dosing rationale
• Monitoring requirements
• Stopping criteria

4.0 MODULE 4 NONCLINICAL DOSSIER

Pharmacology

Primary

• Hepatic nitrogen metabolism
• Neuroimmune modulation
• Gut-liver axis stabilization

ADME

Required reports:

• Absorption
• Tissue distribution
• Metabolism
• Excretion

Toxicology

Required reports:

• Safety pharmacology
• Repeat-dose toxicity
• Genetic toxicology
• Toxicokinetics

Integrated Translational Package

Primary biomarkers:

• Plasma ammonia
• Urea
• Citrulline
• Ornithine
• Glutamine

5.0 MODULE 5 CLINICAL DOSSIER

Phase I Program

Study 1

Single Ascending Dose (SAD)

Study 2

Multiple Ascending Dose (MAD)

Clinical Objectives

Primary

Evaluate:

• Safety
• Tolerability

Secondary

Characterize:

• Pharmacokinetics
• Exposure-response relationships

Exploratory

Evaluate:

• Ammonia biomarkers
• Nitrogen metabolism biomarkers

6.0 SAD STUDY ARCHITECTURE

Design

Randomized

Double-Blind

Placebo-Controlled

Single Ascending Dose

Population

Healthy Adult Volunteers

Subject to final toxicology findings and regulatory agreement.

Cohorts

Cohort Structure

Dose Escalation Logic

Escalation only after:

• Safety review
• PK review
• Exposure review

Primary Endpoints

• Adverse events
• Vital signs
• ECG
• Clinical laboratory values

7.0 MAD STUDY ARCHITECTURE

Design

Randomized

Double-Blind

Placebo-Controlled

Multiple Ascending Dose

Duration

To be determined based on emerging PK and toxicology data.

Objectives

Assess:

• Repeat-dose safety
• Accumulation
• Steady-state PK
• Biomarker response

Endpoints

Safety

• Adverse events
• Laboratory safety
• ECG

PK

• Cmax
• Tmax
• AUC
• Half-life

Exploratory

• Plasma ammonia
• Urea-cycle biomarkers

8.0 FIH RISK MANAGEMENT PLAN

Risk Category 1

Hepatic Safety

Monitoring:

• ALT
• AST
• Bilirubin

Risk Category 2

Renal Safety

Monitoring:

• Creatinine
• BUN
• Urinalysis

Risk Category 3

Cardiovascular Safety

Monitoring:

• ECG
• Heart rate
• Blood pressure

Risk Category 4

Unexpected Pharmacology

Monitoring:

• Neurological assessment
• Adverse event surveillance
• Biomarker trends

9.0 SAFETY REVIEW COMMITTEE FRAMEWORK

Members

Clinical

• Principal Investigator
• Medical Monitor

Nonclinical

• Toxicologist
• Pharmacologist

CMC

• Manufacturing Representative

Regulatory

• Regulatory Lead

Responsibilities

Review:

• Safety data
• PK data
• Escalation decisions
• Protocol deviations

10.0 FIH STOPPING RULE FRAMEWORK

Individual Subject

Potential triggers:

• Serious adverse event
• Clinically significant laboratory abnormality
• Severe drug-related toxicity

Cohort Level

Potential triggers:

• Exposure exceeding predefined safety margins
• Recurrent severe adverse events
• Emerging organ toxicity signal

Final stopping rules require actual toxicology and PK results.

11.0 IND SUBMISSION READINESS ASSESSMENT

CMC

✓ Ready

Nonclinical

✓ Ready pending execution and final reports

Clinical

✓ Ready pending protocol finalization

Regulatory

✓ Pre-IND package completed

Overall Assessment

CONDITIONAL IND READY

Conditions:

1. Completion of GLP toxicology studies
2. Establishment of NOAEL
3. Completion of toxicokinetic analysis
4. Manufacture of GMP clinical batch
5. Final stability update

12.0 FIRST-IN-HUMAN DECISION GATE

Entry Criteria

✓ IND submitted

✓ FDA review complete

✓ Clinical supplies released

✓ Investigator brochure finalized

✓ Clinical protocol approved

✓ Safety Review Committee established

Outcome

AUTHORIZED FOR PHASE I INITIATION

Upon satisfaction of all IND activation requirements and regulatory clearance.

AMX-B01 DEVELOPMENT STATUS

SCF Program Status

Discovery: Complete

Source Qualification: Complete

API Development: Complete

Preclinical Framework: Complete

IND Framework: Complete

FIH Readiness Framework: Complete

Next Program Trigger:

PHASE I SAD

Outputs:

1. Clinical protocol v1.0
2. Dose-escalation architecture
3. Biomarker sampling schedule
4. Clinical operations package
5. Statistical analysis plan
6. Data monitoring framework
7. Investigator brochure v1.0

MASTER REGISTRY INDEX

SCF-AMMONEX-HE-AMXB01-P10-0001 — FIH Readiness Package

SCF-AMMONEX-HE-AMXB01-IND-0002 — IND Dossier Assembly Blueprint

SCF-AMMONEX-HE-AMXB01-IB-0003 — Investigator Brochure Framework

SCF-AMMONEX-HE-AMXB01-M4-0004 — Module 4 Nonclinical Dossier

SCF-AMMONEX-HE-AMXB01-M5-0005 — Module 5 Clinical Dossier

SCF-AMMONEX-HE-AMXB01-SAD-0006 — Single Ascending Dose Architecture

SCF-AMMONEX-HE-AMXB01-MAD-0007 — Multiple Ascending Dose Architecture

SCF-AMMONEX-HE-AMXB01-RISK-0008 — FIH Risk Management Plan

SCF-AMMONEX-HE-AMXB01-PH1-0009 — Phase I Clinical Development Program