PHASE 9 DELIVERABLE

FDA PRE-IND BRIEFING PACKAGE

AMX-B01 — Geniposide-Enriched Purified Botanical API

PROJECT AMMONEX-HE

Document Code: SCF-AMMONEX-HE-AMXB01-P9-0001

Trigger Executed: PRE-IND

Development Stage: FDA Regulatory Interaction & IND Readiness Assessment

Regulatory Objective:

Obtain FDA feedback regarding the overall development strategy, nonclinical package, CMC package, clinical development plan, and First-In-Human (FIH) readiness prior to IND submission.

1.0 PRE-IND EXECUTIVE SUMMARY

Product

AMX-B01

Development Classification

Purified Botanical-Derived Active Pharmaceutical Ingredient

Botanical Source

Genipa americana

Marker Compound

Geniposide

Proposed Indication

Treatment of hyperammonemia-associated hepatic encephalopathy.

Development Status

Completed:

✓ Source Qualification

✓ Extraction & Purification Development

✓ API Characterization

✓ Pharmacology Profiling

✓ ADME/PK Strategy

✓ Efficacy Development Program

✓ IND-Enabling Toxicology Strategy

✓ IND-Ready CMC Package

Pending:

• Execution of GLP toxicology
• Final PK studies
• GMP clinical batch manufacture
• Final stability package
• IND assembly

2.0 REGULATORY STRATEGY DOSSIER

Proposed Regulatory Pathway

Stage 1

Pre-IND Meeting

↓

Stage 2

IND Submission

↓

Stage 3

Phase I SAD/MAD

↓

Stage 4

Phase II Proof-of-Concept

↓

Stage 5

Phase III Registration Studies

↓

Stage 6

NDA Submission

Regulatory Positioning

Proposed Classification

Botanical-Derived Purified API

Proposed IND Category

Small Molecule Botanical-Derived Drug Candidate

3.0 DEVELOPMENT RATIONALE

Unmet Medical Need

Hepatic encephalopathy remains associated with:

• Elevated ammonia burden
• Neurocognitive dysfunction
• Recurrent hospitalization
• High healthcare utilization

AMX-B01 Therapeutic Hypothesis

AMX-B01 may improve disease management through:

Primary Mechanism

Support of hepatic nitrogen metabolism.

Secondary Mechanisms

• Gut-liver axis stabilization
• Neuroimmune modulation
• Reduction of inflammatory amplification

4.0 NONCLINICAL SUMMARY PACKAGE

Pharmacology

Primary Pharmacology

• Nitrogen metabolism modulation
• Hepatic metabolic support
• Neuroimmune modulation

Biomarker Framework

Primary biomarkers:

• Plasma ammonia
• Urea
• Citrulline
• Ornithine
• Glutamine

Efficacy Models

Planned:

• Hyperammonemia rat
• Portal-systemic shunt model
• Bile duct ligation model
• Carbon tetrachloride cirrhosis model

Nonclinical Development Goal

Demonstrate:

• Mechanistic activity
• Biomarker response
• Dose-response relationship
• Translational relevance

5.0 CMC SUMMARY PACKAGE

Drug Substance

AMX-B01

Geniposide-Enriched Purified Botanical API

Manufacturing Process

Authenticated Botanical Material

↓

Extraction

↓

Enrichment

↓

Purification

↓

Drying

↓

Packaging

Drug Substance Specification

Drug Product

AMX-B01-F2

Phospholipid Complex Capsule

Stability Program

• Accelerated stability initiated
• Long-term stability initiated

6.0 CLINICAL DEVELOPMENT RATIONALE

Phase I Objectives

Primary

Assess:

• Safety
• Tolerability

Secondary

Characterize:

• Pharmacokinetics
• Exposure variability
• Food effect

Exploratory

Evaluate:

• Plasma ammonia
• Nitrogen-metabolism biomarkers

Proposed Study Population

Initial Proposal

Healthy Adult Volunteers

Alternative strategies may be discussed with FDA depending upon emerging toxicology and pharmacology findings.

7.0 FDA INTERACTION STRATEGY

Primary Meeting Goals

Obtain FDA feedback on:

Topic 1

Overall development strategy

Topic 2

CMC package adequacy

Topic 3

Nonclinical development package

Topic 4

Toxicology requirements

Topic 5

Phase I clinical design

Topic 6

Biomarker strategy

Topic 7

Long-term registration pathway

8.0 IND GAP ANALYSIS

CMC

Nonclinical

Clinical

9.0 PRE-IND MEETING QUESTION PACKAGE

Question 1

Does FDA agree that the proposed nonclinical pharmacology program is sufficient to support advancement into IND-enabling studies?

Question 2

Does FDA agree that the proposed efficacy models are appropriate for hepatic encephalopathy development?

Question 3

Does FDA agree with the proposed GLP toxicology strategy consisting of rodent and non-rodent repeat-dose studies?

Question 4

Does FDA agree that the proposed CMC control strategy is sufficient for an initial IND submission?

Question 5

Does FDA agree with the proposed biomarker package:

• Plasma ammonia
• Urea
• Citrulline
• Ornithine
• Glutamine

as translational pharmacodynamic biomarkers?

Question 6

Does FDA agree that a SAD/MAD Phase I program is appropriate for AMX-B01?

Question 7

Does FDA recommend any additional safety assessments prior to IND submission?

10.0 PRE-IND RISK REGISTER

11.0 PRE-IND READINESS SCORECARD

12.0 PHASE 9 DECISION GATE

Advancement Criteria

✓ FDA briefing package completed

✓ Regulatory strategy defined

✓ Nonclinical summary completed

✓ CMC summary completed

✓ Clinical rationale completed

✓ Gap analysis completed

✓ FDA question package completed

Status

ADVANCE TO PHASE 10

Required Next Trigger

FIH READY

Phase 10 will generate:

1. IND dossier assembly blueprint
2. Investigator Brochure framework
3. Module 4 nonclinical dossier
4. Module 5 clinical dossier
5. SAD study architecture
6. MAD study architecture
7. FIH risk management plan
8. IND submission readiness assessment

MASTER REGISTRY INDEX

SCF-AMMONEX-HE-AMXB01-P9-0001 — FDA Pre-IND Briefing Package

SCF-AMMONEX-HE-AMXB01-REG-0002 — Regulatory Strategy Dossier

SCF-AMMONEX-HE-AMXB01-NONCL-0003 — Nonclinical Summary Package

SCF-AMMONEX-HE-AMXB01-CMC-0004 — CMC Summary Package

SCF-AMMONEX-HE-AMXB01-CLIN-0005 — Clinical Development Rationale

SCF-AMMONEX-HE-AMXB01-GAP-0006 — IND Gap Analysis

SCF-AMMONEX-HE-AMXB01-P10-0007 — First-In-Human Readiness Program