1Summary

1.1Background

Disease aetiology and available treatments

1.2Overviewofinvestigationalproduct

What is it? What’s it do? How’sit work? Administered how/

Similarity toother compounds

1.3Chemistry, Manufacturing and Controls

The IP has been manufactured in accordancewith Good Laboratory Practice(GLP) and Good

Manufacturing Practice (GMP) for toxicological andclinicalstudies respectively. The IP is produced utilising a process involving

1.4NonclinicalStudies

1.4.1Pharmacology

There are nofully validated animal models for XXXX. Noinvivoassessment of the efficacy ofIP has been conducted.

1.4.2Pharmacokinetics

Pharmacokineticstudieswere conducted in

1.4.3Toxicology

1.5Clinical Experience

As of the date of this Investigator’s Brochure, the IP has not been administered to humans.

1.6Development plan

Initial PhaseI investigations in healthy volunteers will be used to assessthesafety and tolerability of IP when administered weekly up to doses ofXX mg/kg. Data derived from preliminary pharmacokinetic information will be used to designa subsequent Phase Ib study …..

2Introduction

Overviewof targeted disease and indication

2.1Investigational product

2.2Rationale for clinical development

2.3Dose justification

Table 2-1: Safetyratios forsingleoraldoses

Human SingleDose / Rat NOAELXXmg/kg/day / DogNOAEL XXXmg/kg/day

3Physical,ChemicalandPharmaceuticalPropertiesANDFormulation

Drug substance

The active pharmaceutical ingredient is

API isstructurally similar to (add info)

Table 3-1: Composition and characteristics of activeingredient

NAME
INTERNATIONAL NOMENCLATURE
SPONSORNAME
CAS NUMBER
STRUCTURE
MOLECULAR FORMULA
MOLECULAR WEIGHT
DESCRIPTION / EXAMPLE:IPISA SYNTHETICXXXX.THEACTIVEIS PRODUCEDIN A SINGLESTEPFROMXXXWITHA PURITY TYPICALLYGREATER THAN 99%.
IPISA WHITETOOFF-WHITECRYSTALLINE XXXXSALTWITH A PKA OFXX.THEMELTINGPOINTISAROUND XX°C. THEACTIVEHAS A WATER SOLUBILITYOFXXMG/ML(AT PH XX).
ODOUR
SOLUBILITY
PROPERTIES

3.1.1Manufacture

The active pharmaceutical ingredient XXX, is manufactured and purified through aseries of proprietary processing steps which have been validated and performed inaccordance with GLP/GMP under license at:

State name and address of manufacturer.

3.1.2Analysis and characterisation of IP

The identity of IPisconfirmed by HPLC and MS with a retention time of XXmin inchromatograms etc. Purity isconfirmed by XXX and analyticalassay.Impurities are assessed by …

3.1.3Stability

3.2Investigationalproduct

3.2.1Formulation

The clinical product is formulated in combinationwith the ingredients shown in Table 3-1 using a series of proprietary processing steps prior to sterilisationby XXX anddispensing into XXXX.IP is formulated to contain XX% active pharmaceutical ingredient.

Table 3-2: General investigational drugproduct Information

INGREDIENT / SPECIFICATION / PURPOSE / CONC (MG/ML)
ACTIVE / BP/USP?? / ACTIVE
EXCIPIENT / EXCIPIENT
EXCIPIENT / EXCIPIENT
EXCIPIENT / EXCIPIENT
SOLUTE / SOLVENT

3.2.2Manufacturer

3.2.3Finaldosageform andpresentation

The IP is supplied in a 5mL glass vial and is formulated at XX%of API and stored at RT.

3.2.4Posology

Information on exact dose and dosing regimen is provided in the applicable approved study protocol.

3.2.5Containerandpackaging

5 mL glass vials are packaged in cartons of 5 …..and shipped under ambient conditions to the clinical trialsite.

3.2.6Storage andhandling

The vials areto be storedat RT [15°–30°C (59°–86°F)], protected from light in a secure area with limited access to appropriate pharmacists or studypersonnel.

3.2.7Stability

Current stability information utilising the GMP material has demonstrated that the IP isstable at RT for up to 12 months.

The stabilityprogram iscurrently ongoing.

3.3Development pharmaceutics

If required

4Non-clinicalstudies

NonclinicalPharmacology

4.1.1Summary

4.1.2InvitroPharmacology

4.1.2.1 Individual study summaries

4.1.3In vivo Pharmacology

4.1.3.1 Individual study summaries

Animal models for XXX have not been validated forthe prediction of XXXX efficacy in humans. In vivo

studiestoassessefficacy of XXX inXXX have not been conducted to date.

4.1.4Mechanism ofaction

Brief overview…

Further information regarding the mechanismof action is provided in Section XX.

4.2Pharmacokinetics andProductMetabolisminAnimals

4.2.1Summary

Nonclinical pharmacokineticstudies have characterised basic pharmacokinetic parameters in mice, rats and beagle dogs after single IVdose administration of IP.

4.2.2MethodofAnalysis

4.2.3Single-doseAbsorption,Distribution,MetabolismandExcretion

Table 4-1: Mean plasma pharmacokinetic parameters for IP after single-dose administration

Species / Ref / Dose
(mg/kg) / Route / AUCinf
(μg.h/mL) / Cmax
(μg/mL) / CL
(mL/kg/min) / Vss
(L/kg) / T1/2
(h) / F%
Mouse Rat Rabbit
Dog
Monkey

4.2.3.1 Individual study summaries

4.2.3.2 Absorption

4.2.3.3 Distribution

4.2.3.4 Metabolism

4.2.3.5 Excretion

4.2.4Multiple-doseAbsorption,Distribution,Metabolismand Elimination

4.2.4.1 Individual study summaries

4.2.5Drug interactions

Investigator’s BrochureCONFIDENTIAL

InvestigationalProduct

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Table 4-2: Summary tableof Pharmacology studies

Studynumber/Title / GLP / Species/
strain / No/sex/
group / Formulation / Dose/Regimen / Route of admin. / Duration / Results

4.3Toxicologyandsafetystudies

4.3.1Summary

4.3.2Acute toxicology

4.3.2.1 Individual study summaries

4.3.3 Repeat dose toxicology

4.3.3.1 Individual study summaries

Good to include table of dosing for repeated studies, group, dose, number/sex for main study, TK and

PDarms.

4.3.3.2 Toxicokinetic parameters

4.3.3.3 Mortality and clinical observations

4.3.3.4 Clinical pathology and organ weights

4.3.3.5 Histopathological changes

4.3.4Toxicokinetics

4.3.4.1 Individual study summaries

4.3.5Chronictoxicology

4.3.5.1 Individual study summaries

No studies on chronic toxicologyhave been conducted on IPtodate. Provide justification such as clinicalstudy design.

4.3.6Reproductivetoxicology

No studies on reproductive toxicity have been conducted on IP to date.Provide justification. Repeat dose testing, discuss results of reproductive organs.

4.3.6.1 Individual study summaries

4.3.7Safetypharmacology

4.3.7.1 Individual study summaries

Investigator’s BrochureCONFIDENTIAL

InvestigationalProduct

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Table 4-3: Summary tableof Toxicologystudies

Studynumber/Title / GLP / Species/
strain / No/sex/
group / Formulation / Dose/Regimen / Route of admin. / Duration / Results

Date:;Version;Page 64 of 69

4.3.8Genotoxicity(Mutagenicity)

4.3.8.1 Individual study summaries

4.3.9Carcinogenicity

4.3.9.1 Individual study summaries

No studies on carcinogenicityhave been conducted on IP to date. Provide justification.

4.3.10Specialstudies

4.3.10.1Individual study summaries

5Effectsinhumans

Introduction

5.1Clinical Development Program

The initial clinical study will be a randomised, double-blind, single dose, dose escalation study to evaluate the safety, tolerability and pharmacokinetics of IP following IV infusion in healthy male volunteers. Doses will start at 100 mg, escalating to 500 mg after evaluation of resultsfrom lower dose investigations. Doses willnot exceed 500 mg.

Consideration of the data will lead to a safety, tolerability,pharmacokinetic and pharmacodynamic

Phase Ib study utilising multipleascending doses in XXX participants.

5.2Pharmacokinetics, PharmacodynamicsandProductMetabolisminHumans

Single doses of XX mg IP in healthy participants resulted in linear and neardose-proportional increases in plasma concentrations ofIP with increasing dose(mean Cmaxand AUC values increased XX-fold, respectively, overall). The mean CmaxofIP ranged from XX–XXµg/mL, and the mean AUC0–infranged from XX-XXµg·h/mL.The mean Tmaxwas XX–XXhours after dosing, with amean terminal half-life

(T1/2) ofXX–XX hours. IP was the major component excreted in urine at all dose levels. Approximately

XX–XX% (molecular equivalent) of administered IP was recovered in urine asIP,suggesting that at

least that percentage of IP is absorbed.

Table 5-1: Pharmacokinetic parameters of IPfollowing single-doseadministration in study no.

Parameter / IP
200 mg (n=6) / 500 mg (n=6) / 1000 mg (n=6)
Cmax(μg.h/mL) Tmax(h)
T1/2(h)
AUC0–24 (µg·h/mL) AUC0–inf(µg·h/mL) CL (L/h)

5.3Clinicalexperience

5.3.1Dose response

5.3.2SafetyandEfficacy

5.3.3Laboratorydata andother safetyparameters

5.3.4Individual study summaries

5.3.4.1 Study no.

5.3.4.2 Study no. (ongoing)

5.3.5Benefit – Risk Assessment

5.4RegistrationandMarketing experience

Ta date, IP has not been registered foruse or marketed in any jurisdiction.

6Summaryofdataandguidancefortheinvestigator

Composition

6.1Presentation

IP is presented in 10 mL vials for reconstitution prior to administration.

6.2Posologyandrouteofadministration

6.3Storage andstability

6.4Pharmacokinetics ofinvestigationalproduct

6.5Bioanalytical evaluation

6.6Mitigationofoverdose risk

6.7ExpeditedSafetyReports

6.8Warnings,precautions

Insufficient experience exists with IPto provide comprehensivewarning guidance. The pharmacokinetics of IP iscurrently unknown. The investigational product will be administered at a dose of XXXmg etc.Some brief information on putative drug-drug interactions as related to dosing with similar classof compoundand potential CYT inhibition criteria.

6.9Contraindications

IP iscontraindicated for use in participants with known hypersensitivity totheactive substance or any of the excipients.

6.10Adverse events

6.11Participantpopulations

The investigational compound XXXXX must only be administered in accordance with the approved study protocol inclusion/exclusion criteria.

6.11.1Pregnancy and Breast-Feeding

No studies of IPin pregnant or lactating women have been conducted. Pregnant and nursing women should not receive IP until further information becomes available. Women of childbearingpotential are excluded fromparticipating in IP clinical studies.Sexually active men must use contraception and inform their partners of the possible risks described in this document whereand if applicable.

6.11.2PaediatricUse

No studies on the use of IP inpaediatric participants have beenconducted.

6.11.3Geriatric Use

No studies on the use of IP in geriatricparticipantshave been conducted.

References