NOXOPHARM LIMITED

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Date: 13 November 2017 Sydney, Australia

ASX: NOX

ASX Limited 20 Bridge Street SYDNEY NSW 2000

ABN 50 608 966 123

Noxopharm making three presentations at COSA

Registered Office:

Suite 1 Level 6 50 Queen St Melbourne VIC 3000 Australia

Operational Office:

Suite 3, Level 4 828 Pacific Highway Gordon NSW 2072 Australia

Sydney, 13 November 2017: Noxopharm is pleased to release the 3 presentations being made today at the Annual Scientific Meeting of the Clinical Oncology Society of Australia.

Two presentations concern the Company’s clinical study being conducted in Georgia and now full recruited. A secondary aim of this study is to determine if blood levels of the active drug, idronoxil, and one of its target protein, ENOX2, might prove effective biomarkers in predicting drug efficacy and safety. Today’s presentations are preliminary reports on the successful establishment of the two assays.

Board of Directors Mr Peter Marks

Chairman Non-Executive Director

An update on the clinical response and safety data will be made to the ESMO (Asia) conference in Singapore on 18[th] November, 2017.

The third presentation concerns the clinical trial design of the Company’s PROCART (Prostate Cancer Radio-sensitising Therapy) study to be conducted in 5 Australian radiation oncology centres, and currently recruiting and screening patients.

…………………………

Dr Graham Kelly Chief Executive Officer Managing Director

Dr Ian Dixon Non-Executive Director

About Noxopharm

Noxopharm is an Australian drug development company with offices in Sydney and Hong Kong. The Company has a primary focus on the development of drugs to address the problem of chemotherapy- and radiation-resistance in cancer cells, the major hurdle facing improved survival prospects for cancer patients. NOX66 is the first pipeline product, with later generation drug candidates under development. The Company also has initiated a pipeline of non-oncology drugs.

Investor & Corporate Enquiries: Company Secretary:

Prue Kelly David Franks

E: [email protected] E: [email protected]

www.noxopharm.com

Forward Looking Statements

This announcement may contain forward-looking statements. You can identify these statements by the fact they use words such as “aim”, “anticipate”, “assume”, “believe”, “continue”, “could”, “estimate”, “expect”, “intend”, “may”, “plan”, “predict”, “project”, “plan”, “should”, “target”, “will” or “would” or the negative of

such terms or other similar expressions. Forward-looking statements are based on estimates, projections and assumptions made by Noxopharm about circumstances and events that have not yet taken place. Although Noxopharm believes the forward-looking statements to be reasonable, they are not certain. Forward-looking statements involve known and unknown risks, uncertainties and other factors that are in some cases beyond the Company’s control that could cause the actual results, performance or achievements to differ materially from those expressed or implied by the forward-looking statement. No representation, warranty or assurance (express or implied) is given or made by Noxopharm that the forward-looking statements contained in this announcement are accurate and undue reliance should not be placed upon such statements.

ENOX2 levels of patients receiving NOX66

Ian Minns, Sue Khouri, Marinella Messina and Graham Kelly

INTRODUCTION

METHODS

The ECTO-NOX, or ENOX, proteins are a family of NAD(P)H oxidase proteins present on the cell surface of plants and animals. These proteins have two known and distinct biochemical activities, namely hydroquinone (NAD(P)H) oxidation and protein disulphide-thiol interchange, and are believed to play an important role in cell growth. In its constitutive form (CNOX, or ENOX1) these activities oscillate consistently at 24 min intervals. A second form of ENOX (tNOX, or ENOX2) has been identified, which has been found to be expressed on tumour cell surface and detected in sera of cancer patients[1] . Whilst ENOX2 performs the same dual function as ENOX1, the oscillation between functions occurs at 22 min intervals. From this, it is hypothesised that ENOX2 represents an important role in tumour cell growth and proliferation[2] .

Samples for analysis were collected from patients participating in the study “NOX66-001: Safety, PK and Efficacy of NOX66 as a Monotherapy and Combined with Carboplatin in Refractory Solid Tumours” (ClinicalTrials.gov identifier NCT02941523). Commercially available lung and prostate tumour plasma controls were used as reference for qualitative review and non-tumour plasma was used as negative control.

Determination of plasma ENOX2 levels was conducted at Crux Biolab, Melbourne, Victoria, using the Human Ecto-NOX Disulfide-Thiol Exchanger 2 (ENOX2) ELISA Assay. This assay employs a quantitative sandwich linked immunoassay sorbent procedure with microplates pre -coated with an antibody specific to ENOX2. Following exposure of a sample to the antibody, any unbound substance is removed and a biotin-conjugated antibody (specific for ENOX2) is added. Avidin-enzyme conjugated horseradish peroxidase is introduced, followed by a substrate solution initiating colour development then an acid based solution is used to stop the reaction. Colour intensity is measured and correlated to ENOX2 concentration (pg/mL). In order to assess samples within the range of the assay, control samples were diluted 5-10-fold and patient samples analysed at 5-fold dilution. All samples were analysed in duplicate.

Importantly, while ENOX1 is refractory to quinone site inhibitors, the activity of ENOX2 may be suppressed by such inhibitors. It is this property which has led to investigation of ENOX2 inhibition as a target for anti-cancer therapy and the development of the isoflavone compound Idronoxil as a first-in-class inhibitor of ENOX2. The imputed pathway of ENOX2, and the mechanism by which inhibition of ENOX2 by Idronoxil may directly (via apoptosis) and indirectly (in combination with chemotherapy and / or radiotherapy via inhibition of DNA repair mechanisms) is outlined in Figure 1.

RESULTS

The compound NOX66, is a novel formulation and delivery mechanism for Idronoxil and is under clinical investigation for use in combination with standard chemotherapy and radiotherapy. The first-in-human study of NOX66, as a monotherapy (for safety evaluation) and in combination with carboplatin, is currently ongoing. Sixteen (16) patients with late stage metastatic disease (of primary origin prostate, lung, breast or ovarian) receive one of two doses of NOX66 (400mg, 800mg) as monotherapy (for 14 consecutive days) followed by low dose (AUC4) carboplatin for 3 x 28-day cycles and standard dose (AUC6) carboplatin for 3 x 28-day cycles. This poster presents interim results for the analysis of plasma ENOX2 levels in this cohort of patients.

Figure 2. ENOX2 levels of control tumour plasma samples (measured by 5x and 10x dilu�on)

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4000
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P1 Lung P2 Lung P3 Lung P4 Prostrate P5 Prostrate P6 Prostrate C1 Normal
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Figure 1. Puta�ve biochemical pathway associated with idronoxil.

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Figure 3. ENOX2 levels of pa�ent samples, NOX66-001 study
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CONCLUSION

The cascade of events outlined above is as follows[2-5] :

Idronoxil binds to ENOX2, leading to inhibi�on of the trans membrane electron pump which, in turn, leads to an accumula�on of proton ions within the plasma membrane.
Accumula�on of protons disrupts sphingomyelin pathway with blockage of ceramide conversion to S1P – leading to a decrease in S1P and an increase in Ceramide within the plasma membrane.
Decrease of S1P leads to a reduc�on in PI3K, Akt and XIAP and an increase in Caspase 2.
Reduc�on in Akt leads to reduc�on in NF-κB and allows up regula�on of the intrinsic (mitochondrial) pathway of apoptosis, via an increase in Caspase 9 and Caspase 3, leading to cell death.
Reduc�on in Akt also results in an inhibi�on of FLIP resul�ng in an increase in Caspase 8 (ac�vated via the Death Receptor on the Protein Membrane) – leading directly and indirectly (via the intrinsic pathway) to an increase in Caspase 3 and apoptosis.
Reduc�on in XIAP prevents down regula�on of Caspase 9 and Caspase 3, suppor�ng apoptosis.

The human ENOX2 ELISA assay allows for the measurement of ENOX2 in human plasma samples.

Intra-patient comparison of plasma ENOX2 shows variation in concentrations between samples, suggesting that shedding of ENOX2 protein may not remain consistent and indirect measurement of ENOX2 via plasma concentrations may not provide a quantitative assessment of ENOX2 activity.

Further validation of the ELISA based ENOX2 assay, and direct analysis of tumours (e.g. via biopsy) are required to allow relationship of ENOX2 level and efficacy of NOX66 to be assessed.

REFERENCES

Cho et al (2002). “Monoclonal an�body to a cancer- specific and drug-responsive hydroquinone (NADH) oxidase from the sera of cancer pa�ents”. Cancer Immunol. Immunother. Vol 51 (3); pp 121–129
Morre and Morre (2003). “Cell Surface NADH Oxidases (ECTO-NOX Proteins) with Roles in Cancer, Cellular Time-Keeping, Growth, Aging and Neurodegenera�ve Diseases”. Free Rad. Res. Vol 37 (8); pp 795-808
Morre et al (2007). “ECTO-NOX Target for the An�cancer Isoflavene Phenoxodiol.” Oncol Res. Vol 16; pp 299-312

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De Luca et al (2008). “Downstream Targets of Altered Sphingolipid Metabolism in Response to Inhibi�on of ENOX2 by Phenoxodiol.” Biofactors. Vol 34 (3); pp 253-260
Huang et al (2011). “Roles of Sphingosine-1-Phosphate on Tumorigenesis” World J. Biol. Chem. Vol 2 (2); pp 25-34

Financial Disclosures: The authors are employees of Noxopharm Limited, the sponsor company of this study

Idronoxil levels of patients receiving NOX66

Ian Minns, Marinella Messina and Graham Kelly

BACKGROUND

ANALYTICAL METHOD

The experimental an�-cancer drug Idronoxil is a first-in-class inhibitor of the oncogene external NADH oxidase Type 2 (ENOX2). ENOX2 maintains the trans-membrane electron poten�al (TMEP) of the cancer cell plasma membrane, with loss of TMEP disrup�ng a wide range of func�ons of the plasma membrane. Inhibi�on of sphingosine kinase is a major outcome, resul�ng in loss of a range of pro-survival signalling pathways, notably PI3K and Akt, and consequent loss of func�on of DNA repair enzymes including PARP 1 and topoisomerases 1 and 2.

Idronoxil was previously inves�gated as a chemo-sensi�ser, u�lising its ability to block repair of DNA damage in order to op�mise chemotherapy-induced tumour damage whilst minimising non-tumour toxicity. In vitro and in vivo (mouse xenogra�s) data have shown that idronoxil sensi�ses by up to 2000-fold the cytotoxic effects of standard cytotoxic drugs including cispla�n, carbopla�n, paclitaxel, gemcitabine, toptecan, doxorubicin and captothecin.

Promising early phase results led to a Phase 3 study of oral idronoxil as a sensi�ser of carbopla�n in pa�ents with carbopla�n-refractory ovarian cancer, however this study was discon�nued early with data showing no improved efficacy with idronoxil. Subsequent review of the mechanism of ac�on of idronoxil suggested that, for significant biological effect, a constant presence of the parent drug must be present. With a short elimina�on half life and extensive Phase 2 metabolism in oral and IV formula�ons, administra�on of idronoxil in standard form is unsuitable as a drug candidate.

NOX66 is under development as a formula�on of idronoxil, specifically designed to overcome the issues iden�fied with oral and IV formula�on. Pre-clinical inves�ga�ons in rats (Table 1) show that NOX66 delivered rectally leads to an extended elimina�on half life of parent drug in comparison with IV idronoxil.

A first-in-human study of NOX66 as monotherapy and in combina�on with carbopla�n was commenced in March 2017, with preliminary results presented at the ESMO Annual Scien�fic Mee�ng in September (summarized below). As part of this study, plasma and urine samples are collected to review and assess the detectable levels of parent idronoxil in pa�ent plasma and urine. Here we outline the assay method, and preliminary finding for monotherapy samples.

Table 1: Comparison of pharmacokine�c parameters of idronoxil administered intravenously in a lipidfree co-solvent formula�on and rectally administered NOX66 in rats (n=4 per arm).

Parameter:	IV idronoxil	NOX66 (rectal)
Dose (mg/kg)	3.5a	35
Cmax (ng/mL)	4647 ± 315	62.3 ± 8.7
Tmax (h)	-	0.12 ± 0.04
AUC0-30(ng.h/mL)	8129 ± 166	1187 ± 389
Half-life (h)	0.32 ± 0.07b	9.6; 6.1c
Bioavailability (%F from 0-30h)	100	14.6 ± 4.8

a 3.5 mg/kg administered, however PK parameters have been normalised to equivalent of 35 mg/kg

b Half life es�mate using values from 0.17h. No measurable drug was seen in any rat beyond 2h

c Values for 2 rats only

Plasma and 24h urine samples from 8 patients receiving NOX66 (400mg) were collected and extracts prepared using protein precipitation with acetonitrile then analysed at HMSTrust Laboratory, Monash University. LC-MS analysis was performed on a Shimadzu 8050 triple quadrupole instrument coupled with a Shimadzu Nexera X2 UHPLC. An internal standard of diazepam was used in all samples.

RESULTS

Figures 1-4 show representative chromatograms of control human plasma and standard solvent and of representative plasma and urine extracts from cohort 1 patients.

Chromatograms show internal standard diazepam peak, parent idronoxil peak and metabolite peaks in patient extracts only.

All urine samples analysed have shown detectable levels of parent drug (idronoxil) and metabolites, whilst parent drug was consistently detected in six of eight patients’ plasma samples, with all showing evidence of metabolites. Table 2 shows Idronoxil levels measured in plasma (Day 1, 2 hours post NOX66 administration and Day 8, prior to next NOX66 administration) and urine (24h sample from Day 1)

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Table 2: Parent idronoxil levels of pa�ents receiving NOX66 400mg.

Plasma samples were collected at 2 hours following administra�on of first dose of NOX66, and prior to next dose administra�on on Day 8. post 7 days of consecu�ve daily NOX66 dosing) 24h Urine sample was collected across Day 1 of administra�on of NOX66 .

Subject Number	101	102	201	202	203	301	401	402
Pa�ent No.	1	2	3	4	8	5	6	7
Plasma Idronoxil: Day 1, 2h (ng/mL)	6.7	25.2	ND	22.1	15.0	ND	<LLOQ	24.9
Plasma Idronoxil: Day 8, 0h (ng/mL)	5.7	26.4	ND	24.2	9.5	ND	ND	26.9
Urine Idronoxila: Day 1 24h (μg/mL)	0.59	0.22	<LLOQ	0.03	0.05	0.95	0.24	0.20
LLOQ = Lowest Level of Quan�fca�on; ND = Not Detected

CONCLUSION

Parent idronoxil can be detected using LC-MS analysis in patients receiving 400mg NOX66 daily, with initial data suggesting a constant presence of parent drug and minimal accumulation. Further PK studies are required to confirm initial findings. Development and confirmation of this method allows for further determination of idronoxil and its metabolites in relation to response to treatment with NOX66.

(Presented at ESMO, September 2017)

		NOX66-001 STUDY - INTERIM DATA FOR COHORT 1	NOX66-001 STUDY - INTERIM DATA FOR COHORT 1	NOX66-001 STUDY - INTERIM DATA FOR COHORT 1
Pt	Tumour	Monotherapy	Combina�on Therapy	Response#(Cycle 3 ) Adverse Events
	Type	(21 day cycle)	(28 day cycles )	Target Lesion (Phase 1B)		Related to
1 2	Ovarian Lung	Phase 1a Status Complete Complete	Phase 1b Status Ongoing - Cycle 6 Withdrawn	RECIST 1.1 criteria ALL Stable Disease Stable disease (Cycle 6) Nausea Progressive Disease NIL	Severity* Grade 1/mild	NOX66 UR
3	Lung	Complete	Ongoing - Cycle 4	Stable Disease Pulmonary embolism	Grade 1/mild	UR
4 5	Lung Breast	Complete Complete	Withdrawn (pt decision) Ongoing - Cycle 4	Arterial embolism ND Stable Disease Exuda�ve pericardi�s Bilateral hydrothorax	Grade 1/mild Grade 1/mild Grade 2/mod	UR
				WBC eleva�on	Grade 2/mod
6	Breast	Complete	Ongoing - Cycle 3	ND Hypocalcaemia	Grade 2/mod	UR
7	Breast	Complete	Ongoing - Cycle 3	ND Asthenia Peripheral neuropathy	Grade 2/mod Grade 1/mild	UR
8	Prostate	Complete	Ongoing - Cycle 3	ND NIL
#First response assessment by Inves�gator; NCTCAE v4.03 ; ND=Not Determined; UR= unrelated*

��Phase I open label, 2 -step dose escala�on study of NOX66, a suppository formula�on, in pa�ents with refractory solid tumours.
��Tumours selected for 5 phenotypes: breast, head and neck, lung, prostate and ovarian.
��Total 16 evaluable pa�ents: n=8 allocated to 400mg NOX66 dosage Cohort 1; n=8 allocated to 800mg dosage Cohort
��The study comprises 2 stages of assessment:
Monotherapy: NOX66 is administered for daily for 14 consecu�ve days
plasma and urine samples collected throughout
Combina�on therapy: NOX66 plus IV Carbopla�n
Up to 6 x 28 day cycles; NOX66 Days 1-7, Carbopla�n Day 2
Cycles 1-3 = Low Dose (AUC4); Cycles 4-6 = Standard Dose (AUC6)
��Pa�ent assessed for safety parameters
��Preliminary response on CT images by inves�gator per RECIST 1.1 at 3 months (Cycle 3) and 6 months (end cycle 6)
��Replacement of non-evaluable pa�ents is permi�ed

Financial Disclosures: The authors are employees of Noxopharm Limited, the sponsor company of this study

Trial Design: Safety of NOX66 in Combination with Palliative Dose Radiotherapy - A Phase 1 Dose Escalation Study

Ian Minns, Marinella Messina and Graham Kelly

Background

Study Objec�ves

The experimental an�-cancer drug Idronoxil is a first-in-class inhibitor of the oncogene external NADH oxidase Type 2 (ENOX2). Inhibi�on of ENOX2 in tumour cells can cause a cascade of events which ul�mately promote cell apoptosis and prevent DNA repair in damaged cells.[1-4 ] It has further been shown in vitro that inhibi�ng Sphingolipid metabolism, which can be achieved through ENOX2 inhibi�on, can enhance the effect of radia�on in causing cell injury and death.[5-6 ]

NOX66, a novel formula�on containing Idronoxil as an ac�ve ingredient and designed for rectal administra�on, is under clinical inves�ga�on in combina�on with chemotherapy and radiotherapy. It is hypothesised that NOX66, through delivery of Idronoxil to tumour cells and inhibi�on of ENOX2, may enhance the effects of radiotherapy in target tumours and provide improved efficacy in irradiated tumours. Furthermore, the Idronoxil-ENOX2 interac�on may facilitate the s�mula�on of an abscopal response within non-irradiated tumour cells due to the direct pro-apotosis effects of Idronoxil. Here we describe the design of the first-in-human study of NOX66 in combina�on with radiotherapy in pa�ents with late-stage prostate cancer, inves�ga�ng the safety of three dose levels of NOX66.

Study Title: NOX66 and Palliative Radiotherapy in Patients with Late-Stage Prostate Cancer - A Phase 1b Proof of Concept and Dose Confirmation Study

ClinicalTrials.gov Identifier: NCT03307629

KEY Inclusion criteria

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Study Methodology

A total of 24 pa�ents will be recruited into the trial, in four cohorts

�� Cohort 1 (n=4): NOX66 400mg

�� Cohort 2 (n=4): NOX66 800mg (subject to dose escala�on criteria being met)

�� Cohort 3 (n=4): NOX66 1200mg (subject to dose escala�on criteria being met)

�� Cohort 4 (n=12): NOX66 dose to be determined from assessment of cohorts 1-3

Histologically confirmed prostate cancer and/or PSA of >100 ng/mL at original diagnosis

Metasta�c disease evidenced by either CT/MRI imaging or bone scan

Objec�ve evidence of disease progression

Eligible to receive pallia�ve radia�on therapy for management of disease

At least two lesions, one of which is measurable and one which is suitable for radia�on thera-

Ongoing androgen depriva�on therapy with luteinizing hormone-releasing hormone (LHRH) agonist or antagonist

ECOG Performance status 0-2

KEY Exclusion criteria

Tumour involvement of the central nervous system

Concurrent systemic chemotherapy or biological therapy.

Any situa�on where the use of suppository therapy is contra-indicated or imprac�cal (eg.

The Study will involve treatment with NOX66 and radia�on therapy as follows:

Baseline: Tumour assessment scan using CT/MRI, screening laboratory assessments (including PSA levels), and pain assessment (Brief Pain Inventory-Short Form)

Day 1-15: NOX66 will be administered rectally (one, two or three suppositories daily, depending on cohort alloca�on)

Day 2-8: Lesions selected for irradia�on will receive pallia�ve dose (20Gy) radia�on therapy in 5 frac�onated doses over 7 days (no radia�on therapy on weekends).

Week 6: Ini�al follow up scan using CT/MRI, follow up laboratory assessments (including PSA levels), and pain assessment

Week 12: Second follow up scan using CT/MRI, follow up laboratory assessments (including PSA levels), and pain assessment

Week 24: third follow up scan using CT/MRI, follow up laboratory assessments (including PSA levels), and pain assessment

Pa�ents will con�nue to be followed up a�er 24 weeks at the discre�on of the inves�gator.

Dose Escala�on:

Each of Cohorts 1-3 will be reviewed following the comple�on of NOX66 therapy within the cohort (4th pa�ent, Day 15).

Provided no acute safety signals are noted, the next cohort shall commence at the escalated dose.

Following the Week 6 Scan for pa�ent 12 (cohort 3) a determina�on of dose for cohort 4 will be made

References

Morre and Morre (2003). “ Cell Surface NADH Oxidases (ECTO-NOX Proteins) with Roles in Cancer, Cellular Time-Keeping, Growth, Aging and Neurodegenera�ve Diseases ”. Free Rad. Res. Vol 37 (8); pp 795-808
Morre et al (2007). “ ECTO-NOX Target for the An�cancer Isoflavene Phenoxodiol.” Oncol Res. Vol 16; pp 299-312

Study Loca�ons

The Study is being conducted at Radia�on Oncology Centres in NSW and Queensland

De Luca et al (2009). “ Downstream Targets of Altered Sphingolipid Metabolism in Response to Inhibi�on of ENOX2 by Phenoxodiol.” The Prostate. Vol. 70; pp 1211-1221
Huang et al (2011). “ Roles of Sphingosine-1-Phosphate on Tumorigenesis ” World J. Chem. Pp 25-34
Rodriguez-Lafrasse et al (2002). “ Increasing Endogenous Ceramadie Using Inhibitors of Sphingolipid Metaboilism Maximizes Ionizing Radia�on-Induced Mitochondrial Injury and Apopto�c Cell Killing.” Int. J. Cancer. Vol 101; pp589-598
Kolesnick and Fuks (2003). “ Radia�on and Ceramide Induced Apoptosis” Oncogene. Vol 22; pp 5897-5906

Acknowledgement

This trial is being conducted in collabora�on with TROG Cancer Research Australia

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Financial Disclosures: The authors are employees of Noxopharm Limited, the sponsor company of this study

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NOXOPHARM LIMITED AGM Information 2017

65437_rns_2017-11-12_374eb6ab-a9ba-4705-8229-e144124dbf32.pdf

Date: 13 November 2017 Sydney, Australia

ASX: NOX