6/8/2017. Disclosure. High MBD Genetic vs hormonal effects. Hypotheses

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1 1 Disclosure Stephen N Birrell MD PhD FRACS Co-Founder Chief Medical Officer Nicholas D Birrell BSc (Hons), MSc, PhD Scientific Advisor An open labelled evaluation of subcutaneous combined testosterone / anastrozole (T+Ai) implants in pre-menopausal women with high volumetric mammographic density I am a major shareholding in Havah Therapeutics Pty and Wellend Health Pty Ltd; and I have received major funding from AstraZenca not for the data presented today Havah Therapeutics Pty Ltd 97 Hewitt Ave, Suite 5 Toorak Gardens, SA 5065 t: +61 (0) e: sb@havahtx.com w: JUNE 2017 Hypotheses High MBD Genetic vs hormonal effects PATIENT 1 PATIENT 2 MAMMOGRAM 2017 MAMMOGRAM 2017 That mammographic breast density (MBD) is a surrogate marker for breast cancer risk That MBD is the only current practical modifiable risk factor That MBD can be altered by hormonal manipulation That altering the testosterone to estradiol ratio in breast tissue will reduce mammographic breast density (MBD) Breast Ca at 42 now 61 yo Breast Ca at 38 now 68 yo 3 4 1

2 High MBD Genetic vs hormonal effects DAUGHTER 1 DAUGHTER 2 MAMMOGRAM 2017 MAMMOGRAM 2017 Justification The breast demonstrates all the hormonal features of skin appendages eg the oral contraceptive Treats acne Increases breast size Androgen receptors (AR) are copious in the embryonal breast mesenchyme and regulates epithelial-mesenchymal signaling Reynaud demonstrated the profound effect of testosterone retarding breast development in both male and female mice Diagnosed with pituitary failure at age 2 now 36 yo Diagnosed with pituitary failure at age 5 now 39 yo We have demonstrated a profound and synergistic effect of testosterone and an aromatase inhibitor on normal human breast explant tissue Proliferation Apoptosis CD36 levels 5 6 Effects on breast tissue of an increased androgen to estradiol ratio The importance of combined therapy Transgender F to Ms on high dose testosterone rarely develop breast cancer Body-builders abusing androgens use tamoxifen or aromatase inhibitors to retard breast development. Lower incidence of breast cancer in women with PCOS chrt (CEE and MPA) has been demonstrated to increase MBD In the adult breast there are extremely high levels of aromatase and 5α-reductase, especially in HMBD tissue In women taking testosterone in trials to reduce the side-effects of an aromatase inhibitors (Ai) we have demonstrated reduction in breast pain (inflammation) Breast cancer initiation needs to be enacted at a younger pre-menopausal age but, AIs contraindicated in pre-menopausal breast cancer women due to hypothalamicpituitary axis (HPA) hyper-stimulation The addition of increased levels of androgen should keep the HPA suppressed 7 8 2

3 Anticipated effects of T+Ai therapy Trial design Lower levels of serum estradiol Lower levels of intra-mammary estradiol due to Lower serum estradiol Aromatase blockade in the breast resulting blockade of exogenous and endogenous testosterone to estradiol conversion Higher levels of serum testosterone resulting in higher breast tissue levels of the potent AR ligand 5α-dihydrotestosterone Only high MBD tissue is affected due to intense enzymatic conversions allowing effect without the side-effects of tamoxifen and potential stabilization of perimenopausal hormonal dysfunction. Open labeled cohort study of 74 pre-menopausal women with age matched controls undergoing routine mammographic screening MBD 15.5% on Volpara measurement (BiRADS D) Not on any other hormonal therapy No previous breast malignancy (including in-situ disease) Treatment arm received a subcutaneous implant containing Testosterone 80mg combined with Anastrozole 2 mg replaced every 4 months for 1 year Primary endpoint-mbd at after 1 year of therapy 9 10 Results Example VBD (%) Control Treatment VBD(%) VBD (CC) Baseline year (-0.5) -19.5% (- 5.4) VBD (CCm)) Control Treatment Baseline year % -14.7% Before After 20.0% 14.7%

4 MMG Baseline MRI MMG Post-Treatment MRI Adverse Events Conclusions Extreme MBD in pre-menopausal women can be reduced by combined T+Ai therapy No subject withdrawal Very well tolerated Minor androgenic side-effects 2 implant insertion inflammations not requiring treatment No alteration in FSH, LH levels Well tolerated 82% of women achieved >10% reduction in MBD (compared to 47% in tamoxifen trial) Subcutaneous insertion Well accepted Excellent compliance Unique low dose anastrozole delivery system Fully automated volumetric density is an excellent tool for biomarker measurement of a therapeutic intervention MBD is an excellent surrogate end-point in prevention trials

5 Thank you. 5