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2 Outline of the presentation Breast cancer subtypes and classification Clinical need in estrogen-positive (ER+) metastatic breast cancer (mbc) Sulforaphane and SFX-01: the preclinical evidence STEM Phase IIa trial: objectives, trial design, current status and interim update Patient case studies SFX-01 positioning in tomorrow s treatment paradigm Next steps

3 Breast cancer subtypes BC most frequent cancer and most common cause of death in females <55 in UK Mortality rate improving due to improved therapies Incidence of breast cancer continues to rise All breast cancers are not equal Multiple breast cancer sub-classification systems predominantly genomic based designed to improve prognostication and prediction of treatment (usually chemotherapy responsiveness) Bottom line is that we use Estrogen Receptor (ER), Progesterone receptor (PR) and Her2 expression to define most systemic treatments (absence of all 3 receptors is called Triple Negative breast cancer)

4 ER+ and Triple-Negative subtypes behave differently Chemotherapy Endocrine therapy

5 ER+ metastatic breast cancer ER+ breast cancer is the most prevalent breast cancer sub-type Metastatic breast cancer (also known as Advanced or Stage 4 ) means that the cancer has spread to other parts of the body 5-year survival rates are 22% 1 - incurable First-line hormone therapy can provide c.9-15 months of progression free survival 2 This has now been extended to c.25 months, by the combination of hormone therapy with CDK4/6 inhibitors 2 Limited options thereafter and new therapies needed Image: Cancer Research UK 1 American Cancer Society; 2 Palbociclib and Letrozole in Advanced Breast Cancer (2016) N Engl J Med

6 Breast cancer stem cells (CSCs) as drivers of resistance to hormone therapies in ER+ mbc Simoes et al., Cell Reports, 2015

7 First preclinical evidence for sulforaphane targeting CSCs in breast cancer Clin Cancer Res; 16(9) May 1, 2010 A B Inhibitory effect of sulforaphane on mammosphere formation in MCF7 and SUM 159 cells Sulforaphane abrogated the tumorigenicity of breast cancer CSCs in vivo as assessed by reimplantation in secondary mice

8 Sulforaphane shows promise but a lack of stability is a real issue for clinical development SFX-01 is a complex of sulforaphane and cyclodextrin: a robust pharmaceutical development product

9 SFX-01 reduces breast CSC activity in 80% of metastatic BC patient derived-samples B) Mammosphere formation efficiency (%) 2.5 Metastatic Breast Cancer 2 ** Vehicle 1.5 SFX-01 * ** ** ** ** ** ** ** ** ** 0 ** BB3RC b TUMOURS: ER+ HER2+ Triple negative

10 SFX-01 abrogates tamoxifen-induced enrichment of breast CSCs SF in patient-derived tumours Measures of stemness Preclinical data from the University of Manchester (presented at AACR 2015)

11 SFX-01 deactivates STAT3 and reduces metastases to the lungs A B Tamoxifen (50% of mice) SFX-01 + Tamoxifen (0% of mice) Activated (phosphorylated) STAT3 plays an important role in maintaining stem cell renewal, promoting metastases and evading immune surveillance Activated STAT3 is elevated by hormone therapy but near eliminated by SFX-01 Fulvestrant (60% of mice) SFX-01 + Fulvestrant (0% of mice)

12 SFX-01 in the treatment and evaluation of metastatic breast cancer (STEM) RATIONALE: Resistance to hormone therapy is driven by the growth in the population cancer stems cells (CSCs) SFX-01 reduces CSCs in patient-derived xenograft tumours treated with hormone therapy SFX-01 may extend the utility of hormones and defer resistance; and/or SFX-01 may even reverse hormone resistance one established STEM investigates the latter - the highest hurdle - if one gets a signal here, that would bode well for deferring resistance in subsequent trials

13 SFX-01 in the treatment and evaluation of metastatic breast cancer (STEM) OBJECTIVE: The STEM trial is an exploratory trial designed to demonstrate safety and tolerability with long-term exposure to SFX-01 and to provide evidence that it has anti-tumour activity after failure of at least one and up to three prior hormone therapies TRIAL DESIGN: Open-label Phase II, multicentre, study on patients who are taking either a third generation aromatase inhibitor (AI), tamoxifen or fulvestrant and have a documented evidence of progressive disease after (1) a period of stable disease (for at least 6 months) or (2) an objective response on the current treatment indicating the development of secondary resistance 60 patients Patients will have 6-weekly scans and will discontinue from the study upon clinical progression, up to a maximum of 28 weeks

14 SFX-01 in the treatment and evaluation of metastatic breast cancer (STEM) PRIMARY ENDPOINTS Treatment-Emergent Adverse Events (Safety and Tolerability) to determine the safety and tolerability of SFX-01 in combination with AI, tamoxifen and fulvestrant Clinical benefit rate (CBR, where CBR = Complete Response + Partial Response + Stable Disease) at 24 weeks using RECIST v1.1 STUDY STATUS: Interim update on first 20 patients announced in June 2018 Patient recruitment concluded in July 2018 with 47 evaluable patients on the basis that the study objectives had been met Final reporting expected around the end of the year

15 STEM Interim Update (June 2018) First 20 patients SFX-01 is proving to be well tolerated with no safety concerns arising SFX-01 shows encouraging early signs of anti-tumour activity: - 2 objective partial responses - 4 patients had stable disease to 6 months - 2 additional patients has stable disease to 18 weeks

16 Patient case study I Diagnosed age 40 ER+ Her2- BC Chemotherapy Tamoxifen for 5 years Diagnosed with pleural nodules Biopsy metastatic ER+ Her2- BC Enrolled into STEM trial May 2017 tamoxifen + SFX-01 Objective response to treatment, very well tolerated, able to continue her life caring for her 2 young children and husband with terminal cancer (update: latest September scan confirms ongoing disease stability)

17 Patient case study II Liver metastasis

18 SFX-01 presents a unique mechanism of action in the metastatic breast cancer therapy landscape Aromatase inhibitors Anastrazole, Letrozole, Exemestane Estradiol PI3K AKT mtor inhibitors Everolimus ER modulators mtor SFX-01 Tamoxifen, Fulvestrant ER CDK4/6 inhibitors STAT3 Palbociclib, Ribociclib Abemaciclib Cyclin D CDK CDK4/6 4-6 TUMOUR RENEWAL THERAPY RESISTANCE IMMUNE EVASION3UMOUR CELL PROLIFERATION

19 The best point of entry into the market landscape is the extension of second-line hormone therapy First-line therapy Second-line therapy Aromatase Inhibitors (AI) 1 CDK4/6i 2 Median PFS c.15 months for AI, extended to c.25 months in combination with CDK4/6i 3 Fulvestrant/Exemestane Everolimus Median PFS months for Fulvestrant and 3.2 months for Exemestane, extended to 7.8 months for the combination of Everolimus with Exemestane 4 Chemotherapy Fulvestrant/Exemestane SFX-01 Improved Median PFS? More favourable safety and tolerance? 1 First-line in post-menopausal for premenopausal, tamoxifen can also be given as 1 st -line therapy 2 Palbociclib is approved in 1 st and 2 nd -line settings, Ribociclib is approved in the 1 st -line setting, Abemaciclib is approved in the 1 st -line setting and also later lines as monotherapy 3 Palbociclib and Letrozole in Advanced Breast Cancer (2016) N Engl J Med 4 BOLERO-2: Everolimus in Postmenopausal Hormone-Receptor Positive Advanced Breast Cancer N Engl J Med 2012; 366: ; Fulvestrant in advanced breast cancer: evidence to date and place in therapy (2017) Ther Adv Med Oncol

20 A clinical development pathway for SFX-01 as a potential second line therapy post CDK4/6i Phase II Phase IIb/III SFX-01 (300mg BID) + Fulv/Exem (20 patients) 2 nd line ER+ mbc post CDK4/6i SFX-01 + Fulv/Exem (100+ patients) 2 nd Line ER+ mbc post CDK4/6i SFX-01 (300mg QD) + Fulv/Exem (20 patients) 2 nd line ER+ mbc post CDK4/6i Placebo + Fulv/Exem (20 patients) 2nd line ER+ mbc post CDK4/6i Final analysis Placebo + Fulv/Exem (100+ patients) 2 nd Line ER+ mbc post CDK4/6i Final Analysis 14 months Current SFX-01 formulation EU 1 o : Tumour 18 weeks 2 o : Biomarkers 28 months New solid dose SFX-01 formulation US and EU 1 o : PFS (progression-free survival) 2 o : CBR (clinical benefit rate), OS (overall survival), biomarkers

21 Summary and next steps for SFX-01 Significant clinical need associated with extending the utility of hormone therapies in ER+ mbc The success of CDK4/6 inhibitors validate that need but even those ultimately fail In the most difficult of settings, SFX-01 has demonstrated anti-tumour activity with good safety and tolerability although the full detail of the read-out will only be known at the end of the year Next step should be a randomised, double-blind, placebo controlled Phase II study in ER+ breast cancer 2 nd line after CDK4/6 inhibitors and if approved in this setting could potentially move earlier in the treatment pathway New data from the University of Manchester demonstrates SFX-01 having a similar effect in triple negative breast cancer (PDX model)

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