Outline of the presentation - Evgen Pharmaevgen.com/wp-content/uploads/2018/09/EVG-Investor...Outline of the presentation •Breast cancer subtypes and classification •Clinical need

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

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)

ER+ and Triple-Negative subtypes behave differently

Chemotherapy Endocrine therapy

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 survival2

• This has now been extended to c.25 months, by the combinationof hormone therapy with CDK4/6 inhibitors2

• Limited options thereafter and new therapies needed

Image: Cancer Research UK

1American Cancer Society; 2Palbociclib and Letrozole in Advanced Breast Cancer (2016) N Engl J Med

Breast cancer stem cells (CSCs) as drivers of resistance to hormone therapies in ER+ mBC

Simoes et al., Cell Reports, 2015

First preclinical evidence for sulforaphane targeting CSCs in breast cancer

A B

Clin Cancer Res; 16(9) May 1, 2010

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

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

SFX-01 reduces breast CSC activity in 80% of metastatic BC patient derived-samples

SFX-01 reduces breast CSC activity in primary (67%, n=8/12) and metastatic (80%, n=12/15) breast cancer patient derived-samples

Early Breast Cancer Metastatic Breast Cancer

0

0.5

1

1.5

2

2.5

59 60 66 68 70 72 74 77 77b 81 82 83 71 76 790

0.5

1

1.5

2

2.5

80 174 180 183 87 100 160 163 72 94 141 164

Mam

mosphere form

ation e

ffic

iency (

%)

Mam

mosphere form

ation e

ffic

iency (

%)

Vehicle

SFX-01

Vehicle

SFX-01

BB3RCBB6RC

ER+ HER2+ Triple negative ER+ HER2+ Triple negativeTUMOURS: TUMOURS:

**

**

**

**

****

** **

**

*

**

**

****

****

****

**

*

Figure 1: Mammosphere formation efficiency (MFE) of freshly isolated early (A) and metastatic (pleural effusions and ascites) (B) patient-derived samples

cultured in the presence of SFX-01 (5 μM, blue bars) or vehicle control (black bars). MFE data for each individual patient sample is represented. MFE was

determined on day 7-9 and calculated by dividing the number of mammospheres formed (≥ 50μm) by the original number of single cells seeded (500 cells/cm2)

and is expressed as the mean percentage ± SEM. * p < 0.05; ** p < 0.01

A) B)

SF

SFX-01 abrogates tamoxifen-induced enrichment of breast CSCs in patient-derived tumours

Preclinical data from the University of Manchester (presented at AACR 2015)

Measures of “stemness”

SFX-01 deactivates STAT3 and reduces metastases to the lungs

BA Tamoxifen (50% of mice) Fulvestrant (60% of mice)

SFX-01 + Tamoxifen (0% of mice) SFX-01 + Fulvestrant (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

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

SFX-01 in the treatment and evaluation of metastatic breast cancer (STEM)

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

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

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

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

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)

Patient case study II

Liver metastasis

SFX-01 presents a unique mechanism of action in the metastatic breast cancer therapy landscape

mTOR inhibitors

CDK 4-6

ER

Estradiol

Cyclin D

mTOR

AKT

PI3KAromatase inhibitors

ER modulators

CDK4/6 inhibitors

Anastrazole, Letrozole, Exemestane

Tamoxifen, Fulvestrant

Palbociclib, RibociclibAbemaciclib

Everolimus

SFX-01

STAT3

CDK4/6

TUMOUR RENEWALTHERAPY RESISTANCEIMMUNE EVASION3UMOUR

CELL PROLIFERATION

The best point of entry into the market landscape is the extension of second-line hormone therapy

CDK4/6i2Chemotherapy

1First-line in post-menopausal – for premenopausal, tamoxifen can also be given as 1st-line therapy2Palbociclib is approved in 1st and 2nd-line settings, Ribociclib is approved in the 1st-line setting, Abemaciclib is approved in the 1st-line setting and also later lines as monotherapy3Palbociclib and Letrozole in Advanced Breast Cancer (2016) N Engl J Med4BOLERO-2: Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer N Engl J Med 2012; 366:520-529; Fulvestrant in advanced breast cancer: evidence to date and place in therapy (2017) Ther Adv Med Oncol

Everolimus

Aromatase Inhibitors (AI)1

First-line therapy Second-line therapy

Median PFS c.15 months for AI, extended to c.25 months in combination with

CDK4/6i3

Fulvestrant/Exemestane

SFX-01

Fulvestrant/Exemestane

Improved Median PFS ?More favourable safety and tolerance ?

Median PFS 3.7-6.5 months for Fulvestrant and 3.2 months for Exemestane, extended

to 7.8 months for the combination of Everolimus with Exemestane4

A clinical development pathway for SFX-01 as a potential second line therapy post CDK4/6i

SFX-01 (300mg QD) + Fulv/Exem (20 patients)2nd line ER+ mBC post CDK4/6i

Placebo + Fulv/Exem (20 patients) 2nd line ER+ mBC post CDK4/6i

SFX-01 + Fulv/Exem (100+ patients)2nd Line ER+ mBC post CDK4/6i

Placebo + Fulv/Exem (100+ patients)2nd Line ER+ mBC post CDK4/6i

1o: Tumour size @ 18 weeks

2o: Biomarkers

1o: PFS (progression-free survival)2o: CBR (clinical benefit rate), OS (overall survival),

biomarkers

Final analysis

Final AnalysisPhase II Phase IIb/III

14 monthsCurrent SFX-01 formulationEU

28 monthsNew solid dose SFX-01 formulationUS and EU

SFX-01 (300mg BID) + Fulv/Exem (20 patients)2nd line ER+ mBC post CDK4/6i

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 – 2nd 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)