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SixOne Solutions LLC is an early-stage preclinical company developing targeted small-molecule breast cancer drugs.
We are pursuing a streamlined, cost-effective development plan for first in class products that address a cancer pathway not addressed by any current cancer drugs.
The compounds we are developing may be broad-spectrum cancer drugs, as the pathway targeted by our compounds is implicated in many hard-to-treat cancers.
SixOne Solutions LLC
Scientific founders Prof. Heide Ford and Assoc. Prof. Rui Zhao
◦ Discovered new cancer pathway
◦ Comprehensively validated a key pathway protein complex as a drug discovery target Target validation subsequently confirmed by others Key review paper: http://informahealthcare.com/doi/abs/10.1517/
14728222.2014.978860
◦ Through a 10-year collaboration determined the target structure, developed assays, and identified small molecule compounds that disrupt this target protein complex
SixOne is commercially developing these compounds to treat breast cancer and potentially other cancers.
Proof of Concept Validated
Breast cancer is the second leading cause of cancer death for women (after lung cancer)
Each year 450,000 women die of breast cancer globally.
Metastasis (spread of cancer to other organs) is the primary cause of death.
Critical market need: new therapies to prevent or treat metastasis.
Breast cancer treatment = $10 B global market
Unmet need for targeted therapy for metastatic breast cancer
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SixOne Solutions is developing breast cancer drugs to treat/prevent metastatic breast cancer
SixOne drugs
Radiation/chemotherapy
Herceptin (targeted therapy)*
Targeted to cancer cells
Yes No
(debilitating side effects)
Target found in normal cells but higher amount in
cancer cells
Prevent or treat metastases
Yes Yes- but soon recur
Yes – but soon recur
Triple-negative patients
Yes Yes -but soon relapse
No
% Patients 50% + All – but soon relapse
25%
*Leading targeted therapy on the market today with $1.8 B in annual sales
SixOne Solutions is developing first in class small molecule products for treating metastatic breast cancer. • Our products address Eya/Six, not targeted by current cancer
drugs. • The central role of Eya/Six1 in breast cancer, and, importantly, in
metastasis, was discovered by our scientific founder Dr. Heide Ford.
• The Eya/Six1-controlled cancer pathway is found in a majority of breast cancer patients and 90% of metastatic breast tumors
• Eya/Six1 has been shown to turn on genes leading to metastasis (spread) of cancer cells from the original breast tumor, thus drugs targeting Eya/Six1are expected to block cancer growth and metastasis.
• SixOne’s drugs are expected cause few side effects because they will be specific to Eya/Six1, which is present in cancer cells but generally not found in normal cells. Non-toxic drugs are critical as breast cancer treatment is expected to shift to combinations of targeted drugs in place of chemotherapy.
SixOne’s products
Eya Six1
ProliferationSurvivalInvasionMigration
ProliferationSurvivalInvasionMigration
Tumors
Metastasis
Eya/Six1 complex may be a key control point in a widespread cancer pathway; they have been implicated in breast, ovarian, lung, pancreatic, brain, and other cancers.
Target DiscoveryThe proteins Eya and Six1, abundant during embryo growth, are generally absent in adult cells. When aberrantly active in adult cells, their usual functions result in tumor growth and metastasis.
Target Validation: Six1
Six1 gene manipulation also inhibits growth/metastasis of other cancers in mouse models:- Rhabdomyosarcoma (Yu et al., Nat Med 2004)- Hepatocellular Carcinoma Ng et al., Int J Cancer (2010)- Kidney cancers (Imam et al., Oncogene 2010)- Colorectal Cancer (Li et al., Int J Clin Exp Path 2014)
The impact of Six1 has been established in mouse models: Manipulation of Six1 genes in mice dramatically decreases tumor growth and metastasis.
Target Validation: Eya Required
Six1 does not act alone: metastasis increases and survival decreases in mouse models when Six1 binds with Eya
Six1/Eya
Six1 mutants not able to bind to Eya
Six1 mutants not able to bind to Eya
Six1/Eya
Tumor growth and metastasis
Survival
Target Validation: Human patientsHigh Six1 + high Eya2 levels in human breast cancer patients = poor prognosis
Farabaugh et al, Oncogene, 2012
Six1/Eya: Target for Many Tumor Types
SIX1 EYA1 References
Wilms’ Tumor Wilms’ Tumor Li et al., Am J Pathol 2002; Imam et al., Oncogene, 2010
Acute Leukemia Acute Leukemia Wang et al., Blood, 2011
Glioma Glioma Auvergne et al., Cell Reports, 2013
Breast Cancer Breast Cancer Pandey et al., Oncogene 2010; Farabaugh et al., Oncogene 2012
SIX1 EYA2
Ovarian Cancer Ovarian Cancer Zhang et al., Cancer Res, 2005; Behbakht et al., Cancer Res, 2007
Lung Cancer Lung Cancer Huang et al., J Clin Oncol, 2009; Mimae et al., Clin Cancer Res, 2012
Cervical Cancer Cervical Cancer Wan et al., Int J Cancer, 2008; Bierkens et al., Genes Chromosomes Cancer, 2013
Breast Cancer Breast Cancer Pandey, Oncogene 2010; Farabaugh et al., Oncogene, 2012; Patrick et al, Nature SMB 2013
SIX1 EYA3
Ewing Sarcoma Ewing Sarcoma Robin et al., Mol Cancer Res, 2012 and unpublished data
Breast Cancer Breast Cancer McCoy et al., J Clin Invest 2009; Micalizzi et al., J Clin Invest 2009; Pandey et al., Oncogene 2010
Drugs Targeting Six1/Eya Expected to block tumor growth/metastasis at early and later stages for broader efficacy
Discovery of Anti-Six1/Eya Compounds
We identified small molecule compounds that disrupt the Eya/Six1 complex by two different modes: Group 1 compounds inhibit a key catalytic function of Eya. Group 2 compounds prevent Eya and Six1 from binding to form the active complex.
Effective in Breast Cancer Cell Assays
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Group 1 compounds
Inhibit Eya catalytic activity (uM) through an allosteric mechanism
Group 2 compounds
And block tumor cell motility – a hallmark of cancer
Intellectual PropertyPioneering Patent Portfolio
Issued and Pending Patent Applications:
• Protein complex target
• Methods of treatment
• Proprietary small molecule compounds
Optimize compounds for greater potency ◦ Straightforward medicinal chemistry to improve
compounds and select best compound to commercialize
Demonstrate efficacy in animal disease models◦ Standard industry accepted breast cancer mouse models
Upon successful completion of these milestones, we believe we will be able to attract a strategic partner who will complete clinical development and launch products.
Next Milestones
Strategy and Financing Plan
RESEARCH/CLINICAL DEVELOPMENT MILESTONESACCOMPLISHED TO BE COMPLETED
2004-2012
2013 2014 2015 2016 2017
TARGET DISCOVERY/VALIDATION
DRUG DISCOVERY
MEDICINAL CHEMISTRY/OPTIMIZATION
IN VIVO EFFICACY
FINANCING: Funding to date Funding requirements
Pre-founding grantsNon-dilutive grantsInvestment (current raise)
$1.0M $0.5M $0.5M$340K
$800K
Once efficacy demonstrated in mouse model - potential EXIT to strategic partner
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Ginny Orndorff, CEO ◦ Founder/CEO of Evolutionary Genomics. ◦ Previously with GenoPlex, NeXstar, and Genex.
Scientific Founders actively involved◦ Dr. Heide Ford and Dr. Rui Zhao, CU Denver AMC
Dr. Xicheng Sun, Chemistry Consultant ◦ 3D Partners, N30, Replidyne, Array Biopharma
Dr. Cathy McCall, Regulatory Consultant ◦ Clinipace Boulder
Team
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Novel, well-validated target for breast cancer and potentially a broad range of cancers.
Compounds targeting this pathway are expected to be effective in metastatic breast cancer and have low toxicity.
Compounds in hand have demonstrated efficacy in standard human breast cancer cell assays.
Clear medicinal chemistry optimization path.
Pioneering IP portfolio including issued patent.
Shareholder exit through merger/sale to strategic partner possible in approximately 18 – 24 months.
Summary
