# Presentation: 002160

## From Wall Street to the Laboratory....
April 13, 2005

Dr. Howard W. Bruckner
Daniel M. Laifer
William A. Schubin

- April 13, 2005
- Dr. Howard W. Bruckner
- Daniel M. Laifer
- William A. Schubin

## A lawyer, a banker and a scientist go into a bar......

## Management Team

- Dr. Howard Bruckner is the Director of Medical Oncology at Lutheran Medical Center in New York and has over 30 years experience as a clinician and researcher.  He has extensively published in the area of innovative multidisciplinary chemotherapy
- Daniel Laifer is an attorney with experience at several large corporate law firms and a hedge fund
- William Schubin is a former investment banker who spent several years at a hedge fund

## The Oncovation Companies

- Founded in March 2004
- Commercialize novel work of Dr. Howard Bruckner focusing on drug interaction and chemosensitivity
- Unique record of “bench to clinic” translational success

## The Oncovation Companies

- Oncovation Pharmaceuticals develops novel drug combinations that strategically add to the efficacy of “standard” and even “standard failed” drugs
- Oncovation Laboratories is a innovative laboratory services company focusing on oncology
- individualized treatment regimens
- triage support for clinical trials

## Viable Business

- Proprietary technology
- Commercially viable
- Market acceptance

## Academic Approach

- Desire to publish early
- Share knowledge to promote innovation
- Perceived tendency to dabble

## Success breeds success

- Promoting protected technologies yields partners and further opportunities
- Viable products addressing obvious needs attract substantial funding and collaborations
- Developing profitable technologies creates interest for the next project

## Work With Us

- Along with novel compounds, we reposition “failed” therapeutics
- Our platform is particularly robust, focusing on cytotoxins, cytostatics, signal pathway inhibitors, monoclonal antibodies and hormones
- Anti-angiogenesis therapeutics and compounds are also well-suited for our technology

## If you build it, they will come...

- We invite proposals from scientists and academics who want to commercialize their discoveries and build innovative companies with the potential to change the world (or at least part of it)

## 

For Selected Patient Practices 
and Strategic Drug Development

Howard W. Bruckner, M.D.

- For Selected Patient Practices
- and Strategic Drug Development
- Howard W. Bruckner, M.D.

- New Solutions for Predictive Testing of Ex Vivo Human Tumors

## Oncovation’s Approach

**Five new lines of development**
- Clinically validated; Prospective development
- Superior technology
- More questions (quantitative)
- Better questions and discover new objectives (qualitative)
- Model-based realistic objectives.
- Individual and empirical
- Opportunities for rapid Phase III validation
- Recommendations are supportable
- Physician/patient friendly empirical therapy with no conflicts
- Empowers drug development, rescues fallen angels
- Applicability to five classes of therapeutics
- Many ideal agents, multiply success

## Clinical Validation

- Retrospective _ovarian_ [response] Cisplatin – taxol
- Retrospective _breast_ [response]
- Prospective development, empirical regimens
- 	_pancreatic_, bilary, _gastric_, small bowel, _lung_ (prostate), ovarian
- 	[Response and survival, reversal of resistance]
- Prospective individual ATC, gastric, colon, ovarian and breast
- 	[Response and survival, reversal of resistance, complete remissions]
- Prospective _ovarian_ – Phase III [response (survival)]
- 	‘too good’, oncologists abandoned standard controls early in trial

## G-FLIP

**Includes over 100 patients**
**median survival of 17 (15-22) months**
- Reproduced in Stage III, previously treated, also patients failing adjuvant therapy and radiotherapy, six series
- Note:  ~ 40% two years

## Clinically Demonstrated

- Response – 40-65% (pair) - individual
- Additional 50% vs. predicted empirical rate – disease specific
- Resistance – 90% predictive
- Reversing resistance – breast, ovary, pancreatic, colon
- Drugs get a second chance
- Survival – pancreatic, cholangio, gallbladder, lung, stomach
- Low dose intensity very feasible, competitive, improved quality of life
- Heterogeneity – turned to advantage _only_ with LDT; ovary, breast, pancreatic
- ___________________
- NCI ‘11% benefit’ in current empirical trials
- Ex vivo 40-60% benefit and multiple choices (triage) improved
- 	**Better than a new drug for **_**every**_** major disease**

## Oncovation’s TCR Assay

**Superior technology**
- Sensitivity (2-5,000 cells)
- Better standard error and dose response
- Always full dose response curves
- Added tests/samples analogue and mechanism confirmation
- Sets higher threshold for discovery
- Tests true resistance
- Tests at low concentrations
- High yield
- 90% of tumors provide information (no colonies)
- Speed (6-7 days)
- Separation (other cells), proprietary
- Path quality check(s) – extra wells, ability to duplicate
- Follow-up, cryopreserve and short term nude mice
- Fewer laboratory artifacts
- More relevant treatment history (prior drugs)
- Representative mixed tumor population

## Better Questions; Algorithm

**Turns tumor heterogeneity to an advantage**
- Disease specific algorithm(s)
- Strategic
- Trade single best pair for multiple singles and pairs
- Recruit added drugs otherwise lost
- Avoid antagonism
- Synergism
- single drug activity doesn’t predict benefit in combination, 50% fail, but the drug is good with another partner
- Reverses Extreme Drug Resistance
- Low doses (1/4- 1/8 concentration) avoids loss of effective drug
- Can focus on a specific drug
- Translational priority for qualitative findings
- ADM/TAXOL e.g., NOV/ADM, PT/DT, CIS/PT, LOHP/IRINO

## Synergism vs. Antagonism

## Reversing Resistance

- Type I – [R1&S2] > [R1]+[S2] or S1+S2
- Type II – [R1&R2] > [R1] +[R2] or S sometimes [S1]+[S2] or [S1&S2]
- Example - Clinical [G-FLIP] pancreatic, A/N  T/P - ovarian, breast
- Metronomic approach
- Resistant Pancreatic Cancer – Avastin
- MDR Models (Kerbel)

## Strategic Direction

**Assay recruits additional drugs and sequential regimens**
**Better partners avoid antagonism and add potency**
- 95% reasonable and compatible with empirical choices
- First empirical choice/ half can be improved
- 25% end stage can be improved
- Compatible with metronomic, biologic therapy

## Strategic Partnering

- Example:  Taxol Platinum [1+] Gemcitabine [0], Taxol [1+], Platinum [1+], Topotecan [0]
- 	Gemcitabine Platinum [2+]
- 	Topotecan, Taxol [2+]

## Breast Cancer Dose Response Curve

- TXT > A
- G not alone
- TXT > TAX (?)
- GT not strategic

## Disease Specific Panel Positions Position (Ex vivo)/Response Rates (empirical)

**Translation ratios – 6 point dose response curves**
- Best 30th percentile can beat best 20th percentiles:
- 30/50 vs. 20/20
- 50% inhibition can beat 70% inhibition
- 40/60 vs. 20/20

## Mathematical Modeling Identifies Highest Yield Applications

- Individual – when empirical prospects are intermediate
- < 30-40% response, median < 1 year survival
- Many competing options exist – heterogeneity –
- Ideally 3 options @ 20% each:  40 + 12 + 12 + 12
- For example:  GOLF, TAG, G-FLIP
- Choice of research, triage to clinical trials, Phase I, II, III
- Efficiency and safety
- Rapid development, design, prioritization tool, tests can parallel ongoing trials [five trials in one, avoid losers]
**Assays improve therapy for the majority of cancer patients**

## Phase III Rapid Validation Priorities  

- < 30-40%, response survival < 1 year MST; crossover option  3
- Examples with _five_ options
**BREAST** – secondary response
- 	[ADM/TAX] [XELODA/TAXOTERE] GEM, NAV, HERC, CISP, TOPO
**GASTRIC** – primary
- 	[FU/CISP] TAXOL IRINOTECAN EPIRUBICIN MITOMYCIN TAXOTERE
**LUNG** – primary or secondary
- 	[TAX/CISP] GEM, NAV, IRINOTECAN, IPX, MMC
- 	Each more than 100,000 patients per year per disease application

## Model Selected Objectives (rapid < 12 months, 18 months)

- Prospective randomized trial – Primary objectives
- Response rate 40 → 64-76%
- Relative risks (0.66), improve survival, median 12+ months
- Secondary objectives - Solutions to heterogeneity and crossover choices
- Stable disease
- Added test of development options (look ahead)
- Validation assay, drug disease specific
- (20 → 30-40%)
- Triage assistance
- Ex vivo and clinical 10-20% → 40%, 40% → 60%
- Phase II individual trials or consortium
- Phase I consortium of trials
- Parallel testing of new drugs, regimens, next options (look ahead)

## Realistic Objectives

- • 	Empirical plus options
- Limited questions simplify, biopsy volume  size
- Disease and prior therapy specific
- Selected development options – look ahead
- Support selected practices (criteria), Multi-disciplinary, Uniform feedback, Assistance, Customized protocols
- High Volume - 50-100 (disease and protocol specific)
- Rescue fallen angels
- Academic Leadership
- 	Orphan Diseases
- 	Pediatric Leadership
- 	Individual Care, Disease Specialists
- Spin-off development parallel tests, specific assays, genetic support, tissue pathology, micro assays, signal phosphorylation apoptosis

## New Era for Drug DevelopmentNew Drug Questions and Opportunities

**Cytotoxins**	Concentration; schedule; interactions; select best partner
**Cytostatics**	Impact on cytotoxins
**Biologics**	Impact alone and on cytotoxins (added methods)
**Hormones**	Impact on cytotoxins, (added methods, polypeptide, steroid)
**Antibodies**	Impact alone and on cytotoxins (interaction), Erbitux, Herceptin
- Micro gell electrophoresis assays
- Micro apoptotic assays
- Agonist – antagonist interactions +/- Erbitux
- 	_____________
- New drugs, many chances to pick a winner,
- New methods, powerful and qualitatively different
**Cannot do it the old fashioned way, unique questions**

## Top 10 List of Benefits of Oncovation Methods 

- Combination therapy errors corrected
- Reverse high dose resistance, solutions to EDR
- Mathematical models and evidence-based development
- Counterintuitive solutions for clinical translation
- Better clinical support, physician-friendly goals
- Parallel development evidence base looks forward
- Clinical protocols facilitate use of findings
- Clinical success translation hierarchy criteria
- Improve market share of second line drugs, second chances
- Efficient triage for individuals and drug development

## Thank You

- Please feel free to contact us with any questions or comments
- Oncovation LLC
- 74 Broad Street
- New York, NY 10004
- 212-514-2422
- info@oncovation.com