CARE Therapy Backgrounder September 2015

KEY CANCER TRENDS

The US has about 12% of the world’s cancer cases 1.7M new cases in the US in M cases Worldwide in 2014 Prevalence is highest where lifespan is longest 5 types of cancer make up nearly half of all cases

Population (M) New Cases (M) Incidence (per 100K) Mortality (per 100K) Source: US Census Bureau (population), SEER-9 Cancer Statistics Factsheets (all cancer sites, M+F) Despite improvements in incidence and mortality, US cancer diagnoses are growing faster than the population CAGR % 0.97% -0.21% -0.98% (slowing growth, aging, becoming more diverse) (improving due to lower smoking rates, better screening, and diet) (due to improved therapies) (accelerating – see next slide) Trend

An aging population with higher cancer prevalence rates is driving the outsized growth in cancer diagnoses

Growth in US Cancer diagnoses is projected to accelerate from 1.6% to 2% CAGR, reaching 2.3M by 2030 Source: Journal of Clinical Oncology April 2009 Driving Factors: Aging Population More minorities “Demographic changes in the United States will result in a marked increase in the number of cancer diagnoses over the next 20 years. Continued efforts are needed to improve cancer care (especially) for older adults and minorities.” 2% CAGR 1.6% CAGR 2,300

The prevalence cost of cancer care in the US was estimated at $138B in 2014 $10,298 per cancer survivor per year Total cost of care is projected to grow at 3.3% CAGR, assuming current trends in incidence, mortality, and costs The cost of cancer care is expected to increase even faster; Insurers are pressured to mitigate cost Medicare, Medicaid, and Private Insurance pay for most of the cost of care

CANCER TREATMENT

The Cancer Treatment Spectrum 1.Surgery – used to remove or de-bulk cancers 2.Chemotherapy – broad spectrum therapy, best for cancer that has spread 3.Radiation Therapy – targeted therapy, best for cancer that is localized 4.Immune Therapy – getting the body to recognize and fight cancer with immune response 5.Targeted Therapy – includes Gene therapy 6.Transplantation – Bone marrow, stem cells, etc.

Radiation Therapy Facts About 2/3 of all cancer patients receive radiation therapy – Approx 1.1M US patients in 2014 Breast, Prostate, and Lung cancer made up slightly more than half of all US patients – Around 88% of radiotherapy patients were treated with a linear accelerator in 2004 – The average cost of radiation therapy is estimated at $17,400 The average patient undergoes 29 treatments (2003 data) $600 average Medicare reimbursement cost per session (2015 data) In 2008, there were about 4,500 licensed radiation oncologists in the US – The average oncologist sees between 200 and 300 patients annually (avg = 244) There are an estimated 2,100 radiation therapy locations in the US – These locations employ an estimated 35K people full-time About 2/3 of these are regularly trained on new equipment and therapies Sources: Physician characteristics and distribution in the US (2010) 2004 IMV medical information division 2003 Society for Radiation oncology Administrators Benchmarking Survey Answers.org

Step 1: Imaging Precise shape and location of tumor are determined Step 2: Treatment Plan Total Dosage (typically Grey) Number of sessions (averages 29) Dose per session (typically 1.8 to 2.0 Grey) Step 3: Radiotherapy Tumor is exposed to radiation (typically x-rays) from multiple angles Targeting typically includes some healthy tissue to ensure the cancer is exposed entirely Radiation Therapy Treatment Process

How Radiation Therapy Works Radiation is targeted at the tumor cells The objective is to cause un-repairable DNA breaks and reproductive cell death DNA breaks are caused by one of two ways: Indirect route: water ionization Direct route: linear energy transfer

Complications with Radiotherapy Skin and organs can absorb radiation Stray ionization into healthy tissue Absorption by surrounding healthy tissue These complications can create unwanted side-effects

The Side Effects of Radiotherapy can be serious Acute Side Effects Damage to epithelial surfaces Nausea/vomiting Mouth/throat/stomach sores Intestinal discomfort Swelling/Inflammation Chronic Side Effects Fibrosis Hair loss Dryness (salivary/tears) Cognitive decline Infertility Radiation proctosis (rarely) cancer, heart disease Mitigation Techniques More accurate ionizing beams 3D conformal (IGRT, 3DCRT, IMRT) Stereotactic (SRS/SBRS) Volumetric modulated arc (VMAT) Proton/particle therapy Delivers more energy to the tumor / less to healthy cells On average, is 2.4X more costly* than standard IMRT Drugs To treat the side effects …and now: CARE therapy Priming the body to withstand higher doses of radiation * (2004). Advantage of protons compared to conventional X-ray or IMRT in the treatment of a pediatric patient with medulloblastoma. Int. J. Radiat. Oncol. Biol. Phys. 58, 727–734.

What is CARE Therapy TM ? C.A.R.E. stands for Cell Adaptive Response Effect CARE therapy is used in conjunction with Radiotherapy – A small pre-dose is used to ‘prime’ the healthy cells near the cancer to withstand subsequent large doses of radiation Dose is between 0.02 and 0.1 Gy – The pre-dose induces a well-known phenomena called Adaptive Response – Adaptive response is the body’s reaction to low levels of stress Cells prepares themselves to withstand a larger subsequent stress In this application, CARE prepares healthy cells to withstand the subsequent higher doses of radiation therapy CARE therapy is patented – US Patent: – Issue Date: June 21, 2011

What is Adaptive Response? Adaptive response is the body’s genetic response to environmental stress Examples of adaptive response: – Exercise  muscle mass – Calorie Restriction  longer life – Alcohol  “tolerance” – Sunlight  tanning of skin – Radiation  cellular repair Things that are beneficial in low amounts, but harmful in high amounts

What we know about Pre-Dose Adaptive Response Radiation Dose (Gy) 30 Day Survival % Lifespan (days) 0 (control) – 24hr – Repair of broken Chromosomes - Human fibroblasts Low Dose Wait High Dose DNA Breaks (Gy) Time (Gy) per cell (control) High Dose hr hr Based on full body dose experiments on MICE et.al. 1. Pre-dose can lengthen lifespan and survival 2. Pre-dose with a wait time induces cellular repair mechanisms* Source: Dose-Response Sept pp Based on experiments with dogs 3. Pre-dose can reduce unwanted side effects Impaired saliva production was avoided in dogs that received pre-dose Source: REJ Mitchel, (2015) Low-Dose Irradiation Affects Expression of Inflammatory Markers in the Heart of ApoE -/- Mice, PLoS ONE 10(3): e Red numbers indicate pre-dose amount * We also know which cellular repair genes are switched on

How CARE Pre-Dose Therapy Works Low Intensity beam irradiates around the cancer site (but not into it) Particle Beam Induces adaptive response in healthy tissue surrounding the cancer site

Standard Treatment Follow-up ~24 hours later High intensity beam targeted at cancer site Previously induced adaptive response minimizes ‘good’ tissue damage and unwanted side effects. Higher doses are possible at the cancer site

How can CARE therapy be used? CARE therapy is a treatment protocol to be used with existing radiotherapy equipment and software controls – It’s just another programmed dose session (29  30 on average) CARE therapy can be used in multiple ways: – To minimize unwanted side effects and tissue damage CARE may also reduce the side effects of chemotherapy – To deliver more radiation to the cancer site Saves cost through fewer treatments (hypofractionation) Improve outcomes with a higher cancer kill rate Note: More details are available in a White Paper on CARE therapy.

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