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 2014

14M cases Worldwide in 2014

Prevalence is highest where lifespan is longest

5 types of cancer make up nearly half of all cases

1994 2004 2014

Population (M) 263.1 292.8 318.9

New Cases (M) 1.21 1.37 1.67

Incidence (per 100K) 0.484 0.476 0.460

Mortality (per 100K) 211.7 186.8 173.8

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 94-14

1.62%

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 division2003 Society for Radiation oncology Administrators Benchmarking Surveywww.RT Answers.org

Step 1: Imaging• Precise shape and location of

tumor are determined

Step 2: Treatment Plan• Total Dosage (typically 45-60 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 causeun-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 TherapyTM?• 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: 20090114846 – 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) 100 727 1.0 30 486 0.1 – 24hr – 1.0 70 578 Repair of broken Chromosomes - Human fibroblasts Low Dose Wait High Dose DNA Breaks (Gy) Time (Gy) per cell 0 - 0 0.06 (control) 0.5 - 0 0.09

0 - 4 1.1 High Dose 0.5 0 hr 4 0.7 0.5 5 hr 4 0.45

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. 2010 pp 534-542

Based on experiments with dogs3. 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): e0119661

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* 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.

THANK YOU