Each year nearly 150,000 Americans are diagnosed with a blood cancer—account-ing for about 9 percent of all new cancer diagnoses. The major types of blood cancer include leukemia, lymphoma and myeloma. According to the American Cancer Society, 149,990 new cases of these three blood cancers will be diag-nosed in 2013 in the United States. And, more than 54,000 people will die.

Biopharmaceutical research companies are developing 241 medicines targeting leukemia, lymphoma, myeloma and other cancers of the blood. The medicines in development include:

• 98 for lymphoma—including Hodgkin and non-Hodgkin lymphoma—which impacts nearly 80,000 Americans each year.

• 97 for leukemia, including the four ma-jor types, which affect nearly 50,000 people in the United States each year.

• 52 for myeloma, a cancer of the plasma cells, which affects more than 22,000 people each year in the United States.

• 24 medicines are targeting hematolog-ical malignancies, which affect bone marrow, blood and lymph nodes.

• 15 for myeloproliferative neoplasms, such as myelofibrosis, polycythemia vera and essential thrombocythemia.

• 15 for myelodysplastic syndromes, which are diseases affecting the blood and bone marrow.

All of the medicines in the report are either in human clinical trials or under review by the U.S. Food and Drug Administration (FDA). Facts about blood cancers can be found on page 7.

This overview highlights some of the innovative medicines listed in the report, recent scientific advances in treating leukemia and lymphoma, the role of personalized medicine in the detection and treatment of blood cancers, and the value of cancer research and the incre-mental nature of innovation.

More Than 240 Medicines in Development for Leukemia, Lymphoma and Other Blood Cancers

2013 REPO

RT

Mye

lom

a

Leuk

emia

24

97 98

Lym

phom

a

52

Hem

atol

ogica

l

Mali

gnan

cies

Application Submitted

Phase III

Phase II

Phase I

Medicines in Development For Leading Blood Cancers

2 OVERVIEW • Medicines in developMent LEukEmIa & LymphOma

The Future of Innovation— The Changing Cancer Care EcosystemPrior to the 1950s—when the first treatments for leukemia and lymphoma were developed—a diagnosis of blood cancer was usually fatal. In the 1960s, the first combination treat-ment for childhood leukemia was developed and in the 1970s the first successful bone marrow transplant was performed. In the years since, survival rates have been on the rise and deaths are declining.

Cancer care and research are evolving quickly as science and technology advance. A recent Boston Healthcare study outlined several trends that are expected to increase the pace and complexity of developing new cancer medicines, these include:

Scientific advances are expanding our understanding of cancer. Studying cancer on the molecular and genetic level has revealed that cancer is actually at least 200 separate diseases. Even within a single tumor gene expression and mutations can vary from cell to cell.

Cancer treatment is increasingly moving towards targeted therapies. The use of drugs along with diagnostics is helping to increase efficacy and reduce toxicity by targeting specific tumor pathways.

Combination treatments show promising results. Given the constantly changing nature of cancer, attacking it from multi-ple angles is an important approach. Researchers are studying many different combinations of medicines to increase efficacy.

Many of the 241 medicines in the pipeline are building on these scientific approaches and looking at new ways to treat blood cancers. Some examples of these new innovative treat-ments in development include:

• Blocking Mutated Receptors in Cancer Cells—A medicine for leukemia that may block the activation of the FLT-3 cell receptor that is mutated in about one-third of all patients with acute myeloid leukemia (AML). Activation of this receptor by different types of mutations appears to play an import-

0

2

4

6

8

10

LeukemiaNon-Hodgkin LymphomaHodgkin Lymphoma

200905200019951990198519801975

U.S. Mortality Rate

U.S.

Mor

talit

y Ra

te p

er 10

0,00

0

Year

0

20

40

60

80

100

LeukemiaNon-Hodgkin LymphomaHodgkin Lymphoma

2004/

U.S. 5-Year Survival

U.S.

5-Y

ear S

urvi

val i

n Pe

rcen

t

U.S. Mortality and Survival Rates, 1975-2009

Cancer sites include invasive cases only unless otherwise noted. Mortality source: US Mortality Files, National Center for Health Statistics, CDC. Rates are per 100,000 and are age-adjusted to the 2000 US Std Population (19 age groups—Census P25-1130). Regression lines are calculated using the Joinpoint Regression Program Version 3.5, April 2011, National Cancer Institute. The 5-year survival estimates are calculated using monthly intervals. Survival source: SEER 9 areas (San Francisco, Connecticut, Detroit, Hawaii, Iowa, New Mexico, Seattle, Utah, and Atlanta).

Treatment Advance

Rituxan® (rituximab) was approved in 1997 for the treatment of non-Hodgkin lymphoma and was the first targeted drug therapy approved in the United States. Unlike the typical four- to six-month chemotherapy regimen or high-dose radiation treatment, Rituxan is administered in four infusions on an outpatient basis over 22 days.

Treatment Advance

Sprycel® (dasatinib) was approved in 2006 for the treatment of adults in all phases of chronic myeloid leukemia (CML)—chronic, accelerated, or myeloid or lymphoid blast phase—with resistance to or intolerance of prior therapy. It was also approved for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) with resistance or intolerance to prior therapy. By targeting certain kinases, Sprycel inhibits the overproduction of leukemia cells in the bone marrow of patients with CML and Ph+ALL and allows normal blood red cell, white cell, and blood platelet production to resume.

32013 RepoRt

ant role in tumor cell proliferation, resistance to apoptosis (cell death), and prevention of normal cell development.

• Reducing Treatment Toxicity—Tumor hypoxia, or low oxy-gen concentration, is a result of chaotic vasculature (blood vessel structure) found in all solid tumors and, in the bone marrow of some patients with hematological malignancies, but not in healthy tissues. A medicine in development for leukemia and myeloma consists of two components, a toxic portion and an attached trigger molecule that prevents gen-eral toxicity in these diseases. The trigger molecule keeps the toxin inactive until the drug is in the hypoxic region of the tumor, where it is then activated by the low oxygen concentration, killing the cells in its vicinity.

• Two Targets to Fight Leukemia—A potential first-in-class medicine for acute lymphoblastic leukemia (ALL) is a bispecific T-cell engager antibody designed to focus the body’s cell- destroying T-cells against cells expressing CD19, a protein found on the surface of B-cell-derived leukemia and lymphoma. The modified antibodies are designed to engage two differ-ent targets simultaneously, linking the T-cells to cancer cells.

• Easier Delivery of Treatment—An oral version of an approved injectable medicine is a DNA methyltransferase inhibitor for myelodysplastic syndromes and other hemato-logical malignancies. It regulates the expression of certain genes such as tumor suppressor genes, which are often silenced by methylation during tumor cell transformation. By switching deregulated genes on or off, the medicine stops the uncontrolled proliferation of malignant cells.

24

15

97

98

15

52Myeloma

Myeloproliferative Neoplasms

Myelodysplastic Syndromes

Leukemia

Lymphoma

Hematological Malignancies

Application Submitted

Phase III

Phase II

Phase I

Medicines in Development for Blood Cancers, By Type and Phase of Development

Some medicines are listed in more than one category

Treatment Advance

Adcetris® (brentuximab vedotin), approved in 2011, was the first in a new class of antibody-drug conjugates (ADCs). It was approved to treat Hodgkin lymphoma and systemic anaplastic large cell lymphoma. ADCs combine a monoclonal antibody (an immune system protein) and a therapeutic drug, so the antibody can direct the therapeutic to the cancerous cells.

4 OVERVIEW • Medicines in developMent LEukEmIa & LymphOma

Childhood Leukemia—Expanding Research

This year, more than 11,000 new cases of cancer will be diagnosed in children 0 to 14 years of age, representing less than 1 percent of all cancers, according to the American Cancer Society (ACS). Leukemia accounts for 31 percent of all childhood cancers. About one-third all childhood cancer deaths—1,130 estimated deaths in 2013—are from leukemia.

The good news is that mortality rates for childhood cancer have declined by 68 percent in the last 40 years. According to the ACS, this substantial progress is largely due to improvements in treatment and high rates of participation in clinical trials. And, new treatments are being approved for use against childhood leukemia.

Acute lymphoblastic leukemia (ALL) accounts for every three out of four cases of childhood leukemia and is the most common cancer in children seven years of age and younger. This year FDA approved a new treatment to be used in combination with chemotherapy in children with newly-diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). In clinical

trials, the medicine, when used in combination with chemotherapy, doubled the cure rate in pediatric ALL. The medicine is also approved for treatment of newly-diagnosed pediatric Ph+ chronic myelogenous leukemia (CML).

In 2012, Congress made two provisions affecting pediatric research permanent. The “Best Pharma-ceuticals for Children Act” (BPCA) and the “Pediatric Research Equity Act” (PREA), work together to encourage pediatric research. The combination of BPCA and PREA has resulted in a wealth of useful information about dosing, safety, and efficacy. Together, BPCA and PREA have driven research and greatly advanced American children’s medical care.

BPCA and PREA have led to hundreds of pediatric studies covering more than 16 broad categories of diseases that affect children. Significant progress has been made in our ability to treat pediatric patients thanks to the research conducted as a result of BPCA and PREA. Today, pediatricians have more information than ever about which medicines are safe and effective for children and at what doses. Since 1998, BPCA and PREA have resulted in 467 pediatric labeling changes, according the FDA.

Biopharmaceutical Researchers Are Dedicated to Advancing Personalized MedicineThe sequencing of the human genome produced a “map” of the human genes in DNA. This new genetic knowledge has opened up opportunities to predict, diagnose, and better target treatments for disease. Personalized medicine is the tailoring of medical treatment and delivery of health care to the individual characteristics of each patient—including their genetic, molecular, imaging and other personal determinants. Using this approach—which is becoming more common in cancer care—has the potential to speed accurate diagnosis, decrease side effects, and increase the likelihood that a medi-cine will work for an individual patient.

A 2010 report from the Tufts Center for the Study of Drug Development, Impact Report: Personalized Medicine Is

Playing a Growing Role in Development Pipelines, finds that biopharmaceutical research companies are committed to researching and developing personalized medicines. The data show, for the first time, the extent to which companies are embracing this new research.

The authors concluded, “The industry as a whole is committed to pushing strongly ahead,” and “early indications show that development of personalized medicines is commanding more resources and fomenting more corresponding organization change than is generally appreciated outside the industry.”

• Of the companies surveyed, 94 percent said they are investing in personalized medicine research.

• In many instances, companies’ investments are translating to development of therapies that have a companion diag-nostic. Companies report that within their development pipelines, 12–50 percent of compounds are personalized medicines.

52013 RepoRt

• In the last 5 years, companies report that they have seen a roughly 75 percent increase in investment in personalized medicine. What’s more, they expect an additional 53 per-cent increase in the next five years.

• Personalized medicine is changing the way biopharma-ceutical companies research new medicines. One hundred percent of companies surveyed said that they are using biomarkers in the discovery stage of research to help learn more about a compound. Biomarkers are molecular, biolog-ical or physical characteristics that can help identify risk for disease, make a diagnosis, or guide treatment, and they are a key component of personalized medicine.

• Personalized medicine research now appears to be expand-ing into new therapeutic areas, according to the report. Oncology is on the leading edge and personalized medicine is integrated into most new programs.

• Many of the most promising personalized medicines are still in the early stages of research. Among treatments in preclinical development nearly 60 percent rely on biomarker data. In early clinical research that proportion is close to 50 percent and in late clinical development about 30 percent use biomarkers.

Evolving Value in Oncology InnovationIn recent years, the United States has experienced significant progress in the fight against cancer—death rates are falling and survival rates are increasing. New cancer medicines are a significant factor in this progress. In fact, one study showed that medicines account for 50–60 percent of sur-vival rate increases since 1975.

Understanding how we have come so far is important to continuing innovation. A recent report by Boston Healthcare Associates examined this process and found that it is not typ-ically driven by individual developments, but more commonly it is the result of a series of improved treatments over time. Researchers and clinicians learn more about individual medi-cines and combinations of medicines over time as real-world evidence accumulates and builds on research done leading up to approval. Initial FDA approval is often the starting point for

“…our understanding of the benefits of the therapy evolves over time through

the continual testing and validation that is common in oncology.”

Every 4 minutes a person is diagnosed with leukemia, lymphoma or myeloma;

Accounting for

9% of all cancers diagnosed each year

6 OVERVIEW • Medicines in developMent LEukEmIa & LymphOma

fully understanding the value of a medicine and the best way to use it for patients.

Here are some of the pathways that researchers and clini-cians use to better understand medicines and make progress against cancer:

Initial FDA-Approved Indication

For many cancer medicines safety and efficacy studies continue following approval so the impact on overall survival and tumor progression will be better understood using the long-term clinical outcomes data. This is particularly true in cases where current treatment options are lacking or ineffec-tive and the FDA may approve a new cancer treatment based on compelling endpoints (e.g., tumor shrinkage) before the completion of the long-term studies.

Treatment and Disease Stage

Oncology research is—out of necessity and ethical consider-ations—often initially focused on sicker patients, who have often failed on other available treatments. Following FDA ap-proval of a medicine for advanced disease, additional testing of the treatment may show that the medicine actually delivers greater benefits for patients earlier in the progression of the disease.

Additional Disease Indications

Research and development conducted after the initial ap-proval, commonly explores additional indications and can demonstrate clinical benefit in a different type of cancer. This is becoming more common as researchers increase their un-derstanding of the underpinnings of various cancers and can find common molecular pathways driving disease.

Combination Treatment

Combining cancer treatments can improve outcomes for patients by attacking the tumor from different angles and also making it possible for patients to receive higher doses

of medicines while still managing side effects. A significant amount of cancer research involves testing different combina-tions of new and existing therapies that may improve treat-ment outcomes.

Combination Treatment with Specific Biomarkers

Biomarkers are molecules or genetic markers that can be used to predict response to a specific treatment and/or sensitivity to adverse events. This allows health care provid-ers to treat patients who are most likely to benefit from a therapy. This personalized approach is becoming a mainstay of cancer treatment.

A Case Study: Understanding the Value of a New Medicine—Gleevec® (imatinib)

In 2001, the FDA approved Gleevec for second-line treatment of chronic myeloid leukemia (CML). Approval was based on surrogate endpoints showing that patients responded to the treatment at the cellular level. In 2007, the clinical benefit was confirmed with survival data, which showed 88 percent survival for patients after six years of treatment compared with an average five-year survival rate of 48 percent prior to Gleevec.

In 2006, Gleevec moved earlier in the CML treatment line when it was approved for first-line therapy in Philadelphia-positive CML (Ph+CML) in chronic phase patients.

The clinical development of Gleevec, for example, did not end with the original CML indication. Gleevec’s approved indications expanded to the treatment of unresectable and/or metastatic gastrointestinal stromal cancer (GIST) in February 2002 based on surrogate endpoints, less than a year after initial approval for the CML indication.

72013 RepoRt

Facts About Leukemia, Lymphoma and Other Blood Cancers• Every four minutes someone in the United States is diag-

nosed with a blood cancer.1

• Someone dies from a blood cancer every 10 minutes in the U.S., about 145 people each day.1

• Leukemia, lymphoma and myeloma will account for 9 percent of the more than 1.6 million new cases of cancer expected to be diagnosed in 2013.2

• This year, more than 11,000 new cases of cancer will be diagnosed in children 0 to 14 years of age, representing less than 1 percent of all cancers. Leukemia accounts for 31 percent of all childhood cancers. About one-third all childhood cancer deaths—1,130 estimated deaths in 2013—are from leukemia.2

• Mortality rates for childhood cancer have declined by 68 percent in the last 40 years. According to the ACS, this substantial progress is largely due to improvements in treatment and high rates of participation in clinical trials.2

Sources:

1. Leukemia & Lymphoma Society, www.lls.org

2. American Cancer Society, www.cancer.org

2013 Estimated New Cases and Deaths2

Type 2013 New Cases 2013 Deaths

Leukemia 48,610 23,720

— acute lymphocytic leukemia (ALL) 6,070 1,430

— chronic lymphocytic leukemia (CLL) 15,680 4,580

— acute myeloid leukemia (AML) 14,590 10,370

— chronic myeloid leukemia (CML) 5,920 610

— other leukemia* 6,350 6,730

Lymphoma 79,030 20,200

— Hodgkin lymphoma (HL) 9,290 1,180

— non-Hodgkin lymphoma (NHL) 69,740 19,020

Myeloma 22,350 10,710

* More deaths than cases may be due to a lack of specificity in recording the underlying cause of death and/or an undercount of the case estimate.

Pharmaceutical Research and Manufacturers of America 950 F Street, NW, Washington, DC 20004

www.phrma.org

The U.S. system of new drug approvals is perhaps the most rigorous in the world.

It takes 10-15 years, on average, for an experi-mental drug to travel from lab to U.S. patients, according to the Tufts Center for the Study of Drug Development. Only five in 5,000 com-pounds that enter preclinical testing make it to human testing. And only one of those five is approved for sale.

On average, it costs a company $1.2 billion, including the cost of failures, to get one new medicine from the laboratory to U.S. patients, according to a recent study by the Tufts Center for the Study of Drug Development.

Once a new compound has been identified in the laboratory, medicines are usually developed as follows:

Preclinical Testing. A pharmaceutical company conducts laboratory and animal studies to show biological activity of the compound against the targeted disease, and the compound is evaluat-ed for safety.

Investigational New Drug Application (IND). After completing preclinical testing, a compa-ny files an IND with the U.S. Food and Drug

Administration (FDA) to begin to test the drug in people. The IND shows results of previous experiments; how, where and by whom the new studies will be conducted; the chemical structure of the compound; how it is thought to work in the body; any toxic effects found in the animal studies; and how the compound is manufac-tured. All clinical trials must be reviewed and ap-proved by the Institutional Review Board (IRB) where the trials will be conducted. Progress reports on clinical trials must be submitted at least annually to FDA and the IRB.

Clinical Trials, Phase I—Researchers test the drug in a small group of people, usually between 20 and 80 healthy adult volunteers, to evaluate its initial safety and tolerability profile, deter-mine a safe dosage range, and identify potential side effects.

Clinical Trials, Phase II—The drug is given to volunteer patients, usually between 100 and 300, to see if it is effective, identify an optimal dose, and to further evaluate its short-term safety.

Clinical Trials, Phase III—The drug is given to a larger, more diverse patient population, often involving between 1,000 and 3,000 patients (but sometime many more thousands), to

generate statistically significant evidence to confirm its safety and effectiveness. They are the longest studies, and usually take place in multiple sites around the world.

New Drug Application (NDA)/Biologic License Application (BLA). Following the completion of all three phases of clinical trials, a company analyzes all of the data and files an NDA or BLA with FDA if the data successfully demonstrate both safety and effectiveness. The applications contain all of the scientific information that the company has gathered. Applications typically run 100,000 pages or more.

Approval. Once FDA approves an NDA or BLA, the new medicine becomes available for physi-cians to prescribe. A company must continue to submit periodic reports to FDA, including any cases of adverse reactions and appropriate qual-ity-control records. For some medicines, FDA requires additional trials (Phase IV) to evaluate long-term effects.

Discovering and developing safe and effective new medicines is a long, difficult, and expensive process. PhRMA member companies invested an estimated $48.5 billion in research and develop-ment in 2012.

Developing a new medicine takes an average of 10-15 years; For every 5,000-10,000 compounds in the pipeline, only 1 is approved.

The Drug Development and Approval Process

PRE-

DIS

COV

ERY

DRUG DISCOVERY PRECLINICAL CLINICAL TRIALS FDA REVIEW LG-SCALE MFG

3 – 6 Y E A RS 6 – 7 Y E A RS 0. 5 – 2 Y E A RS

100 – 300 1,000 – 3,00020 –80

PHASE 2

PHASE 3

PHASE 1

IND

SU

BM

ITTE

D

ND

A S

UB

MIT

TED

PHA

SE 4

: PO

ST-M

AR

KET

ING

SU

RVEI

LLA

NCE

NUMBER OF VOLUNTEERS

ONE FDA-APPROVED

DRUG

5,000 – 10,000

COMPOUNDS

250 5

Drug Discovery and Development: A LONG, RISKY ROAD