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

2013 REPORT Medicines in Development For Leading Blood Cancers Application Submitted Phase III Phase II Phase I 97 98 52 24 More Than 240 Medici...
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2013 REPORT

Medicines in Development For Leading Blood Cancers

Application Submitted Phase III Phase II Phase I 97

98

52

24

More Than 240 Medicines in Development for Leukemia, Lymphoma and Other Blood Cancers Each year nearly 150,000 Americans are diagnosed with a blood cancer—accounting 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 diagnosed in 2013 in the United States. And, more than 54,000 people will die.

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

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

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.

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

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 incremental nature of innovation.

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• 97 for leukemia, including the four major 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.

• 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.

Prior 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 treatment 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.

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 treatments 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-

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:

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.

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.

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

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. 2

U.S. Mortality Rate per 100,000

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

10

100

8

80

6

60

4

40

2

0 1975

U.S. Mortality Rate Leukemia Non-Hodgkin Lymphoma Hodgkin Lymphoma

1980

1985

U.S. 5-Year Survival Leukemia Non-Hodgkin Lymphoma Hodgkin Lymphoma

1990

1995

2000

U.S. 5-Year Survival in Percent

The Future of Innovation— The Changing Cancer Care Ecosystem

20

0 2004/05 2009

Year 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).

OVERVIEW • Medicines in Development Leukemia & Lymphoma

• Easier Delivery of Treatment—An oral version of an approved injectable medicine is a DNA methyltransferase inhibitor for myelodysplastic syndromes and other hematological 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.

ant role in tumor cell proliferation, resistance to apoptosis (cell death), and prevention of normal cell development. • Reducing Treatment Toxicity—Tumor hypoxia, or low oxygen 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 general 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.

Treatment Advance Adcetris® (brentuximab vedotin), approved in 2011, was the first in a new class of antibodydrug 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.

• 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 celldestroying 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 different targets simultaneously, linking the T-cells to cancer cells.

Medicines in Development for Blood Cancers, By Type and Phase of Development Some medicines are listed in more than one category

Hematological Malignancies

Application Submitted

24

Phase III Phase II

Leukemia

97

Lymphoma

Myelodysplastic Syndromes

98

15

Myeloma

Myeloproliferative Neoplasms

2013 Report

Phase I

52

15

3

Biopharmaceutical Researchers Are Dedicated to Advancing Personalized Medicine The 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 medicine will work for an individual patient. A 2010 report from the Tufts Center for the Study of Drug Development, Impact Report: Personalized Medicine Is

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

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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 diagnostic. Companies report that within their development pipelines, 12–50 percent of compounds are personalized medicines.

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 Pharmaceuticals 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.

OVERVIEW • Medicines in Development Leukemia & Lymphoma

• 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 percent increase in the next five years. • Personalized medicine is changing the way biopharmaceutical 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, biological 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 expanding into new therapeutic areas, according to the report. Oncology is on the leading edge and personalized medicine is integrated into most new programs.

“…our understanding of the benefits of the therapy evolves over time through the continual testing and validation that is common in oncology.”

• 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 Innovation In 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 survival 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 typically 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 medicines 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

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

9% of all cancers

diagnosed each year 2013 Report

5

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 clinicians 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 ineffective 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 considerations—often initially focused on sicker patients, who have often failed on other available treatments. Following FDA approval 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 approval, commonly explores additional indications and can demonstrate clinical benefit in a different type of cancer. This is becoming more common as researchers increase their understanding 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

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of medicines while still managing side effects. A significant amount of cancer research involves testing different combinations of new and existing therapies that may improve treatment 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 providers 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.

OVERVIEW • Medicines in Development Leukemia & Lymphoma

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

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.

Sources: 1. Leukemia & Lymphoma Society, www.lls.org 2. American Cancer Society, www.cancer.org

2013 Report

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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.

PRECLINICAL

5,000 – 10,000

CLINICAL TRIALS

FDA REVIEW LG-SCALE MFG

5

250

ONE FDAAPPROVED DRUG

3 – 6 YEARS

PHASE 1

PHASE 3

PHASE 2

NUMBER OF VOLUNTEERS 20 –80

100 – 300

1,000 – 3,000

6 – 7 YEARS

NDA SU BM ITTED

COMPOUNDS

IND SU BM ITTED

P RE - D IS COV E RY

DRUG DISCOVERY

LONG, RISKY ROAD

0.5 – 2 YEARS

PHASE 4: POST-M ARKETING SU RV EIL L ANCE

Drug Discovery and Development: A

The Drug Development and Approval Process 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 experimental 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 compounds 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 evaluated for safety. Investigational New Drug Application (IND). After completing preclinical testing, a company 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 manufactured. All clinical trials must be reviewed and approved 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, determine 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 physicians to prescribe. A company must continue to submit periodic reports to FDA, including any cases of adverse reactions and appropriate quality-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 development in 2012.

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

www.phrma.org

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