Pipelines of Promise and Profits? - Drug Discovery and Development

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Cancer is one of the leading health threats—and one of the leading arenas for drug research. Health and financial experts diagnose the market.

According to the World Health Organization (WHO), more than 11 million people are diagnosed with cancer annually, leading to seven million deaths—or 12.5% of deaths worldwide each year. WHO estimates that by 2020 there will be 16 million new cancer cases every year.

In the US, cancer is the second leading cause of death, exceeded only by heart disease. In addition, the change in growth of population age 65 and over is projected to significantly outpace the overall population growth, thus doubling the number of elderly people between 2005 and 2030 from 36.5 million people to 72 million, according to the US Census Bureau. Since about 76% of all cancers are diagnosed in people ages 55 and older, the burden of this disease is expected to rise in the upcoming years.

Although improvements in the diagnosis and treatment of cancer have increased the chances of surviving the disease, cancer remains a large, unmet medical need. Even among the four most prevalent cancer types—breast, prostate, lung, and colon—mortality remains high, particularly for the latter two cancer types (Table 1). And, some cancers, such as pancreatic, liver, and brain have virtually no therapeutic options that can produce long-term survival benefit, reflected by exceedingly high mortality numbers within the first year of diagnosis. Therefore, the demand for new therapies that could extend life expectancy and improve quality of life continues to rise.

Table 1. Estimated New Cases and Mortality Numbers for Selected Cancer Types, 2007
Cancer Type	Estimated New Cases	Estimated Deaths
All Sites	1,444,920	559,650
Colon and Rectum	153,760	52,180
Lung and Bronchus	213,380	160,390
Female Breast	178,480	40,460
Prostate	218,890	27,050
Liver	19,160	16,780
Pancreas	37,170	33,370
Brain/Nervous System	20,500	12,740
Source: American Cancer Society

The growing number of cancer patients, combined with the continual need for adoption of novel therapies that will command premium pricing, is expected to drive the expansion of the global oncology market. In addition, as new medicines increase survival and prolong life, some of the agents that are currently used for short periods of time could see extended usage, thereby generating additional sales.

Despite the wealth of potential targets that have been discovered as researchers increase the understanding of cancer, currently marketed drugs address only a handful of the best-characterized pathways. However, the number of targets pursued by the drug development companies has been growing exponentially. While not all of these targets will work, consultants with investment bank Leerink Swann’s MEDACorp, a proprietary network of 25,000 physicians, researchers, and healthcare professionals, have identified several molecules that have the potential to improve efficacy for the majority of tumor types.

The descriptions below are based on information provided by the biopharmaceutical companies, Leerink Swann information, and analysis by consultants with MEDACorp. This article is a summary of a Future in Focus white paper prepared by Leerink Swann.

Bcl-2 Family Inhibitors
The establishment and maintenance of tumors rely in part on the ability of cancer cells to evade cell death or apoptosis. The network of interactions between anti-apoptotic and pro-apoptotic proteins of the Bcl-2 family is critical for the regulation of cell survival and death. In human cancer, anti-apoptotic proteins, such as Bcl-2, Bcl-xL, Mcl-1, are often expressed at high levels, which leads to increased cell survival and resistance to therapy, and poor clinical prognosis. Bcl-2 is known to be a contributing factor to the development of a number of B-cell malignancies. More recently, Bcl-2, along with Bcl-xL and Mcl-1, has been shown to be over-expressed in a number of solid tumors as well.

Therefore, Bcl-2 and other anti-apoptotic proteins represent attractive targets for therapeutic intervention. Combining Bcl-2 inhibitors with chemotherapy or radiation is expected to sensitize tumors to these conventional treatments and potentially to overcome issues of resistance to traditional therapy.

Companies developing small molecule inhibitors of the Bcl-2 proteins (Table 2) include:

Abbott (Abbott Park, Ill.)/Genentech (South San Francisco, Calif.)
Infinity (Cambridge, Mass.)/Novartis (Basel, Switzerland)
Ascenta Therapeutics (Malvern, Pa)
Gemin X (Malvern, Pa. and Montreal, Canada

Table 2. Selected Small Molecule Inhibitors of Bcl-2 protein family
Company	Program	Target/s	Status	Indications
Abbott/Genentech	ABT-263	Bcl-2, Bcl-xL, Bcl-w	Phase 1	Lymphoma, chronic lymphocitic leukemia (CLL), solid tumors, including small cell lung cancer
Infinity/Novartis	No named compounds	Bcl-2-specific and Bcl-2/Bcl-xL dual active	Preclinical
Ascenta Therapeutics	AT-101	Bcl-2, Bcl-X, Mcl-1	Phase 2	Non-small cell lung cancer (NSCLC), hormone refractory prostate cancer (HRPC)
GeminX	obatoclax (GX15-070)	Bcl-2, Bcl-xL, Bcl-w and Mcl-1	Phase 1/2	Hematological malignancies, NSCLC, myelodysplastic syndrome
Sources: Company information

HSP90 Inhibitors
Molecular chaperones are some of the most abundant cellular proteins. They are required for both the proper folding of other proteins (referred to as client proteins) upon synthesis and their refolding under conditions of denaturing stress. Heat shock protein 90 (HSP90) is a molecular chaperone that is essential for maintaining the activity of numerous client proteins involved in the regulation of the cell cycle, cell growth and survival, apoptosis, and angiogenesis. Significantly, many HSP90 client proteins include those crucial for cancer cell proliferation and survival (Clincal Cancer Research, 13(6), p.1625-1628, 2007). In addition, HSP90 is known to be over-expressed in tumor cells compared to normal tissues (two- to 10-fold). Elevated levels of HSP90 have been documented in a variety of human cancers including breast, lung, colon, and brain. Collectively, these observations make HSP90 an attractive oncology target.

Targeting HSP90 could provide a unique way of simultaneously blocking multiple pathways involved in tumorigenesis through the depletion of oncogenic factors essential for cancer cell proliferation and survival. Inhibition of HSP90 should lead to misfolding of client proteins, their destabilization, and subsequent degradation by the proteasome-mediated pathway. Furthermore, combination therapy of HSP90 inhibitors with other targeted agents and/or traditional cancer therapeutics might result in significantly enhanced efficacy especially in resistant tumors.

Companies developing HSP 90 inhibitors (Table 3) include:

Kosan (Hayward, Calif.)
Infinity/MedImmune (Gaithersburg, Md.)/AstraZeneca (London)
Abraxis Biosciences (Los Angeles)
BiogenIdec (Conforma) (San Diego, Calif.)
Synta (Lexington, Mass.)
Pfizer (through recent acquisition of Serenex, Durham, N.C.)
Vernalis (Winnersh, UK)/Novartis

Table 3. Selected HSP90 Inhibitors in Development
Company	Compound	Type	Formulation	Status
Kosan	Tanespimycin (KOS-953)	17-AAG	Intavenous (IV) suspension	Phase 2/3 multiple myeloma (MM) Phase 2 melanoma and breast cancer
Infinity/ MedImmune/ AstraZeneca	IPI-504	Water-soluble 17-AAG	IV Oral	Phase 1 GIST Phase 1/2 NSCLC Phase 2 HRPC Phase 1 MM completed Preclinical
Infinity/ MedImmune/ AstraZeneca	IPI-493		Oral	Preclinical
Abraxis Bioscience	ABI-010	Geldanamycin analog	IV	Phase 1
BiogenIdec (Conforma)	CNF2024	Purine analog	Oral	Phase 1 breast cancer Phase 1 CLL Phase 1 solid tumors
Synta	STA-9090	Unrelated to geldanamycin	IV	Phase 1 solid tumors
Serenex/Pfizer	SNX-5422	Unrelated to geldanamycin	Oral	Phase 1 solid tumors Phase 1 hematological tumors
Veranlis/Novartis	No named compounds	Unrelated to geldanamycin	IV and oral	Preclinical
Sources: Company information, ClinicaTrials.gov

Proteasome Inhibitors
The proteasome is the primary component of the protein degradation system in the cell and is involved in the regulation of a number of cellular processes including proliferation, survival, and apoptosis. Proteasome substrates comprise proteins involved in the regulation of the cell cycle, DNA repair, stress responses, apoptosis, as well as misfolded and misassembled proteins.

Proteasome inhibition results in accumulation of these proteins in the cell and subsequent cell death. The proteasome is a validated target for cancer therapy. Currently, Millennium Pharmaceuticals‘ (Cambridge, Mass.) Velcade (bortezomib), approved for the treatment of multiple myeloma (MM) and mantel cell lymphoma (MCL), is the only proteasome inhibitor on the market. Despite the clinical successes of Velcade, a significant number of patients fall into the relapsed/refractory category. MEDAcorp consultants noted that inconvenient dosing (twice a week IV injection) and painful peripheral neuropathy limit Velcade use. But newer agents, also targeting the proteasome, could potentially address these issues.

Two new proteasome inhibitors—carfilzomib (PR-171, Proteolix, South San Francisco, Calif.), and NPI-0052 (Nereus, San Diego, Calif.)—are currently in clinical development, Compared to Velcade, carfilzomib and NPI-0052 belong to distinct chemical classes, are irreversible inhibitors, and have different selectivities against the three proteolytic components of the proteasome. Proteolix’s carfilzomib is the most selective of the three agents.

According to MEDACorp consultants, it is too early to tell whether broad-spectrum inhibition or more selective proteolytic activity inhibition would result in better safety and/or efficacy profile for a proteasome targeting agent. However, it should be pointed out that in clinical trials conducted to date, carfilzomib-treated patients experienced no painful peripheral neuropathy, which has been associated with Velcade use. Better tolerability also allows Proteolix to dose carfilzomib in a manner that prevents the full recovery of proteasome activity after completion of dosing, and this might translate into improved efficacy compared to Velcade.

“Smart Drugs”—Folate Receptor-Targeted Therapeutics
The concept of targeted therapies for cancer emerged from the desire to provide highly effective treatments that would have minimal side effects. Conventional chemotherapeutics kill rapidly dividing cells by acting on the cell division process. Unfortunately, in addition to killing tumor cells, chemotherapy also destroys normal cells. A potential solution to current chemotherapy limitations would be to deliver anti-cancer agents to the tumor tissues with very high specificity, thereby sparing normal cells. Several approaches to achieving a high degree of specificity, including conjugation of anti-cancer drugs to hormones, antibodies and vitamin derivatives, have been investigated by the industry.

Endocyte (West Lafayette, Ind.) has focused on the development of receptor-targeted therapeutics based on the vitamin folate (folic acid). Folate plays an essential role in cell survival by participating in the biosynthesis of nucleic and amino acids. Tumor cells have greater dependence on folate than normal cells. Folate exerts its activity by binding to folate receptor (FR) and rapidly dividing cancer cells over-express a unique high affinity receptor for folate. This FR has been demonstrated to be over-expressed in a number of human cancers, including ovarian, brain, endometrial, kidney, lung, and breast carcinomas. In addition, the FR density has been shown to increase with tumor progression.

Endocyte has developed proprietary linker technology that allows conjugation of a variety of anticancer drugs to folate. Overall, this approach is supposed to dramatically increase the therapeutic index of potent anticancer drugs by significantly decreasing their dose—limiting toxicities through targeted delivery to tumor cells. Furthermore, MEDAcorp consultants comment that the ability to optimize patient selection through the use of a companion diagnostic—an FR-imaging agent—could improve the probability of success of Endocyte’s approach compared to other cell-targeting strategies.

Improving Probability of Success in Oncology Drug Development
Compared to other therapeutic areas, oncology drugs candidates have one of the highest attrition rates in the industry. Approximately, 95% of anticancer drugs fail in clinical development (Nature Reviews in Drug Discovery). Among other factors, these numbers underscore poor predictability of animal models used in cancer research and drug development.

Human cancer xenografts—a present day standard—are created by culturing cells, derived from a human tumor, and then injecting these cells into a mouse, which results in subsequent tumor growth. However, lesions that develop in a xenograft mouse often lose certain characteristics of the original human cancers. Furthermore, they inadequately reflect any given tumor’s heterogeneity on the molecular, cellular, and population levels.

AVEO Pharmaceuticals (Cambridge, Mass.) has developed a proprietary platform for generation of inducible in vivo cancer models for target identification, validation, and drug screening. The Human Response Prediction (HRP) platform allows to produce tissue-specific tumors (e.g., breast, lung, colon), engineered to contain relevant genetic mutations found in human cancers in a mouse model. Furthermore, over time, the resultant lesions acquire spontaneous mutations—a process that mimics natural genetic heterogeneity that develops in human tumors during the disease progression.

Overall, compared with traditional tumor xenografts, AVEO’s cancer models, generated using the HRP platform, should be better predictors of human responses to anti-neoplastic therapy, thereby increasing the probability of clinical success. AVEO is deploying the HRP platform for both internal drug development and collaborations.

About the Author
Irena Melnikova, PhD authors syndicated reports that analyze issues shaping the biopharmaceutical industry for Leerink Swann. Previously, she was a Senior Analyst at Life Science Insights and a project leader at Transform Pharmaceuticals, a Johnson and Johnson company. She has a PhD in Molecular Medicine from the University of Texas, has authored over 20 manuscripts and review articles, and is a co-inventor on a patent application.

Leerink Swann Strategic Advisors has received compensation for providing non-securities services to Abbott Laboratories, Amgen Corporation, Biogen-Idec, Genentech, Pfizer and Wyeth Corporation in the past 12 months. Leerink Swann LLC has received compensation for investment banking services from Kosan Biosciences in the past 12 months.