Recognizing the Disruptive Potential of Cancer Immunotherapy

This article from MDB Communications discusses ten cancer vaccine programs in mid- and late-stage development with important catalysts expected during the balance of 2013 and into 2014. The article also highlights how several of these newer products seem to work better and address the limitations of prior cancer vaccine approaches. The 11-page report is available electronically as a PDF file.  To view/download a complimentary copy of the report, please click here.

Thinking of Spring – Tulips and Cancer Stem Cell Mania

According to the American Cancer Society, approximately 1.6 million new cancer cases are expected to be diagnosed and approximately 577,000 Americans are expected to die from the disease in 2012[1].  The direct medical costs of cancer in 2007 were $103.8 billion and another $123.0 billion can be attributed to indirect costs, such as lost productivity[2].

With hundreds of billions at stake, it’s not surprising that there is often a tulipomania effect on companies that report significant scientific advances in the treatment of cancer.  Many investors recall the meteoric rise and subsequent plummet of EntreMed, Inc.’s (ENMD) stock following reports of the company’s breakthrough in disrupting the growth of blood vessels [angiogenesis] to kill cancer in mice back in 1998.

As spring is around the corner, it seemed an appropriate time to examine Wall Street’s latest tulip obsession, which relates to the potential of targeting cancer stem cells [CSCs] as a novel approach to eradicating the disease.  Stem cells are unique due to their ability to self-renew and/or mature into another type of cell with a more specialized function, such as a muscle cell, a red blood cell, or a brain cell[3].  Accordingly, stem cells hold great promise to potentially replace or repair damaged cells or tissues for a wide range of diseases.  Genetic mutations or other factors may give rise to CSCs that possess the same capacity for self-renewal and can mature into cancer cells that comprise the tumor.

For example, normal hematopoietic [blood-forming] stem cells have the potential for self-renewal, a property that enables life-long blood production.  These particular stem cells give rise to all of the types of red and white blood cells as well as some other types of cells[4].  Underscoring the importance of hematopoietic stem cells, red blood cells only have a lifespan of approximately 120 days and therefore must be completely replaced every four months[5].

Genetic mutations or other factors, however, may cause hematopoietic stem cells or their progeny to go awry.  In 1994, researchers identified a rare population of stem-like cells in the blood of patients with acute myeloid leukemia [AML][6].  These unique cells represented less than 1% of the total AML cell population found in the blood.  When transplanted into mice with impaired immune systems, these rare cells could recapitulate the entire cellular diversity of human AML in the animals.  This was the first time that researchers isolated CSCs.

Traditional cancer treatments, such as chemotherapy and radiation, have limited selectivity.  They exert their killing effect on rapidly dividing cells and do not discriminate between normal and cancerous targets.  In view of the fact that stem cells as a class tend to be relatively dormant[7], CSCs are unlikely to be destroyed by such therapeutic approaches.  In other words, the “seeds” of the tumor may remain intact – able to grow and spread.  Eradicating CSCs in addition to other cancerous cells may hold great promise for the treatment of cancer.

Enthusiasm for targeting CSC’s was recently bolstered by the March 1st announcement that Dainippon Sumitomo Pharma Co., Ltd. would acquire privately-held Boston Biomedical, Inc. for up to $2.63 billion.  The deal included $200 million upfront, up to $540 million in development milestone payments, and up to $1.89 billion in sales milestone payments.  Boston Biomedical’s lead program for inhibiting CSCs in addition to other cancer cells, BBI608, is entering Phase 3 trials in patients with colorectal cancer.

In addition to Boston Biomedical and other programs currently in development by large pharmaceutical companies, the following is a partial list of emerging public companies with programs also targeting the destruction of CSCs for the treatment of cancer:

Geron Corporation (GERN)

After announcing that the company would discontinue development of its human embryonic stem cell programs, Geron is focusing on novel cancer programs, including lead program Imetelstat [GRN163L], a telomerase inhibitor that has been shown to effectively inhibit CSCs from a broad range of tumors.  Imetelstat is in Phase 2 trials for non-small cell lung cancer, metastatic breast cancer, essential thrombocythemia and multiple myeloma.

ImmunoCellular Therapeutics Ltd. (IMUC.OB)

ImmunoCellular is developing active immunotherapies that target not only regular tumor cells, but also CSCs.  The company’s most advanced product candidate, ICT-107, is a dendritic cell-based vaccine in Phase 2 development for the treatment of glioblastoma multiforme [GBM].  Underscoring interest in therapeutic approaches targeting CSCs, shares of ImmunoCellular are up more than 67% since the start of the year.

Verastem, Inc. (VSTM)

While unusual for a biotechnology company to pursue an initial public offering [IPO] without having a product candidate in human clinical trials, Verastem successfully priced its IPO at $10 in January 2012 and currently has a market capitalization greater than $236 million.  According to the prospectus, Verastem has identified a pipeline of small molecule compounds with the potential to target CSCs.  The company’s most advanced product candidates are VS-507, VS-4718 and VS-5095.  In late 2012, Verastem expect to file an investigational new drug application [IND] with the U.S. Food and Drug Administration [FDA] to initiate a Phase 1 clinical trial of VS-507.

Private companies also working in the area of CSCs include:

Eclipse Therapeutics, Inc.

Eclipse has developed a CSC discovery platform to identify antibody therapeutics that inhibit the growth of cancer stem cells.  Eclipse’s lead program is ET-101, a novel therapeutic antibody designed to target CSCs.  ET-101 is expected to advance towards human clinical trials by 2013.

Formula Pharmaceuticals

Formula’s lead product candidate, FPI-01, is an active immunotherapy in Phase 2 clinical development for the maintenance of first-remission in AML and other cancers that originated at Memorial-Sloan Kettering Cancer Center.  The vaccine targets Wilms Tumor 1 [WT1], an antigen ranked first in a list of 75 cancer vaccine target antigens by the National Cancer Institute [NCI] prioritization project.  Stem cell expression was among the criteria used to rank the antigens.

KaloBios Pharmaceuticals, Inc.

KaloBios has initiated a Phase 1 dose-escalating clinical trial for KB004, its first-in-class Humaneered™ monoclonal antibody, in EphA3-expressing hematologic malignancies, including chronic myelogenous leukemia, AML, acute lymphocytic leukemia, and myelodysplastic syndromes, who are refractory to, have failed, or have not received standard-of-care treatment. EphA3 is an onco-fetal protein that is expressed in a range of cancers, including hematologic malignancies and possibly on leukemic stem cells. Studies have shown that expression of EphA3, a receptor tyrosine kinase, is associated with B, T and myeloid neoplasms and certain solid tumors. EphA3 appears to be upregulated on tumor cells, including stem cells, tumor stromal cells, and tumor neovasculature. A biomarker assay is being developed to identify EphA3 expression.

OncoMed Pharmaceuticals

OncoMed’s lead CSC therapeutic, OMP-21M18, is a monoclonal antibody designed to block Delta-like ligand 4 [DLL4], an activator of Notch signaling, which is a pathway known to be important in CSCs and cancer.  OMP-21M18 has demonstrated single-agent activity in a Phase 1 study in heavily-pretreated solid tumor patients, and is currently advancing into combination studies with standard chemotherapy in advanced non-small cell lung and pancreatic cancers.

Stemica LLC

Stemica was founded in 2011 to focus on late-breaking cancer biology discoveries pinpointing cancer stem cells as the reason for not being able to currently cure cancer.  Stemica is currently developing novel molecules that inhibit these “cancer sleeper cells” in hopes of providing long-term survival for cancer patients.

Stemline Therapeutics

Lead programs SL-401, which targets IL-3R, and SL-701, which targets multiple defined epitopes, are in Phase 1 and Phase 2 development for the treatment of AML and glioma, respectively.  According to the company’s website, Stemline also possesses a landmark portfolio of intellectual property that includes the earliest filings in the CSC field covering CSC-directed therapeutics, diagnostics, and drug discovery.

In conclusion, targeting CSCs may hold great promise for the treatment of cancer following their initial discovery in 1994.  Enthusiasm for the approach has been bolstered by the recent $2.3 billion acquisition of Boston Biomedical, which may prove that targeting CSCs is more than a passing phase.  Using the breakthrough with anti-angiogenesis approaches to treat cancer as a model, however, it may be too early to determine which programs will ultimately succeed [e.g., Avastin®, bevacizumab] versus those that fail [e.g., endostatin and angiostatin].


[1] American Cancer Society. Cancer Facts & Figures 2012. Atlanta: American Cancer Society; 2012.

[2] National Heart Lung and Blood Institute. LHLBI Factbook, Fiscal Year 2010. National Institutes of Health; 2011.

[3] Melton DA, Cowan Clanza R, Blau HM (2004). Elsevier Academic Press, San Diego. Handbook of Stem Cells. 1: 450-510.

[4] Molecular Biology of the Cell. 4th edition. Alberts B, Johnson A, Lewis J, et al. New York: Garland Science; 2002.

[5] Exercise, training and red blood cell turnover. Smith JA. Sports Med. 1995 Jan;19(1):9-31.

[6] Acute myeloid leukemia stem cells. Dick JE. Ann N Y Acad Sci. 2005 Jun;1044:1-5. Review.

[7] Morrison M, Weissman E (2000). The biology of hematopoietic stem cells. Annu. Rev. Cell Dev. Biol. 11: 371-378.

Adjuvants May Hold Key to Unlocking Cancer Immunotherapy Revolution

The FDA approval of sipuleucel-T [Provenge®], a patient-specific immunotherapy for androgen independent prostate cancer developed by Dendreon Corporation (DNDN), and ipilimumab [Yervoy®], the first immune check point molecule for melanoma by Bristol-Myers Squibb (BMY), has renewed interest in the concept of immunotherapy as an approach to cancer treatment. Often overlooked, however, adjuvants can be an essential part of an effective vaccine and could help advance the field even further.

Adjuvants are substances that can:

  • Accelerate the generation of robust, longer lasting immune responses
  • Generate antibodies with increased avidity and neutralization capacity
  • Enhance immune responses in individuals with weakened immune systems
  • Reduce the amount of antigen and number of doses needed; reducing the cost of vaccination programs
  • Activate the cellular arm of the adaptive response, specifically T helper type 1 and cytotoxic T cell responses

For next generation cancer vaccines that require T cell immunity or a broader range of antibody response, adjuvants are playing an essential and central role[1]. For example, GlaxoSmithKline’s (GSK) melanoma antigen epitope-3 [MAGE-A3] antigen-specific cancer immunotherapeutic [ASCI] uses the company’s AS15 adjuvant system[2], which incorporates three different adjuvants [QS-21, MPL, and CpG] and is currently in pivotal Phase III trials for both non-small cell lung cancer [NSCLC] and melanoma with data expected in 2012.


During the last 80 years many adjuvants have been used in experimental settings, but due to various shortcomings of most of them only three have made it into regular clinical usage[3] – largely for infectious diseases.  Of the three adjuvants, only two have been used in vaccines licensed by the US Food and Drug Administration [FDA].

Alum (1930s)

For infectious disease vaccines, the most commonly used adjuvants are aluminum salt based [aluminum phosphate and aluminum hydroxide; alum], which are safe and effective for antibody induction.  Alum is a component of many licensed human vaccines, including diphtheria-pertussis-tetanus [DPT], diphtheria-tetanus [DT], DT combined with Hepatitis B virus [HBV], Haemophilus influenza B or inactivated polio virus [IPV], hepatitis A [HAV], Streptococcus pneumonia, meningococcal, and human papilloma virus [HPV].

MF59™ (1997)

MF59 is a potent vaccine adjuvant that has been licensed for more than 13 years for use in an influenza vaccine focused on elderly subjects [Fluad®] by Novartis (NVS)[4].  It consists of an oil-in-water nano-emulsion composed of shark oil [squalene] and has been licensed in Europe for use in influenza vaccines, but not in the US.

MPL® (2009)

MPL [monophosphoryl lipid A] is a derivative of bacterial endotoxin and a potent immunostimulant.  MPL was the second FDA licensed adjuvant molecule and is used in Cervarix® by GlaxoSmithKline, which is a prophylactic vaccine against HPV types 16 and 18.  GlaxoSmithKline obtained MPL through the $300 million acquisition of Corixa Corporation in 2005.  MPL is also the first and only toll-like receptor [TLR] ligand approved in a human vaccine.  TLRs are a class of proteins that play a key role in the innate immune system[5].

Few adjuvants approved

Adjuvants do not receive FDA approval as stand-alone products, but rather as part of a registered vaccine adjuvant–antigen combination[6].  The fact that safety regulations are often much more stringent with vaccines, as they are prophylactic and the main targets are often pediatric patients, partly explains why there are so few adjuvants approved to date[7].

Several recent developments have favorably altered the landscape for adjuvant development.  First, GSK’s Cervarix vaccine received approval in 2009 and contained the first adjuvant [MPL] licensed by the FDA since the approval of Alum back in the 1930s.  The second development has been FDA approval of sipuleucel-T [Provenge®] by Dendreon and ipilimumab [Yervoy®] by Bristol-Myers Squibb, which has renewed interest in the concept of immunotherapy as an approach to cancer treatment.  In the cancer setting, adjuvants are being tested as part of a therapeutic vaccine as opposed to being use as a prophylactic vaccine, which may result in a shorter duration of exposure and reduced safety concerns.  Third, if an influenza pandemic were to occur, such as the 2009-10 H1N1 pandemic, the potential vaccine supply would fall several billion doses short of the amount needed to provide protection to the global population[8]. The antigen-sparing effect of adjuvants could allow for expansion of vaccine supply to meet the necessary global demands during a pandemic, as evidenced by supporting grants from the Biomedical Advanced Research and Development Authority [BARDA], part of the US Department of Health and Human Services.

Investigational adjuvants

Several companies are developing promising new candidates that may finally adjunct or displace aluminum substances as a popular adjuvant:

Agenus (AGEN)

Agenus Inc. (AGEN) is developing QS-21, a saponin extracted from the bark of the Quillaja saponaria tree, also known as the soap bark tree or Soapbark, an evergreen tree native to warm temperate central Chile.  Quillaia raw material has been used for decades as an ingredient to create the foaming in beverages such as root beer, low-alcohol beers and foaming carbonated beverages.  It has also been widely used as an adjuvant in veterinary vaccines.

QS-21 has extensive clinical experience with thousands of patients receiving vaccines containing QS-21 adjuvant.  Agenus has licensed QS-21 to various Big Pharma partners and today there are 15 vaccine candidates using QS-21 in clinical development for infectious diseases, oncology, and central nervous system disorders, including the following Phase III programs by GlaxoSmithKline that could address large markets:

  • MAGE-A3 ASCI vaccine candidate, which is being studied in the largest-ever trial in the adjuvant treatment of NSCLC and also in Phase III trials for melanoma, with data expected in 2012
  • Mosquirix (RTS,S), the world’s most advanced malaria vaccine candidate, with Phase III data expected by the end of 2011

Agenus is entitled to receive milestone payments and royalties from corporate partners that have licensed QS-21.

Antigen Express, Inc., a wholly-owned subsidiary of Generex Biotechnology Corporation (GNBT)

Antigen Express is advancing its proprietary Ii-Key hybrid technology.  Ii-Key modification entails attaching a four-amino acid peptide [LRMK] to virtually any antigen and results in increased stimulation of CD4+ helper T cells and a more robust specific response to the antigen.  Using this technology platform, Antigen Express is building a deep pipeline of therapeutics aimed at a variety of major diseases, including cancer, infectious diseases and autoimmune-based syndromes.

The company’s lead product candidate using Ii-Key modification is AE37, a peptide vaccine derived from a fragment of the HER-2/neu protein, which is expressed in a variety of tumors including 75-80% of breast cancers as well as a high percentage of prostate, ovarian and other cancers[9].

A controlled, randomized, and single-blinded Phase II clinical study of AE37 in HER-2 expressing breast cancer patients is currently underway to establish clinical efficacy.  The study endpoint is a reduction in cancer relapse after two years compared to the current standard of care treatment.  There are currently over 200 patients enrolled in the study with either node positive or high-risk node-negative breast cancer.

Celldex Therapeutics (CLDX) and 3M Company (MMM)

3M Drug Delivery Systems has a portfolio of patent protected TLR agonists that have shown promise as vaccine adjuvants. The lead candidate, resiquimod [TLR7/8 agonist] has shown promising results in a number of animal models and has an extensive toxicology and clinical data package to support further development as a vaccine adjuvant.

Celldex Therapeutics entered into a non-exclusive clinical research collaboration with 3M Drug Delivery Systems to access resiquimod for clinical study with the company’s Antigen Presenting Cell [APC] Targeting Technology™ in exchange for an undisclosed licensing fee, milestones and royalties.  Celldex is developing CDX-1401, a fusion protein consisting of a fully human monoclonal antibody with specificity for the dendritic cell receptor DEC-205 linked to the NY-ESO-1 tumor antigen, which is currently in a Phase I/II trial in combination with immune stimulating agents [resiquimod and/or poly-ICLC] for advanced cancers of the bladder, breast, ovary, non-small cell lung cancer, myeloma, sarcoma or melanoma.

Colby Pharmaceutical Company (private) and Juvaris BioTherapeutics (private)

In September 2011, Juvaris BioTherapeutics, Inc. entered into an exclusive license agreement with Colby Pharmaceutical Company for the worldwide development and commercialization of Juvaris’ Cationic Lipid-DNA Complex [CLDC] technology and related JVRS-100 product candidate. Gene array studies with JVRS-100 show up-regulation of multiple immune response pathways compared to competing technologies. When combined with a vaccine antigen, JVRS-100 stimulates the adaptive immune response including specific antibodies and T-cell responses.

Idera Pharmaceuticals (IDRA)

Idera is developing numerous compounds that act as agonists for TLRs 3, 7, 8, or 9, which the company believes have the potential to be used as adjuvants in vaccines.  In preclinical animal models, Idera’s TLR agonists have shown adjuvant activity when combined with various types of antigens.

In December 2007, Idera entered into an exclusive, worldwide licensing and collaboration agreement with Merck KGaA for the research, development, and commercialization of Idera’s TLR9 agonists, including IMO-2055, for the treatment of cancer, excluding vaccines.  Merck KGaA refers to IMO-2055 as EMD 1201081.

Merck KGaA expects to complete an ongoing Phase 2 clinical trial of IMO-2055 in combination with cetuximab [Erbitux®] in second-line cetuximab-naïve patients with recurrent or metastatic squamous cell carcinoma of the head and neck [SCCHN].  However, based on increased incidence of neutropenia and electrolyte imbalances reported in its Phase 1 trial of IMO-2055 in combination with cisplatin/5-FU and cetuximab in patients with first-line SCCHN and subsequent re-evaluation of its clinical development program, in July 2011 Merck KGaA informed Idera that it will not conduct further clinical development of IMO-2055.

Immune Design Corporation (private)

Founded by the co-founder of Corixa Corporation, Immune Design Corporation is developing its proprietary adjuvant known as glucopyranosyl lipid A [GLA].  GLA is a novel, clinical-stage, human TLR-4 agonist, representing the next generation of MPL.  According to the company, GLA is unique because: it is a pure synthetic small molecule, straightforward to manufacture with excellent stability, rationally designed to optimally activate human TLR-4 receptors, induces Th1 CD4 helper cells and elicits broad humoral immunity and active in multiple formulations and compatible with most antigens.  GLA was also shown to be safe and well-tolerated in humans subjects in a Phase I clinical study in combination with the influenza virus vaccine Fluzone® by Sanofi Pasteur, the vaccines division of sanofi-aventis Group (SNY).  Immune Design Corporation is developing its own proprietary pipeline of vaccine candidates formulated with the GLA adjuvant for evaluation in further human clinical trials.

Vical Inc. (VICL)

Vical is developing Vaxfectin®, a novel proprietary cationic lipid-based formulation that has been shown to effectively enhance plasmid DNA-based [as well as protein- and peptide-based] vaccines. It is a commixture of a cationic lipid [GAP-DMORIE] and a neutral phospholipid [DPyPE] which, when combined in an aqueous vehicle, self-assemble to form liposomes.  In mechanism of action studies, Vaxfectin® has been shown to increase a number of cytokines and chemokines, while Toll-like receptor signaling was contributory.

Vical is developing several products that utilize Vaxfectin® as an adjuvant. These include CyMVectin™, the company’s prophylactic vaccine against cytomegalovirus [CMV] infection, and its pandemic influenza vaccines.


Beyond their established role in infectious diseases, adjuvants will also likely become important in cancer immunotherapy where they will be critical for targeting weakly immunogenic tumor antigens in order to overcome various tolerance mechanisms and facilitate induction of cytotoxic T lymphocytes.  Several promising new adjuvants are currently being developed that offer superior properties and a set of desired characteristics, with clinical data expected in the near future.

The topic of adjuvants in cancer immunotherapy will covered in an upcoming panel session at the second annual Cancer Immunotherapy: A Long-Awaited Reality conference being held in New York City on October 6, 2011.


[1] Adjuvants for cancer vaccines. Dubensky TW Jr, Reed SG. Semin Immunol. 2010 Jun;22(3):155-61. Epub 2010 May 21. Review.

[2] Recent clinical experience with vaccines using MPL- and QS-21-containing adjuvant systems. Garçon N, Van Mechelen M. Expert Rev Vaccines. 2011 Apr;10(4):471-86. Review.

[3] The ABC of clinical and experimental adjuvants–a brief overview. Brunner R, Jensen-Jarolim E, Pali-Schöll I. Immunol Lett. 2010 Jan 18;128(1):29-35. Epub 2009 Nov 4.

[4] MF59 adjuvant: the best insurance against influenza strain diversity. O’Hagan DT, Rappuoli R, De Gregorio E, Tsai T, Del Giudice G. Expert Rev Vaccines. 2011 Apr;10(4):447-62.

[5] Impaired TLR3/IFN-beta signaling in monocyte-derived dendritic cells from patients with acute-on-chronic hepatitis B liver failure: relevance to the severity of liver damage. Li N, Li Q, Qian Z, Zhang Y, Chen M, Shi G. Biochem Biophys Res Commun. 2009 Dec 18;390(3):630-5. Epub 2009 Oct 13.

[6] Adjuvants for malaria vaccines. Coler RN, Carter D, Friede M, Reed SG. Parasite Immunol. 2009 Sep;31(9):520-8. Review.

[7] Delivery Technologies for Biopharmaceuticals: Peptides, Proteins, Nucleic Acids and Vaccines edited by Lene Jorgensen and Hanne Mørck Nielsen

[8] Global pandemic influenza action plan to increase vaccine supply by the World Health Organization at

[9] AE37: a novel T-cell-eliciting vaccine for breast cancer. Sears AK, Perez SA, Clifton GT, Benavides LC, Gates JD, Clive KS, Holmes JP, Shumway NM, Van Echo DC, Carmichael MG, Ponniah S, Baxevanis CN, Mittendorf EA, Papamichail M, Peoples GE.

Three Late-Stage Leukemia Company Previews for ASCO

At the upcoming ASCO Annual Meeting being held June 3-7, 2011, in Chicago, Illinois, Eisai Co., Ltd. (ESALF) is expected to report detailed results from its DACO-016 Phase 3 trial of Dacogen® [decitabine] as a frontline treatment for elderly patients [65+ years old] with acute myelogenous leukemia [AML].  As announced less than one year ago, Dacogen’s top-line results did not meet the primary endpoint of superiority over low-dose cytarabine in terms of overall survival in this study, although a trend was reported to be evident.

Shares of SuperGen, Inc. (SUPG), which climbed as high as $2.89 on expectations for positive trial results, reached a new 52-week low of $1.71 in July 2010 following the negative top-line news.  SuperGen receives a 20-30% royalty on worldwide sales of Dacogen from its development and commercialization partners – Eisai in North America and Johnson & Johnson (JNJ) outside of North America.

Despite the negative top-line results, shares of SuperGen have since rebounded and reached a new 52-week high in April 2011.  Optimism may stem from the fact that both Eisai and Johnson & Johnson are continuing to analyze the data and planning to move forward with North America and European regulatory filings in 2011 based on the primary analysis and secondary endpoints.  Accordingly, investors will anxiously await the detailed Phase 3 results being presented on Monday, June 6, 2011 at ASCO to better gauge the likelihood of FDA approval in AML [Abstract #6504 “Results from a randomized phase III trial of decitabine versus supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed AML”].

Results from the Dacogen study may also be of interest to investors in Cyclacel Pharmaceuticals, Inc. (CYCC), which recently launched a multicenter, randomized, pivotal Phase 3 trial for the company’s sapacitabine oral capsules as a front-line treatment of elderly patients aged 70 years or older with newly diagnosed AML who are not candidates for intensive induction chemotherapy.  Unique among drugs available to treat AML patients, sapacitabine is the only oral agent in late-stage clinical development.  It is also the only candidate to progress into a pivotal study on the basis of survival data from a randomized Phase 2 study.  Historically, sponsors advanced molecules to pivotal development in AML based on Phase 2 studies with primary endpoints of complete remission [CR].

The pivotal Phase 3 study is being conducted under a Special Protocol Assessment [SPA] agreement that Cyclacel reached with the FDA.  The primary efficacy endpoint for the study is an improvement in overall survival from either of the two pairwise comparisons [Arm A versus Arm C, or Arm B versus Arm C] in the following three arms consisting of approximately 150 patients per arm:

  • Arm A: sapacitabine administered in alternating cycles with Dacogen
  • Arm B: sapacitabine administered alone
  • Arm C: Dacogen administered alone

Cyclacel is testing the treatment regimen of sapacitabine administered in alternating cycles with Dacogen [Arm A] in an on-going pilot study, with data expected at ASCO 2011 [Abstract #6587 “Phase I/II study of sapacitabine and decitabine administered sequentially in elderly patients with newly diagnosed acute myeloid leukemia”].  Thirty-day and sixty-day mortality outcomes from this pilot study may be helpful in determining the odds of success in the Phase 3 pivotal study.  To put this in perspective, thirty-day mortality in AML patients aged 70 years or older ranged from 17% to 21% in a recently published Phase 3 study [Harousseau JL, et al, Blood, 2009:114:1166].  Accordingly, results from the pilot study that demonstrate thirty-day mortality with sapacitabine is equal or less than 21% could be encouraging for Cyclacel.

The Phase 3 study builds on promising 1-year survival observed in elderly patients aged 70 years or older with newly diagnosed AML or AML in first relapse enrolled in a Phase 2 study of single agent sapacitabine.  In a disease setting where patients are typically treated with chemotherapy agents like cytarabine for an average of 1 to 2 cycles, patients in Cyclacel’s Phase 2 study achieved a median of 12 cycles of treatment with sapacitabine.

In addition, approximately 45% of patients in the Phase 2 study had transformed into AML after being diagnosed with myelodysplastic syndromes [MDS] and were previously treated with Dacogen or Celgene Corporation’s (CELG) Vidaza® [azacitidine].  Only newly diagnosed AML patients are expected to be enrolled in the ongoing Phase 3 trial, none of whom had been previously treated with Dacogen or Vidaza and none of whom had relapsed, potentially increasing the odds for a successful trial.

Finally, Sunesis Pharmaceuticals, Inc. (SNSS) will also be presenting at ASCO [Abstract #TPS201, “Adaptive design of VALOR, a phase III trial of vosaroxin or placebo in combination with cytarabine for patients with first relapsed or refractory acute myeloid leukemia”].  Unlike the aforementioned frontline trials being conducted under SPA’s, Sunesis is studying vosaroxin in relapsed/refractory AML in an ongoing Phase 3 trial.  Approximately 450 patients will be randomized to receive either vosaroxin or placebo in combination with cytarabine.

Cytarabine, a generic chemotherapy drug introduced several decades ago, is already a critical part of the treatment for younger patients with AML who are fit to withstand its toxicity.  Unfortunately, several companies that make cytarabine have recently experienced production difficulties and others cannot make the drug fast enough to keep up with demand.  This has resulted in a severe shortage of cytarabine that has reportedly affected leukemia clinical trials being run by the Cancer and Leukemia Group B [CALGB].  Accordingly, investors will be looking to Sunesis for an update on enrollment in the VALOR Phase 3 trial to determine whether or not the cytarabine shortage has been a factor.

Beyond the aforementioned investigational therapies, a researcher in the field of oncology noted that newer, targeted agents will be required to advance the treatment of AML: “My personal opinion on AML affecting the elderly population is that the field is in need of a total revamp whereby certain chemotherapy agents need to be combined with targeted therapies to overcome drug resistance and provide meaningful survival data,” said Daruka Mahadevan, M.D. Ph.D., Director, Phase I Program, Arizona Cancer Center.  “If you can increase the survival of a 70-year old patient by ten years, that would be a real achievement.  Sapacitabine is interesting as it is an oral agent, while vosaroxin in combination of cytarabine may provide short term control – but is unlikely to provide a survival benefit.”

Similarities Between Two Immunotherapies in Cancer

Approval of Bristol-Myers Squibb’s (BMY) Yervoy® [ipilimumab] for melanoma in March 2011 marked the second victory for the field of immunotherapy in oncology within a year, with the first being the U.S. Food and Drug Administration [FDA] approval of Dendreon Corporation’s (DNDN) Provenge® [sipuleucel-T] for metastatic castrate-resistant prostate cancer [CRPC] in April 2010.  Ipilimumab was the first immune check point molecule and sipuleucel-T was the first active immunotherapy for cancer to demonstrate improved survival in randomized Phase 3 trials.  Both were published in the prestigious New England Journal of Medicine within one month of each other.

The similarities don’t end there, as both ipilimumab and sipuleucel-T have reignited enthusiasm for the field of active immunotherapy.  Accordingly, the purpose of this article is to highlight some of the other parallels between these two innovative agents.

Both Studied in Prostate Cancer

While ipilimumab was recently approved for the treatment of melanoma, the product has also been extensively studied in prostate cancer.  In fact, there are eight clinical studies with ipilimumab in prostate cancer according to, including five that are currently active or recruiting.

One particular prostate cancer study made headlines in June 2009 when investigators at the Mayo Clinic reported in the online research magazine Discovery’s Edge that the combination of a single dose of ipilimumab [3 mg/kg] with androgen ablation therapy dramatically reduced the tumor size in two patients, making surgery possible for both patients whose prostate cancer had been previously considered inoperable. The controversial results from a handful of patients were met with skepticism and the complete Phase 2 results with 108 patients with advanced prostate cancer were later reported at the American Society of Clinical Oncology [ASCO] 2010 Genitourinary Cancers Symposium [abstract #168].  According to the ASCO abstract, patients treated with androgen ablation either alone or in combination with ipilimumab demonstrated a greater than 97% decline in testosterone levels, underscoring the possibility that the tumor reductions in a few patients could have been associated with androgen ablation.  Patients treated with ipilimumab, however, were more likely to have undetectable prostate specific antigen [PSA] by three months [55% vs. 38%].

A Phase 3 trial with ipilimumab following radiation therapy in patients with CRPC that have received prior treatment with docetaxel is ongoing [ identifier NCT00861614].

Two is Better than One

As the first two active immunotherapies approved for the treatment of cancer, it wouldn’t be surprising to see the products studied in combination in prostate cancer – especially in view of the fact that ipilimumab has already been studied in this disease.  Sipuleucel-T may help build an effective immune response to kill tumor cells, while ipilimumab may stimulate the immune system through T-cell activation and proliferation and stop tumor cells from growing.  Accordingly, giving vaccine therapy together with ipilimumab may be an effective treatment for prostate cancer.  Interestingly, the only such combination study listed on relates to a completed Phase 1 trial with ipilimumab in combination with Bavarian Nordic’s (BAVA.CO) Prostvac®, an “off-the-shelf” therapeutic cancer vaccine moving into pivotal Phase 3 clinical development [ identifier NCT00124670].

Pricing Controversy

Both Dendreon’s sipuleucel-T and Bristol-Myers’ ipilimumab have been criticized as overly expensive new therapies.

The cost of sipuleucel-T is approximately $93,000 for a course of treatment, which consists of three infusions at two-week intervals.  In view of the fact that the product has been demonstrated to extend median survival by 4.1 months, this translates into an average cost of $23,000 per month of added survival.

In comparison, Taxotere® [docetaxel] by Sanofi-aventis (SNY) is indicated for the treatment of CRPC and is administered every 3 weeks for 10 cycles.  Assuming an average monthly cost of $4,000 for docetaxel [source: Cancer Res 2009;69(24 Suppl):Abstract nr 1076], this is an approximate total cost of $40,000 per patient.  In the pivotal TAX 327 study, median survival for prostate cancer patients receiving docetaxel was 18.9 months versus 16.5 months in the control arm, which results in an average cost of $16,666 per month of added survival or about 28% less than sipuleucel-T.  Updated survival analysis of the TAX 327 study demonstrates a 2.9-month survival advantage, which lowers the average cost to $13,793 per month of added survival or about 40% less than sipuleucel-T.  Unlike sipuleucel-T, however, treating common adverse reactions with docetaxel, such as infections, neutropenia, anemia, nausea, diarrhea, and others, increases the total cost of therapy – and more importantly negatively impacts the patient’s quality of life.  As such, the pricing of sipuleucel-T doesn’t appear completely out of line.

According to the prescribing information, ipilimumab is administered intravenously [3 mg/kg] over 90 minutes every 3 weeks for a total of four doses.  Bristol-Myers is pricing each dose at $30,000, which translates into a total cost of $120,000 for a full course of therapy.  In the pivotal ‘020 study, median survival for melanoma patients receiving ipilimumab was 10.1 months versus 6.4 months in the control arm.  The average cost per month of added survival is approximately $32,432, which is 41% higher than the only other active immunotherapy for cancer, sipuleucel-T.

However, on March 21, 2011, Bristol-Myers announced that the ‘024 study [ identifier NCT00324155] met its primary endpoint of overall survival.  Minimal details were provided, but an abstract of the ‘024 data is expected to be submitted to ASCO for potential presentation at the Annual Meeting in June 2011.  The ‘024 study is in patients with untreated Stage III [unresectable] or IV melanoma receiving dacarbazine plus 10 mg/kg ipilimumab versus dacarbazine with placebo.  If the median survival for patients in the ipilimumab arm is 5.2 months or greater than the placebo arm [versus 3.7 month difference in the ‘020 study], then the pricing of ipilimumab per month of added survival would be comparable to sipuleucel-T.

Prostate and Melanoma Highly Competitive

Melanoma and prostate cancer are the two most crowded clinical development segments within the active immunotherapy field.  As such, both ipilimumab and sipuleucel-T may face competition from other active immunotherapies in the near future.  In addition, the products may soon encounter small molecule rivals.

For example, Johnson & Johnson’s (JNJ) abiraterone acetate significantly improved overall survival for patients with metastatic advanced prostate cancer.  Based on the positive Phase 3 results, the company has filed marketing applications for abiraterone acetate with regulatory authorities worldwide for the treatment of metastatic advanced prostate cancer that has developed resistance to conventional hormonal therapies. Not far behind, Medivation, Inc. (MDVN) is evaluating its MDV3100 product candidate in collaboration with Astellas Pharma, Inc. (ALPMY.PK).  The Phase 3 AFFIRM trial with MDV3100 has completed enrollment of men with advanced prostate cancer who were previously treated with docetaxel-based chemotherapy and the Phase 3 PREVAIL trial with MDV3100 is currently enrolling men who have not yet received chemotherapy

In addition, Plexxikon, Inc. [being acquired by Daiichi Sankyo Company, Limited] and co-development partner Roche Holding (ROG.VX) are advancing PLX4032, an oral drug candidate that targets the oncogenic BRAF mutation present in about half of melanoma cancers and about eight percent of all solid tumors.  Interim data from a Phase 3 controlled study of PLX4032 in previously untreated metastatic melanoma patients with the BRAF mutation met both co-primary endpoints.  Patients treated with PLX4032 had improved overall survival (OS) and improved progression-free survival (PFS) compared to patients treated with dacarbazine, the current standard of care.  A New Drug Application [NDA] for PLX4032 is expected in 2011.

Some new agents might actually be synergistic with active immunotherapies instead of representing potential competition.  This was a central theme at the recent Cancer Immunotherapy Consortium’s 2011 Scientific Colloquium titled “Schedule and Dose for Combination Therapy.”


Both ipilimumab and sipuleucel-T represent important clinical advances for the field of active immunotherapy in oncology and for patients with melanoma and prostate cancer, respectively.  Further, with nearly 50 clinical programs currently underway, including nearly a dozen that are in pivotal Phase 3 development, we expect to see five active cancer immunotherapies approved by 2015.  Beyond these clinical accomplishments, however, industry observers will be closely monitoring the commercial success of these innovative agents in view of the product pricing, supply constraints, and competitive dynamics identified to date.

Ipilimumab Approval Highlights Immunotherapy Renaissance

On Friday, March 25, 2011, the U.S. Food and Drug Administration [FDA] approved Yervoy® [ipilimumab] by Bristol-Myers Squibb (BMY) for the treatment of patients with late-stage [metastatic] melanoma. With the news, ipilimumab becomes the eleventh monoclonal antibody [mAb] approved for the treatment of cancer.  The first mAb approved for cancer treatment was Biogen Idec, Inc’s (BIIB) Rituxan® [rituximab] back in November 1997 [click here to see graph of mAb approvals].

Approval of ipilimumab is the second victory for the field of active immunotherapy in oncology within a year.   On April 29, 2010, the FDA approved the very first active immunotherapy for the treatment of cancer – Dendreon Corporation’s (DNDN) Provenge® [sipuleucel-T] for metastatic castrate-resistant prostate cancer [CRPC].  The fact that two active immunotherapies have demonstrated improved survival in randomized Phase 3 trials and subsequently been approved by the FDA has reignited enthusiasm for the field of active immunotherapy, which has experienced nearly a dozen failures in Phase 3 clinical trials.

A Long Time in the Making

The idea to stimulate one’s own immune system to treat cancer dates back to 1891 when William Coley, Professor of Clinical Surgery at Cornell University, noticed the curative effect of an accidental bacterial infection in a patient with inoperable sarcoma.  It would be 119 years since Dr. Coley’s discovery before the FDA approved the first active immunotherapy for the treatment of cancer.

As the scientific understanding of the immune system has significantly increased since Dr. Coley’s time, scientists and physicians developed successful immune system related strategies to fight cancer, viral infection and autoimmune diseases.  Today, mAbs are among the most successful modern immunotherapies and provide clinical benefit to a vast array of diseases – with three blockbuster mAbs generating approximately $17 billion in sales in 2009.

Melanoma Losing Streak

In addition to helping renew interest in the field of active immunotherapy, the FDA’s approval of ipilimumab provides a much-needed boost to companies developing product candidates for melanoma.  Among the eleven Phase 3 failures with active immunotherapies for the treatment of cancer, more than one-third of them have occurred in melanoma [see Table 1].

Table 1. Select Active Immunotherapy Failures in Phase 3 Trials

Company Product Candidate Description Result
CancerVax Canvaxin Allogeneic, whole cell tumor derived No improvement in overall survival
Progenics Pharmaceuticals, Inc. (PGNX) GMK vaccine GM2 ganglioside coupled with KLH and formulated with QS-21 No improvement in relapse-free or overall survival
Corixa Melacine Allogeneic, Mel S/Mel D cell lines No improvement in relapse-free or overall survival
Agenus, Inc. (AGEN), formerly Antigenics Oncophage® Autologous, whole cell tumor derived heat shock proteins No improvement in overall survival

Crowded Market

While ipilimumab is the first new drug approved for the treatment of melanoma in 13 years, there are four competitive active immunotherapy programs in Phase 3 development [see Table 2].  In fact, melanoma is second only to prostate cancer as the most crowded clinical development segment within the active immunotherapy field.

Table 2. Select Phase 3 Active Immunotherapy Product Candidates in Melanoma

Company Product Disease(s) Type Stage
Amgen (AMGN) through the acquisition of BioVex Group OncoVEX[GM-CSF] Melanoma [unresectable Stage III b-c and Stage IV M1a-c], and head & neck Allogeneic, oncolytic herpes simplex virus encoding GM-CSF for direct injection into lesions Phase 3 ongoing
AVAX Technologies (AVXT.PK) MVAX Melanoma [Stage IV], and ovarian Autologous, whole cell, hapten modified SPA approved for Phase 3
GlaxoSmithKline plc (GSK) MAGE-A3 ASCI Melanoma [metastatic – stage III-IVa progressive],  and NSCLC Allogeneic, peptide Phase 3 ongoing
Vical, Inc. (VICL) and AnGes Allovectin-7® Melanoma [1st line Stage III and IV] Allogeneic, DNA plasmid/lipid complex Phase 3 ongoing

Five by 2015

As highlighted in our firm’s April 2010 report titled “Cancer Vaccine Therapies: Failures and Future Opportunities,” there are a number of additional catalysts that could ignite further interest in the field of active immunotherapy for cancer.  Nearly 50 clinical programs are currently underway, including nearly a dozen that are in pivotal Phase 3 development.

Using the history of passive immunotherapy development as a guide, it would not be surprising to see five active cancer immunotherapies approved within five years, which leads to our “5 x 2015” projection.  With the approvals of both sipuleucel-T and ipilimumab in hand, the next three may come from the following list of Phase 3 product candidates [in alphabetical order]:

  • Amgen (AMGN), OncoVEX[GM-CSF], melanoma and head & neck
  • AVAX Technologies (AVXT.PK), MVAX, melanoma
  • Bavarian Nordic (BAVA.CO), Prostvac®, prostate cancer
  • Biovest International (OTCQB: BVTI), BiovaxID®, NHL
  • Cel-Sci (CVM), multikine, head & neck
  • Celldex Therapeutics (CLDX), rindopepimut/CDX-110, glioblastoma
  • GlaxoSmithKline (GSK), MAGE-A3 ASCI, NSCLC and melanoma
  • Novarx (private), Lucanix™/belagenpumatucel-L, NSCLC
  • Oncothyreon (ONTY)/Merck KGaA, Stimuvax®/BLP25 liposome vaccine, NSCLC
  • Oxford BioMedica plc (OXB.L), Trovax®, renal cell
  • Transgene (TNG.PA)/Novartis (NVS), TG4010/MVA-MUC1-IL2, NSCLC
  • Vical (VICL)/AnGes, Allovectin-7®, melanoma

Investment Opportunities with Five Frontline Therapies for AML

Acute myelogenous leukemia [AML] is a fast-growing cancer of the blood and bone marrow.  Unformed cells called myeloblasts, or “blasts,” reside in the bone marrow and normally become a particular kind of cell – a white blood cell, red blood cell, or platelet.  In AML, abnormal blasts produce white blood cells that do not function properly.  They do not fight infections and, as they build up, they inhibit the production of normal white blood cells, red blood cells, and platelets that the body needs.

Standard frontline therapy for AML patients under the age of 60 consists of cytarabine  [AraC] combined with an anthracycline [such as daunorubicin or idarubicin] in what is commonly referred to as the 7+3 regimen.  While 45% of elderly patients with AML [70+ years old] achieved a complete response [CR] using this regimen, there was no improvement in overall survival and more than a third of patients died within the first eight weeks of treatment according to a recent study published in the journal Blood[i].  This is consistent with the CR rates of 40%–60% with conventional chemotherapy and disease-free survival of less than 20% at three years referenced in the literature[ii].

Since more than half of AML cases occur in patients over 60 years old, there is a need to develop better frontline therapies in this setting.  With five agents being investigated as frontline therapy for elderly AML patients in late-stage trials, the purpose of this article is to compare and contrast these programs – several of which have near-term catalysts for investors.

Hypomethylating Agents

SuperGen, Inc. (SUPG), Eisai Co. Ltd. (ESALF), and Johnson & Johnson (JNJ)

On June 30, 2010, preliminary results from a Phase III trial of Dacogen® [decitabine] as a frontline treatment for elderly patients [65+ years old] with AML were released.  While Dacogen did not meet the primary endpoint of overall survival, a trend was reported to be evident.  However, the failure to demonstrate an improvement in overall survival was surprising given the favorable Phase II results and the fact that the comparator arm received low dose AraC instead of the aforementioned 7+3 regimen.  Low dose AraC predominantly works in patients with favorable cytogenetics, so it should have been relatively easy for Dacogen to demonstrate a survival benefit.

Shares of SuperGen, which climbed as high as $2.89 on expectations for positive trial results, reached a new 52-week low of $1.71 in July.  Supergen receives a 20-30% royalty on worldwide sales of Dacogen from its development and commercialization partners – Eisai in North America and Johnson & Johnson outside of North America.

While investors appear to be discounting approval of Dacogen as a frontline therapy for elderly AML, there may be reasons for optimism.  For example, both Eisai and Johnson & Johnson are continuing to analyze the data and planning to move forward with North America and European regulatory filings in 2011 based on the primary analysis and secondary endpoints.  In addition, the Phase III study was conducted under a special protocol assessment [SPA] with the U.S. Food and Drug Administration [FDA].

Celgene Corporation (CELG)

In view of Dacogen’s negative Phase III trial results, investors may be skeptical about Vidaza® [azacitidine], another hypomethylating agent currently approved for the treatment of myelodysplastic syndromes [MDS], a pre-cancerous condition that can often progress to AML.  According to [Identifier NCT01074047], Celgene is currently enrolling patients in a Phase III, multicenter, randomized, open-label, study of Vidaza versus conventional care regimens for the frontline treatment of elderly patients [65+ years old] with AML.

In December 2008, the European Commission granted marketing authorization for Vidaza as a treatment for patients with higher-risk MDS, chronic myelomonocytic leukemia [CMML], and MDS that transforms into AML with a blast percentage of 20-30% in the peripheral blood or bone marrow.  While Vidaza demonstrated a clinically relevant increase in median survival of 9.4 months [24.4 vs. 15 months] in these settings[iii], it is unclear how the drug will work in AML de novo patients with a higher blast percentage [greater than 50%] that represent half of the elderly patient population.  In view of the fact that Dacogen is more myelosuppressive than Vidaza [see Table 1], and for this reason may be preferred over Vidaza for off-label use in AML, the recent failure of Dacogen only adds to this uncertainty.

Table 1. Percentage of Patients with Myelosuppression from Prescribing Information

Adverse Event Dacogen Vidaza
Anemia 82.0% 69.5%
Neutropenia 90.0% 32.2%
Thrombocytopenia 89.0% 65.5%

Monoclonal Antibodies

Seattle Genetics, Inc. (SGEN)

Seattle Genetics is developing SGN-33 [lintuzumab], an unconjugated IgG1 antibody for the treatment of AML.  Lintuzumab has been shown to induce cell death by both complement and/or antibody-directed cellular cytotoxicity, or as a direct effect of the engagement of the CD33 receptor, which is expressed in most leukemic blast cells but also in normal hematopoietic cells.

In a Phase II study in relapsed/refractory AML patients, single agent lintuzumab demonstrated efficacy in patients with advanced AML; however, the positive effects were confined to patients with low disease burden [blast percentage 5% to 30%].  This suggested that additional development of this agent would be best achieved by combining lintuzumab with chemotherapy.  However, while the addition of lintuzumab to salvage induction chemotherapy was safe, it did not result in a statistically significant improvement in response rate or survival in patients with refractory/relapsed AML in a subsequent Phase III trial[iv].

Seattle Genetics is now conducting a 210 patient Phase IIb study in frontline treatment of elderly patients [60+ years old] with AML with results expected in the August to October 2010 timeframe.  See [Identifier NCT00528333] for more information.

While lintuzumab relies on a different mechanism of action, investor’s are understandably skeptical about the success of another anti-CD33 monoclonal antibody in AML.  In June 2010, Pfizer, Inc. (PFE) agreed to withdraw Mylotarg® [gemtuzumab ozogamicin] from the U.S. market, effective October 15.  Mylotarg is an IgG4 monoclonal antibody to CD33 linked to a cytotoxic agent from the class of calicheamicins.  Developed by Wyeth, the drug was fast-tracked to treat patients ages 60 and older with recurrent AML who were not candidates for other chemotherapy.  The FDA approved Mylotarg in May 2000 based upon a surrogate endpoint due to the fact it treated relapsed disease with no other viable therapy.

Four years later, a confirmatory trial was begun to confirm the results of the 142 patients who participated in the three previous clinical trials.  The 2004 trial showed that adding Mylotarg to existing chemotherapy for the treatment of AML provided no benefit and even showed a higher death rate.

Nucleoside Analogs

Genzyme Corporation (GENZ)

In September 2009, the FDA’s Oncologic Drugs Advisory Committee [ODAC] voted 9 to 3 that a randomized, controlled trial is needed to support the proposed label expansion for Clolar® (clofarabine) as a frontline treatment for elderly [60+ years old] patients with AML.  Consistent with the decisions for both Johnson & Johnson’s Zarnestra® [tipifarnib] and Vion Pharmaceuticals’ Onrigin® [laromustine], the committee determined that single-arm clinical study results were not sufficient for approval.

Despite the setback, Genzyme stated in a press release that the company remains committed to the clinical development of clofarabine in this patient population and that the drug is being investigated in clinical trials by most of the leading AML experts and major cooperative leukemia investigation groups in the United States and Europe.

Beyond the frontline setting, Genzyme is also conducting a randomized Phase III trial comparing clofarabine in combination with AraC to AraC alone in relapsed and refractory adult AML patients 55 years old or older [ Identifier NCT00317642]. Results are expected in 2011.

Note: At the time of writing, Sanofi-Aventis (SNY) has offered to acquire Genzyme for $69 per share.

Cyclacel Pharmaceuticals, Inc. (CYCC)

Cyclacel is developing sapacitabine for the treatment of AML, MDS and non-small cell lung cancer [NSCLC].  Sapacitabine is unique among the frontline, elderly AML landscape as it represents the only oral agent in late-stage clinical development and the only product candidate to demonstrate a survival benefit in a randomized study.

In December 2009, Cyclacel reported interim results from an ongoing Phase II study involving 60 patients aged 70 or older with either untreated AML [80%] or AML in first relapse [20%] randomized across three dosing schedules of sapacitabine [ Identifier NCT00590187].  The three-day dosing schedule in Arm C was selected for further clinical development in elderly patients with de novo AML based on a 1-year survival rate of 30% and an overall response rate of 35%.

In the first quarter of 2010, Cyclacel submitted a SPA request for a randomized, registration-directed, Phase III study of sapacitabine in elderly patients with AML and, pending the response, expects to initiate a pivotal Phase III study in 2010.


While many companies are developing therapies for AML [see Table 2], there is a need to focus on better frontline therapies for elderly patients given the lack of efficacy and significant toxicity associated with the current 7+3 treatment regimen.  Investors will be watching the following catalysts to help handicap which of the five product candidates [decitabine, azacitidine, clofarabine, sapacitabine, or lintuzumab] will win the race and become the first agent approved by the FDA in this setting:

  • Phase IIb results for lintuzumab expected in the August to October 2010 timeframe
  • FDA response to SPA request for Phase III study of sapacitabine; initiation of pivotal Phase III study in 2010
  • Supplemental new drug application [sNDA] for decitabine by March 31, 2011 and subsequent response from FDA
  • Results from frontline clofarabine clinical trials by AML experts and major cooperative leukemia investigation groups in the United States and Europe; relapsed/refractory AML Phase III results in 2011
  • Phase III results for azacitidine expected around 2013

NEWClick here to view this article in PDF format.

Table 2. Late-stage Therapeutic Landscape for AML

Sponsor(s) Route Class SPA Setting Comments
Dacogen® (decitabine) Supergen, Eisai, Johnson & Johnson i.v./s.c. Hypomethylating agents Yes Frontline and relapsed/refractory Failed overall survival endpoint versus low-dose ara-C in frontline elderly AML (≥65), expect to file with FDA on secondary endpoints in March 2011.  Phase 3 trial underway in relapsed/refractory setting.
Vidaza® (azacitidine) Celgene Corp s.c. Hypomethylating agents No Frontline Phase 3 study underway (NCT01074047)
Clolar® (clofarabine) Genzyme Corp i.v. Nucleoside analogs No Frontline Rejected by FDA in elderly AML (≥60) due to single-arm
Mylotarg® (gemtuzumab ozogamicin) Pfizer/Wyeth i.v. Monoclonal antibodies n/a Relapse/refractory Accelerated approval, but withdrawn from market
Lintuzumab Seattle Genetics i.v. Monoclonal antibodies No Frontline Phase 2b data from 210 pts expected late August to October 2010 timeframe
Sapacitabine Cyclacel Pharma oral Nucleoside analog Pending Frontline Phase 2 demonstrated 30% survival in elderly AML (≥70); SPA pending
Vosaroxin (a.k.a. voreloxin) Sunesis Pharma (SNSS) i.v. Topoisomerase II inhibitors No Relapse/refractory Pivotal Phase 3 being planned
Zarnestra™ (tipifarnib) Johnson & Johnson oral Farnesyltransferase inhibitors No Frontline Rejected by FDA in elderly AML (≥60) due to single-arm, subsequent randomized study failed ‘09
Onrigin™ (laromustine) Vion Pharma i.v. Alkylating agents No Frontline Rejected by FDA in elderly AML (≥60) due to single-arm
Lestaurtinib Cephalon (CEPH) oral Tyrosine kinase inhibitors No Relapse/refractory Failed Phase 2 reported ASH ‘09
AC220 Ambit Biosciences/Astellas Pharma oral Tyrosine kinase inhibitors No Relapse/refractory Entered pivotal Phase 2, single-arm trial in December 2009


[i] Kantarjian H, Ravandi F, O’Brien S, Cortes J, Faderl S, Garcia-Manero G, Jabbour E, Wierda W, Kadia T, Pierce S, Shan J, Keating M, Freireich EJ.  Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood. 2010 Jul 28. [Epub ahead of print]


[ii] Amadori S, Suciu S, Willemze R, Mandelli F, Selleslag D, Stauder R, Ho A, Denzlinger C, Leone G, Fabris P, Muus P, Vignetti M, Hagemeijer A, Beeldens F, Anak O, De Witte T; EORTC leukemia group; GIMEMA leukemia group.  Sequential administration of gemtuzumab ozogamicin and conventional chemotherapy as first line therapy in elderly patients with acute myeloid leukemia: a phase II study (AML-15) of the EORTC and GIMEMA leukemia groups.  Haematologica. 2004 Aug;89(8):950-6.

[iii] Edlin R, Connock M, Tubeuf S, Round J, Fry-Smith A, Hyde C, Greenheld W.  Azacitidine for the treatment of myelodysplastic syndrome, chronic myelomonocytic leukaemia and acute myeloid leukaemia. Health Technol Assess. 2010 May;14 Suppl 1:69-74.

[iv] Eric J. Feldman, Joseph Brandwein, Richard Stone, Matt Kalaycio, Joseph Moore, Julie O’Connor, Nancy Wedel, Gail J. Roboz, Carole Miller, Raj Chopra, Joseph C. Jurcic, Randy Brown, W. Christopher Ehmann, Philip Schulman, Stanley R. Frankel, Daniel De Angelo, David Scheinberg.  Phase III Randomized Multicenter Study of a Humanized Anti-CD33 Monoclonal Antibody, Lintuzumab, in Combination With Chemotherapy, Versus Chemotherapy Alone in Patients With Refractory or First-Relapsed Acute Myeloid Leukemia. Journal of Clinical Oncology, Vol 23, No 18 (June 20), 2005: pp. 4110-4116.

Five Key Factors Weighing on Dendreon

Shares of Dendreon Corporation (DNDN) have declined significantly from an all-time high of $57.67 in late April 2010 when the company received U.S. Food and Drug Administration [FDA] approval for Provenge® [sipuleucel-T], the first active immunotherapy approved for the treatment of cancer in the U.S.  Today, shares of Dendreon traded as low as $28.01, down more than 50% from their high, prompting us to briefly review some of the key factors weighing on the company at this time.

Product pricing and reimbursement

The cost of Provenge has been set at $93,000 for a course of treatment, which consists of three infusions at approximately two-week intervals.  In view of the fact that Provenge has been demonstrated to extend survival by 4.1 months, this translates into an average cost of $23,000 per month of added survival.

In comparison, Taxotere® [docetaxel] by Sanofi-aventis (SNY) is indicated for the treatment of patients with androgen independent [hormone refractory] metastatic prostate cancer and administered every 3 weeks for 10 cycles.  Assuming an average monthly cost of $4,000 for Taxotere [source: Cancer Res 2009;69(24 Suppl):Abstract nr 1076], this is an approximate total cost of $40,000 per patient. In the pivotal TAX 327 study, median survival for prostate cancer patients receiving Taxotere was 18.9 months versus 16.5 months in the control arm, which results in an average cost of $16,666 per month of added survival.  Unlike Provenge, however, treating common adverse reactions with Taxotere, such as infections, neutropenia, anemia, nausea, diarrhea, and others, increases the total cost of therapy – so the pricing of Provenge doesn’t appear completely out of line. [note: updated survival analysis of the TAX 327 study demonstrates a 2.9 month survival advantage, which lowers the average cost to $13,793 per month of added survival with Taxotere.  Source: Journal of Clinical Oncology, Vol 26, No 2 (January 10), 2008: pp. 242-245.]

Nonetheless, the Centers for Medicare and Medicaid Services [CMS] has initiated a National Coverage Analysis [NCA] of Provenge. In CMS’s announcement of the NCA, CMS is requesting public comments on the effects of Provenge on health outcomes in patients with prostate cancer. While the news doesn’t reflect a change in Medicare coverage policy or impact existing coverage decisions and a decision isn’t expected for a year, it does highlight sensitivity on the part of payors over the pricing of certain cancer treatments.

Supply constraints

Dendreon is making Provenge available through approximately 50 centers, all of which were approved Provenge clinical trial sites, and expects to increase capacity over the next year.  The increased capacity will be a result of the anticipated licensure of its expanded New Jersey, Georgia and California facilities in mid-2011.

In the short term, however, Dendreon officials have indicated that the company will only be able to supply 2,000 treatments to patients.  At a cost of $93,000 per treatment, this limits potential sales to approximately $186 million.

According to a June 28 article by Bloomberg reporter Tom Randall, Dendreon’s Chief Operating Officer Hans Bishop indicated that facilities will be able to churn out medicine each year valued at between $1.25 billion and $2.5 billion by the end of 2011.

Competitive landscape

In early April 2010, we published a 150-page industry report titled “Cancer Vaccine Therapies: Failures and Future Opportunities,” which included an overview of the cancer immunotherapy market, interviews with several key opinion leaders, profiles of nearly 40 companies, and a discussion of the scientific, clinical, and commercial considerations for the major industry participants.

In the report, we highlighted the fact that numerous active immunotherapies are in late-stage clinical development for prostate cancer.  In fact, nine product candidates are in clinical trials for the treatment of prostate cancer, representing the largest therapeutic area within the active immunotherapy market.  Beyond competition from other active immunotherapies, however, Provenge could also face competition from small molecule products.

For example, Johnson & Johnson (JNJ) acquired Cougar Biotechnology, Inc. for approximately $1.0 billion in cash in 2009.  Cougar Biotechnology’s oncology portfolio included abiraterone acetate [CB7630], an orally active acetate salt of the steroidal compound abiraterone.  Abiraterone acetate, which can suppress testosterone production by both the testes and the adrenals to castrate-range levels, is currently in two Phase III clinical trials for the treatment of prostate cancer according to [Trial identifier numbers NCT00638690 and NCT00887198].  Both studies list a primary completion date of mid-2011.

Insider sales

Trading conducted by corporate officers, key employees, directors, or significant shareholders must be reported to the Securities and Exchange Commission [SEC], usually within a few business days of the trade.  Some investors follow the activity of insiders, believing that they might have better insights into the health of a corporation and that their trades convey important information – although this isn’t always the case.

In this regard, according to a Form 4 filed with the SEC, Dendreon’s Chief Executive Officer [CEO] beneficially owned 555,211 shares of the company’s common stock as of April 29, 2010 – the day Provenge was approved by the FDA.  The CEO sold more than half of those shares at prices ranging from $51 to $54.70, reducing his beneficial holdings to 224,359 the next day.  Other insiders also sold during the period.

Priced for perfection

Recall that Eli Lilly & Co. (LLY) purchased ImClone Systems for $6.5 billion back in 2008.  ImClone’s only product – Erbitux® [cetuximab] – had generated annual sales of approximately $1.3 billion in 2007.  Therefore, ImClone was valued at a 5x multiple to prior year sales.

At its 52-week high, Dendreon had a market capitalization of approximately $7.8 billion.  At a 5x multiple, this would imply an annual revenue run rate of $1.56 billion, which is consistent with the company’s planned manufacturing capacity by the end of 2011 and many analyst projections over the coming years.

But Dendreon isn’t generating $1.56 billion in annual sales yet and concerns over pricing, reimbursement, and competition, combined with insider selling, help explain the decrease in market valuation since the approval of Provenge.

Cancer Immunotherapy to Take Center Stage at ASCO

In early April 2010, we published a 150-page industry report titled “Cancer Vaccine Therapies: Failures and Future Opportunities,” which included an overview of the cancer immunotherapy market, interviews with several key opinion leaders, profiles of nearly 40 companies, and a discussion of the scientific, clinical, and commercial considerations for the major industry participants.   An executive summary of the report can be found by clicking here.

Some of the key messages from the report include the following:

  • Reminiscent of monoclonal antibodies in the late 1990’s, the field of active immunotherapy is poised for dramatic growth in the coming years
  • Nearly 50 clinical programs involving active immunotherapies for the treatment of cancer are currently underway, including nearly a dozen that are in pivotal Phase III development with several biologic license application [BLA] submissions planned in 2010
  • Using the history of passive immunotherapy [monoclonal antibodies] as a guide, we expect five active cancer immunotherapies approved within the next five years that will revolutionize the treatment of cancer
  • Beyond Dendreon Corporation’s (DNDN) Provenge®, there are a number of additional catalysts in 2010 that could ignite further interest in the field of cancer immunotherapy

A list of potential catalysts for cancer vaccine companies in 2010 was included in our initial report, such as the presentation of new clinical data during the American Society for Clinical Oncology [ASCO] annual meeting being held June 4-8, 2010. However, following a review of the abstracts published online, we identified three additional vaccine companies worth watching at ASCO.

Interestingly, the three companies span the largest segments of cancer vaccine development – allogeneic peptides [17 programs in development], gene transfer [15 programs in development], and autologous dendritic cell approaches [9 programs in development]. The first two approaches represent “off the shelf” cancer vaccines, while the latter is a “personalized” approach. To date, the only active immunotherapy approved for the treatment of cancer in the US is Dendreon’s Provenge, which is an autologous approach.

Bavarian Nordic A/S (BAVA.CO)

Bavarian Nordic, who’s stock price reached a multi-year high following approval of Dendreon’s Provenge, is developing Prostvac™ [also known as PSA-TRICOM], under a license from the National Cancer Institute [NCI]. Prostvac is a vector-based vaccine that targets prostate-specific antigen [PSA] and includes the transgenes for three human costimulatory molecules to enhance T-cell activation.  Following the recent publication of encouraging Phase II results and receipt of Fast Track designation from the FDA, Bavarian Nordic is planning to initiate a pivotal Phase III prostate cancer trial in 2010.

At ASCO, Bavarian Nordic is scheduled to present “Overall survival [OS] analysis of a phase l trial of a vector-based vaccine [PSA-TRICOM] and ipilimumab [Ipi] in the treatment of metastatic castration-resistant prostate cancer [mCRPC]” during the Developmental Therapeutics – Clinical Pharmacology and Immunotherapy General Poster Session held Monday, June 7, 8:00am to 12:00pm in S Hall A2. Separately, the company announced an investor and analyst briefing to be held in conjunction with ASCO on Saturday, June 5, 2010, in Chicago, IL.

Generex Biotechnology Corporation (GNBT)

While Canada’s Generex is perhaps better known for its $250 million lawsuit against and senior columnist Adam Feuerstein regarding two articles expressing doubts about the company’s oral insulin spray for the treatment of diabetes, its wholly owned subsidiary [Antigen Express, Inc.] is scheduled to present “Effect of a novel II-key hybrid HER2/neu peptide (AE37) vaccine with GM-CSF as compared to GM-CSF alone on levels of regulatory T-cell (Treg) populations” during the Developmental Therapeutics – Clinical Pharmacology and Immunotherapy General Poster Session held Monday June 7, 8:00am to 12:00pm in S Hall A2.

HER-2 is a growth factor receptor that is over-expressed by approximately 20-30% of patients with localized breast cancer and is the target for Herceptin® [trastuzumab] by the Roche Group (RHHBY). However, Generex isn’t the only company targeting HER-2/neu for the treatment of breast cancer. Other cancer vaccine developers working with the target include Dendreon, Bavarian Nordic, Apthera, Inc., and others.

Prima Biomed Ltd. (PRR.AX)

Similar to the concept behind Dendreon’s Provenge, Prima Biomed is developing an autologous dendritic cell vaccine for the treatment of cancer. The company’s lead product candidate is called CVac™, which incorporates the MUC-1 antigen that is overexpressed in cancer, including epithelial ovarian carcinoma. According to the company, prior phase I and II studies conducted in Australia in heavily pretreated, advanced disease patients showed minimal toxicities and prolonged disease stabilization.

Prima Biomed is scheduled to present “A randomized, open-label phase IIb study of maintenance therapy with a MUC-1 dendritic cell vaccine in patients with epithelial ovarian cancer in first or second remission” during the Trials in Progress Poster Session held Monday, June 7, from 8:00am to 12:00pm in S Hall A2.

Consistent with ASCO’s policies, we won’t report on research information represented by the aforementioned abstracts until the information is publicly released in conjunction with the annual meeting. Suffice it to say that we believe active immunotherapy for the treatment of cancer will take center stage at this year’s meeting.

Cyclin-dependent Cancer Confab Preview

For more than a century, the American Association of Cancer Research [AACR] has held its annual meeting and this weekend will kick off the 101st event in Washington, DC, which is being held April 17-21, 2010.  Many pharmaceutical and biotechnology companies will be presenting new data and approximately 6,300 abstracts will be discussed in oral and poster presentations.

While a comprehensive preview of AACR is beyond the scope of this article, we note that two companies working in the area of cyclin-dependent kinase [CDK] inhibition made headlines in the months leading up to AACR.  Further evidence of interest in the area is demonstrated by the fact that the 2001 Nobel Prize in Physiology or Medicine was awarded for the discovery of CDKs and cyclins and the complete description of cyclin and cyclin-dependent kinase mechanisms.

By selectively interrupting the cell cycle regulation in cancer cells, inhibition of CDKs represents a promising strategy for cancer therapy.  Accordingly, with more than 50 abstracts related to CDK inhibition scheduled for presentation at this year’s AACR annual meeting, we provide an overview of the target and highlight some of the companies and programs being discussed.

CDK overview

Each time a cell divides it undergoes a series of events collectively known as the cell cycle.  Controlled and regulated cellular division is a normal part of cell physiology.

Cancer is characterized by uncontrolled cellular division and growth, which can be caused by mutations in DNA resulting in the overexpression of cancer-promoting oncogenes or repression of tumor suppressor genes.  There are many examples of oncogenes and tumor suppressor genes but some of the more common ones include signaling proteins [PI3K], receptors [HER2], and DNA damage and repair regulating proteins that control cell cycle check-points such as p53 and BRCA.

CDKs are a group of signaling kinases that play a direct role in the regulation and progression of the cell cycle.  CDK activity is dependent on the availability of their regulatory subunits called cyclins, which CDKs phosphorylate in order to stop cell cycle progression in cancerous cells.  Production and destruction of cyclins are tightly regulated in coordination with cell cycle progression.  Targeting CDK/cyclin macromolecular complexes is an attractive strategy for the design of novel anticancer drugs.

There are over a dozen known CDK/cyclin complexes.  The most extensively studied subtypes are CDK2/cyclin E, CDK2/cyclin A, CDK7/cyclin H, and CDK9/cyclin T which are key components of the p53 pathway and CDK4 and CDK6 interacting with cyclin D1, which are key components of the retinoblastoma or Rb pathway.

Many tumor mutations interfere or deregulate the tight control of cyclin-CDK interactions leading to overactive CDKs, resulting in continuous cellular proliferation or unscheduled re-entry into the cell cycle.  In addition, deregulated CDK activity can result in genomic and chromosome instability, a feature observed in many advanced or aggressive tumors.

Early Failures

First generation, pan-CDK inhibitors have not demonstrated improved clinical outcomes.  Reasons for early failures include non-specific drug targets or suboptimal dosing and scheduling.    Also, pan-CDK inhibitors may not have an acceptable pharmacological window due to high toxic side effects or limited efficacy.

For example, CDK7, CDK8, and CDK9 play a role in DNA transcription.  While it may be advantageous to target these CDK/cyclins as part of a multikinase drug profile, strong inhibition may result in the broad disruption of transcription, which is not desirable.

This may have been the case with BMS-387032 [subsequently known as SNS-032], a small molecule cell-cycle modulator that targets CDKs 1, 2, 4, 7, and 9.  The compound demonstrated significant safety risks in Phase I studies conducted by Bristol-Myers Squibb (BMY), including increases in certain phases of the cardiac cycle, known as the QT interval.

In 2005, Sunesis Pharmaceuticals, Inc. (SNSS) acquired rights to BMS-387032 for an up-front payment of $8 million in Sunesis’ stock, future milestone payments totaling $78 million, and royalties on net sales.  However, in December 2008, Sunesis notified Bristol-Myers that the company was terminating the license agreement for SNS-032 after no responses demonstrating efficacy were observed in a Phase I trial.

Next generation CDK inhibitors target select CDK sub-types and have shown improved potency along with other drug-like properties.  The various CDK sub-types are active at different points within the cell cycle and discrete cancers are dependent on specific CDK sub-types.  Therefore, each CDK inhibitor sub-type may be relevant to different tumors or genetic mutations.

For example, CDK4 is frequently deregulated in glioblastoma and CDK2 activity is commonly altered in colon cancer.  Recently published evidence implicates certain cyclins and in particular cyclin E, the partner of CDK2, as a mediator of acquired resistance in several cancers, such as lung and breast cancer.  Some of these next-generation programs are highlighted below [also refer to Table 1]:

Pfizer, Inc. (PFE)

In late March 2010, Pfizer made headlines with a preclinical study published in the journal Cancer Research.  Results from the study demonstrated that PD-0332991, a drug being developed by Pfizer, could arrest the growth of glioblastoma multiforme [GBM] in animals.  PD-0332991 is an oral agent that inhibits certain CDKs, mainly CDK4 and CDK6.  Six abstracts related to PD-0332991 are scheduled for presentation at AACR.  Pfizer is managing and funding all clinical development of PD-0332991, which the company licensed from Onyx Pharmaceuticals, Inc. (ONXX).  PD-0332991 is the subject of various clinical trials in multiple myeloma, NHL, mantle-cell lymphoma, glioblastoma and breast cancer.

Cyclacel Pharmaceuticals, Inc. (CYCC)

Cyclacel Pharmaceuticals, which is developing a clinical stage CDK inhibitor candidate, also made headlines earlier this year.  The company’s oral compound seliciclib [CYC202 or R-roscovitine], inhibits CDK2/E, CDK2/A, CDK7/H, and to a lesser degree CDK9/T.  Seliciclib is currently in Phase IIb clinical trials for non-small cell lung cancer [NSCLC] and nasopharyngeal cancer.

Shares of Cyclacel Pharmaceuticals jumped from $1 to more than $4 in January 2010 when independent investigators published data in the peer-reviewed journal Clinical Cancer Research showing that both seliciclib and a second-generation CDK inhibitor from Cyclacel reversed resistance to lung cancer cells with K-Ras or N-Ras mutations.  Cancers with Ras-activating mutations are thought to be among the most difficult to treat and are not responsive to modern targeted drug therapy, such as EGFR inhibitors.  The data also showed that lung cancer cells are addicted to cyclin E/CDK2.  Cyclacel expects to report top line results from its APPRAISE NSCLC Phase IIb trial with seliciclib later this year.

A different investigator group also recently published data in the peer-reviewed journal Clinical Cancer Research demonstrating that seliciclib reversed resistance to the aromatase inhibitor Femara® [letrozole].  Seliciclib killed hormone receptor-positive breast cancer cells that had become insensitive to the effects of letrozole because of over expression of low molecular weight Cyclin E.

At AACR, Cyclacel is introducing a second-generation CDK product candidate, which is currently in investigational new drug [IND]-directed development.  The undisclosed molecule is a second generation oral CDK inhibitor with increased potency.  Three abstracts related to both seliciclib and the second-generation compound are scheduled for presentation at AACR.

Sanofi-Aventis SA (SNY)

Sanofi-Aventis is developing its lead CDK inhibitor, flavopiridol [HMR-1275, alvocidib] for the treatment of both solid and hematologic malignancies.  Flavopiridol is a pan–CDK inhibitor that blocks CDK9, -2, -4, and -6 at nanomolar concentrations.  Published data from flavopiridol clinical trials suggest that its main toxicities are induction of neutropenia and secretory diarrhea.  Phase II studies of flavopiridol as a single agent have been completed in metastatic melanoma, endometrial adenocarcinoma, and multiple myeloma demonstrating limited efficacy as a monotherapy.  However, flavopiridol has shown promise as a combination therapy, with the best responses observed in CLL patients in combination with fludarabine and cyclophosphamide.  Four abstracts related to flavopiridol are scheduled for presentation at AACR.

Merck & Co., Inc. (MRK)

Merck is developing its lead CDK inhibitor, SCH 727965 [dinaciclib], for multiple indications including solid tumors, NHL, multiple myeloma, ACL, and ALL.  SCH 727965 is an intravenously-delivered CDK1, CDK2, CDK5, and CDK9 inhibitor.  The drug is administered by a 2-hour IV infusion once every 21 days.  Merck is currently recruiting patients for a Phase II study evaluating SCH 727965 to determine the activity of SCH 727965 in patients with breast cancer and in patients with lung cancer compared to standard treatment, capecitabine and erlotinib respectively.  One abstract regarding the activity of SCH 727965 in cell lines for childhood cancers is scheduled for presentation at AACR.

Bayer (BAY.DE)

Bayer will introduce its CDK inhibitor, BAY 1000394, in an abstract scheduled for presentation at AACR.  BAY 1000394 is a nanomolar pan-CDK inhibitor targeting CDK1/Cyclin B, CDK2/Cyclin E, CDK4/Cyclin D1, and CDK9/Cyclin T1.  The maximum tolerated dose for BAY 1000394 was found to be 2.0 mg/kg on QD schedule and 2.5 mg/kg on a BID intermittent schedule.  BAY 1000394 is being tested in a broad range of histological tumor subtypes.

Tragara Pharmaceuticals (private)

Tragara Pharmaceuticals is developing TG02 [also known as SB1317], an oral multi-kinase inhibitor that targets CDK 1, 2, 7 and 9, as well as two other kinases – JAK2 and FLT3.  TG02, which was licensed from S*BIO Pte Ltd in January 2009, is being prepared for IND filing in Q2 2010 with plans to proceed in hematology and solid tumors.  Tragara recently received a $1 million grant form the Multiple Myeloma Research Foundation [MMRF] to fund the early-stage drug development TG02 in treating multiple myeloma.  One abstract regarding the activity of TG02 in leukemia cell lines is scheduled for presentation at AACR.


CDKs play a pivotal role in a cell’s entry into division; de-regulated CDK activity is a well-documented player in tumor progression and represents an attractive therapeutic anti-cancer option.   However, first generation CDK inhibitors have not demonstrated improved clinical outcomes.  Next generation CDK inhibitors, such as those being discussed at AACR, are CDK sub-type specific and have shown improved potency along with other drug like properties.  In addition, next generation CDKs are demonstrating their importance in several difficult to treat cancers, such as those dependent on Ras-activating mutations.

Table 1: Abstracts for CDK Inhibitors at AACR

Compound Abstract #/poster#: Title Date/Time
PD-0332991 25: PD 0332991, a selective CDK 4/6 inhibitor, preferentially inhibits growth of ovarian cancer cells with high Rb and low p16 [CDKN2A] expression Sun, Apr 18, 1:00 PM – 3:30 PM
1758/1: Preclinical assessment of using [18F]FLT-PET imaging as a surrogate proof-of-mechanism biomarker for early drug development candidates Mon, Apr 19, 9:00 AM – 12:00 PM
3887/20: Reversible inhibition of CDK4/CDK6 sensitizes hematological tumor cells for cytotoxic killing by inducing sequential G1 arrest and synchronous S phase entry that enhances the intrinsic apoptosis pathway Tue, Apr 20, 2:00 PM – 5:00 PM
3888/21: Therapeutically activating the RB pathway in breast cancer: Key mechanisms of response and failure Tue, Apr 20, 2:00 PM – 5:00 PM
3884/17: Beta-2 spectrin opposes the CDK4-mediated suppression of TGF-beta signaling by rescuing Smad3 nuclear localization Tue, Apr 20, 2:00 PM – 5:00 PM
5047/26: Synergistic anti-cancer activity of the CDK4/6 inhibitor PD-0332991 in combination with 5-fluorouracil-based chemotherapy in human colon cancer cells Wed, Apr 21, 8:00 AM-11:00 AM
Seliciclib & 2nd generation compound 22: Cyclin E amplification, a novel mechanism of resistance to trastuzumab in HER2 amplified breast cancer Sun, Apr 18, 1:00 PM – 3:30 PM
3886/19: Therapeutic potential of CDK inhibitors in MLL leukemias Tue, Apr 20, 2:00 PM – 5:00 PM
4431/20: A novel derivative of the Cdk inhibitor roscovitine that induces apoptosis in CLL and overcomes stromal cell-mediated protection Tue, Apr 20, 2:00 PM – 5:00 PM
Flavopiridol 575/10: A subset of small cell lung cancer [SCLC] cell lines are Mcl-1-dependent and undergo apoptosis in response to Flavopiridol-mediated inhibition of cyclin-dependent kinase [cdk] 9 Sun, Apr 18, 2:00 PM – 5:00 PM
667/4: Mechanisms underlying synergistic interactions between the CDK inhibitor flavopiridol [Alvocidib] and the BH3 mimetic GX15-070 [Obatoclax] in human multiple myeloma cells Sun, Apr 18, 2:00 PM – 5:00 PM
650/17: Response prediction to a multitargeted tyrosine kinase inhibitor by profiling serine/threonine kinase activity and inhibition Sun, Apr 18, 2:00 PM – 5:00 PM
3544/19: Assessment of chemo-response in cells derived from patients with malignant ascites Tue, Apr 20, 9:00 AM – 12:00 PM
SCH 727965 5266/20: Pediatric Preclinical Testing Program [PPTP] evaluation of the CDK inhibitor SCH 727965 Wed, Apr 21, 8:00 AM – 11:00 AM
BAY 1000394 3883/16: Pharmacologic profile of the oral novel pan-CDK inhibitor BAY 1000394 in chemosensitive and chemorefractory tumor models Tue, Apr 20, 2:00 PM – 5:00 PM
TG02 2542/29: TG02, a novel multi-kinase inhibitor with potent anti-leukemic activity Mon, Apr 19, 2:00 PM – 5:00 PM