New insights into the immunopathogenesis of psoriasis have opened the door for future therapies. Research into the cause of psoriasis may lead to new, less toxic and more efficacious therapeutic alternatives for patients. More than a dozen products with different mechanisms of action than currently available treatments are currently in Phase II or Phase III clinical trials with key data expected in the next 6-12 months.

For example, Celgene Corporation’s (CELG) apremilast is expected to be the next systemic oral small molecule and first PDE4 inhibitor treatment for psoriasis that will be submitted to the FDA for approval in the second half of 2013. Based on available clinical data, apremilast given orally at 20 or 30mg twice daily, appears to be efficacious, safe, and tolerable for patients with moderate-to-severe plaque psoriasis.

Other late-stage product candidates are advancing, with Phase III clinical trial results for Pfizer Inc.’s (PFE) tofacitinib, a JAK inhibitor, and Novartis’ (NVS) AIN457, an IL-17 inhibitor, also expected in 2013. These two compounds will be the first to announce Phase III trial data for the treatment of psoriasis in their respective classes and, if positive, will offer new therapeutic options for patients.

In 2013, Eli Lilly (LLY) and Incyte (INCY) should report Phase IIb data for baricitinib, an orally administered selective JAK1 and JAK2 inhibitor that unlike Pfizer’s tofacitinib is JAK3-sparing. The data from ongoing trials in psoriasis may demonstrate differences in the safety and efficacy of the different JAK inhibitors.

In the near-term, results from several randomized mid-stage trials are expected before the end of 2012. For example, data from Idera Pharmaceuticals’ (IDRA) Phase II trial with IMO-3100, which has completed enrollment, and data from Actelion’s (ALIOF) Phase II trial with ponesimod are both expected to be announced before the end of 2012.

Going forward, new insight into the cause of psoriasis, more effective treatments, and identification of novel drug targets could provide new hope for the treatment of one of the most prevalent autoimmune diseases.  Accordingly, we produced a comprehensive white paper titled “Medical Advances May Help Improve Psoriasis Outcomes” to provide an overview of product candidates in clinical trials and the life science companies developing novel therapies for this disease.

To receive a free copy of the white paper, please click here.

Scleroderma, derived from the Greek words “sklerosis,” meaning hardness, and “derma,” meaning skin, is another autoimmune disorder.  While the cause is unknown, this chronic disease stems from the over-production of collagen, which results in the hardening of the skin and internal organs such as the lungs, kidneys, heart, and gastrointestinal tract.  In terms of outward appearance, one of the most common and recognizable symptoms of the disease is the formation of thick scar tissue (fibrosis) and hardening of the skin.

Neerja Bhagat, board member of the Scleroderma Foundation’s Delaware Valley Chapter and a patient diagnosed with dcSSc 14-years ago at the age of 35, demonstrates how an automatic jar opener can help overcome decreased hand dexterity resulting from stiffening of joints that affects many scleroderma patients.

Because the disease is relatively rare, the exact incidence and prevalence of scleroderma is unknown.  It is estimated that approximately 250 persons per million American adults are affected by scleroderma, which usually develops between the ages of 35 and 55.

Due to the low incidence, some generalists may not have extensive patient experience with scleroderma.  Accordingly, education and awareness of the disease in addition to groups such as the Scleroderma Foundation, a national nonprofit health organization, can be the greatest resources for managing scleroderma and helping patients reduce the risk of further complications.

“The rheumatologist is the physician that coordinates the care of scleroderma patients and seeing a specialist who knows about this disease is important,” said Christine Gaydos, Executive Director of the Scleroderma Foundation’s Delaware Valley Chapter, in an interview with Life Science Digest.  “We get calls in the office from people outside of the major cities where physicians see less scleroderma patients and may not be as up-to-date on the current research and clinical studies that are available.  In these cases, we help the patient find experts familiar with the hallmarks of the disease in the Philadelphia region.”

As just one example of the nuances associated with the disease, many scleroderma patients have some sort of functional heart problem and echocardiograms are among the most cost-effective and least invasive methods available for screening cardiac anatomy.  While generalists most commonly request an echocardiogram to assess left ventricular dysfunction and determine if high blood pressure has damaged the heart or blood vessels, scleroderma patients often experience pulmonary arterial hypertension (PAH), where the arteries from the heart to the lungs narrow down and generate high pressure on the right side of the heart.  In addition, results from an echocardiogram can be very different from a more comprehensive right heart catheterization (RHC), which is more accurate in diagnosing PAH.

Heterogeneous Clinical Presentation and Outcomes

There are two main forms of scleroderma: systemic and localized.  More common in children, the localized form or scleroderma affects a local area of skin in patches (morphea), in a line down an arm or leg (linear scleroderma), or in a line down the forehead (scleroderma en coup de sabre).  Systemic sclerosis (SSc), which usually affects internal organs and systems as well as the skin, is more common in adults – especially women.  Systemic sclerosis can be further divided into two subtypes based on the extent of skin involvement: limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc).  In lcSSc, skin thickening only involves the hands and forearms, lower legs, and feet.  In dcSSc, the upper arms, thighs, or trunk are affected.

Raynaud’s phenomenon, which manifests as recurrent vasospasm of the fingers and toes usually in response to stress or cold exposures, occurs in the majority of patients with SSc and may be the first sign of the scleroderma disease process.  Raynaud’s phenomenon is more common in adults than SSc and only a fraction of patients diagnosed with Raynaud’s phenomenon will have or develop SSc.

For patients with either localized scleroderma or lcSSc, scleroderma may be a mild condition.  In contrast, SSc has high mortality and morbidity.  Due to a better understanding of the condition, and more treatments available for specific organ-based complications, outcomes have improved in SSc.

For example, in a retrospective cohort analysis of 520 SSc patients, 5-year survival among dcSSc patients has improved from 69% in the historical cohort (1990–1993) to 84% in the contemporary cohort (2000–2003)[1].   Five-year survival among lcSSc patients was relatively unchanged at greater than 91% for both the historical and contemporary cohorts.  Ten-year survival data from time of SSc disease diagnosis ranges from 66%[2] to 82%[3] based on data from other cohort studies.

Renal, cardiac, and pulmonary involvement, however, remain the major complications that limit survival.  Interstitial lung disease (ILD), a condition in which the lung tissue has become scarred or inflamed, develops in up to 75% of patients with SSc and represents one of the two main causes of death[4].  High blood pressure in the blood vessels of the lungs is another highly lethal condition that affects SSc patients.  However, there are now many medications to treat PAH and the earlier it is detected and treated, the better the result will be.  In the past, kidney disease was the leading cause of death, but early detection and treatment have brought this largely under control.

Current Treatments

Although there are medications to slow down disease progression and help with symptoms, including pain, dry eyes and mouth, stomach irritation, etc. there is as yet no cure for scleroderma.

Traditional immunosuppressive medications, primarily available for cancer chemotherapy (cyclophosphamide) or to prevent rejection after organ transplantation, have been used for decades to treat autoimmune disorders, including many rheumatologic conditions such as systemic lupus erythematosus and rheumatoid arthritis[5].  While they have demonstrated some efficacy during early skin involvement and active lung inflammation, they do not appear to provide benefits during the later phases of the disease.

Investigational Approaches

In a previous study, the Scleroderma Lung Study I (SLS I), investigators evaluated a 1-year cyclophosphamide (CYC) treatment for people with scleroderma-related ILD.  The study results demonstrated statistically significant improvements in forced vital capacity, total lung capacity, dyspnea, Rodnan skin scores, and several measures of quality of life.  However, when patients were followed for another year after completing their CYC therapy, the beneficial effects of CYC waned and were no longer significant by the 24-month follow-up.  Preliminary information suggests that an alternative immunosuppressive medication, CellCept® (mycophenolate mofetil, or MMF, by the Roche Group), may be effective in treating this disease, be given for longer periods, and result in fewer side effects.

An ongoing study with a targeted enrollment of 150 patients, the Scleroderma Lung Study II (SLS II), will compare the safety and efficacy of a 2-year treatment with MMF versus a 1-year treatment with CYC.  Specifically, investigators will determine whether MMF produces similar or better improvements in lung capacity and fewer side effects throughout the entire 2-year period (ClinicalTrials.gov identifier: NCT00883129).  Study completion for SLS II is targeted for 2014.

Non-randomized studies of haemopoietic stem-cell transplantation (HSCT) in SSc have shown improvements in lung function and skin flexibility, but with high treatment-related mortality.  In 2011, preliminary results from an open-label, randomized, controlled phase 2 trial by investigators at Northwestern Memorial Hospital were published[6].  The study enrolled 19 patients who were aged younger than 60 years with dcSSc (ClinicalTrials.gov identifier NCT00278525).  All ten patients randomly allocated to receive HSCT improved at or before 12 months’ follow-up, compared with none of nine allocated to cyclophosphamide.  Eight of nine control patients had disease progression compared with no patients treated by HSCT, and seven patients switched to HSCT.  Compared with baseline, data for 11 patients with follow-up to 2 years after HSCT suggested that improvements in modified Rodnan skin scores and forced vital capacity persisted.  Longer follow-up is needed and the study’s estimated completion date is September 2012.

In 2010, the first study to provide evidence of clinical benefit (improved lung function) for rituximab (Rituxan®, Genentech, Inc. and Biogen Idec, Inc.) in SSc patients with interstitial lung disease was published[7].  According to the study results, patients randomized to receive rituximab had a median 10.25% increase in forced vital capacity (FVC) compared with baseline, while those who received standard treatment had a deterioration of 5.04% (P=0.002), at 1-year.  There also was a significant 19.46% increase in diffusing capacity of carbon monoxide (DLco) in the rituximab-treated patients, while the controls showed deterioration of 7.5% (P=0.023).  Skin fibrosis, assessed with the Modified Rodnan Skin Score, also improved by a median of 38.33%, while it worsened by 5.23% in controls.  Due to the study’s small size and the fact that most patients had longstanding disease, had been treated with multiple immunosuppressive agents in the past, and were receiving concurrent therapies during the study, the results need to be replicated in a multicenter randomized trial.

Conclusion

The rarity of scleroderma and the heterogeneity of its clinical presentation hamper efforts to develop new treatments for the disease.  In fact, according to a search of ClinicalTrials.gov, there are only 36 clinical studies currently open to investigate new treatment options for scleroderma.  More investment in research, education, and awareness for scleroderma is clearly needed, as evidenced by the introduction of S. 649, the Scleroderma Research and Awareness Act, by Senator Kristen Gillibrand (D-NY) on March 17, 2011.  The bill is a companion to H.R. 1672 and both bills would increase funding for expanded scleroderma research at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).  You can help make a difference through participation in various events and activities being held in connection with Scleroderma Awareness Month during the month of June and by contacting public officials to support passage of the Scleroderma Research and Awareness Act.

According to the Alzheimer’s Association, AD is the sixth-leading cause of death in the country and the only cause of death among the top 10 in the United States that cannot be prevented, cured or even slowed. Estimates vary, but experts suggest that as many as 5.4 million Americans may have AD.

A fatal form of dementia, AD is a chronic neurogenetic disorder that results in a progressive decline in cognitive functions including memory, judgment, decision-making, orientation to physical surroundings and language. With the increasing life expectancy and the accelerated aging of the population, there is an urgent need to develop treatments for AD.

As of 2010, there are an estimated 36 million people in the world with dementia and this number is expected to increase to 66 million in 2030 and 115 million in 2050.  As many as 28 million of the world’s 36 million people with dementia have yet to receive a diagnosis, and therefore do not have access to treatment, information, and care.

Most people with dementia will be cared for at home by a family member.  Caring for a person with such a disease can cause emotional, psychological and physical problems.

Due in part to the high projected cost of the treatment, supportive care, and the emotional stress on families, in 2011 the US Congress passed and President Obama signed the National Alzheimer’s Project Act that instructs the US government to develop a strategic plan to slow the progression, delay the onset, and prevent AD by 2025.

New federal funding has been committed prior to the completion of the strategic plan.  In February 2012, the Obama administration announced it plans to spend an additional $50 million this year and will seek an extra $80 million in fiscal 2013 to bolster research for AD.  An additional $26 million will be allocated to goals outside pure research, including public awareness and support for caregivers.  The National Alzheimer’s Project Act also established an Advisory Council on AD research, which brings together some of the foremost experts in the field.  The next meeting for the Advisory Council is scheduled for April 17, 2012, and the plan is expected to be completed in 2012.

Beyond the government initiatives, 2012 represents a pivotal year for AD drug development, especially in view of expected results from ongoing Phase 3 trials, including solanezumab by Eli Lilly & Co. (LLY), bapineuzumab by Johnson & Johnson (JNJ), Pfizer Inc. (PFE), and Elan Corporation plc (ELN), and tideglusib by Noscira/Grupo Zeltia.

Positive results from other ongoing clinical trials, the introduction of new tools for detection, such as Eli Lilly’s Amyvid™ imaging agent, and advances in understanding the causes and biology of AD could also enhance interest and much needed investment in the life science companies developing treatments for this disease.

New data in the field will be reported at the two main AD conferences in 2012.  The first event is the Alzheimer’s Association International Conference (AAIC) annual meeting being held July 14-19, 2012 in Vancouver, British Columbia, Canada.  The second is the International Conference on Alzheimer’s’ Disease (ICAD) annual meeting being held October 8-9, 2012 in Dubai, United Arab Emirates.

In view of recent progress, we believe that therapeutic success in AD could indeed occur as early as this year.  Accordingly, we produced a white paper titled “2012: A Pivotal Year for Alzheimer’s Disease Drug Development” to provide an overview of product candidates in clinical trials and the more than 30 life science companies developing novel therapies for AD.

To request a free copy of the white paper, please click here.

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 1^st 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].

References

Immunotherapy for cancers of the central nervous system [CNS], however, continues to be met with skepticism.  Amongst the reasons for such incredulity are concerns that the nervous system may be immunologically privileged[i] and the presence of the blood-brain barrier, which only allows entry of select immune cells from the peripheral blood into the brain.  However, all of these premises have now been substantially discounted and tumors in the CNS should not be considered “off-limits” to immunotherapy[ii].

In addition, recent observations of how the CNS system behaves and interacts with the immune system have shed some light into the potential role of immunotherapy in the treatment of brain cancer.  Consider the following facts:

• People with impaired immune systems have an increased risk of developing CNS lymphomas[iii], suggesting that the immune system has a role in the manifestation of tumors in these patients.  People with compromised immune systems include organ transplantation patients taking immunosuppressive drugs, HIV patients, and cancer patients being treated with chemotherapy, which can weaken immune functionality.
• Bridget McCarthy, Ph.D. of the University of Illinois at Chicago found that patients with gliomas were significantly less likely to report having any type of allergy.  In fact, patients who had more types of allergies, such as seasonal, medication, pet, or food allergies, had up to a 64% reduction in risk of developing glioma[iv]. This suggests a relationship between immunological activity and potential protection from the development of CNS tumors.
• Neurologists and neurosurgeons provide anecdotal reports that glioma patients who experience postoperative infections near the tumor bed seem to do better than the average patient similar to the observations made over a century ago by Coley[v].  This suggests that exogenous factors, such as infections, may result in the activation of the immune system and improve the odds of combating CNS tumors.

Collectively, these observations suggest that proper activation of the immune system in patients with CNS tumors could be beneficial.  Accordingly, we sought to review select companies advancing immunotherapy approaches for brain tumors [see Table 1].

Table 1. Eight Companies with Immunotherapy Approaches for Brain Tumors

* Marketed in Russia as Oncophage® for intermediate-risk renal cell carcinoma, ** Marketed in Korea for hepatocellular carcinoma

About Glioma

Glioma is the most common form of primary brain tumors.  They are solid tumors that arise from glial cells, which help support the function of the neurons.  Glial cells include astrocytes, oligodendrocytes and ependymal cells.  The overgrowth of abnormal glial cells may begin in the brain or spinal cord tissues.

Gliomas can be divided into two categories: low-grade, which are not benign but have a better prognosis, or high-grade, which are malignant and often cause death within months, despite surgery or treatment with chemotherapy or radiation, according to the National Cancer Institute.

Glioblastoma multiforme [GBM], a high-grade glioma, is the most common and aggressive primary brain tumor.  In contrast, tumors originating from astrocytes [astrocytoma] range from Grade 1, which are very benign, to Grade 4, which is the same as a glioblastoma.

Amenable to Immunotherapy

Beyond recent observations suggesting a role for immunotherapy in treating brain tumors, several other factors make glioma an ideal indication for immunotherapy.  First, glioma rarely metastasizes beyond the brain, resulting in a low overall tumor burden within the body.  Second, while the blood-brain barrier is thought to restrict entry of immune cells from the peripheral blood into the brain of healthy individuals, glioma disrupts the blood brain barrier, allowing for the freer trafficking of T-cells.  Finally, glioma tumor tissue, especially in patients who are newly diagnosed, is amenable to surgical resection therefore lowering tumor burden at time of vaccination [minimal residual disease].  Studying cancer immunotherapy in settings with bulky or metastatic disease might help explain some of the past failures, as the immune system may not be able to thwart such extensive disease.  Accordingly, minimal disease settings are ideal for cancer immunotherapy.

Strategies for Immunotherapy in Glioma

In general, two categories of immunotherapeutic approaches for the treatment of glioma are currently being pursued: cell-free vaccines and cell-based vaccines.

Cell-free vaccines

Cell-free vaccines may contain heat-shock protein-peptide (HSP) complexes derived from the patient’s tumor following surgery [autologous] or incorporate one or more defined tumor peptides plus an adjuvant [non-autologous].  The following companies are advancing cell-free vaccines:

• Agenus, Inc.: autologous HSPs that elicit both CD4+ and CD8+ T-cell response and also innate response
• Celldex Therapeutics: a single EGFRvIII peptide
• Immatics Biotechnologies: 11 tumor associated, synthetic peptides

Cell-based vaccines

Cell-based vaccines often incorporate dendritic cells [DC] pulsed with defined tumor peptides, tumor cell lysate, brain tumor stem cell mRNA.  Alternatively, some cell-based vaccines consist of adoptive lymphocyte infusion and/or irradiated tumor cells.  The following companies are advancing cell-based vaccines:

• ImmunoCellular Therapeutics: DCs pulsed with shared HLA-A1/A2 tumor peptides
• Innocell Corp: adaptive transfer of cytokine-induced T-cells/NK cells
• Northwest Biotherapeutics: DCs pulsed with tumor lysate
• Oncovir, Inc.: a-type 1 polarized DCs pulsed with defined HLA-A2 peptides plus poly-ICLC adjuvant
• TVAX Biomedical: whole cell vaccination plus adoptive transfer of lymphocytes

To date, commercializing cell-based vaccines has been challenging.  For example, Dendreon’s (DNDN) Provenge® [sipuleucel-T] for prostate cancer is a cell-based vaccine that fell short of Wall Street analyst expectations during the first full year of commercial launch.  Provenge and other DC-based cancer vaccines require leukopherisis to acquire a patient’s dendritic cells.  This process adds to the overall cost of producing the vaccine and makes the logistics somewhat complicated.  In contrast, cell-free vaccines can be derived from synthetic peptides or from the patient’s tumor following standard surgical resection, making the treatment process more user friendly from both a physician and patient perspective.

Clinical Development of Immunotherapy for GBM

The current standard of care for GBM, based on a prospective, randomized controlled trial published in 2005, involves maximal surgical resection with adjuvant radiation therapy and temozolomide[vi].  Despite this therapeutic regimen, median overall survival is between 14.6 and 19.6 months for newly diagnosed patients and between 6 and 9 months for recurrent GBM[vii]^,[viii].

While immunotherapy approaches for GBM would be expected to perform better in the newly diagnosed setting, some companies first established proof-of-concept for their product candidates in the relapsed setting.  Due to the shorter expected survival, these Phase I/II studies may be faster and less expensive.  If hints of efficacy are observed in the relapsed disease setting, the product candidates can then be explored in the newly diagnosed setting.

In view of differences among histologies, ages, trial designs, and the small number of patients with immunotherapy studies published to date in the recurrent GBM setting, comparing and contrasting the findings is difficult [see Table 2].  For example, in the largest single study [56 patients] from the Catholic University of Leuven, the median age was the lowest [45 years] due to the inclusion of children above the age of seven.  In addition, some of the studies included patients that were not diagnosed with GBM, such as astrocytomas that can vary in grade.

In contrast to the results obtained with current standard of care, several of the studies with cancer vaccines for recurrent GBM have demonstrated a median overall survival greater than nine months.  Some of these trials where immune responses have been measured, such as the Prophage G-200 [HSPPC-96] trial, have shown impressive immunological activity post vaccination.  More impressive and certainly more relevant, these responses have also been measurable locally at the tumor site, which suggests such a response may be more meaningful from the perspective of effectively combating the disease.

Table 2. Recurrent GBM Vaccine Data

Several companies are also currently conducting immunotherapy trials in newly diagnosed GBM, with encouraging results presented to date, including Agenus [ClinicalTrials.gov: NCT00905060], Celldex Therapeutics [ClinicalTrials.gov: NCT01480479], Immatics [ClinicalTrials.gov: NCT01222221], ImmunoCellular [ClinicalTrials.gov: NCT01280552], Innocell Corporation [ClinicalTrials.gov: NCT00807027], and Northwest Biotherapeutics [ClinicalTrials.gov: NCT00045968].

An important future direction for the successful treatment of these very difficult tumors may involve the combination of immunotherapeutic agents with other synergistic treatments.  Such approaches could simultaneously address the immunosuppressive, angiogenic, invasive, and hypoxic nature of GBM.  In this regard, combination approaches with Avastin® [bevacizumab] and other potentially synergistic agents would make imminent sense to pursue.

Note: For further information on this topic, click here to view a replay of the plenary session “Advances in immunotherapy for glioma” by Andrew T. Parsa, M.D., Ph.D., University of California, San Francisco, from MD Becker Partners’ 2nd Annual “Cancer Immunotherapy: A Long-Awaited Reality” Conference held October 6, 2011.

References

On the heels of such a miserable year, it may have seemed counterintuitive to provide a positive outlook for the speculative biotechnology industry in 2009, but that’s exactly what we did.  Our bullish thesis was reiterated for both 2010 and 2011.

The AMEX Biotechnology Index (BTK) ended 2008 at 647.17 and climbed to 1,091.42 by the end of 2011 for a gain of approximately 69% during this three-year period.  Comparing this performance with the general market, the NASDAQ Composite increased 65% from 1,577.03 to 2,605.15 during the same period.

Our favorable outlook for the biotechnology industry remains intact for 2012 and is based on the following key drivers, which build upon many of the catalysts we first proposed in 2009:

• Sector’s defensive characteristics and impact on future economic growth
• Improving number of annual new product approvals since the low set in 2007
• Record number of products in clinical trials and annual industry R&D investment
• Improving access to capital
• Brisk pace of industry consolidation and licensing transactions
• Many micro, small and mid-capitalization companies remain undervalued

Defensive Sector and Economic Driver

During periods of economic uncertainty, the biotechnology sector is often portrayed as defensive given that disease is relentless in both good economic times and bad.  Despite recent medical advances, there remains a need for quality, innovative products to diagnose and treat a broad variety of diseases such as cancer, central nervous system disorders, cardiovascular diseases, diabetes, respiratory and infectious diseases.

Beyond its defensive characteristics, the sector plays a critical role in the United States [US] economy.  Innovative new medicines developed by life science companies provide better patient outcomes, improved quality of care, increased life expectancy, and lead to economic gains and job creation.

While the strengths and weaknesses of the US healthcare system remain the subject of great debate, we believe new medicines should be viewed as investments in the future, not only in patient health – but also in economic recovery and growth.  For example, as indicated in our article “Innovative New Medicines are Key to Economic Growth,” a permanent 1% reduction in mortality from cancer alone has a present value to current and future generations of Americans of nearly $500 billion and a cure would be worth about $50 trillion.

New Drug Approvals

As we highlighted in recent years, legislation passed in 2008 gave the FDA more money and resources, but hiring and training hundreds of new employees takes time.  With that process well underway, combined with increased familiarity of the risk evaluation and mitigation strategies [REMS] program, we expected the drug approval process to gradually improve.

Encouragingly, the total number of approvals for new molecular entities and biologic license applications by the US Food and Drug Administration’s [FDA] Center for Drug Evaluation and Research [CDER] in fiscal year 2011 was 35.  This is an improvement from 21 approvals in 2010 and 25 approvals in 2009.  In fact, according to a press announcement by the FDA, this is among the highest number of approvals in the past decade, surpassed only by 37 approvals in 2009.

However, an article in Nature Reviews by Asher Mullard listing the annual number of drug approvals going back to 1996 shows that 36 approvals in 2004 [not 2009] was the record for the past decade.  The same article also shows that new drug approvals peaked at a high of 56 in 1996.

Notable new drug approvals in 2011 include Johnson & Johnson’s (JNJ) Zytiga® [abiraterone] for late-stage prostate cancer, Roche’s Zelboraf® [vemurafenib] and Bristol-Myers Squibb’s (BMY) Yervoy™ [ipilimumab] both for melanoma, Human Genome Sciences’ (HGSI) Benlysta® [belimumab] – the first new drug for lupus in 50 years, and Seattle Genetics’ Adcetris™ [brentuximab vedotin] for a rare lymphoma known as systemic anaplastic large cell lymphoma [ALCL].

Record Pipeline and Investment

According to the latest report by the Pharmaceutical Research and Manufacturers of America [PhRMA], there are a record number of biotechnology product candidates currently in development.  In the US alone, there are more than 900 biotechnology products in development, including 300 monoclonal antibodies, 298 vaccines, 78 recombinant proteins, 50 gene therapy products, 64 cell therapy products, and 23 antisense products.  More than one-third of these product candidates are targeting cancer and related conditions and more than 20% are targeting infectious diseases.

Annual research and development expenditures by PhRMA member companies for 2009 was an estimated $45.8 billion, more than tripling the $15.2 billion level of investment in 1995.  However, skeptics will point to the fact that despite growing R&D expenditures, the number of new drug approvals has declined since the mid-1990s [see chart below].

Access to Capital

During the second week of January, more than 8,000 registrants gathered in San Francisco, California for the 30^th Annual J.P. Morgan Healthcare Conference [JPMHC] to hear 25-minute presentations from 395 life science companies.  For industry executives and investors, the annual event typically serves as a good barometer for the rest of the year.

Between meetings, we roamed the familiar halls of the Westin St. Francis Hotel to assess the mood among participants and also monitored social media outlets throughout the event.  In general, the plane flights and networking receptions were crowded as usual, industry observers “Tweeted” a sense of optimism, and attendees appeared more upbeat than in 2011.

The recent closing of three new funds may support increased optimism as it relates to access to capital.  First, on January 3, 2012, Vivo Ventures announced the final closing of a $375 million fund targeting later development stage pharmaceutical and medical device companies in the US and in revenue stage healthcare companies in greater China.  Second, during the JPMHC Canaan Partners announced the closing of a $600 million fund, with one-third of the fund designated to healthcare investments in biopharmaceutical, medical device and healthcare infrastructure companies.  Also during the JPMHC, Flagship Ventures announced the closing of a $270 million life sciences fund, its largest fund to date.   According to Flagship’s press release, in addition to investing in early-stage companies, a portion of the new fund will be dedicated to “later-stage value investing opportunities resulting from the current capital-constrained environment.”  Finally, Luke Timmerman of Xconomy recently reported that Frazier Healthcare is also aiming for its first biotechnology fund since 2007.

Last year wasn’t too bad either.  In 2011, venture capitalists invested $28.4 billion in 3,673 deals, an increase of 22% in dollars and a 4% rise in deals over the prior year, according to the MoneyTree™ Report by PricewaterhouseCoopers LLP and the National Venture Capital Association [NVCA], based on data from Thomson Reuters.  In fact, venture capital investing in 2011 ranks in the top three years for venture capital investing in the past decade.  Biotechnology was the second largest investment sector, with $4.7 billion going into 446 deals.  This represents a 22% increase in investment dollars, but a 9% drop in terms of the number of deals.

2012 is also off to a solid start with regard to follow-on financings.  Synageva (GEVA), Arena Pharmaceuticals (ARNA), iBio (IBIO), Talon Therapeutics (TLON), ImmunoCelluar Therapeutics (IMUC), Vical (VICL), Synta Pharmaceuticals (SNTA), Chelsea Therapeutics (CHTP), Sequenom (SQNM), ZIOPHARM Oncology (ZIOP), Neurocrine Biosciences (NBIX), and NeuroMetrix (NURO) have each announced offerings since the start of the year.

Consolidation and Licensing

Adding to the optimism among industry executives and investors during the JPMHC, Bristol-Myers Squibb announced its $2.5 billion acquisition of Inhibitex, Inc. (INHX) on January 7, 2012.  In view of the fact that US pharmaceutical companies stand to lose billions of revenue due to patent expirations from 2010 to 2012, we expect merger and acquisition [M&A] activity to remain brisk.

In other M&A news, ISTA Pharmaceuticals (ISTA) is still being pursued by Valeant Pharmaceuticals (VRX), which recently increased its previously proposed price to acquire ISTA from $6.50 to $7.50 per share in cash. Valeant also communicated to ISTA that it could achieve a price of up to $8.50 per share following confirmatory due diligence.

Licensing deal activity is also off to a strong start in 2012, as evidence by Xenon Pharmaceuticals’ strategic alliance with Genentech, a member of the Roche Group (RHHBY), to discover and develop compounds and companion diagnostics for the potential treatment of pain.

According to the deal, which was announced during JPMHC, Xenon is eligible to receive research, development and commercialization milestone payments, totaling up to $646 million for multiple products and indications.  In addition, Xenon will receive royalties on sales of products resulting from the collaboration.

In other licensing news, BioDelivery Sciences (BDSI) recently signed a worldwide license and development agreement with Endo Pharmaceuticals (ENDP) for the exclusive rights to develop and commercialize BEMA Buprenorphine for the treatment of chronic pain.

Small Versus Large

Similar to recent years, we expect that small and mid-capitalization companies with late-stage programs and/or positive fundamental catalysts will continue to outperform their larger industry peers in 2012.

For example, after being the third worst performer in the prior year, Medivation (MDVN) became the largest percentage gainer within the NASDAQ Biotech Index during 2011 based on encouraging results with MDV3100, the company’s lead product candidate in Phase 3 development for the treatment of castration-resistant prostate cancer.

In another dramatic reversal of fortune, after declining 22% in 2009 shares of Akorn, Inc. (AKRX), a niche generic pharmaceutical company, made an impressive comeback by becoming the largest percentage gainer within the NASDAQ Biotech Index during 2010 and again making the list of top ten gainers in 2011 [see Table 1].

However, the prior year’s winners may not always stay hot.  Both Human Genome Sciences (HGSI) and Dendreon Corporation (DNDN) were among the top ten gainers from the NASDAQ Biotech Index in 2009 with dizzying returns of 1,342% and 474%, respectively.  In 2011, both names appear on the list of top ten decliners [see Table 2].

Table 1. Top ten gainers from NASDAQ Biotech Index (NBI) in 2011

Table 2. Top ten decliners from NASDAQ Biotech Index (NBI) in 2011

2012 Outlook

The drivers supporting our favorable outlook for the biotechnology industry remain intact for 2012, such as the record number of products in clinical trials and annual industry R&D investment, improving access to capital, brisk pace of industry consolidation and licensing transactions, and attractive valuations among many small- and mid-capitalization companies, which should continue to outperform their larger industry peers.  In particular, 2012 represents a period with particularly robust news flow for emerging immuno-oncology companies, as indicated in our article “2012 Preview: Cancer Immunotherapy Catalysts.”

One recent example of this inherent volatility and achieving a lofty valuation prior to commercialization is Dendreon Corporation (DNDN).  On April 29, 2010, the FDA approved the very first active immunotherapy for the treatment of cancer – Dendreon’s Provenge® [sipuleucel-T] for metastatic castrate-resistant prostate cancer [CRPC].  This event reignited enthusiasm for the field of active immunotherapy for cancer and shares of Dendreon, which traded below $5 in March 2009, subsequently reached an all-time high above $57 and a market capitalization of approximately $7.8 billion.

It has been said that a rising tide raises all boats and Dendreon’s success lifted shares of other companies working in the field of active immunotherapy for the treatment of cancer.  Table 1 below depicts the stock price performance of select cancer immunotherapy companies from April 1, 2010 to April 30, 2010, the month Provenge was approved by the FDA.

Table 1: High Tide for Cancer Immunotherapy Around Approval of Provenge

On August 3, 2011, however, Dendreon withdrew its previous guidance of $350-400 million in revenue for 2011, with modest quarter over quarter revenue growth expected for the remainder of the year.  The news not only caused a dramatic decline in Dendreon’s stock, but also cast a shadow on other companies working in the emerging field of active immunotherapy for cancer.  Table 2 below depicts the stock price performance of select cancer immunotherapy companies from August 1, 2011 to August 31, 2011, the month that Dendreon withdrew its revenue guidance.  Dendreon’s stock recently traded around $7 per share, down nearly $50 from its all-time high, and the company’s market capitalization is just over $1 billion.

Table 2: Low Tide for Cancer Immunotherapy Around Dendreon’s Withdrawal of Revenue Guidance

While FDA approval of the first active immunotherapy for cancer was a watershed event for the industry, the future for companies working in this emerging area should not be judged solely by the commercial success of this product.  Growing evidence indicates that the field of cancer immunotherapy, broadly defined as including passive immunization, active immunization, and immunostimulation, is undergoing a renaissance.

Beyond the approval of Provenge in 2010, the FDA approved Yervoy™ [ipilimumab] by Bristol-Myers Squibb (BMY) for the treatment of patients with unresectable or metastatic melanoma on March 25, 2011.  With the news, ipilimumab became the eleventh monoclonal antibody [mAb] approved for the treatment of cancer since 1997.  Ipilimumab is unique among other mAbs for cancer treatment, as it represents the first immune checkpoint modulator.

In addition, positive results from several randomized studies with active immunotherapies have recently been published in peer-reviewed journals.  The first study published in the March 1, 2010, edition of the Journal of Clinical Oncology was a Phase II randomized controlled trial of Bavarian Nordic’s (BAVA) poxviral-based, PSA-targeted immunotherapy [Prostvac®] in metastatic CRPC.  Patients receiving Prostvac had an 8.5-month improvement in median overall survival versus control. These provocative data supported initiation of a pivotal Phase 3 trial that began enrolling patients in November 2011.

Another study published in the June 2, 2011, edition of the New England Journal of Medicine, demonstrated that patients with metastatic melanoma receiving high-dose interleukin-2 (IL-2) plus a gp100 peptide vaccine had a significant improvement in centrally verified overall clinical response (16% vs. 6%; P=0.03), as well as longer progression-free survival (2.2 months versus 1.6 months; P=0.008).  There was a trend toward longer overall survival in the gp100 vaccine arm (17.8 months versus 11.1 months; P=0.06), although the results were not statistically significant.

As discussed in our report published in June 2011 titled “Cancer Immunotherapy: A Roundtable Discussion,” there are more than 40 unique active cancer immunotherapies currently being tested in over 60 clinical trials, including nearly a dozen that are in pivotal Phase 3 development.  With nearly a dozen readouts from randomized Phase 2 or Phase 3 trials expected during the next 12-months, 2012 could be a breakout year for the field [see Table 3 below].  While not all programs will be positive, success with even just one of these key trials could reignite investor interest in the field and demonstrate that the clinical success with Provenge was not a fluke.

Table 3. Expected Active Immunotherapy Catalysts for 2012

* Based on company reports, analyst reports, and/or MD Becker Partners’ projection

It is worth noting that mAbs were hailed as “magic bullets” when they were developed in the 1970s.   However, clinical results with these passive immunotherapies were largely disappointing for the first 10 years of development.  It wasn’t until November 1997 that the first mAb for cancer therapy, Rituxan® [rituximab], was approved by the FDA for the treatment of non-Hodgkin’s Lymphoma [NHL].  Today, mAbs represent one of the most successful therapeutic classes and eleven such products have been approved for cancer therapy.  Three blockbuster products sold by the Roche Group (RHHBY) – Avastin® [bevacizumab], Rituxan, and Herceptin® [trastuzumab] – collectively represented nearly $17 billion in revenue for 2009.

As stated in our firm’s April 2010 report titled “Cancer Vaccine Therapies: Failures and Future Opportunities,” using the history of mAb development as a guide, we expect to see five active cancer immunotherapies approved by 2015 [5x15] that will revolutionize the treatment of cancer owing to their potential to be more targeted, more effective, and less toxic.  2012 represents a period with robust news flow for emerging immuno-oncology companies and while volatility is expected, any good news could serve as a spark to reignite investor enthusiasm for companies working in the area and raise the tide once again.  In addition to clinical progress, major licensing and/or merger & acquisition transactions could also serve as catalysts for the sector.

Visibility for the disease is on the rise following the recent deaths of Apple, Inc. (AAPL) co-founder Steve Jobs and Ralph Steinman, a cell biologist who died several days before being named one of three winners for the 2011 Nobel Prize in Medicine.  While awareness is increasing, there is an urgent need for more effective treatments and diagnostics to detect the disease earlier due to the fact that the number of new pancreatic cancer cases is projected to increase by 55% from 2010 to 2030[3].

Difficult Disease

The disease remains one of the most difficult to treat due to its extreme resistance to treatment and few early symptoms.  At the time of initial diagnosis, 50% of patients have distant metastases to the liver or peritoneal surface, and more than 80% of the remaining patients have locally advanced tumors [confined to the pancreas but unresectable][4]. The majority of pancreatic tumors [95%] are adenocarcinomas that mainly develop from exocrine cells in the tissues of the pancreas[5]. The tumors are characterized by an aggressive behavior with a fast progression rate that makes them highly metastatic. In contrast, neuroendocrine tumors of pancreatic origin [pancreatic NET, also known as islet cell tumors] are not as common [<2%] and are considered less deadly[6].

Illustrating the difference between the two, Hollywood actor Patrick Swayze was diagnosed with stage IV pancreatic exocrine cancer that had already spread to the liver in March 2008 and lost his battle with the disease in September 2009 at the age of 57.  Apple’s Steve Jobs underwent surgery for pancreatic NET in 2004 and didn’t succumb to the disease until October 2011 at the age of 56.

Treatment for Organ Confined Disease

In terms of treatment, surgical removal of the tumor represents the best option for pancreatic cancer patients without invasion into surrounding organs or distant metastasis.  Unfortunately, only 15–20% of all patients are candidates for potentially curative surgery[7].  Depending on the tumor localization, pancreaticoduodenectomy [Whipple procedure], distal, or total pancreatectomy can be performed.  However, even with an optimal curative surgery, metastases often occur.  Median survival time without evidence of recurrent disease is 21.2 months after surgical resection[8].

Treatment for Locally Advanced/Metastatic Disease

For locally advanced or metastatic disease, an effective single agent for pancreatic cancer remains elusive and treatment is still palliative rather than curative.  Since its approval in 1997, Eli Lilly’s (LLY) Gemzar® [gemcitabine] is the only single agent that improves symptoms and overall survival [OS] in patients with locally advanced or metastatic pancreatic exocrine cancer.  However, gemcitabine is associated with a modest median OS of 5.7 months and one-year probability of survival rate of 18%[9]. No confirmed objective tumor responses were observed in the pivotal study.

Beyond Single Agent Gemcitabine

At least 35 Phase II trials of gemcitabine-containing regimens and 11 randomized Phase III trials have been performed to improve the efficacy of gemcitabine alone, but the progress to date has been incremental at best[10].  In these 46 trials, overall response rates ranged from 5% to 58% in the Phase II studies and 4.4% to 38.5% in the Phase III studies.  Median OS ranged from 4 months to 13.1 months in the Phase II studies and 5.4 months to 9 months in the Phase III studies.  Inclusion of heterogeneous patient populations in many of these studies may have confounded the results, as the median survival time for patients with metastatic disease and locally advanced disease is 3–6 and 9-13 months, respectively[11].  The only successful combination approved by the FDA in 2005 is gemcitabine plus Roche/Astellas Pharma’s Tarceva® [erlotinib], which modestly increased the median OS to 6.4 months and one-year survival to 23%.

Hope on the Horizon

Despite the long list of past failures, drug developers continue to explore new options for treating pancreatic cancer and more than a dozen new treatments are currently being evaluated in clinical trials [see Table 1].  One product was recently approved and several programs have demonstrated encouraging results with data from pivotal trials due in the next 6-12 months.  While a comprehensive review of investigational pancreatic cancer therapies is beyond the scope of this article, we briefly highlight some of the more high profile pancreatic treatments below:

Amgen, Inc. (AMGN)

Amgen is developing ganitumab (also known as AMG 479), an investigational fully human monoclonal antibody that targets type 1 insulin-like growth factor receptor [IGF-1R], which plays an important role in the regulation of cell growth and survival.  At the 2010 American Society of Clinical Oncology [ASCO] Annual Meeting, Amgen announced results from a Phase 2 study demonstrating that the addition of AMG 479 to gemcitabine resulted in an OS rate at six months of 56.6% versus 50.1% with gemcitabine alone[12]. Median OS was 7.3 months versus 6.2 months in the gemcitabine arm.  Amgen initiated a Phase III trial with AMG 479 for metastatic pancreatic cancer in the second quarter of 2011 with data expected in late 2013 or 2014 [ClinicalTrials.gov identifier NCT01231347].  This trial focuses on metastatic disease and therefore should represent a homogeneous patient population where the median OS is expected to be 3–6 months in the control arm.

Celgene Corporation (CELG)

Historically known more for its franchise in treating blood cancers, Celgene moved into the realm of solid tumors through its 2010 acquisition of Abraxis BioScience, Inc. for $2.9 billion.  As a result, Celgene is now developing Abraxane® [paclitaxel protein-bound particles for injectable suspension] for the treatment of metastatic pancreatic cancer.  Abraxane is currently approved for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy[13].

In October 2011, positive Phase I/II study results with Abraxane in combination with gemcitabine in 67 patients with advanced pancreatic cancer were published in the Journal of Clinical Oncology[14].  In the Phase II component of the study, the overall response rate was 48% [21/44 patients], median OS was 12.2 months, and the one-year survival rate for patients was 48%.  This compares favorably with the median OS of 5.7 months and one-year probability of survival rate of 18% with single-agent gemcitabine.

The combination of Abraxane and gemcitabine is now the treatment arm of an ongoing, international, randomized Phase III clinical trial for patients with metastatic pancreatic cancer [ClinicalTrials.gov identifier NCT00844649].  Importantly, this study specifically excludes patients with only locally advanced disease and therefore represents a homogeneous patient population where the median OS is expected to be 3–6 months in the control arm.

Clovis Oncology, Inc. (private)

In November 2009, Clovis licensed rights from Clavis Pharma for CO-101 in the U.S., E.U., and select other countries.  CO-101 is an investigational, lipid-conjugated derivative of gemcitabine, currently in a pivotal Phase II randomized, open-label, multicenter study comparing CO-101 with gemcitabine as first-line therapy in patients with metastatic pancreatic adenocarcinoma [ClinicalTrials.gov identifier NCT01124786].  CO-101 is designed to improve upon the efficacy of gemcitabine by enabling the drug to enter cancer cells without requiring membrane expression of transporter proteins.  As a hydrophilic molecule, the entry of gemcitabine into tumor cells is dependent upon the expression of specific membrane transporter proteins, particularly human equilibrative nucleoside transporter 1 [hENT1].  Data from the pivotal Phase II trial are expected in the first half of 2012 and the inclusion criteria for only Stage IV patients [metastatic] represents a homogeneous population to study in this trial.

In April 2010, Clovis Oncology, Inc. and Ventana Medical Systems, Inc. entered into a collaboration for the development of a hENT1 immunohistochemistry [IHC] assay, which will be used in Clovis’ CO-101 clinical trials to identify patients with low level tumor expression of hENT1 protein.  Approximately 50% of pancreatic cancer patients have been shown to have low tumor expression of hENT1 and low levels of tumor hENT1 expression have been shown to correlate with poor survival outcomes after gemcitabine therapy[15].  These observations support the hypothesis that limited tumor uptake of gemcitabine in hENT1-low patients is responsible for a poor treatment effect in many patients and is an excellent example of a biomarker-driven clinical strategy.

Novartis AG (NVS)

In May 2011, the FDA approved Afinitor® (everolimus) by Novartis AG (NVS) for the treatment of progressive pancreatic NET in patients with unresectable, locally advanced or metastatic disease. Afinitor is an allosteric inhibitor of mammalian target of rapamycin [mTOR], a serine-threonine kinase, downstream of the PI3K/AKT pathway that is dysregulated in several human cancers.  Approval of Afinitor represents the first new therapy for pancreatic NET in the US in nearly 30 years[16].  The approval was based on Phase III data from the RADIANT-3 [RAD001 In Advanced Neuroendocrine Tumors] trial, showing treatment with Afinitor plus best supportive care more than doubled median progression-free survival [PFS], or time without tumor growth, from 4.6 to 11.0 months and reduced the risk of cancer progression by 65% when compared with placebo in patients with advanced pancreatic NET.

Threshold Pharmaceuticals, Inc. (THLD)

At the 2011 ASCO Gastro Intestinal Cancers Symposium, Threshold Pharmaceuticals presented results with its hypoxia-activated prodrug, TH-302, in combination with gemcitabine in 47 patients with previously untreated, locally advanced, unresectable or metastatic pancreatic adenocarcinoma[17].  Of the 43 evaluable patients, one patient [2%] demonstrated a complete response as measured by RECIST [Response Evaluation Criteria In Solid Tumors] and 8 patients [19%] had a partial response.  In the gemcitabine plus TH-302 treatment arms, median OS was 8.5 months.  While this compares favorably with the median OS of 5.7 months with single-agent gemcitabine, recall that in 35 Phase II trials of gemcitabine-containing regimens in heterogeneous patient populations the median OS ranged from 4 months to 13.1 months.

In June 2011, Threshold Pharmaceuticals completed enrollment of patients with first-line, locally advanced, unresectable or metastatic pancreatic adenocarcinoma.  The company expanded the study’s enrollment target from the original 165 patients to at least 200 patients.  As mentioned earlier, inclusion of a heterogeneous patient population may confound the study results [expected before the end of 2011], as the median OS for patients with metastatic disease and locally advanced disease is different.

Conclusion

As we approach Pancreatic Cancer Awareness Month in November, visibility for the disease is on the rise following recent high-profile deaths.  Despite numerous late-stage failures, more than a dozen products are currently in clinical trials with key data expected in the next 6-12 months.  Going forward, early detection using biomarkers, more effective treatments, and novel drug targets could provide new hope for the treatment of this deadly disease.

NOTE: For more information, please visit the Pancreatic Cancer Action Network [http://www.pancan.org], a national organization creating hope in a comprehensive way through research, patient support, community outreach and advocacy for a cure.

Table 1. Baker’s Dozen in Active Clinical Development for Pancreatic Cancer

References

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.

History

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.

Conclusion

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.

References