Zevalin® Receives Positive CHMP Opinion In Europe For First Line Consolidation Treatment
March 24, 2008
Bayer Schering Pharma AG has received a positive opinion from the European Committee for Medicinal Products for Human Use (CHMP) recommending Zevalin® ([90Y]-ibritumomab tiuxetan) as consolidation therapy after remission induction in previously untreated patients with follicular lymphoma (FL) in Europe. The benefit of Zevalin following rituximab in combination with chemotherapy has not been established. The product would receive marketing authorization for all EU member states as a treatment for this indication later this year upon a favorable review by the European Commission. Zevalin is currently approved for adult patients with rituximab relapsed or refractory CD20-positive follicular B-cell Non-Hodgkin’s Lymphoma (NHL) in Europe. It combines the tumor-targeting ability of an anti-CD20 monoclonal antibody and the tumour-destroying power of localised yttrium-90 radiation. Follicular lymphoma is one of the most common types of Non-Hodgkin’s Lymphoma (NHL), a tumor of the lymphatic system.
“The CHMP’s recommendation represents an important milestone for Zevalin, as it recognizes the potential value that consolidation therapy with Zevalin can offer to patients with follicular lymphoma,” said Dr. Gunnar Riemann, member of the Board of Management of Bayer Schering Pharma AG. “This therapy option will provide clinicians with a treatment regimen that truly could help many of their patients to an extended progression-free survival.”
The CHMP’s decision is based on data from the pivotal Phase III First-Line Indolent Trial (FIT) that showed Zevalin, when used as first-line consolidation therapy, significantly prolonged progression-free survival time from 13.5 months (control arm) to 37 months (p
About Zevalin First-line Consolidation Therapy
Consolidation therapy is a treatment regimen given after a patient responds to initial first-line induction therapy (e.g. chemotherapy). The aim of consolidation therapy is to rapidly improve the quality of a patient’s response, thereby extending the response duration.
About the FIT study
The Zevalin FIT study (First-line Indolent Trial) is a multinational, randomized, Phase III trial to investigate Zevalin as first-line consolidation therapy, given as a single therapeutic dose, in patients with advanced (stage III or IV) follicular lymphoma who achieved a partial remission or a complete remission after receiving standard first-line chemotherapy regimens. The objective of the FIT study is the evaluation of benefit and safety of consolidation with Zevalin after first-line therapy in follicular lymphoma patients, one of the most common types of Non-Hodgkin’s Lymphoma.
About Zevalin® the immunotherapy with yttrium 90
Zevalin® is currently approved in more than 40 countries for the treatment of B-cell non-Hodgkin’s lymphoma, including Europe, countries in Latin America and, amongst others in Asia, Japan. In Europe, Zevalin has been approved for adult patients with rituximab-relapsed or refractory CD20-positive follicular B-cell non-Hodgkin’s lymphoma since 2004. Zevalin combines the tumor-targeting ability of an anti-CD20 monoclonal antibody and the tumor-destroying power of localized yttrium-90 radiation. The radiolabeled antibodies can specifically bind to the tumor, therefore killing targeted and also neighboring lymphoma cells, and thus destroying the tumor through several layers of tumor cells. The treatment ensures a high bio-availability at tumor sites and prevents the radioactivity from being distributed through the body by circulating lymphocytes.
Bayer Schering Pharma AG has exclusive rights to Zevalin in all countries of the world except the United States of America.
About Non Hodgkin’s Lymphoma
Non-Hodgkin’s Lymphoma is a type of malignant disease that occurs within the lymphatic system. NHL is the fifth most common cancer after breast, prostate, lung and colon cancer. It originates from lymphocytes, a type of white blood cells, which can be divided into two main types, B lymphocytes and T lymphocytes (also called B-cells or T-cells). Non-Hodgkin’s lymphomas can be divided into two general clinical categories: indolent lymphomas, mainly typified as follicular lymphomas, which tend to grow relatively slowly; and aggressive lymphomas, mainly typified as diffuse large B-cell lymphomas (DLBCL), which grow more rapidly. Follicular lymphoma is one of the most common types of indolent NHL, accounting for 70% of all indolent cases. The overall prevalence of NHL in the European Union is approximately 230,000, with an annual incidence of about 70,000. Approximately 18,500 new cases of FL are diagnosed annually in the USA. It is a long-lasting disease and is difficult to treat.
About Bayer Schering Pharma
The Bayer Group is a global enterprise with core competencies in the fields of health care, nutrition and high-tech materials. Bayer HealthCare, a subsidiary of Bayer AG, is one of the world’s leading, innovative companies in the healthcare and medical products industry and is based in Leverkusen, Germany. The company combines the global activities of the Animal Health, Consumer Care, Diabetes Care and Pharmaceuticals divisions. The pharmaceuticals business operates under the name Bayer Schering Pharma AG. Bayer HealthCare’s aim is to discover and manufacture products that will improve human and animal health worldwide. Find more information at http://www.bayerhealthcare.com.
Bayer Schering Pharma is a worldwide leading specialty pharmaceutical company. Its research and business activities are focused on the following areas: Diagnostic Imaging, Hematology/Cardiology, Oncology, Primary Care, Specialized Therapeutics and Women’s Healthcare. With innovative products, Bayer Schering Pharma aims for leading positions in specialized markets worldwide. Using new ideas, Bayer Schering Pharma aims to make a contribution to medical progress and strives to improve the quality of life. Find more information at http://www.bayerscheringpharma.de.
Forward Looking Statements
This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer Group or subgroup management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer’s public reports which are available on the Bayer website at www.bayer.com. The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.
Bioenvision Ltd Withdraws Its Application For An Extension Of Indication For Evoltra (clofarabine) - Europe
March 20, 2008
The European Medicines Agency (EMEA) has been formally notified by Bioenvision Ltd, a whollyowned subsidiary of Genzyme Corporation, of its decision to withdraw its application for an extensionof indication for the centrally authorised medicine Evoltra (clofarabine).
Evoltra was expected to be used for the treatment of acute myeloid leukaemia in elderly patients.Evoltra was first authorised in the European Union on 29 May 2007. It is currently indicated for thetreatment of acute lymphoblastic leukaemia in paediatric patients.
The application for the extension of indication for Evoltra was submitted to the EMEA on 7 February2007. In its official letter, the company stated that the withdrawal of the application was based on theCHMP’s opinion that the data provided did not allow the Committee to conclude that the benefits ofthe medicine outweigh the risks. However, data could be provided in order to support a resubmissionin this indication in the near future.
More information about Evoltra and the state of the scientific assessment at the time of the withdrawalwill be made available in a question-and-answer document. This document, together with thewithdrawal letter from the company, will be published on the EMEA website in due course.
Withdrawal of an application does not prejudice the possibility of a company making a newapplication at a later stage.
European Medicines Agency
Link Found Between Low Micro-RNA Level And High Gene Activity In AML
March 7, 2008
A new study suggests that a type of acute leukemia may occur in part because abnormally low levels of one small molecule result in the over-activity of genes important to the disease.
The research involved patients with acute myeloid leukemia (AML) and a gene mutation called NPM1, an alteration seen in about one-third of adult AML cases.
The findings suggest new therapeutic targets for treating the disease and should improve the understanding of AML, researchers say.
The study showed that a type of microRNA - molecules important in controlling cell development and proliferation - regulates two genes whose elevated activity has been linked to leukemia in humans and proven to cause leukemia in mice.
The two genes belong to the Hox family of genes, known to play a critical role in embryonic development and blood-cell development.
The study, led by researchers at the Ohio State University Comprehensive Cancer Center, was published online Feb. 28 in the Proceedings of the National Academy of Sciences.
“We’ve shown that low levels of a microRNA called miR-204 are at least partly responsible for the high activity of these Hox genes,” says first author Dr. Ramiro Garzon, an Ohio State cancer researcher.
“If this is verified, and if we can develop a drug to modulate this microRNA, it may provide a new therapeutic intervention for these patients.”
For this study, the investigators examined microRNAs levels in leukemia cells from 85 patients. They also looked for mutations in two genes in the leukemic cells: NPM1 and FLT3 (pronounced “Flit-3″).
The pattern of microRNA molecules present in the cells enabled the researchers to distinguish the 55 patients with mutated NPM1 genes from those with a normal gene.
Furthermore, 26 of the 85 patients had FLT3 mutations. These cases also had high levels of a microRNA called miR-155. Further experiments showed that while the high levels of miR-155 were closely associated with FLT3 mutations, they were independent of the mutation (i.e., it did not cause the high levels).
“This is significant,” says Garzon, an assistant professor of internal medicine. “We already have drugs that target FLT3, but they are not effective by themselves. This finding suggests that if we develop a drug that targets miR-155, and combine it with a FLT3 inhibitor, we might achieve a more complete response in these patients.”
Garzon and his colleagues are studying that possibility now.
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Source: Darrell E. Ward
Ohio State University Medical Center
Discovery That Blood Stem Cells Originate And Are Nurtured In The Placenta May Allow Researchers To Mimic Embryonic Environment
March 6, 2008
Solving a long-standing biological mystery, UCLA stem cell researchers have discovered that blood stem cells, the cells that later differentiate into all the cells in the blood supply, originate and are nurtured in the placenta.
The discovery may allow researchers to mimic the specific embryonic microenvironment necessary for development of blood stem cells in cell culture and grow them for use in treating diseases like leukemia and aplastic anemia, said Dr. Hanna Mikkola, a researcher in the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research and senior author of the study.
“It was a big mystery, where these cells originated,” said Mikkola, an assistant professor of molecular, cell and developmental biology. “This is the first time we can really say definitively that blood stem cells are generated in the placenta. There’s no more speculation.”
The study is published March 6, 2008 in the journal Cell Stem Cell. Researchers in Mikkola’s lab are working now to replicate this work, done in mouse models, in humans.
“If we want to fully harness the potential of embryonic stem cells to treat disease, it’s critical for us to learn how to make tissue specific stem cells,” said Mikkola, who also is a researcher at UCLA’s Jonsson Comprehensive Cancer Center. “We can learn that by studying what happens during embryonic development.”
Scientists now can take embryonic stem cells, the cells that can become any tissue type in the body, and coax them into becoming all the cells in the blood supply, such as red and white blood cells and platelets. However, they can’t make blood stem cells that self-new, or make more of themselves, and don’t differentiate prematurely when transplanted into patients. The only way this currently can be achieved is by manipulating the cell’s nuclear regulatory machinery with genes using retroviruses. To generate blood stem cells that are safe for use in patients, it is imperative that scientists learn how to generate self-renewing blood stem cells in a more natural way, by providing the correct developmental cues from the environment in which the cells develop.
Currently, patients with certain types of leukemia have one shot at a cure - a bone marrow transplant. However, there aren’t nearly enough bone marrow donors to provide patients with perfect matches. Use of a less than perfect donor match carries a risk of graft vs. host disease, in which the immune cells from the donated marrow attack the body of the transplant patient. Cord blood contains blood stem cells, but not in large enough quantities to transplant an adult patient, Mikkola said.
If researchers could grow blood stem cells, those cells could be transplanted into these patients. The blood stem cells would then differentiate into a new, and healthy, blood supply. And with the recent success in creating induced pluripotent stem cells (iPS) from human skin cells, a patient’s own skin cells could perhaps be used to create iPS cells. Those cells could then be transformed into blood stem cells, creating an immune-compatible source of blood supply that eliminates the risk of graft vs. host disease.
In her previous research, Mikkola and collaborators in Harvard and France had discovered that the placenta contained a large pool of blood stem cells, but it wasn’t clear if they originated elsewhere and migrated to the placenta to self-renew. Using a unique mouse model, a mouse embryo without a heartbeat, Mikkola and her team were able to find the blood stem cells at the site of their origin because there was no circulation of blood through the body.
“Using this model, we identified that the placenta has the potential to make hematopoietic (blood) stem cells with full differentiation ability to create all the major lineages of blood cells,” Mikkola said. “The placenta acts as a sort of kindergarten for these newly made blood stem cells, giving them the first education they need.”
It was previously known that blood stem cells could be found in the dorsal aorta, but there were so few located there that scientists reasoned it could not be the sole source of blood stem cells in the embryo. Mikkola’s discovery indicates that the blood stem cells are generated in the large arteries of the embryo and placenta, and then move to a specific site, or niche, where they expand and mature.
This recent study indicates that the first niche for expansion of blood stem cells is the placenta’s vascular labyrinth, where oxygen and nutrients are exchanged between the mother and the fetus. The findings show the placenta harbors two different microenvironments, one area where blood stem cells originate and another area, the labyrinth, that nurtures them, allowing them to expand in number. These niches serve different roles and could provide clues to researchers seeking to grow blood stem cells. Mikkola now is seeking to uncover the critical biological signals and cues during embryonic development that drive blood stem cell generation and expansion and keep the cells from differentiating prematurely.
“The labyrinth is a source of many growth factors and cytokines,” Mikkola said. “We just need to identify what those signaling molecules and cues are that are nurturing those cells when in the placenta.”
Mikkola is confident the study can be confirmed in humans.
“Everything we’re learning suggests we will find the same thing in the human placenta,” she said.
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The stem cell center was launched in 2007 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 150 members, the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research is committed to a multi-disciplinary, integrated collaboration of scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The institute supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed towards future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine, UCLA’s Jonsson Cancer Center, the Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science.
Source: Kim Irwin
University of California - Los Angeles
NICE Approves MabThera(R) (Rituximab) As Maintenance Therapy For Patients With Follicular Non-Hodgkin Lymphoma
February 28, 2008
The National Institute for Health and Clinical Excellence (NICE) issued final guidance recommending the use of MabThera(R) (rituximab), as a maintenance therapy for patients with relapsed/refractory follicular non-Hodgkin lymphoma (NHL) responding to induction therapy with chemotherapy with or without rituximab. 1 This is an important breakthrough as it represents a new treatment approach that can allow patients with this potentially fatal disease to manage it as a chronic condition and live for an average of over four years before the disease returns.
Maintenance treatment with rituximab is a new approach to managing NHL, which allows patients who have responded to initial treatment to receive maintenance therapy every three months for up to two years. Data have shown that when treated with rituximab maintenance therapy, patients’ risk of death was reduced by 48%. In addition, their average time of living disease-free was significantly extended to over four years (51.5 months) compared to just 14.9 months when left untreated with maintenance during this remission period (p
Dr Premini Mahendra, Consultant Haematologist at the Queen Elizabeth Hospital, Birmingham, commented “Rituximab is continuing to revolutionise the management of NHL. The positive NICE guidance for rituximab in the maintenance setting represents a significant step forward in the management of one of the most common forms of NHL. By reducing the risk of death and trebling progression free survival in patients living with this disease, the maintenance approach to treatment is moving this cancer to a chronic disease status.”
Rituximab, the world’s first monoclonal antibody licensed for cancer treatment in the UK, has received consistent positive NICE guidance during the 10 years since its launch, with today’s announcement being the fourth positive NICE guidance that the treatment has received across its various NHL indications since 2002. It remains the only therapy that increases overall patient survival when used in combination with chemotherapy to treat aggressive NHL.
Rituximab has many characteristics essential for a maintenance therapy: it is both effective and well tolerated, and can maintain active concentrations in the blood with intervals of several months between administrations. This enables most patients to continue with everyday life whilst on maintenance therapy without having to undergo repeated courses of chemotherapy to treat their disease.
Follicular NHL is the most common type of indolent NHL.3 It is a slow-developing but ultimately often fatal cancer of the lymphatic system, with patients suffering from multiple relapses after treatment, with periods of stable or undetectable disease (a ‘partial’ or ‘complete’ remission) in between. NHL is the sixth most common cancer in the UK.4 Each year there are over 5,200 new cases in men and 4,700 cases in women.5
In the maintenance phase no new safety concerns were reported that were not already known from the use of rituximab as induction therapy. Neutropenia was the most common adverse event with an incidence of 11% in the rituximab group compared with 5.4% in the observation group (p=0.07). This most likely accounted for the significant increase in the grade 3-4 infection rate in the rituximab group compared with observation (9% vs 2.4%, p=0.009). There were no deaths related to rituximab maintenance treatment. Other common side effects can be experienced during the drug’s infusion - mainly fever, chills and rigors.2
With the publication of this final guidance, Primary Care Trusts (PCTs) and NHS Trusts, which manage the implementation of NICE approved therapies, have a maximum of three months in which to fully implement this use of rituximab, ensuring all eligible patients have access to this NICE-recommended option.
About MabThera (rituximab)
Rituximab is currently approved for first-line use for patients with later stages of follicularNHL in combination with the chemotherapy in those resistant to chemotherapy or insecond or subsequent relapse, and as a monotherapy for later stages of follicular NHL. It isalso approved for use as maintenance treatment in patients with relapsed or refractory follicular lymphoma and in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) chemotherapy for patients with diffuse large B-cell (aggressive) NHL.6
It is a therapeutic antibody that binds to a particular protein - the CD20 antigen - on the surface of normal and malignant B-cells. It then recruits the body’s natural defense to attack and kill the marked B-cells. Stem cells in bone marrow lack the CD20 antigen, allowing healthy B-cells to regenerate after treatment and return to normal levels within several months.6
About Roche in the UK
Roche aims to improve people’s health and quality of life with innovative products and services for the early detection, prevention, diagnosis and treatment of disease. Part of one of the world’s leading healthcare groups, Roche in the UK employs nearly 2,000 people in pharmaceuticals and diagnostics. Roche is the leader in diagnostics, and a major supplier of medicines for the treatment of cancer, transplantation, virology, bone and rheumatology, obesity and renal anaemia. Find out more at http://www.rocheuk.com.
References:
1. NICE STA Rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin lymphoma. 27th February 2008
2. Van Oers MH et al. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin’s lymphoma, both in patients with and without rituximab during induction: results of a prospective randomized phase II intergroup trial. Blood 2007; pre-published online (http://www.bloodjournal.org) July 27, 2007.
3. Lymphoma Association UK publication, “Lymphomas”, accessed from Lymphoma Association website, http://www.lymphoma.org.uk/support/ (taken from website on 18.12.07).
4. NHL is the sixth most common cancer in the UK (taken from website on 21.2.08).
5. Each year there are over 5,200 new cases in men and 4,700 cases in women
6. Rituximab summary of product characteristics.
http://www.rocheuk.com
Xenomics Announces License With Warnex Of Acute Myeloid Leukemia Assay
February 27, 2008
Xenomics, Inc. (Pink Sheets:XNOM, FWB:XE7) announces that it has granted Warnex Medical Laboratories, a division of Warnex Inc., nonexclusive rights in Canada to offer NPM1 testing as a laboratory service for the diagnosis, stratification and monitoring of patients with Acute Myeloid Leukemia (AML).
AML is a clinically heterogeneous disease with about 200,000 new cases per year worldwide. The disease subgrouping by karyotypic abnormalities indicates patient prognosis. However, in almost half of AML cases the karyotype appears normal and provides no guide for the physician. A recent discovery by Drs. Falini and Mecucci showed that many AML patients have mutations in the NPM1 gene, a favorable marker for clinical outcome. Xenomics holds exclusive rights to the discovery and has nonexclusively sublicensed its diagnostic applications to Warnex to offer clinical testing. The results of such a test will help physicians select patients with a good prognosis of benefiting from intensive chemotherapy, while sparing others with a low probability of benefit from the toxic treatment.
The NPM1 mutation may also be used to monitor AML patients for residual disease during chemotherapy. Stratification of AML patients is also necessary for anti-AML drug clinical trials.
About Xenomics, Inc.
Xenomics is a molecular diagnostics company developing tests based on Transrenal DNA and safe, simple urine collection techniques. The Company believes its patented technology has a broad range of applications, including prenatal testing, infectious disease detection and tumor detection, among others, and can open significant new markets in the molecular diagnostics field. More information is available on the Company’s website, http://www.xenomics.com.
About Warnex
Warnex is a life sciences company devoted to protecting public health by providing laboratory services to the pharmaceutical and healthcare sectors. Warnex’s analytical services division provides pharmaceutical and biotechnology companies with a variety of quality control services, including traditional chemistry, chromatography, microbiology, method development and validation, and stability studies. Warnex’s bioanalytical services division specializes in bioequivalence and bioavailability studies for clinical trials. Warnex’s medical laboratories division focuses on genetic and biochemical testing for the healthcare industry and has extensive expertise in genetic testing for human identification, molecular diagnostics, and pharmacogenetics.
http://www.warnex.ca
Forward-Looking Statements
Statements about the Company’s expectations, applications of its technology, markets, and other statements that are not historical facts are “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934 and are based on management’s current beliefs, assumptions, estimates and projections. Actual results may differ materially from those projected in the forward-looking statements for various reasons, including risks associated with product development, government regulation, market acceptance, dependence on key personnel, obtaining financing and other factors discussed in Xenomics’ Form 10-KSB filed on May 16, 2007 and other periodic reports filed with the Securities and Exchange Commission.
http://www.warnex.ca
MabCampath Available For First Line Treatment Of B-Cell Chronic Lymphocytic Leukaemia (CLL) For Whom Fludarabine Chemotherapy Is Not Appropriate
February 19, 2008
Bayer Schering Pharma (BSP) and Genzyme Corporation, announced the availability of MabCampath® (alemtuzumab) for the first-line treatment of patients with B-CLL for whom fludarabine combination chemotherapy is not appropriate.[i] MabCampath was previously approved for the treatment of B-CLL in patients who have been previously treated with alkylating agents and have failed fludarabine therapy.
“In the Phase III trial MabCampath® produced the highest response rate in patients with chronic lymphocytic leukaemia for any single agent seen in previous front-line trials,” said Dr Peter Hillmen of the department of clinical haematology and haematological malignancy diagnostic service at Leeds teaching Hospital and principal trial investigator for MabCampath®. “The availability of MabCampath® as a first line treatment is a significant advance for patients with B-CLL and provides a new option for those who are not suitable for treatment with fludarabine combination chemotherapy”.
This news comes as the expert group - International Workshop on Chronic Lymphocytic Leukemia (IWCLL) - pre-publish in peer review journal Blood, new Guidelines on the Diagnosis and Treatment of CLL recommending 17p FISH analysis is always carried out in clinical trials.[ii] Additionally, as genetic defects may be acquired during the course of the disease ‘the repetition of FISH analysis seems justified prior to subsequent, second and third line treatment’. The group say it is desirable to do the same in general practice.
For patients with a particular type of CLL - del(17p) - the prognosis is poorer than with other types as it appears to be more resistant to standard treatments. The fluorescence in-situ hybridization test or FISH test can determine if a person has this type of CLL and can aid treatment decisions.
Philip Ashman, Business Head Unit of BSP’s Oncology Division in the UK noted: “We believe that treatment with MabCampath® earlier in the course of a patient’s B-CLL management represents an important step forward for these patients and we commend the Committee’s thorough review of the MabCampath® clinical data.”
The first line licence has been granted based on data from an international open-label Phase 3 clinical trial comparing MabCampath® with chlorambucil in previously untreated patients with B-CLL.[iii] These data were published in the Journal of Clinical Oncology in December 2007. The study met its primary endpoint by demonstrating superior progression free survival (PFS) in patients treated with MabCampath® versus chlorambucil, with MabCampath reducing the risk of disease progression or death by 42 percent (p=0.0001). Patients receiving MabCampath® also exhibited higher overall and complete response rates with a manageable safety profile, compared to patients who were treated with chlorambucil. Results from this study also demonstrated that patients treated with MabCampath® achieved extended treatment-free intervals, with a median period of two years before requiring additional therapy.
About Chronic Lymphocytic Leukaemia
Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in the Western world,[iv] and has an approximate incidence of 3 people per 100,000 in the UK.[v] It is more common with increasing age, with the incidence rising to more than 20 per 100,000 over 70 years of age.[vi] The disease is most commonly diagnosed among people age 55 or older.[vii] CLL is characterized by the accumulation of functionally immature white blood cells (lymphocytes) in the bone marrow, blood, lymph tissue, and other organs. Two types of lymphocytes are present in the blood, B cells and T cells. The majority of this patient population (95%) suffers from a subtype called B-cell chronic lymphocytic leukaemia, or B-CLL.[viii] Patients with CLL have too many abnormal lymphocytes or B cells. As these abnormal or cancerous B cells have a longer than normal life span, they begin to build up and “crowd out” the normal, healthy blood cells in places like the bone marrow. Bone marrow infiltration leads to a lack of healthy blood cells, thus leading to fatigue, susceptibility to bleedings, a weakening of the immune system exposing the patient to a higher risk of infection and can become fatal. Many people with CLL often don’t experience symptoms at first, the symptoms of CLL include fatigue, bone pain, night sweats, fevers, and decreased appetite and weight loss.[ix]
FISH Analysis
For patients with a particular type of CLL - del(17p) - the prognosis is poorer than with other types as it appears to be more resistant to standard treatments. The fluorescence in-situ hybridization test or FISH test can determine if a person has this type of CLL and can aid treatment decisions. The latest Guidelines on the Diagnosis and Treatment of CLL from the International Workshop on Chronic Lymphocytic Leukaemia (IWCLL), recommend FISH testing as desirable in general clinical practice prior to initiating CLL therapy.
About MabCampath
MabCampath works in an entirely different way than chemotherapy. MabCampath is a monoclonal antibody. Monoclonal antibodies are proteins which specifically recognise and bind to a unique other protein called an antigen. MabCampath® works by targeting CD52 an antigen found on the surface of the abnormal lymphocytes or B cells. When MabCampath® binds to this antigen, it activates the immune system to destroy these targeted cells, while sparing crucial stem cells. The destroyed abnormal cells are gradually removed from the body by normal biological processes.1,[x] MabCampath has shown that it may benefit patients identified as del(17p).[xi],[xii]
Genzyme and Bayer Schering Pharma are developing alemtuzumab in oncology, multiple sclerosis and other indications. Bayer Schering Pharma AG, Germany holds exclusive worldwide marketing and distribution rights to alemtuzumab and participates with Genzyme in the design of clinical protocols and conduct of activities for the development of alemtuzumab. The product was launched in its oncology indication in the U.S. in June 2001, where it is marketed by Bayer HealthCare Pharmaceuticals Inc. as Campath®, and in Europe, where it is named MabCampath®, in August 2001.
About Bayer Schering Pharma
Bayer Schering Pharma is a leading, worldwide speciality pharmaceutical company. Its research and business activities are focussed on the fields of oncology, haematology & cardiology, diagnostic imaging, primary care, specialised therapeutics and women’s healthcare. With innovative products and using new ideas, Bayer Schering Pharma aims to make a contribution to medical progress and strives to improve the quality of life of patients - a factor of particular importance in Oncology.
Bayer Schering Pharma’s portfolio of oncological products includes treatments for both solid and haematological malignancies. Intensive research is ongoing as Bayer Schering Pharma strives to discover and advance therapeutic solutions for the benefit of all cancer patients.
For more information, please visit http://www.bayerscheringpharma.co.uk
About Genzyme
One of the world’s leading biotechnology companies, Genzyme is dedicated to making a major positive impact on the lives of people with serious diseases. Since 1981, the company has grown from a small start-up to a diversified enterprise with more than 9,500 employees in locations spanning the globe and 2007 revenues of $3.2 billion. In 2007, Genzyme was chosen to receive the National Medal of Technology, the highest honour awarded by the President of the United States for technological innovation. In 2007 and 2007, Genzyme was selected by FORTUNE as one of the “100 Best Companies to Work for” in the United States.
With many established products and services helping patients in nearly 90 countries, Genzyme is a leader in the effort to develop and apply the most advanced technologies in the life sciences. The company’s products and services are focused on rare inherited disorders, kidney disease, orthopaedics, cancer, transplant, and diagnostic testing. Genzyme’s commitment to innovation continues today with a substantial development program focused on these fields, as well as immune disease, infectious disease, and other areas of unmet medical need.
Genzyme®, Campath® and MabCampath® are registered trademarks of Genzyme Corporation. All rights reserved.
References
[i] MabCampath SPC
[ii] Michael Hallek, Bruce D. Cheson, Daniel Catovsky, Federico Caligaris-Cappio, Guillaume Dighiero, Hartmut Dohner, Peter Hillmen, Michael J. Keating, Emili Montserrat, Kanti R. Rai and Thomas J. Kipps. Blood. doi:10.1182/blood-2007-06-093906. Prepublished online Jan 23, 2008
[iii] Hillmen et al. Alemtuzumab Compared With Chlorambucil As First-Line Therapy for Chronic Lymphocytic Leukemia. J Clin Oncol. Vol 25, No 35 (December 10), 2007: pp. 5616-5623.
[iv] Elter T., Hallek M., Engert A. Fludarabine in chronic lymphocytic leukaemia. Expert Opin Pharmacother. 2007 Aug; 7(12): 1641-51
[v] ESMO guidelines working group, Annals Oncol; 2007 18 (Suppl 2):ii49-ii50
[vi] Rai K.R. Chronic lymphocytic leukaemia in the elderly population. Clin Geriatr Med. 1997 May; 13(2): 245-9
[vii] Leukaemia Research [last accessed 30.11.07]
[viii] Peter A. Cassileth MD, Bruce Furie MD, Michael B. Atkins MD, Robert J. Mayer. Clinical Hematology and Oncology - Presentation, Diagnosis, and Treatment. Churchill Livingstone published 2003, Chapter 72 page 690.
[ix] UK Cancer Research [last accessed 30.11.07]
[x] MabCampath PIL
[xi] Stilgenbauer S, Dohner H. Campath-1H-induced complete remission of chroniclymphocytic leukemia despite p53 gene mutation and resistance to chemotherapy. N Engl J Med. 2002;347:452-453
[xii] Lozanski G, Heerema NA, Flinn IW, et al. Alemtuzumab is an effective therapy for chroniclymphocytic leukemia with p53 mutations and deletions. Blood. 2004;103:3278-3281.
Bayer Schering Pharma
Novel Anti-CD20 Monoclonal Antibody Ofatumumab Demonstrates Anti-tumour Responses In Patients With Relapsed/refractory B-cell Chronic Leukaemia
February 16, 2008
Data from a Phase I/II study of the novel antiCD20 monoclonal antibody, ofatumumab (formerly HuMax-CD20) in patients with relapsed or refractory B-cell chronic lymphocytic leukaemia (CLL) demonstrate anti-tumour responses in half of the patients treated in one of the three cohorts.[1] The study is published in the February issue of the journal Blood. Ofatumumab is being co-developed by GlaxoSmithKline (GSK) and Genmab A/S and has not received regulatory approval in any market for any indication at this time.
“Almost all patients with CLL experience disease progression after initial therapy, and currently there are limited therapeutic options for this group,” said Professor Bertrand Coiffier, Head of Haematology Department, Centre Hospitalier Universitaire de Lyon, France and lead investigator in the trial. “These early clinical data on ofatumumab are encouraging, with responses seen in half of the patients treated in the highest cohort.”
Ofatumumab is a unique investigational monoclonal antibody (MAb) that targets a distinct antibody binding site (the small loop epitope) of the CD20 molecule on the cell membrane of B cells.[2] This is a different binding site from approved antiCD20 monoclonal antibodies and it is closer to the cell membrane.[3] The CD20 molecule is a key target in CLL therapy because it is expressed in most cancers affecting the B cell.[4]
“CLL is a common but very serious form of leukaemia. Any hope for an effective new therapy may bring promise to those affected by the disease,” said Paolo Paoletti, MD, Senior Vice President, Oncology Medicine Development Centre, GSK. “We are very excited by these data and the potential that ofatumumab has shown to date in treating patients with relapsed or refractory CLL.”
CLL is the most common type of leukaemia and one of the most common malignant lymphoid diseases in the western world.[5] Globally, leukaemia, in all of its forms, accounts for approximately 300,000 new cases each year (2.8% of all new cancer cases) and 222,000 deaths.[6]
Efficacy results1
The primary efficacy endpoint of this study was objective tumour response over the period from screening to week 19. Fifty percent (95% Confidence Interval:30-70%) of patients (N=27) in cohort C experienced remission. Specifically, 12 of these patients had partial remission and one patient had a nodular partial remission. In the study, four weeks after beginning treatment, 62% of patients (N=32) obtained objective response as evaluated by physical examination and peripheral blood. On average, patients achieved an average progression-free survival of 106 days and an average time to next treatment of one year.
Safety Results1
Of the 33 patients enrolled in the study, 32 received four infusions as per the study protocol. One patient withdrew because of a serious adverse event (SAE) the day after the first infusion (cytolytic hepatitis, Grade 3). Twenty seven patients experienced 246 adverse events (AEs) of which 92% were mild (Grade 1-2: transient rigors, pyrexia, fatigue, rash, and increased sweating) and 61% were assessed as related to treatment. Ten of the AEs (reported by nine patients) were serious and included neutropenia, sinusitis, cytolytic hepatitis and infectious interstitial lung disease.
Infections were reported in 51% of patients, with the most frequently observed infection being nasopharyngitis (common cold) and all but one patient recovered within a month. The majority of the infections were Grade 1 or 2. Grade 3 adverse events were herpes zoster (SAE), nasopharyngitis, and pneumonia (SAE); one SAE was fatal (infectious interstitial lung disease).
Study Design1
The study was an international, multi-centre, open-label, dose escalating Phase I/II trial with the primary objective of evaluating the safety and efficacy of ofatumumab in patients with refractory or relapsed CLL. Thirty three CLL patients were divided into three cohorts of 3 (A), 3 (B), and 27 (C) and received four, once-weekly infusions of ofatumumab at the following doses: A 1×100mg + 3×500mg; B 1×300mg + 3×1000mg and C 1×500mg + 3×2000mg. The primary efficacy variable was objective tumour response over the period from screening to week 19 and was reported according to the National Cancer Institute (NCI) Working Group (WG) 1988 and 1996 criteria as complete remission (CR), nodular partial remission (nPR), partial remission (PR), progressive disease (PD), stable disease (SD), and non-evaluable patients (NE). Overall tumour response was assessed on data from physical examinations and evaluation of the peripheral blood and bone marrow as defined by the NCI WG Guidelines in CLL.[7],[8]
About ofatumumab
Ofatumumab is being developed for the treatment of a number of serious conditions including chronic lymphocytic leukaemia, diffuse large B-cell lymphoma, (the most common sub-type of non-Hodgkin’s lymphoma in the Western world), follicular lymphoma (the second most common sub-type of non-Hodgkin’s lymphoma), rheumatoid arthritis and multiple sclerosis. Ofatumumab will be studied further in ongoing clinical trials.2
GlaxoSmithKline and Genmab A/S have a worldwide agreement to co-develop ofatumumab.
GSK in oncology
GSK Oncology is dedicated to producing innovations in cancer that will make profound differences in the lives of patients. Through GSK’s revolutionary “bench to bedside” approach, we are transforming the way treatments are discovered and developed, resulting in one of the most robust pipelines in the oncology sector. Our worldwide research in oncology includes partnerships with more than 160 cancer centres. GSK is closing in on cancer from all sides with a new generation of patient focused cancer treatments in prevention, supportive care, chemotherapy, and targeted therapies.
About GlaxoSmithKline
GlaxoSmithKline one of the world’s leading research-based pharmaceutical and healthcare companies is committed to improving the quality of human life by enabling people to do more, feel better, and live longer. For company information, visit GlaxoSmithKline at http://www.gsk.com.
References
[1] Coiffier, B., Lepretre, S., Pedersen, M.L., et al. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia. A Phase I-II study. Blood 2007; 111/3/1094
[2] GSK data on file
[3] Teeling, J,L., Mackus, W,J., et al. The Biological Activity of Human CD20 Monoclonal Antibodies Is Linked to Unique Epitopes on CD20. J Immunol 2007; 177: 362-371
[4] Glennie, M,J., French, R,R., et al. Mechanisms of killing by anti-CD20 monoclonal antibodies. Molecular Immunology, 2007;44 (16):3823-3837
[5] Shanafelt TD., Byrd JC., et al. Narrative review: initial management of newly diagnosed, early-stage chronic lymphocytic leukemia. Ann Intern Med. 2007 Sep 19;145(6):435-47.
[6] Parkin, D. M., Bray F., et al. Global Cancer Statistics, 2002. CA Cancer J Clin 2007; 55:74-108
[7] Cheson, B.D., Bennett, J.M., Rai, K.R., et al. Guidelines for clinical protocols for chronic lymphocytic leukemia: recommendations of the National Cancer Institute-sponsored working group. Am J Hematol. 1988;29:152-163.
[8] Cheson, B. D., Bennett, J.M., Grever, M., et al. National Cancer Institute-Sponsored Working Group Guidelines For Chronic Lymphocytic Leukemia - Revised Guidelines For Diagnosis and Treatment. Blood. 1996;87:4990-4997.
EMEA Accepts For Review Vidaza(R) Marketing Authorization Application For Higher-Risk Myelodysplastic Syndromes
February 16, 2008
Pharmion Corporation (Nasdaq: PHRM) announced that the European Medicines Agency (EMEA) has accepted for review the Company’s Marketing Authorization Application (MAA) for Vidaza(R) (azacitidine for injection) in patients with higher-risk myelodysplastic syndromes (MDS) and announced its intent to review the application under the Accelerated Assessment Procedure. Pharmion submitted the Vidaza MAA to the EMEA earlier this month.
The Accelerated Assessment Procedure is granted for medicinal products that are expected to be of major public health interest, particularly from the point of view of therapeutic innovation. Accelerated Assessment reduces the time limit for the Committee for Medicinal Products for Human Use (CHMP) to give an opinion from 210 days to 150 days. At any time during the marketing authorization application evaluation, the CHMP may decide to continue the assessment under standard centralized procedure timelines.
The application is based upon clinical data which include the results from the Company’s Phase 3 multi-center, international, randomized study of Vidaza(R) (azacitidine for injection) in the treatment of patients with higher-risk MDS. The primary objective of this Phase 3 trial was to demonstrate superiority in overall survival of Vidaza versus conventional care regimens, and these data were presented at the American Society of Hematology annual meeting in December 2007.
Vidaza has been designated as an Orphan Medicinal Product in the EU for the treatment of MDS, which, if approved, entitles the drug to ten years of market exclusivity for the approved indication. Vidaza has also been designated as an Orphan Medicinal Product in the EU for the treatment of acute myeloid leukemia (AML).
About Vidaza
In May 2004, Vidaza became the first drug approved by the FDA for the treatment of patients with Myelodysplastic Syndromes (MDS). The FDA approved Vidaza, the first in a new class of drugs called demethylation agents, for treatment of all five MDS subtypes, which include both low-risk and high-risk patients. These subtypes include: refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) if accompanied by neutropenia or thrombocytopenia or requiring transfusions; refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB- T), and chronic myelomonocytic leukemia (CMMoL).
Vidaza is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. The concentration of Vidaza required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of Vidaza cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non- proliferating cells are relatively insensitive to Vidaza. Vidaza was approved for IV administration in January 2007.
About Epigenetics
Vidaza is the first of a new class of anti-cancer compounds known as epigenetic therapies. Epigenetics refers to changes in the regulation of gene expression, and DNA methylation and histone deacetylation are two of the more studied epigenetic regulators of gene expression. Epigenetic changes can silence gene expression and, unlike DNA mutations, may be reversed by targeting the mechanisms involved. The silencing of key cell cycle control genes and tumor suppressor genes through these two mechanisms of epigenetic regulation has been demonstrated in vitro and in vivo in hematological malignancies and in solid tumors. These key growth control genes can be re- expressed in cancer cells when DNA hypermethylation is reversed by Vidaza. The epigenetic approach to cancer therapy is that rather than using molecules that kill both normal and tumor cells, the silenced genes are reactivated through targeted epigenetic therapy, re-establishing the cancer cell’s natural mechanisms to control abnormal growth.
About MDS
Myelodysplastic syndromes, or MDS, are a group of diseases in which the bone marrow does not function normally, resulting in the production of malformed or immature blood cells. The majority of patients with higher-risk MDS eventually experience bone marrow failure. Up to 50 percent of MDS patients succumb to complications, such as infection or bleeding, before progressing to acute myeloid leukemia (AML). MDS patients have a median survival of four months to five years depending on risk stratification. Higher-risk patients have a median survival of five to 14 months. Alleviation of disease-related complications, including transfusion requirements and hematologic improvement are key treatment goals in lower-risk MDS. Altering the natural history of disease is one of the most important treatment goals in higher-risk MDS.
Important Safety Information
Vidaza is contraindicated in patients with a known hypersensitivity to Vidaza or mannitol and in patients with advanced malignant hepatic tumors.
In clinical studies, the most commonly occurring adverse reactions by SC route were nausea (70.5%), anemia (69.5%), thrombocytopenia (65.5%), vomiting (54.1%), pyrexia (51.8%), leukopenia (48.2%), diarrhea (36.4%), fatigue (35.9%), injection site erythema (35.0%), constipation (33.6%), neutropenia (32.3%) and ecchymosis (30.5%). Other adverse reactions included dizziness (18.6%), chest pain (16.4%), febrile neutropenia (16.4%), myalgia (15.9%), injection site reaction (13.6%), aggravated fatigue (12.7%) and malaise (10.9%). The most common adverse reactions by IV route also included petechiae (45.8%), rigors (35.4%), weakness (35.4%) and hypokalemia (31.3%).
Because treatment with Vidaza is associated with neutropenia and thrombocytopenia, complete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each dosing cycle.
Because Vidaza is potentially hepatotoxic in patients with severe pre- existing hepatic impairment, caution is needed in patients with liver disease. In addition, Vidaza and its metabolites are substantially excreted by the kidneys and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function.
Vidaza may cause fetal harm. While receiving treatment with Vidaza, women of childbearing potential should avoid becoming pregnant, and men should avoid fathering a child. In addition, women treated with Vidaza should not nurse.
About Pharmion
Pharmion is a leading global oncology company focused on acquiring, developing and commercializing innovative products for the treatment of hematology and oncology patients in the U.S., Europe and additional international markets. Pharmion has a number of products on the market including the world’s first approved epigenetic drug, Vidaza(R), a DNA demethylating agent. For additional information about Pharmion, please visit the Company’s website at http://www.pharmion.com.
Safe Harbor Statement under the Private Securities Litigation Reform Act of 1995: This release contains forward-looking statements, which express the current beliefs and expectations of management. Such statements are based on current expectations and involve a number of known and unknown risks and uncertainties that could cause Pharmion’s future results, performance or achievements to differ significantly from the results, performance or achievements expressed or implied by such forward-looking statements. In particular, Pharmion can not assure you that its MAA for Vidaza will be reviewed on an accelerated assessment schedule or that Vidaza will ultimately receive a marketing authorization in the EU. Important factors that could cause or contribute to such differences include the regulatory status and timing of regulatory approvals for Vidaza; the impact of competition from other products sold by Pharmion’s competitors in the EU; the regulatory environment and changes in the health policies and structure of various countries; acceptance and demand for new pharmaceutical products and new therapies, uncertainties regarding Pharmion’s ability to enforce market exclusivities in member states of the EU; failure of third-party manufacturers to produce the product volumes required on a timely basis, fluctuations in currency exchange rates, and other factors that are discussed in Pharmion’s filings with the U.S. Securities and Exchange Commission. Forward-looking statements speak only as of the date on which they are made, and Pharmion undertakes no obligation to update publicly or revise any forward-looking statement, whether as a result of new information, future developments or otherwise.
Pharmion Corporation
http://www.pharmion.com
Genesis Of Adult Leukemia Being Mapped
February 16, 2008
Long-term bacterial infections like pneumonia may drive a type of white blood cell to transform into tumor cells. A study from Link?ping University in Sweden and elsewhere explains how this can be the initial event of the chronic lymphocytic leukemia (CLL) desease.
Chronic lymphocytic leukemia (CLL)–the most common form of leukemia in adults–arises from a special type of white blood cells, B lymphocytes, which normally produce antibodies to combat bacteria and viruses that we are exposed to. It is not known today what events lead to this disease.
A research team headed by Anders Rosén, professor of cell biology at Link?ping University, has now established for the first time that CLL produced antibodies are highly specialized to recognize certain structures on the surface of bacteria and self-proteins of the human body (e.g. autoantigens).
The findings are being published on Monday in the respected hematological journal Blood. The key point is that the CLL antibodies also bind to damaged and dying (apoptotic) cells, which indicates that the B lymphocytes that give rise to CLL may be frontline defense cells. These are thought to have the extremely important task of using their antibodies to rapidly bind to and recognize the slightest breach in damaged mucous lining or skin, inflicted by bacteria or other microorganisms.
But in long-term infections, these B lymphocytes can start to multiply excessively and rapidly. This increases the risk of chromosome damage, which in turn make them vulnerable for leukemia transformation. The study now being published contributes to our understanding of how these B lymphocytes function and why they can be transformed into tumors.
CLL afflicts 400-500 people in Sweden each year, primarily among those aged 65-70 and more often among men than women. The disease has a highly varied course, with many patients living for decades with hardly any treatment, while others die within a few years despite treatment.
The research team behind the study also includes the doctoral students Eva Hellqvist and Anna Lanemo-Myrhinder, Link?ping University, and Sohvi H?rkk?, Oulu, Finland, and Richard Rosenquist, Uppsala, Sweden.
VETENSKAPSR?DET (THE SWEDISH RESEARCH COUNCIL)
Regeringstgatan 56
103 78 Stockholm
http://www.vr.se
