Posted by rob on March 25, 2005 under Uncategorized | 
Genomic cancer therapy to become reality
25/03/2005 – The wealth of new targets identified from genomics and the discoveries made in the molecular pathology of cancer will give rise to a new generation of cancer treatment, moving one step closer to individualised, target therapy.
In a talk given by Paul Workman, of the Cancer Research UK centre for cancer therapeutics he said that scientists were becoming increasingly optimistic about the future of cancer treatment. While no one expects a cure for cancer in the next decade, he thought it would be demoted to the status of a chronic disease that people can live with.
Cancer drug therapy is undergoing a transition from the previous pregenomic cytotoxic era to the new postgenomic era. Workman predicted that future mechanism-based therapeutic agents would be designed to act on molecular targets that are involved in the malignant progression of human cancers. Such agents would show greater therapeutic selectivity for cancer versus normal cells.
Speaking at the Drug Discovery Technology conference in London last week, Workman identified the features and potential advantages of postgenomic cancer drug development.
He focused particularly on new molecular targets driving the molecular pathology and progression of human cancers, providing an intellectual framework for discovering new drugs with improved efficacy and selectivity.
Workman also identified high throughput screening, structural biology, combinatorial chemistry and microarrays as new technology applications set to further accelerate drug discovery and development.
“Target selection for drug discovery is essentially a matter of judgment, involving a large measure of risk assessment. There will be greater confidence in a target for which all the criteria are met, but this may take several years, by which time any competitive position in the field may be lost,” he said.
Use of pharmacokinetic and pharmacodynamic endpoints was a primary advantage singled out. They had the potential to enhance the rationality and hypothesis-testing power of early clinical trials, provides the basis for early go/no go decisions, and reduces the risk of expensive late stage failure.
“The development of diagnostic, prognostic and pharmacogenomic biomarkers will allow the targeting of individualised treatments to patients most likely to benefit,” he commented.
There is already a glut of novel cancer drugs that act on the cancer genome and while these drugs currently remain one of the most potent weapon medicine has against cancer, so much more can be done to reduce the toxic effects that accompany such treatment.
The majority of current cancer drugs are cytotoxic agents that exert its effects on proliferating cells, both normal and cancerous. This is the case even for recently successful drugs such as irinotecan in colorectal cancer, taxanes in breast, ovarian and lung cancer and carboplatin in ovarian cancer. Since cytotoxic agents have a selectively ‘antiproliferative’ action rather than selective ‘anticancer’ properties, the therapeutic window for tumour versus normal tissue is modest at best
In the industrialised world, one in three people develop cancer and one in four still die from it. World-wide cancer incidence is predicted to double from 10 to 20 million per annum and the death rate is predicted to increase from 6 to 10 million by 2020.
Gleevec is a small molecule that is approved in the treatment of chronic myeloid leukaemia and gastrointestinal stromal tumours via inhibition of the Bcr-Abl and c-Kit receptor tyrosine kinases respectively.
Herceptin is a humanised antibody approved in ErbB2 positive breast cancers while Iressa is a small molecule inhibitor of the EGF receptor tyrosine kinase approved in non-small cell lung cancer and active in other tumour types.
Workman pointed to 17AAG, a small molecule inhibitor of the Hsp90 molecular chaperone, which showed early promise in phase I clinical trials.
The worldwide market for oncology drugs is predicted to be worth at least $15 billion (€11.6 billion) by 2002. Indeed, as a result of the ageing population and improvements in the treatment of other chronic ailments such as cardiovascular diseases, and in addition taking into account the remarkable breakthroughs in our basic understanding of the disease and the technological revolutions that are accelerating the process of drug discovery.
Genomic cancer therapy to become reality
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A Mute Swan flies above the Djurbrunnsgaards canal in Stockholm as migratory birds are on the move with the arrival of Spring.
Posted by rob on March 24, 2005 under Uncategorized |
The leukemias in question are polycythemia vera (PV), essential thrombocythemia (ET) and myeloid metaplasia with myelofibrosis (MMM), which together affect some 100,000 Americans. The discovery, which is published online by the journal Cancer Cell, was led by D. Gary Gilliland, who is also an investigator with the Howard Hughes Medical Institute, and colleagues. The idea was to screen leukemia patients for mutations in genes that code for tyrosine kinases, key enzymes that have been implicated in many other forms of cancer.
In order to find sufficient numbers of patients to conduct the study, Gilliland’s team sought help from an advocacy group for patients with myeloproliferative disease called MPDInfo. Posting a note on the group’s website, they were swamped with more than 600 responses within a matter of weeks.
“There was a huge outpouring of interest,” says a grateful Gilliland. “As far as I know, this is the first time that a research group has used [the Internet] as a protocol for collecting blood samples to identify the cause of a disease.” Gilliland called the Internet-based clinical protocol “a very valuable strategy, especially for studying relatively rare genetic diseases.”
After volunteers had given informed consent, the researchers sent the patients DNA collection kits to obtain cheek swab samples. Local physicians drew blood and provided clinical records.
With the DNA samples in hand, the research team used a DNA sequencing technique developed by co-authors William Sellers and Matthew Myerson of the Dana-Farber Cancer Institute, and sequenced regions of candidate tyrosine kinase genes. Samples from the patients’ blood were compared with their cheek swab DNA, in order to see if any mutations were acquired or inherited.
The results showed that about three-quarters of the PV patients, and one-third of the ET and MMM patients, had acquired a mutation in a tyrosine kinase gene known as JAK2. “It was a surprise to us that the same mutation appears to account for at least a fraction of cases for all three,” says Gilliland. In one-third of the positive PV patients, both copies of the JAK2 gene were mutated, suggesting that the mutation had been duplicated in the second copy of the gene.
Drug Studies
JAK2 is a well-known molecular switch that triggers proliferation of red blood cells in response to events such as blood loss. Studies in mice have previously linked the gene to red blood cell production.
The Brigham team has already identified a drug that inhibits the JAK2 kinase and retards the growth of cells with the mutant gene. According to Gilliland, this suggests, “that inhibition of this kinase — just as Gleevec inhibits the kinase that causes CML — might be an effective therapeutic approach for these diseases.” At a minimum, discovery of the JAK2 mutation will aid in the diagnosis of patients with these specific conditions. The search goes on for other genes that may be mutated in other patients with these cancers.
Gilliland collaborated with researchers from the Dana-Farber Cancer Institute, the Broad Institute, the Mayo Clinic, and groups in Belgium and Germany.
Featured report:
R.L. Levine et al.Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell, published online March 24, 2005.
http://www.bio-itworld.com/news/032405_report7908.html
Posted by rob on under Uncategorized |
By Kevin Davies
Bio-IT World
(03/24/05)—Using an unusual Internet recruitment strategy that found hundreds of volunteers with leukemia, researchers at the Brigham and Women’s Hospital in Boston have discovered mutations in a single gene that are responsible for three forms of the disease.
The leukemias in question are polycythemia vera (PV), essential thrombocythemia (ET) and myeloid metaplasia with myelofibrosis (MMM), which together affect some 100,000 Americans. The discovery, which is published online by the journal Cancer Cell, was led by D. Gary Gilliland, who is also an investigator with the Howard Hughes Medical Institute, and colleagues. The idea was to screen leukemia patients for mutations in genes that code for tyrosine kinases, key enzymes that have been implicated in many other forms of cancer.
In order to find sufficient numbers of patients to conduct the study, Gilliland’s team sought help from an advocacy group for patients with myeloproliferative disease called MPDInfo. Posting a note on the group’s website, they were swamped with more than 600 responses within a matter of weeks.
“There was a huge outpouring of interest,” says a grateful Gilliland. “As far as I know, this is the first time that a research group has used [the Internet] as a protocol for collecting blood samples to identify the cause of a disease.” Gilliland called the Internet-based clinical protocol “a very valuable strategy, especially for studying relatively rare genetic diseases.”
After volunteers had given informed consent, the researchers sent the patients DNA collection kits to obtain cheek swab samples. Local physicians drew blood and provided clinical records.
With the DNA samples in hand, the research team used a DNA sequencing technique developed by co-authors William Sellers and Matthew Myerson of the Dana-Farber Cancer Institute, and sequenced regions of candidate tyrosine kinase genes. Samples from the patients’ blood were compared with their cheek swab DNA, in order to see if any mutations were acquired or inherited.
The results showed that about three-quarters of the PV patients, and one-third of the ET and MMM patients, had acquired a mutation in a tyrosine kinase gene known as JAK2. “It was a surprise to us that the same mutation appears to account for at least a fraction of cases for all three,” says Gilliland. In one-third of the positive PV patients, both copies of the JAK2 gene were mutated, suggesting that the mutation had been duplicated in the second copy of the gene.
Drug Studies
JAK2 is a well-known molecular switch that triggers proliferation of red blood cells in response to events such as blood loss. Studies in mice have previously linked the gene to red blood cell production.
The Brigham team has already identified a drug that inhibits the JAK2 kinase and retards the growth of cells with the mutant gene. According to Gilliland, this suggests, “that inhibition of this kinase — just as Gleevec inhibits the kinase that causes CML — might be an effective therapeutic approach for these diseases.” At a minimum, discovery of the JAK2 mutation will aid in the diagnosis of patients with these specific conditions. The search goes on for other genes that may be mutated in other patients with these cancers.
Gilliland collaborated with researchers from the Dana-Farber Cancer Institute, the Broad Institute, the Mayo Clinic, and groups in Belgium and Germany.
Featured report:
R.L. Levine et al.Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell, published online March 24, 2005.
http://www.bio-itworld.com/news/032405_report7908.html
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Thu Mar 24 09:00:01 2005 Pacific Time
Trio of Leukemias Shares Single Mutation; Internet Aided in Identifying Large Number of Patients for Study
CHEVY CHASE, Md., March 24 (AScribe Newswire) — Three leukemias that affect as many as 100,000 people in the United States are all caused by acquired mutations that alter a specific enzyme controlling blood cell proliferation, according to new studies by Howard Hughes Medical Institute (HHMI) researchers.
Identifying the genetic malfunction that causes these disorders raises the hope that researchers may be able to devise a targeted therapy, just as they have done for chronic myelogenous leukemia (CML), which is presently treated with Gleevec. The three leukemias that share a common genetic cause are polycythemia vera (PV), essential thrombocythemia (ET) and myeloid metaplasia with myelofibrosis (MMM).
The research team, which was led by Gary Gilliland, an HHMI investigator at Brigham and Women’s Hospital and Harvard Medical School, published its findings on March 24, 2005, in an immediate early publication in the journal Cancer Cell. Gilliland and Stephanie Lee of the Dana-Farber Cancer Institute, and co-first authors Ross Levine and Martha Wadleigh, collaborated with researchers from the University of Leuven – Flanders Interuniversity Institute for Biotechnology in Belgium, University Hospital of Ulm in Germany, the Broad Institute, and the Mayo Clinic.
According to Gilliland, the researchers analyzed the blood of patients with the three leukemias for a defect that permanently activated a particular type of enzyme called a tyrosine kinase. Tyrosine kinases are cellular switches that control an array of cellular processes. The researchers concentrated on the enzymes because activated tyrosine kinases had been shown to cause other similar myeloproliferative diseases such as CML, he said. Also, in earlier work, Gilliland and his colleagues had isolated the mutated gene that produces the activated tyrosine kinase responsible for the myeloproliferative disease hypereosinophilic syndrome.
“The three disorders that we studied were the last of these diseases whose causes had not yet been discovered,” said Gilliland. “We thought it was a good bet that the cause would be a constitutively activated tyrosine kinase.” According to Gilliland, while PV, ET and MMM are rare, their prevalence is about five times higher than CML, with about 100,000 cases in the U.S. each year.
The researchers performed high-throughput DNA sequence analysis of blood and mouth-swab samples from 164 PV patients, 115 ET patients and 46 MMM patients. The patients were recruited via a notice posted on the web site of an advocacy group for people with myeloproliferative disease. The researchers used a sequencing technique developed in collaboration with co-authors William Sellers and Matthew Myerson of Dana-Farber. Specifically, they sequenced regions of tyrosine kinases that were likely to be mutated in the leukemias.
Their sequencing analysis revealed that about 75 percent of the PV patients, 32 percent of the ET patients and 35 percent of the MMM patients showed the same defect in the gene for a tyrosine kinase known as JAK2.
“There are some similarities among these three different diseases, and some overlap in the diagnostic criteria, but it was a surprise to us that the same mutation appears to account for at least a fraction of cases for all three,” said Gilliland
By comparing the DNA sequences from the blood with those from the mouth swabs, the researchers could determine which mutations the blood cell progenitors had acquired — since the mouth-swab DNA represents inherited germline DNA that had not undergone mutation. Their comparisons revealed that the characteristic mutation in JAK2 was acquired, not inherited. And since the researchers did not find the mutation in a large number of normal blood samples, they were able to conclude that the mutation was characteristic of a large fraction of the three leukemias.
JAK2 normally functions as a molecular switch to trigger proliferation of red blood cells in response to events such as blood loss, said Gilliland. Also, mice in which the gene has been knocked out exhibit defective red blood cell production. Thus, he said, abnormal activation of the gene for JAK2 would be expected to lead to myeloproliferative disease.
In test tube studies, the researchers found that a drug that inhibits the JAK2 tyrosine kinase did inhibit growth of cells with the mutant JAK2 gene. “While this is a very preliminary finding, and there is much developmental work to be done, it does suggest that inhibition of this kinase — just as Gleevec inhibits the kinase that causes CML — might be an effective therapeutic approach for these diseases,” said Gilliland. He noted that the discovery of the characteristic mutation will have diagnostic value in distinguishing the myeloproliferative diseases from secondary causes of similar blood cell pathologies, such as smoking or cardiac disorders.
Further studies are needed to understand why only a fraction of the three leukemias show the mutation, said Gilliland. For example, there may be other genes whose mutations are also involved in causing the diseases, he said. Furthermore, it is still not understood how the mutation causes permanent activation of the JAK2 enzyme.
The researchers’ approach to finding patients using the internet could be of particular value for studying rare genetic diseases, Gilliland emphasized. To recruit patients with the disorders, the researchers posted a notice on the web site of an advocacy group for patients with myeloproliferative diseases — MPDInfo (www.mpdinfo.org).
“These are relatively rare diseases, and because it is important for these high-throughput genome sequencing strategies to have large numbers of patients, we needed to recruit about a hundred patients for each disease,” said Gilliland. “It would be hopeless to do that at even a large medical center. So, we presented this problem to the patient advocacy group, and there was a huge outpouring of interest. We developed a clinical protocol for internet-based recruitment, posted a questionnaire on their web site, and we had six hundred responses within just a couple of weeks.”
Once candidates for the study had been identified and consent forms obtained, the researchers sent the patients kits that would enable collection of blood and mouth-swab samples by mail, said Gilliland. The patients were instructed to have their blood drawn at their local clinic, and the researchers obtained clinical records from the patients’ physicians.
Gilliland concluded that the internet-based clinical protocol is “a very valuable strategy, especially for studying relatively rare genetic diseases. It has been used by epidemiologists for gathering data using questionnaires about clinical problems. But as far as I know, this is the first time that a research group has used it as a protocol for collecting blood samples to identify the cause of a disease.”
– - – -
CONTACT: Jim Keeley, Howard Hughes Medical Institute Media Relations, 301-215-8858, keeleyj@hhmi.org
http://www.ascribe.org/cgi-bin/behold.pl?ascribeid=20050324.080853&time=09%2000%20PST&year=2005&public=1
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At the March 6 Lace Up for Leukemia fund-raiser at the New England Sports Center, Laura and Kevin Dully pose for a photo with their son, Andrew. (Staff photo by Mary Wenzel)
Lace Up for Leukemia was March 6 at the New England Sports Center with guest stars including the graceful and elegant Nicole Bobek, who joined with award-winning skaters Melanie Lambert and Fred Palascak, and area skaters for the benefit of the Massachusetts Chapter of The Leukemia & Lymphoma Society.
New this year was a hockey game with Black & Gold Legends – former Boston Bruins competing against Team Lace Up.
Created by Laura Dully, Lace Up for Leukemia is a labor of love that she started after her husband, Kevin, was diagnosed with leukemia almost 13 years ago.
”Despite some problems from his treatments, we are thrilled that he just passed his 11th year of remission,” said Laura Dully. “The advances that have been made for leukemia patients in the past decade have been phenomenal. For example, there is now a new miracle drug, Gleevec, that patients with Kevin’s type of cancer can take as a treatment option.
”I’d like to think that we helped play a little part in that success through the fund-raising from Lace Up.”
The fund-raising event has raised more than $400,000 for the Leukemia & Lymphoma Society thats mission is to find cures for leukemia, lymphoma, Hodgkin’s disease and myeloma, and to improve the quality of life of patients and their families.
Lace Up for Leukemia is a pledge event with participants raising money by skating laps in the Skate-A-Thon. The afternoon full of activities also included a silent auction, costumed characters, face painting, massage and a skating exhibition.
The evening culminated with the “Survivor Lap” as survivors of leukemia skated around the rink to be joined with the skating stars for on-ice photographs.
During the Survivor Lap, Karen Fiore sang the event’s signature song, “Hero.”
Opportunities for autograph signing followed the event in the registration area.
http://www2.townonline.com/marlborough/localRegional/view.bg?articleid=209197&format=text
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Dancers are silhouetted against a backdrop before they introduce the new Mercedes R-Class Grand Sports Tourer as it is rolled out for the World Premier during the 2005 New York Auto Show in New York
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Human leukocyte antigen-G (HLA-G) has long been speculated as a beneficial factor for a successful pregnancy for its restricted expression on fetal-maternal extravillous cytotrophoblasts and its capability of modulating uterine natural killer cell (uNK) function such as cytotoxicity and cytokine production through NK cell receptors. HLA class I a1 domain is an important killer cell Ig-like receptor (KIR) recognition site and the Met76 and Gln79 are unique to HLA-G in this region. NK cell receptor KIR2DL4 is a specific receptor for HLA-G, yet the recognition site on HLA-G remains unknown. In this study, retroviral transduction was applied to express the wild type HLA-G (HLA-wtG), mutant HLA-G (HLA-mG) on the chronic myelogenous leukemia cell line K562 cells and KIR2DL4 molecule on NK-92 cells, respectively. KIR2DL4-IgG Fc fusion protein was generated to determine the binding specificity between KIR2DL4 and HLA-G. Our results showed that residue Met76, Gln79 mutated to Ala76,79 in the a1 domain of HLA-G protein could affect the binding affinity between KIR2DL4 and HLA-G, meanwhile, the KIR2DL4 transfected NK-92 cells (NK-92-2DL4) showed a considerably different cytolysis ability against the HLA-wtG and HLA-mG transfected K562 targets. Taken together, our data indicated that residue Met76 and Gln79 in HLA-G a1 domain plays a critical role in the recognition of KIR2DL4, which could be an explanation for the isoforms of HLA-G, all containing the a1 domain, with the potential to regulate NK functions.
http://www.hubmed.org/display.cgi?uids=15780179
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A series of 4(3H)-quinazolinone derivatives with dithiocarbamate side chains were synthesized and tested for their in vitro antitumor activity against human myelogenous leukemia K562 cells. Among them, (3,4-dihydro-2-methyl-4-oxoquinazolin-6-yl)methyl 4-(4-fluorophenyl)piperazine-1-carbodithioate 8q exhibited significant inhibitory activity against K562 cells with IC(50) value of 0.5muM.
http://www.hubmed.org/display.cgi?uids=15780632
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Acute myelogenous leukemia (AML) is the most common leukemia in adults with clonal proliferation of myeloid stem cells. Two or more cooperating mechanisms, namely block in differentiation, enhanced proliferation and resistance to programmed cell death, underlie this neoplastic transformation. Nonrandom, complete and partial deletions of chromosome 5 are common anomalies in AML. Using positional cloning strategies, we characterized an evolutionarily conserved candidate myeloid leukemia suppressor gene encoding sequence-specific single-stranded DNA binding protein 2 (SSBP2) from chromosome 5q13.3, a locus that is frequently deleted in AML. Recent studies in Drosophila and Xenopus demonstrate a pivotal role for SSBPs in embryonic differentiation. In mammals, SSBP2 is one of three highly related and ubiquitously expressed genes. Here, we identify frequent loss of SSBP2 protein expression in human AML cell lines using highly specific antibodies. Furthermore, inducible expression of SSBP2 in the AML cell line U937 leads to loss of clonogenicity, G1 arrest and partial differentiation. Remarkably, inducible expression of SSBP2 is accompanied by downregulation of C-MYC expression. Our findings are consistent with human SSBP2 being a novel regulator of hematopoietic growth and differentiation, whose loss confers a block in differentiation advantage to myeloid leukemic cells.Oncogene advance online publication, 14 March 2005; doi:10.1038/sj.onc.1208167.
http://www.hubmed.org/display.cgi?uids=15782145
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Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia.
Imatinib, a potent inhibitor of the oncogenic tyrosine kinase BCR-ABL, has shown remarkable clinical activity in patients with chronic myelogenous leukaemia (CML). However, this drug does not completely eradicate BCR-ABL-expressing cells from the body, and resistance to imatinib emerges. Although BCR-ABL remains an attractive therapeutic target, it is important to identify other components involved in CML pathogenesis to overcome this resistance. What have clinical trials of imatinib and studies using mouse models for BCR-ABL leukaemogenesis taught us about the functions of BCR-ABL beyond its kinase activity, and how these functions contribute to CML pathogenesis?
http://www.hubmed.org/display.cgi?uids=15719031
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Vaccine development for chronic myelogenous leukaemia.
No abstract yet.
http://www.hubmed.org/display.cgi?uids=15721455
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ABL Oncogenes and Phosphoinositide 3-Kinase: Mechanism of Activation and Downstream Effectors.
The BCR-ABL oncogene is responsible for most cases of chronic myelogenous leukemia and some acute lymphoblastic leukemias. The fusion protein encoded by BCR-ABL possesses an aberrantly regulated tyrosine kinase activity. Imatinib mesylate (Gleevec, STI-571) is an inhibitor of ABL tyrosine kinase activity that has been remarkably effective in slowing disease progression in patients with chronic phase chronic myelogenous leukemia, but the emergence of imatinib resistance underscores the need for additional therapies. Targeting signaling pathways activated by BCR-ABL is a promising approach for drug development. The study of signaling components downstream of BCR-ABL and the related murine oncogene v-Abl has revealed a complex web of signals that promote cell division and survival. Of these, activation of phosphoinositide 3-kinase (PI3K) has emerged as one of the essential signaling mechanisms in ABL leukemogenesis. This review describes molecular mechanisms by which PI3K is activated and the downstream PI3K effectors that propagate the signal to promote myeloid and lymphoid transformation. Of particular recent interest is the mammalian target of rapamycin, a PI3K-regulated kinase that regulates protein synthesis and contributes to leukemogenesis.
http://cmlhope.com/drupal/?q=node/43
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Rosey beats leukemia with clinical drug trial
Gulf Islands Driftwood
Wednesday, March 23, 2005
By Mitchell Sherrin
Rosey Brenan is cruising around Salt Spring in her white Mustang convertible and enjoying the sun with the top down, thanks to an innovative medicine developed in part by B.C. cancer researchers.
“Cancer research has given me my life back. It’s just incredible. Statistically, I’m not supposed to be here.”
After facing a withering death, her life took a miraculous turn due to ground-breaking medical developments in the last few years.
“I’m back to the work I love. I get to live on Salt Spring. I have time in Vancouver working, we are building our house, my kids are so happy. It has changed our lives completely. I am living breathing cancer research. I wouldn’t be here if they didn’t do cancer research; so I’m a huge supporter and fan.”
Brenan had few options for treatment when she was first diagnosed with chronic myelogenous leukemia almost five years ago, she said.
The only known cure at the time was a high-risk bone-marrow transplant and tissue samples from Brenan’s sister — the one viable donor — did not match.
Brenan took daily injections of interferon to prolong her life, but the drug slowly destroyed her body until she was pulled off the medication in 2001.
“My body just couldn’t tolerate it after six months and basically after that they said, ‘We can manage your symptoms but you don’t have all that long. It will kill you.’”
But on March 1, 2004, she began a clinical trial of a new drug in Vancouver that literally saved her life.
“Back then it didn’t even have a name — only a number. Now it’s famous the world over; it’s even appeared on the cover of Time magazine. It’s called Gleevec and it’s a miracle of cancer research.”
Gleevac attacks the genetic malfunction that causes her specific type of cancer, she said.
“I’m not technically in remission, but I might as well be.”
Five years ago, cancer was found in 95 per cent of her blood cells. But her most recent test showed leukemia in only 0.001 per cent of cells.
“In other words, I’m fine. All I have to do is swallow six of these little pills each day — no chemo, no radiation, no surgery — and I’m going to go on being fine.”
The only side effect of Gleevac is some fatigue, she said.
Unfortunately, researchers have not yet been able to replicate the drug for other types of cancers, she said.
“There’s not like one bullseye that you can aim at with other cancers.”
And on March 1 of this year, Brenan offered support for further cancer research by speaking at the official opening of the B.C Cancer Research Centre (BCCRC) in Vancouver.
“The new research centre is amazing. They’ve got floors and floors of labs and all kinds of special equipment and they are attracting some of the best talents in the world.”
Brenan was joined by Premier Gordon Campbell, Vancouver mayor Larry Campbell, federal Minister of Industry David Emerson and numerous other dignitaries during the opening of the $95-million research centre.
According to a press release from the B.C. Cancer Agency, the new 15-storey building provides a unique opportunity to increase the number of clinical and basic research teams brought together to address key issues in cancer control.
Capacity will increase from the 318 researchers housed in the former research centre over the past 26 years to some 600 scientific and medical personnel.
“They are doing incredible research there. We are so lucky. I’m told that if you are going to get cancer, B.C. is one of the best places to be because we have some of the best treatments and some of the best survival rates.”
Now that Brenan can resume cruising the island in her Mustang, it’s clear she speaks from experience.
Gulf Islands Online – Feature
Posted by rob on March 23, 2005 under Uncategorized |
Rules aim to speed personal medicine
Firms can get more FDA feedback on genomic research
By Ross Kerber, Globe Staff | March 23, 2005
Hoping to speed the emerging field of personalized medicine, drug regulators set up new rules yesterday that will allow companies to submit research findings earlier in the process so they can get more feedback sooner.
Increasingly, doctors and researchers are trying determine exactly which drugs will have the best effect on individual patients by studying the patients’ genetic makeup. That would reduce prescription trial-and-error and help in the development of new drugs.
Toward that goal, the US Food and Drug Administration outlined just how pharmaceutical and biotechnology firms should present genomic-based drug research. The FDA also created a process in which companies could submit preliminary data the agency said it wouldn’t hold against drug companies later in the marketing review process.
Larry Lesko, the FDA’s director of clinical pharmacology, said the exemption will let firms start talks with the FDA earlier in the development process and make it easier to spot problems.
Currently companies show their data only after expensive clinical trials. That discourages drug makers from taking chances on new research tools like genomic sciences, he said. ”We’re trying to balance the risk-averse nature of the drug-development enterprises with the new technology that has this high potential,” Lesko said.
At a time when the FDA has been under political fire for approving painkillers and other drugs that later had to be withdrawn, telling companies they are setting aside any data represents a potentially risky step for the agency and its acting commissioner, Lester Crawford.
But Lesko said there have been no objections filed to the agency since it first proposed the new genomic-research guidelines in 2003. Eventually, the FDA may allow companies similar exemptions for other advanced laboratory techniques, he said.
The idea of applying genomic research to drug development and patient care represents a medical breakthrough, but in practice advances have been slow to arrive. In recent years the FDA has approved a few treatments developed from genomics such as Novartis AG’s Gleevec for leukemia and ImClone Systems Inc.’s cancer drug Erbitux.
Lesko said the guidelines include safeguards to make sure firms won’t take advantage of the assurance that early data won’t affect later safety reviews. So far 10 companies have submitted genomic data under a draft of the guidelines. In just one of those cases, the agency told the company to resubmit the data under its standard review process because it could bear on the FDA’s final marketability decision, he said.
Pharmaceutical executives applauded the new submission guidelines and the data exemption, saying they are the best ways for firms and regulators to learn about genomics work quickly.
”For the FDA, this allows them to see the ways in which companies are using genomics technology, and that’s something they couldn’t otherwise get an early sight on,” said Chris Webster, director of regulatory strategy at Millennium Pharmaceuticals Inc. in Cambridge.
Personalized medicine is of particular interest to Millennium since the cancer patients its drugs treat show a variety of responses. In one case submitted under a draft of the new guidelines, Millennium showed the FDA early findings of how its drug Velcade affected certain patients with multiple myeloma, a blood cancer, Webster said. The company is studying whether a certain gene can indicate if some patients will survive longer than others on Velcade, he said.
Also, yesterday the FDA said it approved the first laboratory test for personalized medicine. It said the test made by Roche Molecular Systems Inc. and Affymetrix Inc., both in California, will help doctors use genetic data to select the right dose of certain cancer and cardiac drugs.
According to an FDA summary, the system uses DNA drawn from a patient’s blood to detect common variations of a certain gene that produces an enzyme that might metabolize these drugs too quickly, too slowly, or not at all.
Boston.com / Business / Rules aim to speed personal medicine
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Local Research and Development Company Raises $3 Million for Genetics Studies
By Jenifer Putnam
TBR Staff
A Savannah-based company viewed as having the potential to change the pharmaceutical industry though its DNA research recently raised nearly $3 million recently through a stock offering.
The money will give the publicly-traded Health Discovery Corp. (NASDAQ: HDVY) the means to continue its research and development of biomarkers and pathways. A biomarker is a diagnostic indication that disease could develop. The company’s research can be used for early detection of prostrate or breast cancer or to determine which patients will react negatively to new drugs.
Chairman & CEO Steve Barnhill said the company, which was founded in September 2003, was looking for just $2 million. But the company was so popular – especially with investors in New York – that he had to expand the offering, which closed just $10,000 shy of $3 million.
“It’s a really good company with strong assets and market value,” Barnhill said. “People like a good investment.”
Although young, the company already has registered almost 80 patents. It licenses the patented information to pharmaceutical companies, which use the information to develop new drugs or determine the safety of existing drugs for certain portions of the population.
Barnhill said the use of biomarkers can greatly reduce the time it takes for a drug to make it to market, an attractive quality to both the pharmaceutical industry and the Food and Drug Administration, which last week endorsed the process.
Known as pharmacogenomics, the process allows health care providers to identify sources of an individual’s profile of drug response and predict the best possible treatment option for the individual. The technology has enabled the development of targeted therapies such as Herceptin for metastatic breast cancer, Gleevec for chronic myeloid leukemia and Erbitux for metastatic colorectal cancer.
Janet Woodcock, M.D., acting deputy commissioner for operations at the FDA, said the agency’s endorsement last week of the biomarker research will be significant in speeding up the time it takes to get a drug to market. “FDA’s efforts will bring us one step closer to ‘personalizing’ medical treatment,” said Janet Woodcock, M.D., acting deputy commissioner for operations at the FDA. “This new technology will allow medicines to be uniquely crafted to maximize their therapeutic benefits and minimize their potential risks for each patient,” she said.
Instead of the standard hit-or-miss approach to treating patients, where it can take multiple attempts to find the right drug and the right dose, doctors will eventually analyze a patient’s genetic profile and prescribe the best available drug therapy and dose from the start, according to the FDA. Barnhill said genetic tests also could allow the use of drugs such as Vioxx for the millions without adverse reactions to the drugs while avoiding its use by the hundreds who could be harmed by its use.
“If you can identify genetic biomarkers you can create a diagnostic test,” Barnhill said. “If the genetic profile responds poorly, you don’t give it to them.”
Barnhill said he expects to add 10 more highly educated and skilled workers to his Savannah staff in the next year. Of the 15 people working for him so far, he said 80 percent to 90 percent have medical doctorates or academic doctorates, or both. His staff includes a Nobel Prize winner in genetics and a Humboldt Prize winner in mathematics.
The company also has offices in Texas and California.
The Business Report & Journal
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Dr. Jerome Groopman Chairs Onconova Therapeutics Inc. New Clinical Advisory Board
BIOWIRE2K
PRINCETON, N.J.–(BUSINESS WIRE)–March 23, 2005–
Board to Advise Development Team that Spearheaded Recent Publications on Discovery of Novel Kinase Inhibitors in Two Leading Journals
Onconova Therapeutics, Inc., a privately-held company focused on cancer therapy, announced today the creation of its Clinical Advisory Board (CAB), chaired by Dr. Jerome E. Groopman, and the appointment of its first five members. Onconova’s CAB members are distinguished oncologists from leading medical centers in the U.S. and will advise the company in clinical and regulatory strategies, particularly for the ongoing development of the Company’s lead anticancer agent ON 01910.Na. This novel non-ATP competitive kinase inhibitor selectively blocks several important targets in cancer. The drug candidate entered Phase I clinical trials at the Johns Hopkins Kimmel Cancer Center, Baltimore, MD in July 2004. The CAB met for the first time this month in New York.
Two Onconova kinase inhibitors have been the subject of papers published in early 2005. ON 01910.Na was the subject of a peer-reviewed paper titled “ON 01910, a non-ATP-competitive small molecule inhibitor of PLK1, is a potent anticancer agent,” which appeared in the journal Cancer Cell in March (Vol 7, 275-286, March 2005). The company’s advanced preclinical stage compound targeting BCR-ABL, involved in Chronic Myelogenous Leukemia (CML), was featured in the Proceedings of the National Academy of Sciences in February (PNAS February 8, 2005, vol. 102, no. 6, pp 1992-1997)
Onconova’s Clinical Advisory Board is chaired by Dr. Jerome E. Groopman, who holds the Dina and Raphael Recanati Chair of Medicine at the Harvard Medical School and is Chief of Experimental Medicine at the Beth Israel Deaconess Medical Center. Dr. Groopman was Chairman of the Advisory Committee to the FDA for Biological Response Modifiers. His research has focused on cancer and AIDS. He is also a writer for The New Yorker, and has written three popular books, most recently “The Anatomy of Hope”. Other founding members of the CAB are Dr. James F. Holland, Dr. Ross C. Donehower, Dr. Stephen D. Nimer, and Dr. William N. Hait.
– Dr. James F. Holland, Distinguished Professor of Neoplastic Diseases at Mount Sinai Medical Center, NY, received the prestigious Lasker Award in 1972 for his work in cancer chemotherapy. Dr. Holland has been working closely with Onconova on developing preclinical models for testing ON01910.Na.
– Dr. Ross C. Donehower, Ludwig Professor in Clinical Investigation of Cancer, is Director of the Division of Medical Oncology at the Johns Hopkins Kimmel Cancer Center and is an expert in the pharmacology of chemotherapeutic drugs.
– Dr. Stephen D. Nimer is the Head of the Division of Hematologic Oncology and Chief of the Hematology Service, Memorial Sloan Kettering Cancer Center, NY. Dr. Nimer received one of two awards given to U.S. investigators by The Leukemia & Lymphoma Society as a Specialized Center of Research Excellence in myeloid malignancies.
– Dr. William N. Hait, Director of The Cancer Institute of New Jersey and Professor of Medicine and Pharmacology, UMDNJ/Robert Wood Johnson Medical School, NJ, is an expert in breast cancer and is conducting basic research in signal transduction systems altered in malignancy.
“All of us on the Advisory Board are looking forward to marshalling our energy and expertise to the development of the PLK1 inhibitor (ON 01910.Na) as a novel anti-cancer therapy,” said Dr. Groopman.
ON 01910.Na is the first in a new class of non-ATP competitive kinase inhibitors being developed by Onconova that discriminate between cancerous and normal cells by targeting specific checkpoints in the cell cycle. In pre-clinical animal studies, ON 01910.Na was active against most tumor types, including those resistant to standard chemotherapy, and did not exhibit common toxic effects of chemotherapy such as anemia or weight loss.
The Clinical Advisory Board will also advise Onconova on other drug candidates being developed by the Company. These include ON 01210, Ex-RAD(TM), for protection from whole-body radiation, being developed in partnership with the Armed Forces Radiobiology Research Institute (AFRRI); an advanced preclinical stage compound targeting BCR-ABL involved in Chronic Myelogenous Leukemia (CML). A key attribute of this inhibitor is its potent activity against all mutant forms of BCR-ABL kinase found in drug-resistant CML. The Company also has a strong pipeline of specific enzyme inhibitors, applicable for cancer, autoimmune, ophthalmic, and central nervous system indications, in earlier stages of development.
About Onconova
Onconova Therapeutics, Inc. discovers and develops small molecule, patent protected drugs that employ novel approaches to combating cancer and other diseases. To date, nearly 20 U.S. patents have been issued. In addition to the development stage compounds described above, the Company has a strong pipeline of specific enzyme inhibitors, applicable for cancer, autoimmune, ophthalmic, and central nervous system indications, in earlier stages of development.
For additional information on Onconova Therapeutics Inc., visit the company’s website at www.onconova
Dr. Jerome Groopman Chairs Onconova Therapeutics Inc. New Clinical Advisory Board
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Drugs in Development
Innovation at the core
by Neal Bellucci
Novartis continues to advance one of the pharmaceutical industry’s most robust pipelines. The company has progressed in 75 development projects that aim to address unmet medical needs.
In addition to the 75 projects in clinical development, which include 43 new molecular entities and 52 drugs in Phase II, Phase III, or registration, Novartis has more than 64 candidates in advanced preclinical testing. Key areas of development are oncology and cardiovascular diseases, with promising compounds being developed for the primary care and specialty medicine categories.
“Innovation is the core of our strategy, and our strong investments of $3.5 billion in pharmaceutical R&D in 2004 rank among the highest in the industry,” says Daniel Vasella, M.D., chairman and CEO, Novartis (novartis.com). “In the U.S. alone, our investments have allowed us to bring 13 new medicines to patients over the past four years, the highest number of any pharmaceutical company.
“We continue to focus on novel medicines. Six of our 10 highly innovative compounds in mid-to-late stage development are potential first-in-class medicines, and I am pleased that the expertise of our scientists, improved processes, and advanced technologies have contributed to maintaining a leading position in R&D productivity.”
The Novartis pipeline is highlighted by several innovative compounds. These include SPP100 for the treatment of hypertension, QAB149 for asthma and chronic obstructive pulmonary disease, FTY720 for multiple sclerosis and transplantation, LAF237 for the treatment of type 2 diabetes, and PTK787 for cancer. Many of these projects have the potential to become new standards of care and the first to market in their classes.
Other priority projects are in development. AMN107 is an investigational oral compound being studied in the small subset of advanced chronic myeloid leukemia patients who do not respond or stop responding to Gleevec/Glivec and have no treatment options available. Phase II trials for the compound are expected to start in the first half of 2005. PTK787, comprising vatalanib, is an oral angiogenesis inhibitor in Phase III development for metastatic colorectal cancer. The drug is being developed with Schering AG (schering.de). ICL670, comprised of deferasirox, offers the potential to revolutionize the treatment of iron overload, providing a once-daily oral formulation to replace the cumbersome infusion therapy Desferal. Submissions in the United States and European Union for ICL670, which has orphan-drug status, are planned for the first half of 2005.
In the area of cardiovascular and metabolic drugs, Novartis is developing LAF237, comprised of vildagliptin, a first-in-class incretin enhancer for the treatment of type 2 diabetes. Submission is planned for early 2006. SPP100, composed of aliskiren and first in a new class of antihypertension agents called renin inhibitors, offers once-daily treatment with efficacy and safety comparable to angiotensin-receptor blockers, another class of high-blood-pressure drugs. Regulatory submission for
SPP100 is also planned for early 2006.
In the area of neuroscience, FTY720 is an oral immunomodulator with a novel mechanism of action that has shown efficacy in multiple sclerosis in a Phase II study. The drug has the potential to become the first efficacious oral therapy for multiple sclerosis. Phase III studies are planned to start in mid-2005. Additionally, FTY720 is being developed for transplantation. Phase III data remain on track for completion in 2005. Submissions in the United States and European Union are expected in early 2006.
QAB149 is a once-daily long-acting beta-2 agonist for asthma and chronic obstructive pulmonary disease that offers a quick onset of action and true 24-hour control, with Phase III studies planned to start in 2005 and regulatory submissions planned for 2007. Xolair is on track for regulatory approval in the European Union in 2005. This novel agent offers a breakthrough in treating asthma, particularly as a unique add-on therapy for adults and adolescents with severe persistent asthma who remain inadequately controlled with conventional medicines. Xolair is being developed in collaboration with Genentech (gene.com) and Tanox Inc. (tanox.com).
In the area of bone and joint treatment, Aclasta has the potential to become the gold standard in treating osteoporosis. Aclasta has received priority review status in the United States for Paget disease, and a decision is expected in March 2005. Approval in the European Union is expected in the first half of 2005, while submission for postmenopausal osteoporosis is expected in 2007 following completion of ongoing Phase III trials. AAE581 is an oral once-daily compound aiming to be the first cathepsin K inhibitor for treating osteoporosis. Phase II trials are on schedule, and biomarker data are expected in the fourth quarter of 2005, with Phase III trials planned for the first quarter of 2006.
Novartis also continues to search for drugs to treat infectious disease. LDT600, comprised of telbivudine, is a once-daily drug in tablet formulation for the treatment of hepatitis B infection, a disease estimated to affect about 400 million people worldwide. Novartis plans to submit U.S., EU, and international marketing applications for telbivudine beginning in the fourth quarter of 2005 and extending into 2006.
A total of 12 projects were added to the development portfolio, and 16 left the pipeline through approval or launch, as well as through termination or for being put on hold. Among the terminated projects is TCH346 in Parkinson disease and amyotrophic lateral sclerosis, after Phase II studies did not demonstrate efficacy.
Novartis expects the mutual recognition procedure in the European Union for Prexige, a novel anti-inflammatory medicine being developed for osteoarthritis, to resume in mid-2005 after the European Medicines Agency completes a review of the cox-2 inhibitor class. Submission for approval in the United States is not expected before 2007.
A priority of Novartis research and development efforts is to expedite proof-of-concept trials in humans through a translational medicine approach to better assess a compound’s clinical potential by collecting biomarker data as early as possible. Nine early-stage compounds in Phase I/II offer significant potential based on the results of proof-of-concept testing. Among the priority early-stage projects is LBM642, a novel agonist of PPAR-alpha and PPAR-gamma for the treatment of metabolic syndrome, a group of risk factors that include obesity, insulin resistance, elevated cholesterol, and high blood pressure.
Other early-stage projects include ACZ885, which offers a new mechanism for treating rheumatoid arthritis; AEE788, an anticancer agent with promise in many solid tumors; valopicitabine, also known as NM283, a novel therapy for hepatitis C infection being developed by Idenix Pharmaceuticals (idenix.com), for which Novartis has an exclusive right to in-license; and AEB071, a first-in-class immunomodulator for transplantation.
In 2005, Novartis anticipates making submissions for at least three new molecular entities for regulatory approval: PTK787 in the United States for colorectal cancer; ICL670 in the United States and European Union as the first oral treatment for chronic iron overload; and LDT600 in the United States for the treatment of hepatitis B. The company also plans to make a series of applications for new indications of already-marketed products, including Femara in the United States and European Union for a new indication for treating women with breast cancer in the early adjuvant setting; and Visudyne in the United States for the occult form of age-related macular degeneration.
Seven projects are in registration, including Aclasta for the treatment of Paget disease in the United States and European Union, Xolair in the European Union following approval in the United States in mid-2003, and Zelnorm/Zelmac for treating irritable bowel syndrome in the European Union. Regulatory decisions are expected in 2005.
Novartis has more than 100 alliances with biotechnology and academic institutions looking for a major pharmaceutical company partnership. In 2004, the company’s alliance strategy focused on two key components to strengthen its pipeline: development of research alliances and the in-licensing of new compounds. A key focus of in-licensing was the acquisition of three compounds to complement internal cardiovascular/metabolism programs. D-4F, a novel apoA-I mimetic, was acquired from BruinPharma, and Phase I development has been initiated. An exclusive agreement was signed with Xenon Pharmaceuticals (xeonon-pharm.com) to develop and commercialize compounds from their Stearoyl-CoA Desaturase-1 program, which is in preclinical development. This program is complementary with Novartis programs targeting type 2 diabetes and the metabolic syndrome. An agreement was also signed with Torrent Pharmaceuticals (torrentpharma.com) to develop its advanced glycosylation end-products breaker compound in heart disease and diabetes-related vascular events, which is also in preclinical development.
Complementing internal discovery efforts in oncology, Novartis selected VX-322, a protein kinase inhibitor from Vertex Pharmaceuticals Inc. (vrtx.com) in 2004, and also acquired from Vernalis the exclusive rights to the United Kingdom-based biotechnology company’s development program for Hsp90, a target implicated in a number of different cancers. In addition, Novartis acquired all rights to Triad’s preclinical p38map kinase program, which may deliver a promising oral therapeutic for inflammatory diseases. Novartis will be responsible for full development and commercialization of all compounds covered under Triad’s intellectual property.
Novartis achieved sales of $28.2 billion and net income of $5.8 billion in 2004. The group invested about $4.2 billion in research and development.
Phase III clinical trials
VISTA trial begins
Millennium Pharmaceuticals Inc. has initiated the Vista trial, in collaboration with Johnson & Johnson Pharmaceutical Research & Development LLC. The Vista trial is a multicenter, international Phase III clinical trial of Velcade in combination with melphalan and prednisone versus melphalan and prednisone in patients with newly diagnosed multiple myeloma who are not transplant candidates. This large, international, randomized study will assess efficacy, overall safety, and tolerability of the combination versus melphalan and prednisone alone. Vista stands for Velcade as Initial Standard Therapy in multiple myeloma Assessment with melphalan and prednisone. The Vista trial was reviewed by FDA through the special protocol assessment process.
Velcade is approved in the United States and Europe for the treatment of patients with relapsed and refractory multiple myeloma. FDA is reviewing Millennium’s supplemental new drug application, under priority review designation, for Velcade as a treatment for patients with multiple myeloma who have received at least one prior therapy.
“Millennium, and our partner Johnson and Johnson, are committed to strategically and expeditiously developing Velcade as the cornerstone of care across the multiple myeloma treatment paradigm,” says David Schenkein, M.D., VP, clinical oncology development, Millennium (millennium.com). “The frontline data seen to date have been very promising, and we are eager to explore the potential of Velcade in combination with other therapies so that we may be able to offer new options for patients in need.”
Millennium and Johnson & Johnson are also planning to support two additional large, multi-national Phase III frontline multiple myeloma trials, which are scheduled to be initiated in the first half of this year. These trials will be for patients who plan to undergo stem cell transplantation. In these trials, which are planned to be conducted by major European hematology cooperative groups, Velcade will be integrated into the induction regimen. Additionally, Millennium and Johnson & Johnson will continue to investigate Velcade globally in hematologic and solid tumors and are supporting more than 100 ongoing or planned clinical trials.
Multiple myeloma is a cancer of the bone marrow in which white blood cells called plasma cells are overproduced. Plasma cells are normally responsible for the production of antibodies. The proliferation of these abnormal plasma cells causes decreased production of normal red and white blood cells, and of normal disease-fighting antibodies, as well as the growth of tumors that spread to multiple sites. The decreased white blood cell production damages the immune system while the myeloma tumors cause bone destruction that manifests as pain and fractures. Multiple myeloma is the second most common hematologic malignancy, and although the disease is predominantly a cancer of the elderly, statistics indicate both increasing incidence and younger age of onset. In the United States, more than 40,000 individuals have multiple myeloma, and more than 14,000 new cases of the disease are diagnosed each year. Worldwide there are about 74,000 new cases and more than 45,000 deaths each year.
Millennium is a biopharmaceutical company based in Cambridge, Mass. The company’s research, development, and commercialization activities are focused in three therapeutic areas: oncology, cardiovascular, and inflammation.
Acceleration of development
Myriad Genetics Inc. has initiated enrollment in a Phase III human clinical trial of its lead therapeutic candidate, Flurizan, in patients with Alzheimer disease. Flurizan is also known as MPC-7869. The Phase III trial is designed to determine Flurizan’s ability to alter the course of cognitive decline and behavioral change in patients with Alzheimer disease.
The trial will be conducted in about 750 patients with mild-to-moderate Alzheimer disease, at about 100 centers in the United States. The Phase III study is a double-blind, placebo-controlled trial, with randomization of patients at enrollment into one of three arms. Patients will be given 400 milligrams or 800 milligrams of Flurizan twice daily, or placebo twice daily for the duration of the 12-month study period. The co-lead investigators for this trial are Robert C. Green, M.D., M.P.H., associate professor of neurogenetics, Boston University School of Medicine, and Lon Schneider, M.D., professor of psychiatry, neurology, and gerontology, Keck School of Medicine, University of Southern California.
“There is a critical need for drugs that modify the underlying disease mechanism and progression of Alzheimer’s disease,” says Dr. Schneider. “MPC-7869 has the potential to do this with its effect on reducing amyloid beta levels. We hope to confirm this in a large, well-controlled clinical trial.”
The primary efficacy endpoints for the trial will be the change in cognitive function, as measured by the ADAS-cog test, and the change in activities of daily living.
“Flurizan is an exciting drug candidate due to its potential to change the rate of decline in Alzheimer’s disease patients,” says Adrian Hobden, Ph.D., president, Myriad Pharmaceuticals. “We are pleased to take the opportunity to accelerate Flurizan’s development timeline by initiating this Phase III trial.”
Flurizan is being studied in a Phase II clinical study in about 210 patients with mild-to-moderate Alzheimer disease. All patients have been on the drug for more than nine months. The trial’s data safety monitoring board has reviewed safety data from the trial each calendar quarterly and has determined that the trial should proceed without change. This Phase II trial is expected to conclude its clinical study period in March.
Flurizan is a selective amyloid beta 42 lowering agent that has been shown to modulate gamma-secretase and selectively lower levels of amyloid beta 42, a toxic peptide that is believed to be a chief culprit in the cause of Alzheimer disease. In transgenic mouse studies, Flurizan has demonstrated the ability to reduce brain amyloid levels and prevent memory loss. Flurizan was selected during preclinical testing to avoid cyclooxygenase inhibition and its related side effects.
Myriad (myriad.com) is a biopharmaceutical company focused on the development of novel health-care products. The company develops and markets predictive medicine products, and is developing and intends to market therapeutic products.
Targeted oral therapy for MS
Serono and Ivax Corp. will initiate a Phase III study with Mylinax, a proprietary oral formulation of cladribine, in the first quarter of 2005. This multicenter, multinational study is designed to assess the effectiveness of Mylinax in patients with relapsing forms of multiple sclerosis. Endpoints will include assessments of clinical relapses, disability progression, and MRI brain scans. The study will span two years and involve more than 1,200 patients. Mylinax is being developed by Serono and Ivax under a worldwide agreement signed in October 2002.
“We are committed to providing new treatment options that can further improve the quality of the lives of people with multiple sclerosis,” says Ernesto Bertarelli, CEO, Serono (serono.com). “With the initiation of the Phase III program of Mylinax, we are getting closer to realizing our objective to bring the first oral disease-modifying treatment to people with multiple sclerosis.”
Cladribine is a purine nucleoside analog that interferes with the behavior and the proliferation of certain white blood cells, particularly lymphocytes, which are involved in the pathological process of multiple sclerosis. Through its differentiated mechanism of action, Mylinax may offer an alternative option to patients with multiple sclerosis. Previous clinical trials using a parenteral formulation demonstrated positive effects of cladribine administered via injection in patients with multiple sclerosis. In these trials, reduction in new lesion development in the brain as seen on MRI scans and clinical benefits were observed.
“We are very pleased to have reached this important milestone in the development of Mylinax as a novel therapy for multiple sclerosis,” says Phillip Frost, M.D., chairman and CEO, Ivax (ivax.com). “The initiation of this Phase III study supports our belief in Mylinax and our choice of Serono as a partner that could help maximize its potential.”
Multiple sclerosis is a chronic, inflammatory condition of the nervous system and is the most common, nontraumatic, neurological disease in young adults. Multiple sclerosis affects about 2 million people worldwide. Although symptoms can vary, the most common symptoms of multiple sclerosis include blurred vision, numbness or tingling in the limbs, and problems with strength and coordination. The relapsing forms of multiple sclerosis are the most common.
Serono has strong market positions in neurology, metabolism, and growth, and has recently entered the psoriasis area. The company’s research programs are focused on growing these businesses and on establishing new therapeutic areas.
Ivax discovers, develops, manufactures, and markets branded and generic pharmaceuticals and veterinary products in the United States and internationally. In 2003, Ivax recorded worldwide net revenue of $1.4 billion and net income of $121 million.
Second Phase III trial initiated
Alexion Pharmaceuticals Inc. has initiated treatment in the Phase III Shepherd trial, evaluating the investigational drug eculizumab in patients with the chronic orphan blood disorder paroxysmal nocturnal hemoglobinuria. The Shepherd trial is under way at the same time with the already enrolling pivotal efficacy trial called Triumph.
If successful, the company expects the trials will complete the application that will serve as the primary basis of review for the approval of a biologics license application for eculizumab in the paroxysmal nocturnal hemoglobinuria indication.
A main objective of the Shepherd trial is to generate additional safety data with eculizumab in hemolytic paroxysmal nocturnal hemoglobinuria patients with a history of transfusion. Shepherd is an open-label, nonplacebo-controlled, multicenter clinical trial.
Additional endpoints will include hemolysis and quality of life measures. The study is expected to enroll about 75 patients in the United States, Canada, Europe, and Australia. Results are expected during the second half of 2005.
Alexion initiated treatment in the pivotal Triumph Phase III efficacy trial in November 2004. Triumph, which is a double-blind, randomized, placebo-controlled multi-center clinical trial, is examining the effects of eculizumab on the co-primary endpoints of hemoglobin stabilization and blood transfusion in hemolytic, transfusion-dependent paroxysmal nocturnal hemoglobinuria patients during six months of therapy.
The Shepherd trial marks the third study performed with eculizumab in paroxysmal nocturnal hemoglobinuria patients. Previous trial results showed that patients treated with eculizumab experienced a substantial decrease in the destruction of paroxysmal nocturnal hemoglobinuria red blood cells. Additionally, in this trial, eculizumab appeared safe and well tolerated.
“We are pleased to continue the rapid development of eculizumab in this important indication, first with the enrollment of patients into Triumph, and now with the enrollment of additional patients into the companion Shepherd trial,” says Leonard Bell, M.D., CEO, Alexion. “With a focus on driving the PNH program forward to meet the needs of the severely underserved PNH patient population, we will strive to complete enrollment and the initial six months of treatment in Shepherd, as well as the randomization and treatment of patients in Triumph, in 2005.
“We believe that, if successful, the Triumph pivotal trial, together with results from Shepherd, should provide a solid basis to support licensing applications for the PNH indication in the United States and Europe.”
If approved for paroxysmal nocturnal hemoglobinuria, eculizumab would represent the first of a new class of anti-inflammatory therapeutics-terminal complement inhibitors, as well as the first drug available specifically for patients suffering from this rare blood disease.
In December 2003, Alexion had received orphan-drug status for the use of eculizumab in paroxysmal nocturnal hemoglobinuria from FDA and the European Agency for the Evaluation of Medicinal Products.
Paroxysmal nocturnal hemoglobinuria is a blood disorder characterized by the onset of severe anemia, chronic fatigue, and intermittent episodes of dark-colored urine. Patients are also at increased risk of forming life-threatening blood clots, a leading cause of death in this disease.
People with paroxysmal nocturnal hemoglobinuria have an acquired deficiency of proteins that normally protect red blood cells from a component of the body’s natural defense system. Between 2,000 and 10,000 people in the United States suffer from paroxysmal nocturnal hemoglobinuria. Alexion is engaged in the discovery and development of therapeutic products aimed at treating patients with a wide array of severe disease states, including hematologic and cardiovascular disorders, autoimmune diseases, and cancer.
R&D Directions
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As molecules go, DNA and viruses are relatively large. Many prototype sensors are aimed at detecting large biological molecules, but small organic molecules also play important roles in biological systems, and most pharmaceutical drugs are small molecules.
Researchers from Harvard University have found a way to use transistors made from silicon nanowires to gain information about how small molecules bind to proteins. The nanowires are 20 nanometers in diameter, and the electrical conductance of the devices changes measurably depending on whether target molecules bind to receptor molecules attached to the nanowires. A nanometer is one millionth of a millimeter, or the span of 10 hydrogen atoms.
The nanowire transistors could eventually be used in sensor arrays capable of simultaneously detecting many different molecules, including small organic molecules. The method is potentially capable of rapidly screening drug candidates, according to the researchers.
The researchers’ prototype consists of arrays of several dozen sensors that sense when adenosine triphosphate (ATP) molecules bind to the receptor molecules on the nanowires. The researchers showed that the device could measure how effectively the small molecule drug Gleevec blocked the ATP-receptor binding.
The receptor molecule Abl binding with ATP is part of a cell signaling process that, when altered, plays a role in many diseases. Gleevec is used to treat chronic myelogenous leukemia.
The researchers also showed that it is possible to measure the degree to which four other small molecules blocked the ATP binding.
The sensors could be ready for practical use in two to five years, according to the researchers.
The work appeared in the February 14, 2005 issue of the Proceedings of the National Academy Of Sciences.
Nanowires track molecular activity TRN 032305
