PROLOR Biotech Inc., a company developing next generation biobetter therapeutic proteins, announced initiation of a Phase 2 clinical trial of its long-acting CTP-modified version of human growth hormone (hGH-CTP) in children with growth hormone deficiency.
The pediatric trial follows successful completion of a Phase 2 trial of hGH-CTP in growth hormone deficient adults, which demonstrated that hGH-CTP was safe and well tolerated with the potential to reduce the required dosing frequency of human growth hormone from the current standard of one injection per day to a single weekly injection. A subsequent pilot study suggested that bi-monthly dosing of hGH-CTP may also be feasible.
Growth hormone deficiency (GHD) in children occurs when the pituitary gland fails to secrete adequate amounts of growth hormone. Growth hormone replacement therapy may enable a GHD child to reach a normal height, but the therapy requires daily injections and may require a total of more than 3,000 injections before the child reaches the age of 18.
“Obtaining regulatory clearance for a clinical trial in children is a challenge for any drug developer. We believe that our receipt of regulatory clearance for the initiation of our Phase 2 study in growth hormone deficient children is another indicator of the quality of our hGH-CTP program,” said Dr. Abraham Havron, CEO of PROLOR.
Dr. Havron continued, “Our Phase 2 pediatric study is designed to provide information about the effectiveness and safety of a range of doses of hGH-CTP for a single weekly injection regimen in pediatric patients. We look forward to advancing our comprehensive clinical program for hGH-CTP in 2012, including this Phase 2 pediatric trial and an anticipated Phase 2I trial in growth hormone deficient adults that is targeted for later this year.”
The pediatric hGH-CTP Phase 2 trial is a randomized, open-label, dose-finding study to evaluate the efficacy, safety, tolerability, pharmacokinetics and pharmacodynamic properties of hGH-CTP injected weekly in children with growth hormone deficiency. The trial will compare the 12-month growth velocity of children receiving certain doses of hGH-CTP, injected once weekly, or commercial hGH injected daily, which is the current standard of care. The trial is expected to take place at up to 35 sites in 12 countries.
Date: March 20, 2012
Source: PROLOR Biotech Inc.
martes, 27 de marzo de 2012
Cardium Starts Phase 3 Generx Study
Cardium Therapeutics announced the initiation of the ASPIRE Phase 3 registration study to evaluate the therapeutic effects of Cardium's lead product candidate, Generx (Ad5FGF-4) in patients with myocardial ischemia (insufficient blood flow in the heart due to coronary artery disease).
The ASPIRE study is a 100-patient, randomized and controlled multi-center study being conducted at up to six leading cardiology centers in the Russian Federation. The study is designed to further evaluate the safety and effectiveness of Cardium's Generx DNA-based angiogenic product candidate, which has already been tested in clinical studies involving 650 patients at more than one hundred medical centers in the U.S., Europe and elsewhere. The therapeutic efficacy of Generx will be quantitatively assessed using rest and stress SPECT imaging (Single-Photon Emission Computed Tomography) to sensitively measure improvements in microvascular cardiac perfusion following a one-time, non-surgical, catheter-based administration of Generx. The Cedars-Sinai Medical Center Nuclear Cardiology Core Laboratory in Los Angeles, California, will serve as the central core lab for the ASPIRE study and will be responsible for the analysis of SPECT myocardial imaging data electronically transmitted from the Russian medical centers participating in the ASPIRE study. Advanced Biosciences Research, an affiliate of bioRASI which is a global clinical research organization, is Cardium's Russian sponsor and development partner and is responsible for the ASPIRE program management and regulatory compliance.
Generx is a disease-modifying regenerative medicine biologic that is being developed to offer a one-time, non-surgical option for the treatment of myocardial ischemia in patients with stable angina due to coronary artery disease, who might otherwise require surgical and mechanical interventions, such as coronary artery by-pass surgery or balloon angioplasty and stents. Similar to surgical/mechanical revascularization approaches, the goal of Cardium's Generx product candidate is to improve blood flow to the heart muscle – but to do so non-surgically, following a single administration from a standard cardiac infusion catheter.
"The ASPIRE trial represents a major milestone for Cardium and is the fifth clinical study under Generx's clinical development program that when completed will have enrolled more than 750 patients at over 100 medical centers throughout the U.S., Canada, South America, Western Europe and Russia. With positive safety and efficacy data from this single registration study, a Generx clinical dossier would become eligible for submission for marketing and sales in the Russian Federation, and would also be expected to support submissions seeking approval for marketing and sales of Generx in certain other countries of the Commonwealth of Independent States, comprising former republics under the Soviet Union," stated Christopher J. Reinhard, Cardium's Chairman and Chief Executive Officer.
The ASPIRE study is also specifically designed to provide additional clinical evidence regarding the safety and effectiveness of Generx that would be useful for optimizing and broadening commercial development pathways in other industrialized countries such as Brazil, India, Europe and the United States.
Date: March 20, 2012
Source: Cardium Therapeutics
The ASPIRE study is a 100-patient, randomized and controlled multi-center study being conducted at up to six leading cardiology centers in the Russian Federation. The study is designed to further evaluate the safety and effectiveness of Cardium's Generx DNA-based angiogenic product candidate, which has already been tested in clinical studies involving 650 patients at more than one hundred medical centers in the U.S., Europe and elsewhere. The therapeutic efficacy of Generx will be quantitatively assessed using rest and stress SPECT imaging (Single-Photon Emission Computed Tomography) to sensitively measure improvements in microvascular cardiac perfusion following a one-time, non-surgical, catheter-based administration of Generx. The Cedars-Sinai Medical Center Nuclear Cardiology Core Laboratory in Los Angeles, California, will serve as the central core lab for the ASPIRE study and will be responsible for the analysis of SPECT myocardial imaging data electronically transmitted from the Russian medical centers participating in the ASPIRE study. Advanced Biosciences Research, an affiliate of bioRASI which is a global clinical research organization, is Cardium's Russian sponsor and development partner and is responsible for the ASPIRE program management and regulatory compliance.
Generx is a disease-modifying regenerative medicine biologic that is being developed to offer a one-time, non-surgical option for the treatment of myocardial ischemia in patients with stable angina due to coronary artery disease, who might otherwise require surgical and mechanical interventions, such as coronary artery by-pass surgery or balloon angioplasty and stents. Similar to surgical/mechanical revascularization approaches, the goal of Cardium's Generx product candidate is to improve blood flow to the heart muscle – but to do so non-surgically, following a single administration from a standard cardiac infusion catheter.
"The ASPIRE trial represents a major milestone for Cardium and is the fifth clinical study under Generx's clinical development program that when completed will have enrolled more than 750 patients at over 100 medical centers throughout the U.S., Canada, South America, Western Europe and Russia. With positive safety and efficacy data from this single registration study, a Generx clinical dossier would become eligible for submission for marketing and sales in the Russian Federation, and would also be expected to support submissions seeking approval for marketing and sales of Generx in certain other countries of the Commonwealth of Independent States, comprising former republics under the Soviet Union," stated Christopher J. Reinhard, Cardium's Chairman and Chief Executive Officer.
The ASPIRE study is also specifically designed to provide additional clinical evidence regarding the safety and effectiveness of Generx that would be useful for optimizing and broadening commercial development pathways in other industrialized countries such as Brazil, India, Europe and the United States.
Date: March 20, 2012
Source: Cardium Therapeutics
Merck Ponders Next Step for Vorapaxar
CHICAGO (AP) - Officials at drugmaker Merck & Co. say they will take more time to decide what to do about an experimental blood thinner that gave disappointing results in a second big study.
The study was aimed at preventing repeat heart attacks and strokes in people who had already suffered one or were in danger of one because of hardened arteries in their legs.
The drug, vorapaxar, lowered the risk of those problems but also raised the risk of major bleeding, including dangerous bleeding in the head, which largely canceled out the drug's benefit.
Results of the study were discussed Saturday at an American College of Cardiology conference in Chicago and published by the New England Journal of Medicine.
Merck had hoped vorapaxar would become a new, first-of-its-kind blood thinner.
The company-sponsored study involved more than 26,000 patients in 32 countries. All were given usual heart medicines plus aspirin, and half also received daily vorapaxar pills.
Safety monitors stopped part of the study last year after seeing higher rates of bleeding in the head among people with a history of stroke who were on the experimental drug. The study continued in the rest of the participants.
After three years, about 9 percent of those given vorapaxar had suffered a heart attack or a stroke or had died from heart-related causes versus more than 10 percent of those not given the drug. Moderate or severe bleeding occurred in about 4 percent of those on vorapaxar versus just more than 2 percent of the others, said the study's leader, Dr. David Morrow of Brigham and Women's Hospital in Boston.
Among those with a history of heart attack - two-thirds of study participants - the drug had a net benefit, though, leaving the possibility that Merck might pursue seeking federal approval to sell it for these patients.
However, several experts not connected with the study said the drug's relatively modest benefit and likely high cost would make it a tough sell even if it were allowed on the market.
"This is not a drug that I would put in my personal medicine chest," said Dr. Eduardo Marban of Cedars-Sinai Medical Center in Los Angeles.
Merck officials said they would discuss the results with more scientists before deciding next steps.
Date: March 24, 2012
Source: Associated Press
The study was aimed at preventing repeat heart attacks and strokes in people who had already suffered one or were in danger of one because of hardened arteries in their legs.
The drug, vorapaxar, lowered the risk of those problems but also raised the risk of major bleeding, including dangerous bleeding in the head, which largely canceled out the drug's benefit.
Results of the study were discussed Saturday at an American College of Cardiology conference in Chicago and published by the New England Journal of Medicine.
Merck had hoped vorapaxar would become a new, first-of-its-kind blood thinner.
The company-sponsored study involved more than 26,000 patients in 32 countries. All were given usual heart medicines plus aspirin, and half also received daily vorapaxar pills.
Safety monitors stopped part of the study last year after seeing higher rates of bleeding in the head among people with a history of stroke who were on the experimental drug. The study continued in the rest of the participants.
After three years, about 9 percent of those given vorapaxar had suffered a heart attack or a stroke or had died from heart-related causes versus more than 10 percent of those not given the drug. Moderate or severe bleeding occurred in about 4 percent of those on vorapaxar versus just more than 2 percent of the others, said the study's leader, Dr. David Morrow of Brigham and Women's Hospital in Boston.
Among those with a history of heart attack - two-thirds of study participants - the drug had a net benefit, though, leaving the possibility that Merck might pursue seeking federal approval to sell it for these patients.
However, several experts not connected with the study said the drug's relatively modest benefit and likely high cost would make it a tough sell even if it were allowed on the market.
"This is not a drug that I would put in my personal medicine chest," said Dr. Eduardo Marban of Cedars-Sinai Medical Center in Los Angeles.
Merck officials said they would discuss the results with more scientists before deciding next steps.
Date: March 24, 2012
Source: Associated Press
viernes, 23 de marzo de 2012
SanBio Enrolls Patients in Stroke Trial
SanBio Inc. announced the successful enrollment of the first dose cohort of patients in its Phase 1/2a clinical trial testing the safety and efficacy of a novel allogeneic stem cell therapy product, SB623, in patients suffering from chronic deficits resulting from previous stroke injuries. The first 6 patients, of a total of 18, have been successfully administered SB623. The trial is being conducted at Stanford University and the University of Pittsburgh. No safety concerns have been reported.
SB623 is derived from adult bone marrow and has shown safety and efficacy in rodent models of chronic stroke. "This represents a major milestone in the human clinical testing of this important new approach for regenerative medicine", said Keita Mori, SanBio CEO. "We are pleased to learn that the initial dose level was well tolerated."
SB623 is being delivered to the damaged region of the brains of patients who have suffered an ischemic stroke. Product safety is the primary focus of the study but various measurements of efficacy are also being tested.
"The successful completion of the initial dose cohort is a major step in any first-in-human study", said Dr. Ernest Yankee, SanBio's Vice President of Development. "We are looking forward to initiating the next two dose cohorts and wrapping up the study. The safety findings thus far are very encouraging."
Date: March 20, 2012
SB623 is derived from adult bone marrow and has shown safety and efficacy in rodent models of chronic stroke. "This represents a major milestone in the human clinical testing of this important new approach for regenerative medicine", said Keita Mori, SanBio CEO. "We are pleased to learn that the initial dose level was well tolerated."
SB623 is being delivered to the damaged region of the brains of patients who have suffered an ischemic stroke. Product safety is the primary focus of the study but various measurements of efficacy are also being tested.
"The successful completion of the initial dose cohort is a major step in any first-in-human study", said Dr. Ernest Yankee, SanBio's Vice President of Development. "We are looking forward to initiating the next two dose cohorts and wrapping up the study. The safety findings thus far are very encouraging."
Date: March 20, 2012
Tribute's Cambia Approved for Migraine
Nautilus Neurosciences announced that their Canadian promotional partner, Tribute Pharmaceuticals, a wholly owned subsidiary of Stellar Pharmaceuticals, was granted a Notice of Compliance (NOC) approval from Health Canada for Cambia (diclofenac potassium for oral solution) in the treatment of acute migraine with or without aura in adults. Cambia is expected to be launched in Canada during the second half of 2012. Cambia has been available to patients in the United States since May 2010.
Nautilus Neurosciences has exclusive marketing rights for Cambia in the United States and Canada, which they obtained from APR, a Swiss drug delivery and drug development company. Patents have been granted that protect the product in the United States through 2026.
"We congratulate our partners at Tribute Pharmaceuticals on the Health Canada approval and look forward to continuing to work with them on the Canadian launch of Cambia. We are excited that Cambia will be available as a treatment option for physicians and patients in Canada," said William Maichle, the CEO of Nautilus Neurosciences.
Mr. Maichle added, "[I] expect Nautilus Neurosciences to experience record growth in 2012 as Cambia continues to fill an important unmet need for patients suffering from the debilitating effects of migraine."
Date: March 22, 2012
Nautilus Neurosciences has exclusive marketing rights for Cambia in the United States and Canada, which they obtained from APR, a Swiss drug delivery and drug development company. Patents have been granted that protect the product in the United States through 2026.
"We congratulate our partners at Tribute Pharmaceuticals on the Health Canada approval and look forward to continuing to work with them on the Canadian launch of Cambia. We are excited that Cambia will be available as a treatment option for physicians and patients in Canada," said William Maichle, the CEO of Nautilus Neurosciences.
Mr. Maichle added, "[I] expect Nautilus Neurosciences to experience record growth in 2012 as Cambia continues to fill an important unmet need for patients suffering from the debilitating effects of migraine."
Date: March 22, 2012
Ulcer Drug Clears Late-stage Hurdles
CHAPEL HILL, N.C. (AP) - Pozen Inc. said its experimental ulcer treatment worked in two late-stage clinical trials.
Pozen's drug candidate PA32540 combines omeprazole, the active ingredient in heartburn drugs like Prilosec, with aspirin. The omeprazole is released as soon as the drug is taken and the aspirin is released over time. Pozen said patients who took PA32540 in the clinical trials had fewer gastric ulcers than patients who took a placebo, and the drug also met secondary goals, like reducing gastroduodenal ulcers.
There were a total of 1,049 patients in the studies. All of them were taking aspirin to prevent heart problems, and they were at risk for aspirin-related ulcers. Patients took either PA32540 or placebo once per day for six months.
Pozen said it will file for marketing approval of PA32540 in the third quarter.
Pozen's drugs include the arthritis drug Vimovo. It helped develop the migraine treatment Treximet, although it sold most of its royalty rights to the drug in 2011.
Date: March 22, 2012
Source: Associated Press
Pozen's drug candidate PA32540 combines omeprazole, the active ingredient in heartburn drugs like Prilosec, with aspirin. The omeprazole is released as soon as the drug is taken and the aspirin is released over time. Pozen said patients who took PA32540 in the clinical trials had fewer gastric ulcers than patients who took a placebo, and the drug also met secondary goals, like reducing gastroduodenal ulcers.
There were a total of 1,049 patients in the studies. All of them were taking aspirin to prevent heart problems, and they were at risk for aspirin-related ulcers. Patients took either PA32540 or placebo once per day for six months.
Pozen said it will file for marketing approval of PA32540 in the third quarter.
Pozen's drugs include the arthritis drug Vimovo. It helped develop the migraine treatment Treximet, although it sold most of its royalty rights to the drug in 2011.
Date: March 22, 2012
Source: Associated Press
jueves, 22 de marzo de 2012
First Portion of TMX-101 Study Complete
Telormedix, a clinical stage biopharmaceutical company focused on TLR7 agonists in the treatment of cancer and inflammatory diseases, has successfully completed the safety portion of a Phase 1/2 trial for TMX-101.
This three-part trial is an open-label, multicenter, dose escalation study. In the first part of the study, which has now completed, safety was tested in patients with non-muscle-invasive bladder cancer (NMIBC) who had also undergone a complete transurethral resection (TUR). TMX-101 was administered once a week for a total of six instillations into the bladder of patients after TUR. The second part of the study will be an assessment of the effective biological dose in patients with one marker lesion remaining after TUR. The third part will follow patients for one year for safety and status of the disease. No serious adverse events were reported and all related adverse events were mild to moderate in severity, with immediate resolution, and were mainly limited to the genitourinary system. Based on the results, the Dose Escalation Committee has concluded that intravesical instillation of TMX-101 is safe at doses from 0.05% up to and including 0.4% and recommended the continuation of the trial.
Johanna Holldack, CEO of Telormedix, commented, “Since 1984, no new drugs have been approved for the treatment of non-muscle invasive bladder cancer (NMIBC) .There is a high unmet clinical need for better and innovative therapies and Telormedix hopes to introduce its TMX-101, a TLR7 agonist, as a treatment for bladder cancer. Our study results so far are encouraging and we are excited that we are now able to initiate the marker lesion part of the study in order to evaluate the biological activity.”
The second part of the study will be an assessment of the effective biological dose in patients with one marker lesion remaining after TUR. Specifically, this study will examine TMX-101’s safety on Marker Lesions (MTD) focused on a dose level of 100 mg in 50 mL (0.2%) and is scheduled to start in Q1/Q2 2012. The third and final part of the study will follow patients for one year for safety and status of the disease.
Date: March 19, 2012
This three-part trial is an open-label, multicenter, dose escalation study. In the first part of the study, which has now completed, safety was tested in patients with non-muscle-invasive bladder cancer (NMIBC) who had also undergone a complete transurethral resection (TUR). TMX-101 was administered once a week for a total of six instillations into the bladder of patients after TUR. The second part of the study will be an assessment of the effective biological dose in patients with one marker lesion remaining after TUR. The third part will follow patients for one year for safety and status of the disease. No serious adverse events were reported and all related adverse events were mild to moderate in severity, with immediate resolution, and were mainly limited to the genitourinary system. Based on the results, the Dose Escalation Committee has concluded that intravesical instillation of TMX-101 is safe at doses from 0.05% up to and including 0.4% and recommended the continuation of the trial.
Johanna Holldack, CEO of Telormedix, commented, “Since 1984, no new drugs have been approved for the treatment of non-muscle invasive bladder cancer (NMIBC) .There is a high unmet clinical need for better and innovative therapies and Telormedix hopes to introduce its TMX-101, a TLR7 agonist, as a treatment for bladder cancer. Our study results so far are encouraging and we are excited that we are now able to initiate the marker lesion part of the study in order to evaluate the biological activity.”
The second part of the study will be an assessment of the effective biological dose in patients with one marker lesion remaining after TUR. Specifically, this study will examine TMX-101’s safety on Marker Lesions (MTD) focused on a dose level of 100 mg in 50 mL (0.2%) and is scheduled to start in Q1/Q2 2012. The third and final part of the study will follow patients for one year for safety and status of the disease.
Date: March 19, 2012
miércoles, 21 de marzo de 2012
Curcumin Attacks Parkinson's Disease
Curcumin, a compound found in the spice turmeric, is proving effective at preventing clumping of a protein involved in Parkinson's disease, says a Michigan State University researcher.
A team of researchers led by Basir Ahmad, an MSU postdoctoral researcher, demonstrated earlier this year that slow-wriggling alpha-synuclein proteins are the cause of clumping, or aggregation, which is the first step of diseases such as Parkinson's. A new study led by Ahmad, which appears in the current issue of the Journal of Biological Chemistry, shows that curcumin can help prevent clumping.
"Our research shows that curcumin can rescue proteins from aggregation, the first steps of many debilitating diseases," said Lisa Lapidus, MSU associate professor of physics and astronomy who co-authored the paper with Ahmad. "More specifically, curcumin binds strongly to alpha-synuclein and prevents aggregation at body temperatures."
Lapidus' lab uses lasers to study protein folding. Proteins are chains of amino acids that do most of the work in cells. Scientists understand protein structure, but they don't know how they are built – a process known as folding. Lapidus' team is shedding light on the process by correlating the speed at which protein folds with its tendency to clump or bind with other proteins.
When curcumin attaches to alpha-synuclein it not only stops clumping, but it also raises the protein's folding or reconfiguration rate. By bumping up the speed, curcumin moves the protein out of a dangerous speed zone allowing it to avoid clumping with other proteins.
Finding a compound that can fix a protein when it first begins to misfold can lead scientists to identify drugs that can treat certain diseases. Doctors won't be prescribing curcumin pills any time soon, though, Lapidus said.
"Curcumin's usefulness as an actual drug may be pretty limited since it doesn't go into the brain easily where this misfolding is taking place," she said. "But this kind of study showcases the technique of measuring reconfiguration and opens the door for developing drug treatments."
A team of researchers led by Basir Ahmad, an MSU postdoctoral researcher, demonstrated earlier this year that slow-wriggling alpha-synuclein proteins are the cause of clumping, or aggregation, which is the first step of diseases such as Parkinson's. A new study led by Ahmad, which appears in the current issue of the Journal of Biological Chemistry, shows that curcumin can help prevent clumping.
"Our research shows that curcumin can rescue proteins from aggregation, the first steps of many debilitating diseases," said Lisa Lapidus, MSU associate professor of physics and astronomy who co-authored the paper with Ahmad. "More specifically, curcumin binds strongly to alpha-synuclein and prevents aggregation at body temperatures."
Lapidus' lab uses lasers to study protein folding. Proteins are chains of amino acids that do most of the work in cells. Scientists understand protein structure, but they don't know how they are built – a process known as folding. Lapidus' team is shedding light on the process by correlating the speed at which protein folds with its tendency to clump or bind with other proteins.
When curcumin attaches to alpha-synuclein it not only stops clumping, but it also raises the protein's folding or reconfiguration rate. By bumping up the speed, curcumin moves the protein out of a dangerous speed zone allowing it to avoid clumping with other proteins.
Finding a compound that can fix a protein when it first begins to misfold can lead scientists to identify drugs that can treat certain diseases. Doctors won't be prescribing curcumin pills any time soon, though, Lapidus said.
"Curcumin's usefulness as an actual drug may be pretty limited since it doesn't go into the brain easily where this misfolding is taking place," she said. "But this kind of study showcases the technique of measuring reconfiguration and opens the door for developing drug treatments."
FDA Panel Votes Against Ridaforolimus
A federal regulatory panel has rejected ridaforolimus as a treatment for sarcoma, a rare form of cancer.
An FDA panel of cancer experts voted 13-1 against the drug, which Merck & Co. Inc. acquired from Ariad Pharmaceuticals, saying its side effects outweighed its benefits. Side effects included lung irritation, kidney failure and high blood pressure.
Merck, of Whitehouse Station, N.J., submitted the drug as a maintenance therapy, meaning it would be used to help repress sarcoma of the bone and tissue in patients whose cancer is already in remission. Since such patients are healthier than patients with active disease, panelists said they wanted to see a more dramatic benefit to justify putting patients on a drug with major side effects. The Food and Drug Administration has only approved a handful of cancer drugs for maintenance use.
Company trials showed no survival benefit and a meager seven-week delay in disease progression compared with patients not taking the drug. Sarcoma is a rare class of tumors that form in the fat, muscles and bone in the limbs and abdomen.
The FDA is scheduled to decide on the drug by June. It is not required to follow the advice of its panelists, though it usually does.
If the drug is approved, Merck will pay Ariad $25 million and the two companies will collaborate on marketing.
Date: March 21, 2012
Source: Associated Press
An FDA panel of cancer experts voted 13-1 against the drug, which Merck & Co. Inc. acquired from Ariad Pharmaceuticals, saying its side effects outweighed its benefits. Side effects included lung irritation, kidney failure and high blood pressure.
Merck, of Whitehouse Station, N.J., submitted the drug as a maintenance therapy, meaning it would be used to help repress sarcoma of the bone and tissue in patients whose cancer is already in remission. Since such patients are healthier than patients with active disease, panelists said they wanted to see a more dramatic benefit to justify putting patients on a drug with major side effects. The Food and Drug Administration has only approved a handful of cancer drugs for maintenance use.
Company trials showed no survival benefit and a meager seven-week delay in disease progression compared with patients not taking the drug. Sarcoma is a rare class of tumors that form in the fat, muscles and bone in the limbs and abdomen.
The FDA is scheduled to decide on the drug by June. It is not required to follow the advice of its panelists, though it usually does.
If the drug is approved, Merck will pay Ariad $25 million and the two companies will collaborate on marketing.
Date: March 21, 2012
Source: Associated Press
martes, 20 de marzo de 2012
Messenger RNA–Based Vaccines for Cancer
Ingmar Hoerr, PhD, MBA, Chief Executive Officer and Cofounder; CureVac GmbH, Tübingen, Germany
In molecular medicine, nucleic acids are being extensively investigated for use in gene therapy and in genetic vaccinations in which foreign nucleic acid is translated into proteins by the host cells. Vaccines based on DNA and messenger RNA (mRNA) are able to stimulate all effectors of the adaptive immune response: B lymphocytes, cytotoxic T cells, and T helper cells. This makes them a useful tool in the creation of prophylactic vaccines for infectious diseases and for cancer immunotherapy.
Messenger RNAs are non-toxic molecules that address the shortcomings of recombinant virus or DNA-based vaccination therapies. The physiological role of mRNA is to transfer genetic information from the nucleus to the cytoplasm where this information is translated into the corresponding protein. The safety of mRNA-based treatments supports the use of mRNA-vaccination for therapeutic or prophylactic approaches. RNA vaccines don’t contain the virus-derived promoter elements that DNA vaccines do. Also, as the result of homologous recombination or a random event, DNA is able to integrate into the host genome. This can lead to inactivation or activation of genes, may affect regulatory elements, possibly induce oncogenesis, or induce pathogenic anti-DNA antibodies. Despite this, gene therapy approaches involving nucleic acids have focused mostly on DNA-based strategies due to the instability and rapid degradation of RNA in the human body; RNA is prone to hydrolysis by ubiquitous ribonucleases.1
Nevertheless, it has been shown in studies that local administration of naked mRNA leads to significant protein expression, and mRNA vaccination leads to the expression of the corresponding tumor-derived antigens and the subsequent induction of antigen-specific antitumor responses in mice.2 Although the use of naked RNA for vaccination in a clinical setting is not feasible, the development of protamine-protected RNA—which is more stable than naked RNA and easier to handle—has helped overcome these hurdles.2 Protamine is a small arginine-rich nuclear protein known to stabilize DNA during spermatogenesis. Notably, naked mRNA molecules barely induced maturation of antigen-presenting cells when added to mouse dendritic cells in vitro, but mRNA stabilized by association to a cationic component (like protamine) can mature dendritic cells.3 The complexation of mRNA—also required for strong immune-stimulating activity—may inhibit its translatability. Using a two-component mRNA vaccine that contains free and protamine-complexed mRNA, however, induces balanced adaptive immune responses and provides humoral and T cell-mediated immunity. Importantly, this two-component mRNA-based tumor vaccine supports both antigen expression and immune stimulation, mediated by Toll-like receptor 7 (TLR7).4
CureVac’s mRNA-technology platform, RNActive, modifies and stabilizes mRNA without changing the physiological properties, thus generating mRNA suitable for medical purposes. The technology is currently in clinical trials for castration-resistant prostate cancer. CV9103, a prostate cancer vaccine, contains four antigens as self-adjuvanted full-length mRNAs: prostate-specific antigen (PSA), prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), and six transmembrane epithelial antigene of the prostate 1 (STEAP1). Data from a Phase 2a study showed that antigen-specific T-cells were detected in 79% of patients independent of their HLA-background. Additionally, 58% of the immunological responders reacted against multiple antigens. The frequency of antigen-unspecific B-cells was increased in 74% patients.5
References
1. Pascolo S. Messenger RNA-based vaccines. Expert Opin Biol Ther. 2004.
2. Hoerr I, et al. In vivo application of RNA leads to induction of specific cytotoxic T lymphocytes and antibodies. Eur J Immunol. 2000.
3. Scheel B, et al: Immunostimulating capacities of stabilized RNA. Molecules. Eur J Immunol. 2004.
4. Fotin-Mleczek M, et al: Messenger RNA-based vaccines with dual activity induce balanced TLR-7 dependent adaptive immune responses and provide antitumor activity. J Immunother. 2011.
5. Kübler H, et al: Final analysis of a phase I/IIa study with CV9103, an intradermally administered prostate cancer. ASCO 2011.
In molecular medicine, nucleic acids are being extensively investigated for use in gene therapy and in genetic vaccinations in which foreign nucleic acid is translated into proteins by the host cells. Vaccines based on DNA and messenger RNA (mRNA) are able to stimulate all effectors of the adaptive immune response: B lymphocytes, cytotoxic T cells, and T helper cells. This makes them a useful tool in the creation of prophylactic vaccines for infectious diseases and for cancer immunotherapy.
Messenger RNAs are non-toxic molecules that address the shortcomings of recombinant virus or DNA-based vaccination therapies. The physiological role of mRNA is to transfer genetic information from the nucleus to the cytoplasm where this information is translated into the corresponding protein. The safety of mRNA-based treatments supports the use of mRNA-vaccination for therapeutic or prophylactic approaches. RNA vaccines don’t contain the virus-derived promoter elements that DNA vaccines do. Also, as the result of homologous recombination or a random event, DNA is able to integrate into the host genome. This can lead to inactivation or activation of genes, may affect regulatory elements, possibly induce oncogenesis, or induce pathogenic anti-DNA antibodies. Despite this, gene therapy approaches involving nucleic acids have focused mostly on DNA-based strategies due to the instability and rapid degradation of RNA in the human body; RNA is prone to hydrolysis by ubiquitous ribonucleases.1
|
Nevertheless, it has been shown in studies that local administration of naked mRNA leads to significant protein expression, and mRNA vaccination leads to the expression of the corresponding tumor-derived antigens and the subsequent induction of antigen-specific antitumor responses in mice.2 Although the use of naked RNA for vaccination in a clinical setting is not feasible, the development of protamine-protected RNA—which is more stable than naked RNA and easier to handle—has helped overcome these hurdles.2 Protamine is a small arginine-rich nuclear protein known to stabilize DNA during spermatogenesis. Notably, naked mRNA molecules barely induced maturation of antigen-presenting cells when added to mouse dendritic cells in vitro, but mRNA stabilized by association to a cationic component (like protamine) can mature dendritic cells.3 The complexation of mRNA—also required for strong immune-stimulating activity—may inhibit its translatability. Using a two-component mRNA vaccine that contains free and protamine-complexed mRNA, however, induces balanced adaptive immune responses and provides humoral and T cell-mediated immunity. Importantly, this two-component mRNA-based tumor vaccine supports both antigen expression and immune stimulation, mediated by Toll-like receptor 7 (TLR7).4
CureVac’s mRNA-technology platform, RNActive, modifies and stabilizes mRNA without changing the physiological properties, thus generating mRNA suitable for medical purposes. The technology is currently in clinical trials for castration-resistant prostate cancer. CV9103, a prostate cancer vaccine, contains four antigens as self-adjuvanted full-length mRNAs: prostate-specific antigen (PSA), prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), and six transmembrane epithelial antigene of the prostate 1 (STEAP1). Data from a Phase 2a study showed that antigen-specific T-cells were detected in 79% of patients independent of their HLA-background. Additionally, 58% of the immunological responders reacted against multiple antigens. The frequency of antigen-unspecific B-cells was increased in 74% patients.5
References
1. Pascolo S. Messenger RNA-based vaccines. Expert Opin Biol Ther. 2004.
2. Hoerr I, et al. In vivo application of RNA leads to induction of specific cytotoxic T lymphocytes and antibodies. Eur J Immunol. 2000.
3. Scheel B, et al: Immunostimulating capacities of stabilized RNA. Molecules. Eur J Immunol. 2004.
4. Fotin-Mleczek M, et al: Messenger RNA-based vaccines with dual activity induce balanced TLR-7 dependent adaptive immune responses and provide antitumor activity. J Immunother. 2011.
5. Kübler H, et al: Final analysis of a phase I/IIa study with CV9103, an intradermally administered prostate cancer. ASCO 2011.
Transporting Drug Safety Forward
Catherine Shaffer, Contributing Editor
The role of membrane transporters in drug-drug interactions is emerging as an increasingly important part of the overall picture of drug safety and drug metabolism. Drug metabolizing enzymes are well-characterized; previously, the U.S. Food and Drug Administration (FDA) offered detailed guidance on the design of preclinical and clinical studies to evaluate the interactions of drugs with those enzymes.
In contrast, only recently has information and guidance emerged concerning the study of transporter mediated drug-drug interactions. More than 400 membrane transporters have been identified. Those of most interest in drug development are found in the intestines, liver, kidney, and the blood-brain barrier. Transporter effects of a drug can affect the uptake or clearance of another drug. These effects are largely discovered during clinical testing.
In late February 2012, the FDA issued long-awaited draft guidance which included recommendations for in vitro and in vivo studies for drug transport, drug metabolism, and drug-drug or drug-therapeutic protein interactions. (See the sidebar in Policies & Projection for details.)
A major initiative, spearheaded by the International Transporter Consortium, seeks to provide guidance around tools and methods for characterizing transporter mediated drug interactions in vitro, at the preclinical stage, in order to better design clinical studies and identify potential safety issues at an earlier stage.
Drugs can affect transporters in many ways
There are several potential types of transporter mediated interactions that could be of concern. A compound may inhibit a transporter involved in an endogenous process. Serum chemistry markers provide an in vivo signal for this type of complication. Clinical manifestations resulting from such an interaction—hyperbilirubinemia, for example—can be an obstacle to further development.
Alternate routes of elimination or disposition of the drug can mitigate the risk of a drug interaction. For life-saving drugs, the choice may be made to tolerate a moderate drug interaction in order to achieve the desired outcome. Things can become complicated very quickly when two or more drugs interact with similar transport mechanisms.
Drugs can also be substrates or potentiators of transporters, with effects resulting from increases in transport.
“When compounds are potential perpetrators of drug interactions, an understanding of co-medications becomes even more important so that therapeutic concentrations of a novel agent will not result in subsequent elevations of co-meds that may have narrow therapeutic indices. In the case of chronic dosing, little is understood about the long-term inhibition of transporters,” says Keith Hoffmaster, PhD, a scientist for Novartis Institutes for BioMedical Research (Cambridge, Mass.).Patients with diseases that are managed by polypharmacy are at greater risk of transporter-mediated drug interactions.
Some of the most common of those are cancer, diabetes, cardiovascular disease, and infectious disease. For example, lipid-lowering therapies like statins can interact with other drugs. The immunosuppressant drug cyclosporine increases systemic exposure to all statin drugs. Rosuvastatin is a substrate for the human liver transporter, organic anion transporting polypeptide (OATP-1B1). In one study, rosuvastatin exposure was significantly increased in heart transplant recipients on an antirejection regimen that included cyclosporine. (Clin Pharmacol Ther. 2004; 76(2): 167-77)
Through a better understanding of drug-transporter interactions, it may also be possible to harness interactions such as cyclosporine/rosuvastatin to enhance therapeutic outcomes.
in vitro methods mimic in vivo processes
Currently available in vitro methods for studying transporters include ATPase assays, membrane vesicle assays, and cell-based assays such as transfected cell lines or primary hepatocyte suspensions or cultures.
According to Stephen Ferguson, PhD, a senior staff scientist in ADME/Tox at Life Technologies Inc., tools for studying transporters can be classified into two major categories: specific transporter assays and “clearance” assays, where the net effect of multiple transport processes on drug clearance can be modeled in a physiologically relevant system.
In order to adequately characterize transporter mediated interactions, it is necessary to have tools that include “integrated” whole systems, as well as tools that isolate the behavior of individual transporters.
According to Ferguson, the set of tools needed is similar to those used to study metabolic effects of cytochrome P450s. However, he says, “Unlike P450s, we’re well behind where we need to be to assess in vivo potential of these processes.”
Stephen Wright, PhD, a professor in the Department of Physiology at the University of Arizona, studies transporter interactions of the kidney. His group is interested in the mechanism of renal secretion of organic electrolytes. A large proportion of pharmacological compounds are anionic or cationic in nature, and thus fall into the category of electrolytes. The kidney protects the body from toxins by excreting xenobiotic compound, and its tissues are rich in transporters tailored for that function.
Wright’s lab uses cultured renal cells to stably transfect cloned human transport proteins, and uses radiolabeled substrates or substrates with fluorescent properties. At the tissue level, they work with isolated, intact renal proximal tubules to study electrolyte secretion in the native epithelium.
“We’re teaming up with computational chemists who use powerful analytical computational tools to compare biological activity to the intrinsic structural chemical properties of those compounds,” Wright says.
Wright has used these methods to study multidrug resistance-associated protein 2 (MRP2) in the epithelium of the eye, concluding that calcein, dichlorofluorescein, and doxorubicin accumulated inside the cells in greater quantities in the presence of an MRP2 inhibitor. (J Pharmacol Exp Ther. 329: 479-85.)
Wright has also published studies relating to organic anion transporter 3 (OAT3), organic cation transporter 2 (OCT2) and multidrug and toxin extruder 1 (MATE1).
Kim Brouwer, PharmD, PhD, a professor at the University of North Carolina’s Eschelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, was an innovator of the sandwich-cultured hepatocyte. Suspended primary hepatocytes lose their polarity upon isolation, making it difficult to assess efflux. Culturing hepatocytes in a sandwich configuration between two layers of collagen restores that polarity. Compared to suspended hepatocytes, sandwich-cultured hepatocytes more closely model in vivo biliary clearance. Brouwer’s sandwich-cultured hepatocyte system is called B-Clear, and she co-founded the company Qualyst Inc., a UNC spin-off company, around the technology.
In her UNC laboratory, Brouwer studies hepatotoxicity, specifically the role of bile acid transport proteins.
Bile acids are important in the maintenance of hepatocyte function. Polymorphisms in bile acid transport proteins that decrease transport of those acids can cause serious liver injury. Brouwer recently published results elucidating the mechanisms determining differences in systemic exposure of two very similar active drug metabolites.
Brouwer says that hepatocytes are in short supply because they are obtained from donors. “We’re looking at further development of the sandwich-cultured hepatocyte model, including stem cell-derived hepatocytes,” Brouwer says.
Working together for drug clearance
BD Biosciences, a segment of BD (Franklin Lakes, N.J.) provides tools for studying the two major drug transporter protein families typically involved in drug-interactions: ABC transporters for drug efflux and the SLC transporter family, which are important for drug uptake.
“An area of great interest is the interplay between drug transport and metabolism, and how transporters contribute to the overall clearance of a drug. The uptake and efflux transporters on the sinusoidal (blood) and biliary membranes of the liver can regulate the concentration of the drug in the liver cells, which can ultimately affect the rate of drug clearance from the blood,” says Chris Patten, PhD, a scientist with BD Biosciences, Discovery Labware.
Technology advances in fields such as engineering and analytical chemistry, will also help improve knowledge of transporter mediated drug interactions. “We’re seeing advances in the imaging area,” Brouwer says. Those advances may improve understanding of intracellular drug exposure. Up until about 10 years ago, it was frequently assumed that drugs diffused passively in and out of the blood stream. It is now known that membrane transporters may facilitate those movements. This means plasma levels of drug may not be reflective of every tissue in the body.
These advances, as well as the FDA draft guidance, indicate that transporters are now getting the attention they deserve.
About the Author
Catherine Shaffer is a freelance science writer specializing in biotechnology and related disciplines with a background in laboratory research in the pharmaceutical industry.
The role of membrane transporters in drug-drug interactions is emerging as an increasingly important part of the overall picture of drug safety and drug metabolism. Drug metabolizing enzymes are well-characterized; previously, the U.S. Food and Drug Administration (FDA) offered detailed guidance on the design of preclinical and clinical studies to evaluate the interactions of drugs with those enzymes.
In contrast, only recently has information and guidance emerged concerning the study of transporter mediated drug-drug interactions. More than 400 membrane transporters have been identified. Those of most interest in drug development are found in the intestines, liver, kidney, and the blood-brain barrier. Transporter effects of a drug can affect the uptake or clearance of another drug. These effects are largely discovered during clinical testing.
In late February 2012, the FDA issued long-awaited draft guidance which included recommendations for in vitro and in vivo studies for drug transport, drug metabolism, and drug-drug or drug-therapeutic protein interactions. (See the sidebar in Policies & Projection for details.)
A major initiative, spearheaded by the International Transporter Consortium, seeks to provide guidance around tools and methods for characterizing transporter mediated drug interactions in vitro, at the preclinical stage, in order to better design clinical studies and identify potential safety issues at an earlier stage.
Drugs can affect transporters in many ways
There are several potential types of transporter mediated interactions that could be of concern. A compound may inhibit a transporter involved in an endogenous process. Serum chemistry markers provide an in vivo signal for this type of complication. Clinical manifestations resulting from such an interaction—hyperbilirubinemia, for example—can be an obstacle to further development.
Alternate routes of elimination or disposition of the drug can mitigate the risk of a drug interaction. For life-saving drugs, the choice may be made to tolerate a moderate drug interaction in order to achieve the desired outcome. Things can become complicated very quickly when two or more drugs interact with similar transport mechanisms.
Drugs can also be substrates or potentiators of transporters, with effects resulting from increases in transport.
“When compounds are potential perpetrators of drug interactions, an understanding of co-medications becomes even more important so that therapeutic concentrations of a novel agent will not result in subsequent elevations of co-meds that may have narrow therapeutic indices. In the case of chronic dosing, little is understood about the long-term inhibition of transporters,” says Keith Hoffmaster, PhD, a scientist for Novartis Institutes for BioMedical Research (Cambridge, Mass.).Patients with diseases that are managed by polypharmacy are at greater risk of transporter-mediated drug interactions.
Some of the most common of those are cancer, diabetes, cardiovascular disease, and infectious disease. For example, lipid-lowering therapies like statins can interact with other drugs. The immunosuppressant drug cyclosporine increases systemic exposure to all statin drugs. Rosuvastatin is a substrate for the human liver transporter, organic anion transporting polypeptide (OATP-1B1). In one study, rosuvastatin exposure was significantly increased in heart transplant recipients on an antirejection regimen that included cyclosporine. (Clin Pharmacol Ther. 2004; 76(2): 167-77)
Through a better understanding of drug-transporter interactions, it may also be possible to harness interactions such as cyclosporine/rosuvastatin to enhance therapeutic outcomes.
in vitro methods mimic in vivo processes
Currently available in vitro methods for studying transporters include ATPase assays, membrane vesicle assays, and cell-based assays such as transfected cell lines or primary hepatocyte suspensions or cultures.
According to Stephen Ferguson, PhD, a senior staff scientist in ADME/Tox at Life Technologies Inc., tools for studying transporters can be classified into two major categories: specific transporter assays and “clearance” assays, where the net effect of multiple transport processes on drug clearance can be modeled in a physiologically relevant system.
In order to adequately characterize transporter mediated interactions, it is necessary to have tools that include “integrated” whole systems, as well as tools that isolate the behavior of individual transporters.
According to Ferguson, the set of tools needed is similar to those used to study metabolic effects of cytochrome P450s. However, he says, “Unlike P450s, we’re well behind where we need to be to assess in vivo potential of these processes.”
Stephen Wright, PhD, a professor in the Department of Physiology at the University of Arizona, studies transporter interactions of the kidney. His group is interested in the mechanism of renal secretion of organic electrolytes. A large proportion of pharmacological compounds are anionic or cationic in nature, and thus fall into the category of electrolytes. The kidney protects the body from toxins by excreting xenobiotic compound, and its tissues are rich in transporters tailored for that function.
Wright’s lab uses cultured renal cells to stably transfect cloned human transport proteins, and uses radiolabeled substrates or substrates with fluorescent properties. At the tissue level, they work with isolated, intact renal proximal tubules to study electrolyte secretion in the native epithelium.
“We’re teaming up with computational chemists who use powerful analytical computational tools to compare biological activity to the intrinsic structural chemical properties of those compounds,” Wright says.
Wright has used these methods to study multidrug resistance-associated protein 2 (MRP2) in the epithelium of the eye, concluding that calcein, dichlorofluorescein, and doxorubicin accumulated inside the cells in greater quantities in the presence of an MRP2 inhibitor. (J Pharmacol Exp Ther. 329: 479-85.)
Wright has also published studies relating to organic anion transporter 3 (OAT3), organic cation transporter 2 (OCT2) and multidrug and toxin extruder 1 (MATE1).
Kim Brouwer, PharmD, PhD, a professor at the University of North Carolina’s Eschelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, was an innovator of the sandwich-cultured hepatocyte. Suspended primary hepatocytes lose their polarity upon isolation, making it difficult to assess efflux. Culturing hepatocytes in a sandwich configuration between two layers of collagen restores that polarity. Compared to suspended hepatocytes, sandwich-cultured hepatocytes more closely model in vivo biliary clearance. Brouwer’s sandwich-cultured hepatocyte system is called B-Clear, and she co-founded the company Qualyst Inc., a UNC spin-off company, around the technology.
In her UNC laboratory, Brouwer studies hepatotoxicity, specifically the role of bile acid transport proteins.
Bile acids are important in the maintenance of hepatocyte function. Polymorphisms in bile acid transport proteins that decrease transport of those acids can cause serious liver injury. Brouwer recently published results elucidating the mechanisms determining differences in systemic exposure of two very similar active drug metabolites.
Brouwer says that hepatocytes are in short supply because they are obtained from donors. “We’re looking at further development of the sandwich-cultured hepatocyte model, including stem cell-derived hepatocytes,” Brouwer says.
Working together for drug clearance
BD Biosciences, a segment of BD (Franklin Lakes, N.J.) provides tools for studying the two major drug transporter protein families typically involved in drug-interactions: ABC transporters for drug efflux and the SLC transporter family, which are important for drug uptake.
“An area of great interest is the interplay between drug transport and metabolism, and how transporters contribute to the overall clearance of a drug. The uptake and efflux transporters on the sinusoidal (blood) and biliary membranes of the liver can regulate the concentration of the drug in the liver cells, which can ultimately affect the rate of drug clearance from the blood,” says Chris Patten, PhD, a scientist with BD Biosciences, Discovery Labware.
Technology advances in fields such as engineering and analytical chemistry, will also help improve knowledge of transporter mediated drug interactions. “We’re seeing advances in the imaging area,” Brouwer says. Those advances may improve understanding of intracellular drug exposure. Up until about 10 years ago, it was frequently assumed that drugs diffused passively in and out of the blood stream. It is now known that membrane transporters may facilitate those movements. This means plasma levels of drug may not be reflective of every tissue in the body.
These advances, as well as the FDA draft guidance, indicate that transporters are now getting the attention they deserve.
About the Author
Catherine Shaffer is a freelance science writer specializing in biotechnology and related disciplines with a background in laboratory research in the pharmaceutical industry.
Armed with Peptides, Drug Developers Aim for Tumors
Alan Dove, PhD, Contributing Editor
Cancer drug development is a classic good news, bad news story. The good news is that scientists have developed hundreds of compounds that can kill tumor cells very efficiently. The bad news is that most of those compounds are almost as good at killing healthy cells. As a result, modern oncology is a tricky balancing act, striving to kill the tumor without killing the patient. It often fails.
To address that problem, researchers have tried a variety of strategies to deliver drugs specifically to tumors. Antibodies are a popular choice, but they can be hard to manufacture and deliver. In recent years, investigators have turned their attention to small peptides, some of which are capable of binding tumor cells with exquisite specificity. As scientists continue to study these tumor-targeting peptides, contract research organizations (CROs) and other service companies are increasingly catering to this emerging niche.
Cutting out the carbs
One of the great advantages of peptides is that they are easy to synthesize. Unfortunately, many of the structures that are specific to tumor cells are carbohydrates, not peptides. “We can just order DNA or oligonucleotides or peptides ... but carbohydrates we always have to make the manual way, and it’s very expensive and time-consuming,” explains Michiko Fukuda, PhD, a professor in the tumor microenvironment lab at the University of California, Sanford-Burnham Medical Research Institute in Santa Barbara, Calif.
Rather than try to synthesize tumor-targeting carbohydrates, Fukuda and her colleagues decided to use phage display to find peptides that could mimic certain carbohydrate binding properties. In one recent study, they focused on selectin, which normally binds carbohydrates during tumor cell metastasis. Screening a phage display library of small peptides with a selectin probe identified a peptide that binds selectin. When the researchers injected labeled versions of this peptide into mice with tumors, the peptides homed specifically to the tumors and inhibited metastasis.
Though the team had originally aimed for selectin, they missed slightly; in mice, the new peptide turns out to bind a protein called annexin A1 rather than selectin. But work in other labs demonstrated that annexin A1 is a specific marker for the surfaces of tumor vasculature. Other cells in the body express the protein, but don’t export it to the surface, so an annexin A1-binding peptide injected into the bloodstream should only see its target inside tumors. That explained the specificity Fukuda and her colleagues had seen.
Annexin A1’s expression pattern also suggested a drug-targeting strategy. The “peptide was conjugated with [an] anticancer drug and injected into tumor-bearing mice, and it worked very well without any side-effects, because the targeting is so specific,” says Fukuda. She and her colleagues published those results in December 2011.1
That paper was one of a spate of recent findings that are starting to soften longstanding skepticism about tumor-targeting peptides. “When I started [these] studies people were saying that a peptide is not good for targeting, or even [that] targeting is not a primary interest in pharmaceutical companies,” says Fukuda. She adds that “I think now people think that peptides [are] a really good method.”
Finding the right hook-up
As interest in tumor-targeting peptides has increased, so has the number of potentially useful peptides. Indeed, researchers working in drug development—as well as basic cell biology—can now choose from a whole family of cell-penetrating peptides (CPPs) with different specificities. “The field is growing, and we see more and more requests,” says Miguel Castro, PhD, CEO of Bio-Synthesis in Lewisville, Tex., a company that synthesizes cell-penetrating peptides for researchers in numerous industry and academic labs. Castro adds that “it’s very clear that the activity does work, and [it’s] a very good and strong tool to use.”
CPPs aren’t just a laboratory curiosity anymore, either. Companies such as CDG Therapeutics in Chicago, Ill. have been taking CPP-coupled drugs into clinical trials against different types of tumors, and the initial results look promising. “Big pharmaceuticals, they are looking at this very carefully. They have a keen interest in applying it,” says Castro.
Though the early news is good, drug developers still face many hurdles in trying to turn CPPs into cures. Besides finding small peptides that bind and enter tumor cells, researchers must also figure out how to exploit that activity to treat the tumor, as the peptides themselves are generally not toxic. The most popular approach is to link the peptide to a small molecule or biologic drug that actually does the dirty work, but not just any linkage will do.
As Castro explains, therapeutic proteins generally have multiple potential linking sites on their surfaces, so investigators have to decide how many sites they want to connect CPPs to: “When you conjugate them, depending on what you want to do you may want to conjugate as much as you can, or you may want to find an ideal number where you don’t hinder the activity of the enzyme or the protein.”
For that reason, researchers who send their peptide synthesis work out may want to search for a contractor with specific experience in tumor-targeting peptides. “Whereas the peptide itself can be done by anybody ... having a little more experience in [cancer targeting] may be more helpful to the researcher,” says Castro.
The master key
At least one family of peptides, though, could allow drug developers to send compounds into tumors without having to link them to anything. That was what Erkki Ruoslahti, PhD, one of Fukuda’s colleagues at the Sanford-Burnham Institute, discovered two years ago. While screening phage libraries for peptides that would bind tumor vasculature, Ruoslahti’s team discovered a peptide called iRGD that activates a general transport mechanism in blood vessels.2
“iRGD and other peptides like it, they activate a bulk transport pathway that takes in anything that is around and transports it out of the blood vessels and through tissue,” says Ruoslahti. When the researchers delivered iRGD and various anti-cancer drugs simultaneously to mice with tumors, the drugs migrated very efficiently into the tumors and killed them.
While evidence in the mouse system suggests that iRGD homes specifically to tumor tissue, Ruoslahti cautions that there could be cryptic receptors for the peptide in other tissues, which could lead to off-target effects. However, that possibility also suggests that modified iRGD-like peptides could be developed to increase the drug permeability of other types of tissues. So far, the researchers have found a peptide that targets atherosclerotic plaques, and they are studying other motifs as well. “While we haven’t rigorously proven it, we think that those peptides work the same way in different targets that iRGD works in tumors,” says Ruoslahti.
Since the initial mouse experiments, the iRGD work has been picked up by CendR Therapeutics in Del Mar, Calif., a spinoff company that is now preparing to take iRGD-based therapies into clinical trials.
The iRGD results are also part of what Ruoslahti sees as a growing trend in tumor targeting, in which researchers are increasingly aiming for tumor vasculature instead of trying to develop peptides that bind directly to tumor cells. “[Tumor cells] really aren’t available to probes as well as is the vasculature, so I think a main improvement in the past ten years or so has been the realization that it’s much better to target the tumor vasculature at least initially,” says Ruoslahti.
A big box of tissues
Whether linking compounds to peptides or using the peptides as an adjuvant, companies developing the new therapies will likely need the services of a good CRO. While numerous companies provide contract drug development services for the industry, those specializing in oncology have often carved out special niches for themselves. Crown Bioscience in Santa Clara, Calif., for example, owns a unique repository of tumor grafts derived from actual patient biopsies. In the company’s graft system, “you have the actual tumor environment, intact, of a human patient,” explains Laura Sailor, senior vice president of business development at Crown.
Crucially, the tumors have been isolated from patients in Asian countries where cancer chemotherapy is not widely available yet. That means the tumors are susceptible to a whole range of compounds, just as newly diagnosed tumors will be in the clinic. “It’s naive, so you can push it to metastasis, you can push it to resistance,” says Sailor.
The system should also provide good predictions for clinical trials in Asia, where many companies are now focusing major efforts. “The clinical trials are a little bit easier over there, and the market’s way, way bigger,” says Sailor.
Crown is not the only CRO pursuing the peptide-targeting business, of course. Companies such as Pharmatech in Denver, Colo. have also been working on peptide-based projects, while JPT Peptide Solutions in Berlin, Germany offers a range of services that extends from peptide synthesis to contract research.
While interest in tumor-targeting peptides hasn’t seen the type of sudden boom that has characterized many other biotechnologies, researchers and service providers continue to see promising results from the field. For drug developers, that can only be good news.
About the Author
Originally trained as a virologist, Alan Dove is now a science journalist whose work appears regularly in a variety of trade and scientific journals and online publications. He also co-hosts the popular podcast “This Week in Virology.”
References
1. Hatakeyama S, et al. Targeted drug delivery to tumor vasculature by a carbohydrate mimetic peptide. Proc Natl Acad Sci USA. 2011;108(49):19587-92.
2. Sugahara KN, et al. Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. Science. 2010; 328(5981):1031-5.
Cancer drug development is a classic good news, bad news story. The good news is that scientists have developed hundreds of compounds that can kill tumor cells very efficiently. The bad news is that most of those compounds are almost as good at killing healthy cells. As a result, modern oncology is a tricky balancing act, striving to kill the tumor without killing the patient. It often fails.
To address that problem, researchers have tried a variety of strategies to deliver drugs specifically to tumors. Antibodies are a popular choice, but they can be hard to manufacture and deliver. In recent years, investigators have turned their attention to small peptides, some of which are capable of binding tumor cells with exquisite specificity. As scientists continue to study these tumor-targeting peptides, contract research organizations (CROs) and other service companies are increasingly catering to this emerging niche.
Cutting out the carbs
One of the great advantages of peptides is that they are easy to synthesize. Unfortunately, many of the structures that are specific to tumor cells are carbohydrates, not peptides. “We can just order DNA or oligonucleotides or peptides ... but carbohydrates we always have to make the manual way, and it’s very expensive and time-consuming,” explains Michiko Fukuda, PhD, a professor in the tumor microenvironment lab at the University of California, Sanford-Burnham Medical Research Institute in Santa Barbara, Calif.
Rather than try to synthesize tumor-targeting carbohydrates, Fukuda and her colleagues decided to use phage display to find peptides that could mimic certain carbohydrate binding properties. In one recent study, they focused on selectin, which normally binds carbohydrates during tumor cell metastasis. Screening a phage display library of small peptides with a selectin probe identified a peptide that binds selectin. When the researchers injected labeled versions of this peptide into mice with tumors, the peptides homed specifically to the tumors and inhibited metastasis.
Though the team had originally aimed for selectin, they missed slightly; in mice, the new peptide turns out to bind a protein called annexin A1 rather than selectin. But work in other labs demonstrated that annexin A1 is a specific marker for the surfaces of tumor vasculature. Other cells in the body express the protein, but don’t export it to the surface, so an annexin A1-binding peptide injected into the bloodstream should only see its target inside tumors. That explained the specificity Fukuda and her colleagues had seen.
Annexin A1’s expression pattern also suggested a drug-targeting strategy. The “peptide was conjugated with [an] anticancer drug and injected into tumor-bearing mice, and it worked very well without any side-effects, because the targeting is so specific,” says Fukuda. She and her colleagues published those results in December 2011.1
That paper was one of a spate of recent findings that are starting to soften longstanding skepticism about tumor-targeting peptides. “When I started [these] studies people were saying that a peptide is not good for targeting, or even [that] targeting is not a primary interest in pharmaceutical companies,” says Fukuda. She adds that “I think now people think that peptides [are] a really good method.”
Finding the right hook-up
As interest in tumor-targeting peptides has increased, so has the number of potentially useful peptides. Indeed, researchers working in drug development—as well as basic cell biology—can now choose from a whole family of cell-penetrating peptides (CPPs) with different specificities. “The field is growing, and we see more and more requests,” says Miguel Castro, PhD, CEO of Bio-Synthesis in Lewisville, Tex., a company that synthesizes cell-penetrating peptides for researchers in numerous industry and academic labs. Castro adds that “it’s very clear that the activity does work, and [it’s] a very good and strong tool to use.”
|
CPPs aren’t just a laboratory curiosity anymore, either. Companies such as CDG Therapeutics in Chicago, Ill. have been taking CPP-coupled drugs into clinical trials against different types of tumors, and the initial results look promising. “Big pharmaceuticals, they are looking at this very carefully. They have a keen interest in applying it,” says Castro.
Though the early news is good, drug developers still face many hurdles in trying to turn CPPs into cures. Besides finding small peptides that bind and enter tumor cells, researchers must also figure out how to exploit that activity to treat the tumor, as the peptides themselves are generally not toxic. The most popular approach is to link the peptide to a small molecule or biologic drug that actually does the dirty work, but not just any linkage will do.
As Castro explains, therapeutic proteins generally have multiple potential linking sites on their surfaces, so investigators have to decide how many sites they want to connect CPPs to: “When you conjugate them, depending on what you want to do you may want to conjugate as much as you can, or you may want to find an ideal number where you don’t hinder the activity of the enzyme or the protein.”
For that reason, researchers who send their peptide synthesis work out may want to search for a contractor with specific experience in tumor-targeting peptides. “Whereas the peptide itself can be done by anybody ... having a little more experience in [cancer targeting] may be more helpful to the researcher,” says Castro.
The master key
At least one family of peptides, though, could allow drug developers to send compounds into tumors without having to link them to anything. That was what Erkki Ruoslahti, PhD, one of Fukuda’s colleagues at the Sanford-Burnham Institute, discovered two years ago. While screening phage libraries for peptides that would bind tumor vasculature, Ruoslahti’s team discovered a peptide called iRGD that activates a general transport mechanism in blood vessels.2
“iRGD and other peptides like it, they activate a bulk transport pathway that takes in anything that is around and transports it out of the blood vessels and through tissue,” says Ruoslahti. When the researchers delivered iRGD and various anti-cancer drugs simultaneously to mice with tumors, the drugs migrated very efficiently into the tumors and killed them.
|
While evidence in the mouse system suggests that iRGD homes specifically to tumor tissue, Ruoslahti cautions that there could be cryptic receptors for the peptide in other tissues, which could lead to off-target effects. However, that possibility also suggests that modified iRGD-like peptides could be developed to increase the drug permeability of other types of tissues. So far, the researchers have found a peptide that targets atherosclerotic plaques, and they are studying other motifs as well. “While we haven’t rigorously proven it, we think that those peptides work the same way in different targets that iRGD works in tumors,” says Ruoslahti.
Since the initial mouse experiments, the iRGD work has been picked up by CendR Therapeutics in Del Mar, Calif., a spinoff company that is now preparing to take iRGD-based therapies into clinical trials.
The iRGD results are also part of what Ruoslahti sees as a growing trend in tumor targeting, in which researchers are increasingly aiming for tumor vasculature instead of trying to develop peptides that bind directly to tumor cells. “[Tumor cells] really aren’t available to probes as well as is the vasculature, so I think a main improvement in the past ten years or so has been the realization that it’s much better to target the tumor vasculature at least initially,” says Ruoslahti.
A big box of tissues
Whether linking compounds to peptides or using the peptides as an adjuvant, companies developing the new therapies will likely need the services of a good CRO. While numerous companies provide contract drug development services for the industry, those specializing in oncology have often carved out special niches for themselves. Crown Bioscience in Santa Clara, Calif., for example, owns a unique repository of tumor grafts derived from actual patient biopsies. In the company’s graft system, “you have the actual tumor environment, intact, of a human patient,” explains Laura Sailor, senior vice president of business development at Crown.
Crucially, the tumors have been isolated from patients in Asian countries where cancer chemotherapy is not widely available yet. That means the tumors are susceptible to a whole range of compounds, just as newly diagnosed tumors will be in the clinic. “It’s naive, so you can push it to metastasis, you can push it to resistance,” says Sailor.
The system should also provide good predictions for clinical trials in Asia, where many companies are now focusing major efforts. “The clinical trials are a little bit easier over there, and the market’s way, way bigger,” says Sailor.
Crown is not the only CRO pursuing the peptide-targeting business, of course. Companies such as Pharmatech in Denver, Colo. have also been working on peptide-based projects, while JPT Peptide Solutions in Berlin, Germany offers a range of services that extends from peptide synthesis to contract research.
While interest in tumor-targeting peptides hasn’t seen the type of sudden boom that has characterized many other biotechnologies, researchers and service providers continue to see promising results from the field. For drug developers, that can only be good news.
About the Author
Originally trained as a virologist, Alan Dove is now a science journalist whose work appears regularly in a variety of trade and scientific journals and online publications. He also co-hosts the popular podcast “This Week in Virology.”
References
1. Hatakeyama S, et al. Targeted drug delivery to tumor vasculature by a carbohydrate mimetic peptide. Proc Natl Acad Sci USA. 2011;108(49):19587-92.
2. Sugahara KN, et al. Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. Science. 2010; 328(5981):1031-5.
AstraZeneca, Targacept Nix TC-5214
LONDON (AP) - Drug makers AstraZeneca and Targacept say they have abandoned plans to seek regulatory approval for a drug intended to treat major depressive disorder.
AstraZeneca PLC said that the drug TC-5214 did not perform as hoped in an eight-week trial compared to a placebo.
AstraZeneca says it will take an impairment charge of $50 million as a result.
London-based AstraZeneca and Targacept Inc., based in Winston-Salem, North Carolina, signed a collaboration agreement to develop the drug in 2009.
Date: March 20, 2012
Source: Associated Press
AstraZeneca PLC said that the drug TC-5214 did not perform as hoped in an eight-week trial compared to a placebo.
AstraZeneca says it will take an impairment charge of $50 million as a result.
London-based AstraZeneca and Targacept Inc., based in Winston-Salem, North Carolina, signed a collaboration agreement to develop the drug in 2009.
Date: March 20, 2012
Source: Associated Press
Merck Ends Oral Vernakalant Development
Canadian drug maker Cardiome Pharma Corp. said that Merck & Co. Inc. has quit developing an oral version of the heart drug vernakalant due to regulatory issues.
A Merck spokesman said by email that Merck made the decision "following a very careful assessment of developmental timelines and the anticipated regulatory requirements ahead." He declined to elaborate.
Vernakalant is used to treat a heartbeat irregularity called atrial fibrillation. The oral version was being tested as way to help people prevent atrial fibrillation over long periods of time.
Vancouver-based Cardiome said it will evaluate the impact of Merck's decision on its business and release a review. Cardiome said it already had decided to cut by half the rate at which it is spending cash reserves each year to support its operations.
Merck, based in Whitehouse Station, N.J., said it will working with Cardiome on an intravenous version of vernakalant, which is sold in the European Union and Latin America under the trade name Brinavess.
"We are extremely disappointed with the decision Merck has made," Cardiome CEO Doug Janzen said in the company's announcement. "However, we look forward to continuing to work with Merck on the worldwide development and commercialization of vernakalant IV."
Brinavess is approved for use in adults in 37 countries and Merck has plans to launch the drug in about 30 more countries this year, according to Cardiome Pharma.
Cardiome said it expects to report its full 2011 earnings on March 28.
Date: March 19, 2012
Source: Associated Press
A Merck spokesman said by email that Merck made the decision "following a very careful assessment of developmental timelines and the anticipated regulatory requirements ahead." He declined to elaborate.
Vernakalant is used to treat a heartbeat irregularity called atrial fibrillation. The oral version was being tested as way to help people prevent atrial fibrillation over long periods of time.
Vancouver-based Cardiome said it will evaluate the impact of Merck's decision on its business and release a review. Cardiome said it already had decided to cut by half the rate at which it is spending cash reserves each year to support its operations.
Merck, based in Whitehouse Station, N.J., said it will working with Cardiome on an intravenous version of vernakalant, which is sold in the European Union and Latin America under the trade name Brinavess.
"We are extremely disappointed with the decision Merck has made," Cardiome CEO Doug Janzen said in the company's announcement. "However, we look forward to continuing to work with Merck on the worldwide development and commercialization of vernakalant IV."
Brinavess is approved for use in adults in 37 countries and Merck has plans to launch the drug in about 30 more countries this year, according to Cardiome Pharma.
Cardiome said it expects to report its full 2011 earnings on March 28.
Date: March 19, 2012
Source: Associated Press
viernes, 16 de marzo de 2012
Atomic Force Microscopy and Drug Research
Sophia Hohlbauch, Biological Applications Scientist; Nicholas Geisse, Biological Applications Scientist; Irene Revenko Biological Applications Scientist; Asylum Research, Santa Barbara, Calif.
Atomic force microscopy (AFM) is part of a broad class of scanning probe microscopes (SPMs) that were originally developed in the 1980s. AFMs physically track samples with a microfabricated probe to generate 3D topographical images. Typical resolution is limited by the probe dimensions and the sample and is on the order of angstroms in Z and nanometers in XY. Scans can be on the order of a few nanometers to several tens of microns in XY, allowing for the investigation of processes at multiple spatial scales. This technique does not require sample fixation or staining, and measurements can be made in near-physiological conditions, in biological buffers and culture media.
In addition to imaging, the physical interaction between the probe and sample can be measured and quantified in terms of force. These data are commonly displayed as a force versus distance or indentation curve. As the probe contacts and pushes into the sample, the force versus indentation data can be used to reveal information on sample stiffness via a variety of mechanical models. As the probe is pulled away from the surface, adhesive interactions between the tip and sample―if any―are measured. These adhesion data provide information on inter- or intra-molecular forces.
AFM is well suited to pharmacological research. Fundamental research includes the surface characterization of tablets and their coatings, growth of crystals as a function of manufacturing parameters (concentration, temperature, pH), and size and form of drug delivery vehicles.
AFM can also provide a better understanding of how a drug affects a target molecule or cell. An example is the effect of cisplatin, an anticancer drug, on DNA structure and mechanics. Cisplatin is an intercalative agent, which covalently binds to a specific location on guanine and adenine bases. After treatment with cisplatin, topographic images reveal an elongation of the DNA molecule and force measurements show a change in its unfolding pattern due to structural changes in the molecule.
Because of its ability to operate in aqueous conditions, time-lapse experiments monitoring the effects of drugs on living systems are routine. For example, AFM has been used to observe the effect of natural toxins such as cytochalasin, latrunculin, and jasplakinolide, as well as plant-derived taxol, on cell structure and stiffness. These drugs alter cytoskeletal dynamics, which has subsequent effects on cell motility, division, and overall mechanical function. Similarly, morphological changes of living cerebral endothelial cells have been studied. AFM results showed a decrease in cell height, the emergence of surface protrusions, and a decrease in Young’s Modulus (stiffness) after exposure to hyperosmotic concentrations of mannitol, which is commonly used to open up the blood-brain barrier.
The use of AFMs in pharmacological research has the potential to progress further as the technology is applied and developed with improved resolution and faster scan speeds.
In addition to imaging, the physical interaction between the probe and sample can be measured and quantified in terms of force. These data are commonly displayed as a force versus distance or indentation curve. As the probe contacts and pushes into the sample, the force versus indentation data can be used to reveal information on sample stiffness via a variety of mechanical models. As the probe is pulled away from the surface, adhesive interactions between the tip and sample―if any―are measured. These adhesion data provide information on inter- or intra-molecular forces.
AFM is well suited to pharmacological research. Fundamental research includes the surface characterization of tablets and their coatings, growth of crystals as a function of manufacturing parameters (concentration, temperature, pH), and size and form of drug delivery vehicles.
AFM can also provide a better understanding of how a drug affects a target molecule or cell. An example is the effect of cisplatin, an anticancer drug, on DNA structure and mechanics. Cisplatin is an intercalative agent, which covalently binds to a specific location on guanine and adenine bases. After treatment with cisplatin, topographic images reveal an elongation of the DNA molecule and force measurements show a change in its unfolding pattern due to structural changes in the molecule.
Because of its ability to operate in aqueous conditions, time-lapse experiments monitoring the effects of drugs on living systems are routine. For example, AFM has been used to observe the effect of natural toxins such as cytochalasin, latrunculin, and jasplakinolide, as well as plant-derived taxol, on cell structure and stiffness. These drugs alter cytoskeletal dynamics, which has subsequent effects on cell motility, division, and overall mechanical function. Similarly, morphological changes of living cerebral endothelial cells have been studied. AFM results showed a decrease in cell height, the emergence of surface protrusions, and a decrease in Young’s Modulus (stiffness) after exposure to hyperosmotic concentrations of mannitol, which is commonly used to open up the blood-brain barrier.
The use of AFMs in pharmacological research has the potential to progress further as the technology is applied and developed with improved resolution and faster scan speeds.
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