Vertex Drug Improves Lung Function

Vertex Drug Improves Lung Function
Drug Discovery & Development - February 23, 2011

CAMBRIDGE, Mass. (AP) - Vertex Pharmaceuticals Inc. said that its potential cystic fibrosis drug improved lung function in a key late-stage study.
The company said VX-770 prompted a 10.5 percent improvement in lung function in the study, which focused on patients with a specific gene mutation. The drug is aimed at treating the genetic cause of the lung condition, rather than just symptoms. But, its target is a small swath of cystic fibrosis patients with a specific gene mutation.
Cystic fibrosis causes a fluid imbalance in the lungs, resulting in mucus plugging, infection and inflammation. It affects about 30,000 people in the U.S. and around 70,000 people worldwide, the company has said. The study focused on patients with the G551D mutation and about 4 percent of the U.S. cystic fibrosis population has at least on copy of the mutation.
Vertex said the drug also met secondary goals of improving the symptoms of the condition, which include shortness of breath and difficulty breathing.
"Treating the underlying cause of cystic fibrosis with VX-770 led to clinical improvements that were far beyond our expectations, providing support for an entirely new approach to the treatment of this disease," said Peter Mueller, executive vice president of global research and development and chief scientific officer at Vertex.
He said the company plans on working with regulatory agencies to determine the fastest path for approval of VX-770. Vertex expects data from another late-stage study in mid-2011. The company plans on asking for regulatory approval in the U.S. and Europe in the second half of 2011.
Date: February 22, 2011
Source: Associated Press

Tibotec Launches Two Phase 3 Trials for TMC435

Tibotec Launches Two Phase 3 Trials for TMC435
Drug Discovery & Development - February 24, 2011

Tibotec Pharmaceuticals announced that two global, registrational phase 3 trials are recruiting patients to examine TMC435, its investigational hepatitis C protease inhibitor, in treatment-naïve adults with chronic genotype 1 hepatitis C virus (HCV). A third global phase 3 trial is being conducted in genotype 1 HCV patients who have experienced a viral relapse after prior interferon-based treatment. Approximately 3.2 million people in the U.S. live with chronic hepatitis C disease and more than 170 million people have the disease globally. The response-guided trials will compare the efficacy, safety and tolerability of TMC435 given as a single 150 mg oral tablet once daily for 12 weeks versus placebo; each patient also will be treated with a background regimen of peginterferon and ribavirin for 24 or 48 weeks.
“TMC435 is an important component of our growing HCV pipeline,” said Brian Woodfall M.D., Vice President of Global Clinical Development at Tibotec. “The initiation of the TMC435 phase 3 clinical trial program reinforces our commitment to develop innovative new treatment options that may decrease the duration of treatment for patients with chronic hepatitis C infection.”
The first global, phase 3, double-blind, randomized study, known as TMC435-C208 or QUEST-1 (QD dosing of TMC435 of previoUsly untreated GEnotype 1 patienTs-1), will evaluate a single TMC435 once-daily oral tablet (150 mg) versus placebo in treatment-naïve HCV patients. Both groups will also receive peginterferon alfa-2a (Pegasys) and ribavirin (Copegus) as part of their treatment. The second global, phase 3, double-blind, randomized study, known as TMC435-C216 or QUEST-2 (QD dosing of TMC435 of previoUsly untreated GEnotype 1 patienTs-2), also will evaluate a single TMC435 once-daily oral tablet (150 mg) versus placebo in treatment-naïve HCV patients. However, patients in this trial will either receive peginterferon alfa-2a (Pegasys) and ribavirin (Copegus) or peginterferon alfa-2b (PegIntron) and ribavirin (Rebetol) as part of their treatment. A third global, phase 3, double-blind randomized study, known as TMC435-C3007 or PROMISE (PROtease inhibitor TMC435 In PatientS who have previously rElapsed on IFN/RBV), will evaluate a single TMC435 once-daily oral tablet (150 mg) verses placebo in HCV patients who experienced viral relapse after previous interferon-based therapy. Both groups will receive peginterferon alfa-2a (Pegasys) and ribavirin (Copegus). The complete treatment duration for all three trials will be 24 or 48 weeks, depending on patient response.
The studies will be conducted at more than 160 sites in 24 countries, including the U.S. and countries throughout Europe, and together seek to enroll approximately 1,125 HCV genotype 1 infected patients who are treatment-naïve or have experienced a relapse after previous interferon-based HCV therapy. To be eligible, patients must have chronic hepatitis C infection, and must have had a liver biopsy within three years of the screening visit. For those patients who have not had a liver biopsy in the three years prior to the study, one will be performed before the baseline visit. In addition, eligible patients need to have completed a recent ultrasound with no findings suspicious of hepatocellular carcinoma (HCC). Patients with signs of hepatic decompensation, liver disease of any non-HCV etiology, co-infection with hepatitis B or HIV-1 and 2 or a history of malignancy within 5 years of the screening vitis are ineligible for the study. Patients in QUEST-1 and QUEST-2 trials must not have received any prior treatment for hepatitis C, and patients in the PROMISE trial must have previously received at least 24 weeks of (peg)interferon-based therapy, along with documented negative HCV RNA at last on-treatment measurement, and have relapsed (detectable HCV RNA) within one year of last taking medication. The primary endpoint of the studies is to assess whether TMC435 is superior to placebo in achieving sustained virologic response (SVR), defined as HCV RNA <25 IU/ml undetectable, 24 weeks after the planned end of treatment (SVR 24), with the final analysis being performed after the last patient reaches week 72 of the study. Secondary endpoints include superiority of TMC435 versus placebo at 12 weeks (SVR 12), after planned end of treatment and at week 72 of the study. Evaluations of viral breakthroughs, relapse rates in treatment groups, safety and tolerability also will be assessed.
Phase 3 studies for TMC435 also recently launched in Japan.
Date: February 18, 2011
Source: Tibotec Pharmaceutical 

Trophos Completes TRO40303 Study

Trophos Completes TRO40303 Study
Drug Discovery & Development - February 24, 2011

Trophos SA a clinical stage pharmaceutical company developing innovative therapeutics from discovery to clinical validation for indications with under-served needs in neurology and cardiology, announces the successful completion of its phase 1 dose escalation study of TRO40303, a novel mitochondria pore modulator. TRO40303 could become the first treatment to reduce the cardiac reperfusion injury that contributes significantly to the morbidity and mortality seen after a heart attack (myocardial infarction - MI).

“We are very pleased with the highly satisfactory results of this rigorous and extensive phase 1 study of TRO40303. This will allow us to initiate our important phase 2 proof-of concept trial of TRO40303 in the second half of this year with our consortium partners in the EU funded MitoCare project,” commented Dr Jean-Louis Abitbol, Chief Medical Officer at Trophos. “A treatment is urgently required globally to prevent cardiac reperfusion injury. This is a major problem in the care of MI patients despite the overall improvements in prognosis in recent years. There is no existing treatment for this problem that contributes to long-term morbidity, progression to heart failure and death following a MI. The role of mitochondrial permeability transition in cardiac reperfusion injury has recently been validated clinically making this is a tremendous opportunity for our novel mitochondrial pore modulator, TRO40303, discovered and developed in our laboratories to target this mechanism.”
“There are around 1.6 million cardiac reperfusion procedures performed in hospitals and specialist clinics each year in the western world alone,” added Damian Marron, Trophos’ CEO. “This program fits perfectly with Trophos strategy of creating value by targeting niche, high unmet medical need markets. Trophos is excellently positioned to deliver both on its goals with TRO40303 and with our lead product, olesoxime, in a phase 3 study for the orphan neurological disease of amyotrophic lateral sclerosis as part of the EU funded MitoTarget project.”
The objective of the phase 1 study was to assess the safety, tolerability and pharmacokinetics of single escalating doses of TRO40303 as an intravenous infusion at different rates compared with placebo in 72 healthy volunteers. The results demonstrate that TRO40303 can be safely administered by the i.v. route in humans at doses expected to be pharmacologically active. Trophos plans to present the full results of this study at a major cardiology congress in the second half of 2011.

The phase 2 proof-of-concept study of TRO40303 is to be sponsored by Trophos and performed as part of the EU funded MitoCare project (see release of December 14, 2010) by a consortium of prominent European clinical investigators, all of whom have extensive prior experience conducting and collaborating in large multi-centre clinical trials in cardiac IRI. The principal investigator will be Professor Dan Atar from Oslo University Hospital, Norway. The study will be a placebo-controlled, phase 2 proof-of-concept study in acute MI patients with large myocardial infarct undergoing percutaneous transluminal coronary angioplasty (PTCA also known as coronary or balloon angioplasty) during percutaneous coronary intervention (PCI). TRO40303 will be administered as a single i.v. infusion prior to the reperfusion by angioplasty.
Date: February 23, 2011
Source: Trophos SA 

Roche Seeking Approval for HPV Test

Phase 1 IB1001 Results Announced

Phase 1 IB1001 Results Announced
Drug Discovery & Development - February 25, 2011

Ipsen announced that its partner Inspiration Biopharmaceuticals, Inc. (Inspiration) presented pharmacokinetic (PK) data on its lead product, IB1001, a recombinant factor IX (FIX) for the treatment and prevention of bleeding in individuals with hemophilia B. According to Inspiration, results of the Phase 1 portion of an ongoing IB1001 clinical study demonstrated non-inferiority of IB1001 in achieving overall levels of replacement factor compared to BeneFIX, the only approved recombinant FIX product for the treatment of hemophilia B. Currently, IB1001 is in Phase 3 and safety and efficacy results are expected later this year.
The clinical results were presented at the 4th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD) in Geneva, Switzerland, in a poster presentation titled, “Pharmacokinetics of IB1001, a New Recombinant Factor IX”1.
Marc de Garidel, Chairman and Chief Executive Officer of Ipsen said: “Pharmacokinetic results presented by our partner Inspiration Biopharmaceuticals emphasize the encouraging medical potential of IB1001, a promising factor IX for the treatment of hemophilia B, a disease for which access to adequate care is a significant unmet medical need globally.”
Date: February 25, 2011
Source: Ipsen 

Breaking Down the Barriers

Principal Investigator System Enables CROs to Improve Bioanalytical Study Management

FDA Approves CeNeRx IND

FDA Approves CeNeRx IND
Drug Discovery & Development - February 09, 2011

CeNeRx BioPharma, Inc., a clinical-stage company developing and commercializing innovative treatments for diseases of the central nervous system (CNS), announced FDA approval of its IND and reported the first clinical results in humans for CXB909, a novel agent that has demonstrated utility in preclinical models of neuroprotection and neurodegenerative disorders.  CXB909 is a small molecule, orally active agent that enhances the effects of nerve growth factor (NGF) and is also believed to promote synthesis of acetylcholine.  CeNeRx is now preparing to launch further Phase I studies of CXB909 targeting chemotherapy-induced peripheral neuropathy as its first potential indication.
CXB909 appears to enhance cholinergic tone and is a downstream enhancer of the effects of NGF, a naturally occurring neurotrophic factor that is important for the function and survival of several types of neurons.  NGF may help prevent or reverse the neuronal damage that is implicated in the peripheral neuropathies associated with cancer chemotherapy, diabetes, kidney disease, and other conditions.  The degeneration of certain neurons associated with Alzheimer’s disease and Huntington’s disease may also be ameliorated by increased levels of NGF.
Past attempts to use recombinant versions of NGF to prevent and treat neuron-damaging conditions were stymied by its lack of drug-like properties.  In contrast, CXB909 crosses the blood-brain barrier, has a long half-life and is orally available.  Results from an initial Phase I study in 26 subjects showed that single doses of CXB909 administered orally resulted in good levels of drug exposure and were well-tolerated.
“CXB909 has been shown to increase the action of endogenous NGF and enhance cognition and neuroprotection in multiple preclinical models, and it has demonstrated good safety in animal and early human studies,” said Dr. Daniel Burch, Executive Vice President of R&D and Chief Medical Officer of CeNeRx.  “CXB909’s cognitive-enhancing effects are produced by a mechanism that is complementary to current cholinesterase inhibitors, suggesting that it could be developed as a stand-alone, add-on or combination therapy for the treatment of neurodegenerative disorders.  We look forward to advancing CXB909 in the clinic for its first indication as a potential treatment for chemotherapy-induced neuropathy.”
In preclinical studies, CXB909 enhanced the action of NGF in vitro in biochemical and cellular assays, amplifying its activity almost seven-fold.  CXB909 was neuroprotective in a variety of cellular assays and in animal models of neuropathies and neurodegenerative diseases, including chemotherapy-induced neuropathy, for which there is currently no approved treatment.   In two well-validated preclinical models, CXB909 concomitantly administered with the cancer drug taxane prevented nerve damage as measured by nerve conduction velocity, an objective parameter that is highly predictive of nerve function in humans.
“Our aging population is at risk for devastating neuropathic and neurodegenerative diseases that lack effective therapies, so we view the initiation of our clinical program for CXB909 as especially important,” said Barry Brand, Chief Executive Officer of CeNeRx.  “We intend to assess CXB909 in a number of relevant conditions, beginning with chemotherapy-induced neuropathy, a disabling and dose-limiting side effect of cancer treatment that is an attractive commercial target with a relatively straightforward pathway to clinical development and regulatory review.”
CXB909 was licensed from Krenitsky Pharmaceuticals Inc., which also licensed the RIMA series of selective and reversible monoamine oxidase inhibitor compounds to CeNeRx.  The lead compound in that program, TriRima, is currently in a Phase ll trial for treatment resistant depression.
Date: February 9, 2011
Source: CeNeRx BioPharma, Inc. http://www.cenerx.com/

PolyMedix Starts New Trial for PMX-60056

PolyMedix Starts New Trial for PMX-60056
Drug Discovery & Development - February 09, 2011

PolyMedix, Inc. an emerging biotechnology company focused on developing new therapeutic drugs to treat infectious diseases and acute cardiovascular disorders, has initiated a Phase 2 clinical trial, following conclusion of a review by the United States Food and Drug Administration (FDA) of a protocol submitted by PolyMedix, to assess the safety and efficacy of its heptagonist, PMX-60056, in reversing heparin in patients undergoing Percutaneous Coronary Intervention (PCI) procedures. PMX-60056 is a synthetic, small-molecule designed to reverse the anticoagulation activity of heparin and low molecular weight heparins (LMWH).
"We are excited to move forward with this Phase 2 clinical trial with PMX-60056 in patients," commented Dr. Bozena Korczak, Senior Vice President of Clinical Development and Chief Development Officer of PolyMedix. "In this study, we plan to assess safety and efficacy in reversing heparin using therapeutically appropriate doses of PMX-60056 in patients undergoing PCI."
This multi-center, open-label Phase 2 clinical study is intended to enroll up to 40 patients undergoing PCI in the United States. All patients will receive PMX-60056 by intravenous infusion, in a dose calculated to reduce the post-procedure ACT (activated clotting time) to less than 30 seconds above the baseline level. The primary endpoint of the study is to evaluate the safety and efficacy of PMX-60056 in reversing heparin in a surgical setting. Data collected from this study are intended to support further development of PMX-60056 in larger and more diverse patient populations. The study is expected to be completed by the end of this year.
The anticoagulant heparin is often used in acute surgical applications to prevent life-threatening blood clots. After surgery, patients in need of heparin reversal are administered protamine, which is currently the only agent approved to reverse the action of heparin. Protamine may have potential drawbacks, including bleeding complications and allergic reactions.
"The need for a safer alternative for managing anticoagulation reversal is well understood within the medical community," commented Nicholas Landekic, President and CEO of PolyMedix. "To date, we have successfully completed four clinical trials, including three Phase 1B/2 studies with efficacy assessments where PMX-60056 safely reversed both heparin and LMWH. We are proud to be developing this unique anticoagulant reversing agent to address these important unmet medical needs."
PolyMedix is exploring and evaluating the opportunities for continued clinical development of PMX-60056 for reversal of LMWHs, including potential discussions with regulatory agencies. LMWHs are prescribed to patients in need of long-term anticoagulation outside the hospital. There is currently no drug approved to reverse LMWHs.
Date: February 9, 2011
Source: PolyMedix, Inc.

Dutasteride Not Cost-Effective in Cancer Prevention

Dutasteride Not Cost-Effective in Cancer Prevention
Drug Discovery & Development - February 09, 2011

The popular drug dutasteride may not be a cost-effective way to prevent prostate cancer in men who are at elevated risk of developing the disease, according to findings by a UT Southwestern Medical Center researcher.
In a study available in the January issue of Cancer Prevention Research, investigators found that the medication, at an annual cost of $1,400, is impractical when compared to the marginal impact on survival and quality of life in at-risk groups. The drug is indicated for the treatment of enlarged prostates but also is widely prescribed for chemoprevention.
"Because prostate cancer is the most common cancer in men, the implications of this data are significant since there could be millions of men who would be eligible for anti-cancer drugs," said Dr. Yair Lotan, associate professor of urology at UT Southwestern. "Prior to instituting a chemoprevention strategy to a large population, the utility and cost need to be well understood. Whether a medication improves survival, how it affects quality of life, and what its financial implications will be are all critical issues. Because dutasteride typically is prescribed for the lifetime of the patient, and therefore taken daily for decades, the cost issue is particularly relevant."
Prior research has shown that dutasteride reduced the relative risk of prostate cancer over a four-year period by 22.8 percent, but questions have remained about its cost-effectiveness. The current study analyzed the lifetime health-related costs of the drug in patients at greater risk of developing prostate cancer and compared them to other factors, such as quality and length of life.
Dr. Lotan and his colleague, Dr. Robert Svatek of UT Health Science Center at San Antonio, used a Markov probability model to compare the lifetime cost of taking dutasteride with no therapy. They used data from a previous trial and studies that evaluated outcomes of patients with prostate cancer, including treatment-related complications to create the model. The primary outcome was measured in quality-adjusted life years (QALY), which takes into account both quality and quantity of life.
"The study found that dutasteride was not cost-effective for chemoprevention unless and until a strategy is developed for targeting very high-risk patients and the cost of the drug decreases," said Dr. Lotan. "For the average man, the drug provides minimal survival benefits, and the reduction on treatment-related complications does not compensate for the high costs of every man taking the drug for many years."
Date: February 8, 2011
Source: UT Southwestern Medical Center 

FDA Approves Update to REYATAZ Label

FDA Approves Update to REYATAZ Label
Drug Discovery & Development - February 09, 2011

Bristol-Myers Squibb Company announced that the U.S. Food and Drug Administration (FDA) has approved an update to the labeling for REYATAZ (atazanavir sulfate) to include dose recommendations in HIV-infected pregnant women. In HIV combination therapy, treatment with the recommended adult dose of REYATAZ 300 mg, boosted with 100 mg of ritonavir, achieved minimum plasma concentrations (24 hours post-dose) during the third trimester of pregnancy comparable to that observed historically in HIV-infected adults. During the postpartum period, atazanavir concentrations may be increased; therefore, while no dose adjustment is necessary, patients should be monitored for adverse events for two months after delivery. REYATAZ is indicated in combination with other antiretroviral agents for treatment of HIV-1 infection in patients at least six years of age. REYATAZ should be used during pregnancy only if the benefit outweighs the risk and HIV-1 strains are susceptible to atazanavir. REYATAZ should not be used without ritonavir in pregnant or postpartum women. REYATAZ does not have an indication for prevention of maternal-fetal transmission of HIV-1 infection.
Pregnant women do not require a dose adjustment for REYATAZ/ritonavir except in the case of treatment-experienced pregnant women during the second or third trimester when REYATAZ is co-administered with either tenofovir or an H2-receptor antagonist (H2RA). In that case, REYATAZ 400 mg plus ritonavir 100 mg once daily is recommended. There are insufficient data to recommend a REYATAZ dose for use with both tenofovir and an H2RA in treatment-experienced pregnant women. In addition to dosing instructions during pregnancy, the full prescribing information for REYATAZ includes general dosing recommendations (see About REYATAZ section below) as well as dosing instructions based on renal function, hepatic function, and concomitant drug interactions.
“This labeling update is important news for both healthcare providers and HIV positive women of child-bearing age in that it provides guidance for the use of REYATAZ, as part of combination therapy, during pregnancy and postpartum,” said Dr. Awny Farajallah, MD, FACP, executive director, atazanavir development lead, Bristol-Myers Squibb. “Bristol-Myers Squibb is committed to research that furthers the understanding of how to manage HIV in special populations and to meeting the evolving needs of individuals with this disease.”
The labeling update is based on data from a multicenter, open-label, prospective, single arm, pharmacokinetic study (Study 182) of 41 HIV-infected pregnant women between 12 and 32 weeks gestation (second and third trimester) with CD4 ≥200 cells/mm3.1 Patients were treated with REYATAZ (atazanavir sulfate)/ritonavir 300/100 mg (n=20) or 400/100 mg (n=21) once daily; patients in their second trimester received REYATAZ/ritonavir 300/100 mg. All patients received zidovudine/lamivudine 300/150 mg twice daily.1 The primary objective of Study 182 was to determine the dosing of REYATAZ/ritonavir as part of a regimen that produces adequate drug exposure in pregnant women compared to historical data in HIV-infected adults.1
Atazanavir has been evaluated in a limited number of women during pregnancy and postpartum. Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate. Because the studies in humans cannot rule out the possibility of harm, REYATAZ should be used during pregnancy only if the benefit outweighs the risk. Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using REYATAZ in combination with nucleoside analogues. Nucleoside anologues are associated with an increased risk of lactic acidosis syndrome. Hyperbilirubinemia occurs frequently in patients who take REYATAZ, including pregnant women.
Secondary outcomes in Study 182 evaluated antiviral efficacy and safety in pregnant women and their infants.1 Of the 39 women who completed the study, 38 (97 percent) achieved an HIV RNA <50 copies/mL at the time of delivery. Six of 20 (30 percent) women on REYATAZ/ritonavir 300/100 mg and 13 of 21 (62 percent) women on REYATAZ/ritonavir 400/100 mg experienced hyperbilirubinemia with a total bilirubin greater than or equal to 2.6 times the upper limit of normal. No cases of lactic acidosis were observed.
Among the 40 infants born to 40 HIV-infected pregnant women, all tested negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. All 40 infants received antiretroviral prophylactic treatment containing
Atazanavir drug concentrations in fetal umbilical cord blood were approximately 12-19 percent of maternal concentrations. No evidence of severe hyperbilirubinemia (total bilirubin levels greater than 20 mg/dL) or acute or chronic bilirubin encephalopathy was observed among neonates in this study. A total bilirubin level greater than 20 mg/dL is considered severe hyperbilirubinemia in newborns born to non-HIV-infected women.2 However, 10/36 (28 percent) infants (6 greater than or equal to 38 weeks gestation and 4 less than 38 weeks gestation) had bilirubin levels of 4 mg/dL or greater within the first day of life. All infants, including neonates exposed to REYATAZ (atazanavir sulfate) in-utero, should be monitored for the development of severe hyperbilirubinemia during the first few days of life. During the study, it was also noted that 3/38 (8 percent) infants had glucose levels (from adequately collected serum samples) of less than 40 mg/dL on the first day of life. These glucose levels could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis.
Study limitations included lack of ethnic diversity (83 percent of infants were Black/African American, who have a lower incidence of neonatal hyperbilirubinemia than Caucasians and Asians), exclusion of women with Rh incompatibility, and exclusion of women who had a previous infant with hemolytic disease and/or neonatal jaundice requiring phototherapy.
As of January 2010, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 635 exposures to atazanavir-containing regimens (425 exposed in the first trimester and 160 and 50 exposed in second and third trimester, respectively). Birth defects occurred in 9 of 393 (2.3 percent) live births (first trimester exposure) and 5 of 212 (2.4 percent) live births (second/third trimester exposure). Among pregnant women in the U.S. reference population, the background rate of birth defects is 2.7 percent. There was no association between atazanavir and overall birth defects observed in the APR. The APR was established to monitor maternal-fetal outcomes of pregnant women exposed to antiretrovirals, including REYATAZ (atazanavir sulfate).
Date: February 7, 2011
Source: Bristol-Myers Squibb Company 

Qnaze Meets Study Goals

Qnaze Meets Study Goals
Drug Discovery & Development - February 09, 2011

NEW YORK (AP) - Teva Pharmaceutical Industries Ltd. said its allergy drug Qnaze met its goal in a late-stage study that tested its ability to treat year-round allergies.
Teva said the clinical trial showed Qnaze was more effective than a placebo at treating morning and evening nasal allergy symptoms like congestion, runny nose, itching, and sneezing. In the study, 470 patients were given either Qnaze or placebo once a day for six weeks. The most common side effects were nasal discomfort and nosebleeds. Teva said those side effects occurred at similar rates for Qnaze patients and placebo patients.
Qnaze is a corticosteroid that is delivered into the nose by an aerosol instead of an aqueous or "wet" spray. In November, Teva said a separate late-stage trial showed Qnaze is effective as a treatment for seasonal allergies.
Date: February 9, 2011
Source: Associated Press

Gilead Refiles Truvada/Rilpivirine NDA

Gilead Refiles Truvada/Rilpivirine NDA
Drug Discovery & Development - February 15, 2011

Gilead Sciences, Inc. announced that it has refiled a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) for the single-tablet regimen of Truvada (emtricitabine and tenofovir disoproxil fumarate) and Tibotec Pharmaceuticals' investigational non-nucleoside reverse transcriptase inhibitor TMC278 (rilpivirine hydrochloride) for HIV-1 infection in adults.
Gilead previously submitted an NDA for the single-tablet regimen of Truvada/TMC278 on November 23, 2010. The company announced on January 25, 2011 that it had received a "refuse to file" notification from the FDA regarding that submission. Specifically, the FDA requested additional information on the analytical methodology and qualification data used to establish acceptable levels of recently identified degradants related to emtricitabine; this information has been included in the refiling.
The FDA has up to 60 days to conduct a preliminary review to assess whether the NDA is sufficiently complete to permit a substantive review. The FDA will establish a target action date for the NDA, under the Prescription Drug User Fee Act (PDUFA), if the application is formally filed.
Date: February 15, 2011
Source: Gilead Sciences, Inc.

Red Wine Compound Increases Rapamycin Effectiveness

Red Wine Compound Increases Rapamycin Effectiveness
Drug Discovery & Development - February 15, 2011

Researchers from Cleveland Clinic's Lerner Research Institute have discovered that resveratrol – a compound found in red wine – when combined with rapamycin can have a tumor-suppressing effect on breast cancer cells that are resistant to rapamycin alone.
The research – recently published in Cancer Letters – also indicates that the PTEN tumor-suppressing gene contributes to resveratrol's anti-tumor effects in this treatment combination.
Charis Eng, MD, Ph.D., Chair of the Genomic Medicine Institute of Cleveland Clinic's Lerner Research Institute, led her team to study the effect of combining resveratrol, a chemopreventive drug found in many natural compounds, with rapamycin on breast cancer cells. The research demonstrates an additive effect between these two drugs on breast cancer cell signaling and growth.
"Rapamycin has been used in clinical trials as a cancer treatment. Unfortunately, after a while, the cancer cells develop resistance to rapamycin," Eng said. "Our findings show that resveratrol seems to mitigate rapamycin-induced drug resistance in breast cancers, at least in the laboratory. If these observations hold true in the clinic setting, then enjoying a glass of red wine or eating a bowl of boiled peanuts – which has a higher resveratrol content than red wine – before rapamycin treatment for cancer might be a prudent approach."
Rapamycin, an immunosuppressant drug used to prevent rejection in organ transplantation, has been considered for the use of anti-tumor activity against breast cancer. Resveratrol is a type of polyphenol that is found in the skin of red grapes and is a constituent of red wine, and has been considered for multiple uses regarding cellular therapies.
Despite the potential for tumor suppression, rapamycin's efficacy with respect to growth inhibition differs markedly among various breast cancer cell lines. The effect of resveratrol and rapamycin, alone and in combination, on cell growth of three human breast cancer cell lines was assessed. Rapamycin, resveratrol, and combinations of these agents inhibited cell growth in a dose-dependent manner. In all three cell lines tested, the presence of low concentrations of resveratrol and rapamycin was sufficient to induce 50 percent growth inhibition. Although relatively early, these observations may suggest resveratrol as a powerful integrative medicine adjunct to traditional chemotherapy.
Date: February 14, 2011
Source: Lerner Research Institute 

Efficacy and safety of belimumab

The Lancet, Early Online Publication, 7 February 2011

Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial

Original Text

Sandra V Navarra MD a, Renato M Guzmán MD b, Alberto E Gallacher MD c, Stephen Hall MD d, Roger A Levy MD e, Renato E Jimenez MD f, Edmund K-M Li MD g, Mathew Thomas MD h, Ho-Youn Kim MD i, Manuel G León MD j, Coman Tanasescu MD k, Eugeny Nasonov MD l, Joung-Liang Lan MD m, Lilia Pineda MD n, Z John Zhong PhD n, William Freimuth MD n, Michelle A Petri MD o , for the BLISS-52 Study Group

Summary

Background

Systemic lupus erythematosus is a heterogeneous autoimmune disease that is associated with B-cell hyperactivity, autoantibodies, and increased concentrations of B-lymphocyte stimulator (BLyS). The efficacy and safety of the fully human monoclonal antibody belimumab (BLyS-specific inhibitor) was assessed in patients with active systemic lupus erythematosus.

Methods

Patients (aged ≥18 years) who were seropositive with scores of at least 6 on the Safety of Estrogens in Lupus Erythematosus National Assessment—Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) were enrolled in a multicentre phase 3 study, which was done in Latin America, Asia-Pacific, and eastern Europe. Patients were randomly assigned by use of a central interactive voice response system in a 1:1:1 ratio to belimumab 1 mg/kg or 10 mg/kg, or placebo by intravenous infusion in 1 h on days 0, 14, and 28, and then every 28 days until 48 weeks, with standard of care. Patients, investigators, study coordinators, and sponsors were masked to treatment assignment. Primary efficacy endpoint was improvement in the Systemic Lupus Erythematosus Responder Index (SRI) at week 52 (reduction ≥4 points in SELENA-SLEDAI score; no new British Isles Lupus Assessment Group [BILAG] A organ domain score and no more than 1 new B organ domain score; and no worsening [<0·3 increase] in Physician's Global Assessment [PGA] score) versus baseline. Method of analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00424476.

Findings

867 patients were randomly assigned to belimumab 1 mg/kg (n=289) or 10 mg/kg (n=290), or placebo (n=288). 865 were treated and analysed in the belimumab (1 mg/kg, n=288; 10 mg/kg, n=290) and placebo groups (n=287). Significantly higher SRI rates were noted with belimumab 1 mg/kg (148 [51%], odds ratio 1·55 [95% CI 1·10—2·19]; p=0·0129) and 10 mg/kg (167 [58%], 1·83 [1·30—2·59]; p=0·0006) than with placebo (125 [44%]) at week 52. More patients had their SELENA-SLEDAI score reduced by at least 4 points during 52 weeks with belimumab 1 mg/kg (153 [53%], 1·51 [1·07—2·14]; p=0·0189) and 10 mg/kg (169 [58%], 1·71 [1·21—2·41]; p=0·0024) than with placebo (132 [46%]). More patients given belimumab 1 mg/kg (226 [78%], 1·38 [0·93—2·04]; p=0·1064) and 10 mg/kg (236 [81%], 1·62 [1·09—2·42]; p=0·0181) had no new BILAG A or no more than 1 new B flare than did those in the placebo group (210 [73%]). No worsening in PGA score was noted in more patients with belimumab 1 mg/kg (227 [79%], 1·68 [1·15—2·47]; p=0·0078) and 10 mg/kg (231 [80%], 1·74 [1·18—2·55]; p=0·0048) than with placebo (199 [69%]). Rates of adverse events were similar in the groups given belimumab 1 mg/kg and 10 mg/kg, and placebo: serious infection was reported in 22 (8%), 13 (4%), and 17 (6%) patients, respectively, and severe or serious hypersensitivity reactions on an infusion day were reported in two (<1%), two (<1%), and no patients, respectively. No malignant diseases were reported.

Interpretation

Belimumab has the potential to be the first targeted biological treatment that is approved specifically for systemic lupus erythematosus, providing a new option for the management of this important prototypic autoimmune disease.

Funding

Human Genome Sciences and GlaxoSmithKline.

The angiotensin-receptor blocker candesartan for treatment of acute stroke

The Lancet, Early Online Publication, 11 February 2011

The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial

Original Text

Else Charlotte Sandset MD a b d, Prof Philip MW Bath FRCP e, Prof Gudrun Boysen DMSc f, Dalius Jatuzis MD g, Janika Kõrv MD h, Stephan Lüders MD i, Prof Gordon D Murray PhD j, Przemyslaw S Richter MD k, Prof Risto O Roine MD l, Prof Andreas Terént MD m, Vincent Thijs MD n, Dr Eivind Berge MD a c , on behalf of the SCAST Study Group

Summary

Background

Raised blood pressure is common in acute stroke, and is associated with an increased risk of poor outcomes. We aimed to examine whether careful blood-pressure lowering treatment with the angiotensin-receptor blocker candesartan is beneficial in patients with acute stroke and raised blood pressure.

Methods

Participants in this randomised, placebo-controlled, double-blind trial were recruited from 146 centres in nine north European countries. Patients older than 18 years with acute stroke (ischaemic or haemorrhagic) and systolic blood pressure of 140 mm Hg or higher were included within 30 h of symptom onset. Patients were randomly allocated to candesartan or placebo (1:1) for 7 days, with doses increasing from 4 mg on day 1 to 16 mg on days 3 to 7. Randomisation was stratified by centre, with blocks of six packs of candesartan or placebo. Patients and investigators were masked to treatment allocation. There were two co-primary effect variables: the composite endpoint of vascular death, myocardial infarction, or stroke during the first 6 months; and functional outcome at 6 months, as measured by the modified Rankin Scale. Analyses were by intention to treat. The study is registered, number NCT00120003 (ClinicalTrials.gov), and ISRCTN13643354.

Findings

2029 patients were randomly allocated to treatment groups (1017 candesartan, 1012 placebo), and data for status at 6 months were available for 2004 patients (99%; 1000 candesartan, 1004 placebo). During the 7-day treatment period, blood pressures were significantly lower in patients allocated candesartan than in those on placebo (mean 147/82 mm Hg [SD 23/14] in the candesartan group on day 7 vs 152/84 mm Hg [22/14] in the placebo group; p<0·0001). During 6 months' follow-up, the risk of the composite vascular endpoint did not differ between treatment groups (candesartan, 120 events, vs placebo, 111 events; adjusted hazard ratio 1·09, 95% CI 0·84—1·41; p=0·52). Analysis of functional outcome suggested a higher risk of poor outcome in the candesartan group (adjusted common odds ratio 1·17, 95% CI 1·00—1·38; p=0·048 [not significant at p≤0·025 level]). The observed effects were similar for all prespecified secondary endpoints (including death from any cause, vascular death, ischaemic stroke, haemorrhagic stroke, myocardial infarction, stroke progression, symptomatic hypotension, and renal failure) and outcomes (Scandinavian Stroke Scale score at 7 days and Barthel index at 6 months), and there was no evidence of a differential effect in any of the prespecified subgroups. During follow-up, nine (1%) patients on candesartan and five (<1%) on placebo had symptomatic hypotension, and renal failure was reported for 18 (2%) patients taking candesartan and 13 (1%) allocated placebo.

Interpretation

There was no indication that careful blood-pressure lowering treatment with the angiotensin-receptor blocker candesartan is beneficial in patients with acute stroke and raised blood pressure. If anything, the evidence suggested a harmful effect.

Funding

South-Eastern Norway Regional Health Authority; Oslo University Hospital Ullevål; AstraZeneca; Takeda.

Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA)

The Lancet, Early Online Publication, 15 February 2011

Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomised, double-blind, placebo-controlled trial

Prof Fernando D Martinez MD a , Prof Vernon M Chinchilli PhD b, Prof Wayne J Morgan MD a, Susan J Boehmer MA b, Prof Robert F Lemanske MD c, Prof David T Mauger PhD b, Prof Robert C Strunk MD d, Prof Stanley J Szefler MD e, Prof Robert S Zeiger MD f, Leonard B Bacharier MD d, Elizabeth Bade MD g, Ronina A Covar MD e, Noah J Friedman MD f, Theresa W Guilbert MD c, Hengameh Heidarian-Raissy PharmD h, Prof H William Kelly PharmD h, Jonathan Malka-Rais MD e, Michael H Mellon MD f, Prof Christine A Sorkness PharmD c, Prof Lynn Taussig MD i

Summary

Background

Daily inhaled corticosteroids are an effective treatment for mild persistent asthma, but some children have exacerbations even with good day-to-day control, and many discontinue treatment after becoming asymptomatic. We assessed the effectiveness of an inhaled corticosteroid (beclomethasone dipropionate) used as rescue treatment.

Methods

In this 44-week, randomised, double-blind, placebo-controlled trial we enrolled children and adolescents with mild persistent asthma aged 5—18 years from five clinical centres in the USA. A computer-generated randomisation sequence, stratified by clinical centre and age group, was used to randomly assign participants to one of four treatment groups: twice daily beclomethasone with beclomethasone plus albuterol as rescue (combined group); twice daily beclomethasone with placebo plus albuterol as rescue (daily beclomethasone group); twice daily placebo with beclomethasone plus albuterol as rescue (rescue beclomethasone group); and twice daily placebo with placebo plus albuterol as rescue (placebo group). Twice daily beclomethasone treatment was one puff of beclomethasone (40 μg per puff) or placebo given in the morning and evening. Rescue beclomethasone treatment was two puffs of beclomethasone or placebo for each two puffs of albuterol (180 μg) needed for symptom relief. The primary outcome was time to first exacerbation that required oral corticosteroids. A secondary outcome measured linear growth. Analysis was by intention to treat. This study is registered with clinicaltrials.gov, number NCT00394329.

Results

843 children and adolescents were enrolled into this trial, of whom 288 were assigned to one of four treatment groups; combined (n=71), daily beclomethasone (n=72), rescue beclomethasone (n=71), and placebo (n=74)—555 individuals were excluded during the run-in, according to predefined criteria. Compared with the placebo group (49%, 95% CI 37—61), the frequency of exacerbations was lower in the daily (28%, 18—40, p=0·03), combined (31%, 21—43, p=0·07), and rescue (35%, 24—47, p=0·07) groups. Frequency of treatment failure was 23% (95% CI 14—43) in the placebo group, compared with 5·6% (1·6—14) in the combined (p=0·012), 2·8% (0—10) in the daily (p=0·009), and 8·5% (2—15) in the rescue (p=0·024) groups. Compared with the placebo group, linear growth was 1·1 cm (SD 0·3) less in the combined and daily arms (p<0·0001), but not the rescue group (p=0·26). Only two individuals had severe adverse events; one in the daily beclomethasone group had viral meningitis and one in the combined group had bronchitis.

Interpretation

Children with mild persistent asthma should not be treated with rescue albuterol alone and the most effective treatment to prevent exacerbations is daily inhaled corticosteroids. Inhaled corticosteroids as rescue medication with albuterol might be an effective step-down strategy for children with well controlled, mild asthma because it is more effective at reducing exacerbations than is use of rescue albuterol alone. Use of daily inhaled corticosteroid treatment and related side-effects such as growth impairment can therefore be avoided.

Funding

National Heart, Lung and Blood Institute.

Preclinical Studies Reveal Tumor Death, Reduced Toxicity

Preclinical Studies Reveal Tumor Death, Reduced Toxicity
Drug Discovery & Development - July 06, 2010

Pre-clinical trials show a compound discovered and developed by ENDECE, LLC, (Mequon, Wis.) stops the growth of many types of human cancers at the gene level for genes essential to cancer cell replication. The ENDECE compound not only stops chromosome (DNA) replication, which kills cancer cells, but also stops Hedgehog cancer pathway, present in many aggressive tumors. Preclinical toxicology and dosing studies for the compound, called NDC-1308, are expected to be completed this year, followed with Human Phase 1 clinical studies.
"ENDECE has a completely different approach to treating cancer," said Dr. James Yarger, co-founder, CEO and lead researcher for ENDECE. Yarger explained that currently most cancer drugs target single mutations (targeted to single proteins) to control cancer growth. While the current hot approach of "targeted" therapeutics is leading to novel drugs that prove effective for awhile, said Yarger, they generally extend life by only a few months. In order to survive, cancer cells are great at finding a way around this single target approach. Therefore, cancer cells quickly become resistant to many of the newest cancer drugs—and often within months. "ENDECE’s novel approach to fighting cancer involves targeting and controlling multiple pathways that are essential to cancer replication and ultimately shutting down a tumor’s ability to survive by switching tumor cells’ own pathways from proliferation to death," said Yarger. "Because ENDECE impacts multiple pathways and multiple targets, we believe it will be much more difficult for cancers to become resistant to NDC-1308."
Yarger, who has degrees in molecular biology and metabolic engineering and was a Post doctoral fellow at Harvard, established ENDECE, LLC in 2006 to design compounds with an approach he calls the "BioSwitch Concept". The approach identifies and regulates naturally occurring biomolecular switches thought to be used by normal, non-cancerous tissues to control cell proliferation. Endece’s compound substantially turns these switches down resulting in cancer cell death.
"What is one of the few characteristics all cancer cells have in common?" asks Yarger. "It’s rapid replication of cells. Our lead compound, NDC-1308, binds to an estrogen receptor known as ER-beta, not only shutting down a tumor’s ability to grow but also switching tumor cells from proliferation to death. NDC-1308 does this by controlling at least 21 genes at the "switch level" whose encoded proteins are absolutely required for cell proliferation. To date NDC-1308 has proven effective against a broad panel of human tumors in vitro and against selected human tumors in animal cancer studies.
Unexpectedly, data suggest that when NDC-1308 binds to receptor ER-beta, it also controls at least 4 genes that are essential for aggressive and lethal human cancers driven by the Hedgehog pathway. The Hedgehog signaling pathway is one of the key regulators of human development. Uncontrolled activation of the Hedgehog pathway has been implicated in the development of cancers in various organs, including brain, lung, breast, prostate and skin. As an example, over 80% of pancreatic cancers appear to be driven by mutations in the Hedgehog pathway. Hedgehog represents a new frontier in cancer treatment, and drug companies around the world are racing to generate and test new compounds to control it. With NDC-1308, ENDECE is now at the forefront of research in this area.
NDC-1308 is scheduled to begin Phase 1 human clinical studies in early 2011, but ENDECE’s results with Hedgehog could expedite drug development. "Our oncology board is particularly excited about NDC-1308 not only because it has a unique mechanism of action towards cancers and thus may stop cancers where other drugs have failed (giving oncologists an additional tool to keep their patients alive) but also because it effects Hedgehog," says Yarger. "We believe we have discovered a compound that could provide years of quality life for those patients who today who are dying from so many forms of cancer."

Dynamic Dual-Gated Preclinical PET Imaging
Santosh S. Arcot, PhD., Marketing Manager and Martin Cordell, PhD., Product Manager, Siemens Healthcare
Drug Discovery & Development - March 09, 2010

As is common in all drug discovery and development projects, upon the identification of promising lead compounds, the next steps usually involve initial safety tests in animal subjects.  As part of these safety tests, scientists evaluate ADME properties or “pharmacokinetics” of each lead compound. In order to proceed to the next phase, candidates must demonstrate that they are absorbed into the bloodstream, distributed to the proper site of action, metabolized efficiently and effectively, and then excreted from the body.
In vivo imaging techniques such as positron emission tomography (PET) provide a means to perform dynamic ADME studies in mouse models without sacrificing the animal..Despite this benefit, live-animal pharmacokinetic studies of cardiac drugs pose a unique challenge in mice.  A typical mouse heart rate is between 300-500 beats/min, making it very challenging to perform accurate pharmacokinetic studies using dynamic imaging techniques due to the motion artifacts produced.
With the introduction of dual-gated dynamic imaging technique, it is now possible to obtain high-resolution PET images of “motion-frozen” time points in an ADME study and be able to quantify the amount of drug in the target organ of interest.
How does “dual-gated” dynamic PET imaging work?Physiological motion in a mouse cardiac study is the result of the heart beating and respiratory motion. PET imaging is most effective if motion artifacts can be filtered out. This is typically performed by using physiological monitoring equipment to introduce “gating” tags to the raw PET acquisition data (also referred to as list mode data), indicating the start of the cardiac and respiratory cycles.
The first panel in the figure depicts the introduction of cardiac and respiratory tags into the list mode data (Step 1). Upon the completion of the study, the list mode data is then retrospectively processed by subdividing the data into a number of images to show the uptake of the compound over time and at different phases of the physiological cycles.  The second panel in the figure shows how the time and gating tags allow the user to define the length of each dynamic frame as well as the number of bins for each physiological process (Step 2). Selected images from the various frames in a dynamic study can be subjected to further analysis. The third panel highlights the ability to select a single phase of the physiological cycle for analysis, effectively freezing the physiological motion and eliminating the motion-blurring effects. Regions of interest can then be accurately defined on the images and the data can be quantified for the presence of the experimental labeled drug. This data can then be plotted as time-activity curves and kinetic modeling functionality can be used to calculate the rate of drug uptake (Step 3).
This technique offers several benefits. It allows the use of mice as animal models— without sacrificing large number of subjects—thereby reducing costs. The continued survival, and therefore analysis, of the subject animal minimizes variability and ensures accuracy of data. Lastly, PET imaging provides for measuring rapid kinetics and can therefore generate a more accurate picture of the ADME process.

Principal Investigator System Enables CROs to Improve Bioanalytical Study Management

Principal Investigator System Enables CROs to Improve Bioanalytical Study Management
Richard LeLacheur, Vice President, PharmaNet, Princeton, NJ
Drug Discovery & Development - February 10, 2011

INDUSTRY INSIDER
In order to ensure smooth operation during bioanalytical studies, structured business processes that facilitate rapid performance and internal and external communication are essential. A novel model, where a principal investigator (PI) with direct control over the entire study is the core of the bioanalytical project, has been developed.
This model positions the PI as the main point of contact for the client and extends the traditional project management (PM) role, as the PI has direct control over all aspects of the study including, scientific, technical, and regulatory decision-making. Expanded authority allows the PI to act not only as a client liaison and coordinator but also to respond quickly to client needs and queries, regulate internal resources and deliver results on schedule. This article will discuss how the harnessing of the PI model in a contract research organization (CRO) can improve bioanalytical study management and facilitate meeting stringent quality standards and project timelines.
The PI model consists of a team of laboratory analysts and information management specialists. The PI serves as the leader of the team, acts as a mentor to team members, and has direct control over the project. The central members of the team work together to establish a reliable and effective working relationship.
The PI is a senior scientist with expert knowledge in the development and assessment of analytical chemistry or biology methods. These skills are usually developed over at least five to seven years, during which the prospective PI takes on an expanding role in first performing and later managing laboratory work. As the team’s senior scientist, the PI is able to both perform and supervise significant scientific and technical operations.
The lead laboratory analyst carrying out the method development works under the supervision of the PI to execute an efficient method. Once pre-validation testing is complete, the analyst will continue to perform the validation. In some cases, additional analysts join the team as part of the method validation or perform individual qualifications following method validation.
In many CRO laboratories, once validation is complete, the method will be transferred to a new set of analysts or technicians to perform sample analysis. Direct experience with the method is lost in this transfer. The PI system avoids this setback as the same PI and analyst(s) work continually from method development to validation and through to sample analysis. The PI continues to supervise and analyze all data while the same analysts perform sample extraction, instrument operation, and initial data processing.
Staff continuity means laboratory technique is consistent throughout method operation and avoids “method creep,” where a written method is handed from analyst to analyst resulting in minor changes in unwritten techniques. The PI team with experience from the validation recognizes acceptable method performance and has the expertise to troubleshoot the method if problems occur. For example, asymmetry in chromatographic peak shape from dosed subject samples can be indicative of problems with method performance. These problems will not appear in the calibration standard or quality control sample statistics and can easily be missed by technicians lacking substantial method experience.
The report coordinator (RC) works closely with the PI and analysts to complete and organize all of the documentation of the study. The RC is responsible for all information for the study, from the receipt of the first samples through to completion of the final report. The RC is also responsible for resolving sample identification discrepancies..
Managing change effectively
Throughout the working relationship, the total workload may rise and fall significantly.  In order to meet both the client and CRO operational objectives the PI teams must be flexible.
The team usually consists of a core group of analysts that remain together for extended periods of time. When the workload increases, for example, to accommodate large-scale clinical studies, additional analysts will join the team. The core group with the critical method and compound experience remain engaged and the team’s capacity is simply increased. The same applies if data management capacity needs to be increased, additional report coordinators will then join the core RC team.
Case study: Fast turnaround GLP bioanalysis
A recent case study demonstrates the effective operation of a PI team. A client scheduled multiple clinical programs to have simultaneous studies, all of which required rapid data delivery turnaround (results issued within three to five days of sample receipt, depending on the study). The swift scale-up required by the PI team is reflected in Figure 1, in which the weekly sample receipt volume is represented. The weekly sample flow varied between 300 to 3500 samples, many of which required analysis by multiple analytical methods. Timelines were met due to the flexibility of the PI team and the ability to appropriately adjust its capacity.
Conclusion
The PI system creates a simple approach to bioanalytical study management for the client. By combining the CRO roles of communication, scientific and regulatory decision-making, and resource management and scheduling, the PI can respond rapidly to changing client needs and deliver efficient and effective service to the client. A single point of contact for the client can facilitate initial communication, when the CRO-client work practices and first analytical methods are established. As the relationship grows and the PI begins to manage additional programs for the client, the frequency of timeline change will increase

Keeping Patients in Clinical Trials

Keeping Patients in Clinical Trials
Scott H. Connor, Vice President, Marketing, Acurian, Inc.
Drug Discovery & Development - February 07, 2011


The life-blood of advancing medical science often comes in streams of digital bits—the data flowing from high-grade clinical trials. Beyond the goals of enrolling the right patients in large enough numbers into clinical research protocols, lies the increasingly daunting task of keeping them enrolled—to ensure the supply of essential data.  One recent analysis suggested a full 30% drop-out rate in Phase 3 trials.¹ Another offered a more dire estimate.  The report, “Growing Protocol Design Complexity Stresses Investigators, Volunteers”, showed that clinical trial retention rates in 57 Phase 2 and 3 trials between assessments in 1999-2002 and in 2003-2006 fell from 69% to 48%.²
Such high attrition rates can spell disaster for the reliability and validity of conclusions drawn from research. What lies behind high attrition rates? A variety of general factors may be at work, including competing life demands, logistical issues, and general inconvenience.³ But a deeper explanation may be found in evolving patterns in the nature of clinical trials.  One structural factor degrading retention rates shown in the Tufts study is that the overall duration of clinical trials has increased 74%. Between the two sampling periods, average case report forms grew from 55 to 180 pages and consent forms got longer, as well. Over the same period, trial protocols became more complex with higher average numbers of required procedures per protocol.
Intensified communication  and intervention
The standard approach to supporting patient retention has been to reward the patient’s commitment through informational booklets, invitations to join associations, various tchotchkes, thermoses, tote bags and t-shirts, practical health-related aids to exercise or diet (e.g., diabetes recipes and food guides), and other assorted nominal give-aways. The new ethics code of the Pharmaceutical Research and Manufacturers of America (PhRMA) unveiled in July 2008, banning distribution of pens, mugs, pads or other similar items with drug names, while voluntary, however, has reduced distribution of promotional items and other perks throughout the medical community. A survey of more than 700 site coordinators  found the value of such perks for keeping patients motivated toward ongoing clinical trial participation to be modest.⁴  A further survey looking at patients who had participated in and remained in clinical trials found altruistic aspects, the sense of contributing to “the greater good,” as the strongest motivator for patients who stick with the trial to its conclusion.⁵
The site coordinator at the center
Bringing about that “greater good,” especially with the growing complexity of clinical trials and the demands they put on patients, means fulfilling the tasks that eventually lead to the data stream mentioned earlier. Those tasks fall squarely within the responsibility of the site coordinator. It is the site coordinator who ensures that patients make and keep appointments within the stipulated time windows, schedule and submit to lab tests or imaging as required, and stay with the trial throughout the follow-up period. Relentlessly keeping track of patients’ status with regard to all of this is complex and difficult, as is taking appropriate steps when patients miss or fall behind in their appointments.
All too often, the sheer volume of the site manager’s tasks, is simply overwhelming, rendering attempts to foster patient retention less effective than they could be.
Streamlining workflow
A potential solution is to provide a centralized, integrated, and structured approach to workflow, combining effective human services and well-designed software. Software applications should show which active patients are eligible to come in for an appointment, but have not yet made one. It has to provide warnings showing the number of days until appointment windows open and close. It also needs to stipulate whether laboratory testing is needed for a particular visit. In short, a successful program has to coordinate and structure the sequence of tasks to be accomplished.
Many of these tasks can be taken up through sophisticated software and on-site program personnel.  Among these tasks are informing the patient via calls or text messages about the appointment date, sending reminders about dates of upcoming appointments and any requirements (e.g., no eating after midnight for tests), and notifying the site coordinator when an appointment has been confirmed and kept. When there are long intervals between visits, general encouragement notes to maintain patients’ interest in and engagement with the clinical trial can be sent.
Ensuring that a particular patient has an appointment within the visit window and other critical tasks remain the job of the site coordinator. The likelihood that they will be successfully completed is optimized when there is a constant stream of communication within the system and between the patient and the site coordinator so that each knows what the next step is and what steps have already been taken.
When patients drift awayWhat needs to happen when it becomes apparent to the site coordinator that patients have not merely missed an appointment or two, but have lost interest in or are choosing to discontinue participation? Then retention program personnel need to engage in a regimented recovery process. They need to identify the underlying causes of patients’ dissatisfaction. Are they unhappy with their physicians? Investigators can be switched. Are travel expenses excessive? Addition travel reimbursement can be arranged. Every effort has to be made to quickly identify patients’ issues and to ameliorate their concerns and reconnect them with the clinical trial.
The overall effect
The goal of integrating patient retention software and targeted personal communications is to transform what is often a fragmented set of efforts into a simplified, prioritized, and coordinated stream of tasks and events—without adding to anyone’s workload. The aim is make sure that problems appear “on the radar” with sufficient lead-time for effective intervention, while avoiding compromise to data collection and excessive costs.
Given the clearly growing challenges to ensuring patient retention and research data collection, the modest added program cost of building in such strategies may be easily justified. In fact, many clinical operations directors and trial managers regard patient retention services as an affordable insurance policy to protect against the more severe cost implications caused by lost patients and compromised research aims.
About the AuthorScott Connor has more than 20 years of marketing and software experience in the life sciences and technology arenas. He graduated summa cum laude from Syracuse University.
References
1. Elvidge S. Importance of Patient-Retention Strategies. Life Science Leader. April 2010.
2. Kaitin KI. Growing Protocol Design Complexity Stresses Investigators, Volunteers. Impact Report. Tufts Center for the Study of Drug Development. 2008.
3. Janson S, Alioto M, Boushy H. Attrition and retention of ethnically diverse subjects in a multicenter randomized controlled research trial. Controlled Clinical Trials. 2001, 22(6 Suppl): 236S-43S.
4. Patient Retention Services Assessment. MSP Analytics, Inc. December 2009.
5. Clinical Trial Participation Insights. Survey Gizmo. April 2010.

PROLOR Study to Be Completed by Mid-Year

PROLOR Study to Be Completed by Mid-Year
Drug Discovery & Development - February 14, 2011

PROLOR Biotech, Inc., a company developing next generation biobetter therapeutic proteins, reported that patient enrollment and dosing in the Phase 2 trial of its long-acting version of human growth hormone (hGH-CTP) are proceeding according to plan, with study completion targeted for mid-year 2011. The study is assessing the efficacy of hGH-CTP by measuring IGF-1 levels in growth hormone deficient adults in response to administration of different doses of hGH-CTP, injected once weekly or bi-monthly. Safety and tolerability are also being assessed.
PROLOR also announced that a routinely scheduled review on February 9, 2011 by an independent Data and Safety Monitoring Board (DSMB), which includes world-renowned endocrinologists who are not affiliated with PROLOR, concluded that the hGH-CTP trial was safe to proceed as planned, having identified no serious safety issues associated with the investigational drug in either patients who have already completed the study or those still being dosed.
“Our long-acting version of human growth hormone has the potential to dramatically decrease the burden of daily injections currently faced by growth hormone deficient patients, and we are pleased by the continued progress in our Phase 2 trial,” said Dr. Abraham Havron, CEO of PROLOR. “The positive DSMB review reaffirmed our expectations that hGH-CTP should demonstrate a good safety profile. We look forward to analyzing the Phase 2 efficacy data and conducting the dose estimation modeling needed for Phase 3 as we head towards completion of this trial in the coming months.”
PROLOR is developing hGH-CTP to provide growth hormone deficient adults and children with growth hormone therapy that requires only once-weekly or bi-monthly injections, rather than the multiple injections per week required by current regimens. The hGH-CTP Phase 2 trial is a randomized, open-label, dose-finding study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamic properties of hGH-CTP injected either weekly or twice-monthly in patients who currently receive daily injections of growth hormone. The trial is being conducted at multiple sites in six countries.
Date: February 14, 2011
Source: PROLOR Biotech, Inc. 

Tarsa Finishes Phase 3 Calcitonin Trial

Tarsa Finishes Phase 3 Calcitonin Trial
Drug Discovery & Development - February 14, 2011

Tarsa Therapeutics, Inc. announced completion of its global Phase 3 ORACAL trial testing the company’s once-daily oral recombinant calcitonin for the treatment of postmenopausal osteoporosis. Results from the ORACAL trial are expected in early spring. In addition, Tarsa announced initiation of a new Phase 2 study of its oral calcitonin for the prevention of postmenopausal osteoporosis.
The ORACAL study is a multinational, randomized, double-blind, active and placebo-controlled Phase III trial that enrolled 565 postmenopausal women with osteoporosis. Analysis of the trial data is currently underway.
The new Phase 2 prevention trial is a randomized, double-blind, placebo-controlled study designed to enroll approximately 120 postmenopausal women with low bone mass at increased risk of fracture. The trial will assess the efficacy of Tarsa’s oral calcitonin in the prevention of bone loss in these women, as well as its safety and tolerability. The prevention trial is being conducted at multiple centers in the US.
“The conclusion of our Phase 3 ORACAL osteoporosis treatment trial and initiation of our Phase 2 prevention trial are major milestones in Tarsa’s oral calcitonin program,” said David Brand, President and CEO of Tarsa. “Our tablet has the potential to offer calcitonin’s 30-year record of safety and efficacy with the advantage of once-daily oral administration to the millions of postmenopausal women with osteoporosis or at risk of osteoporosis. We look forward to releasing ORACAL safety and efficacy data in the coming months. If positive, we believe that our product has the potential to be the first FDA-approved oral formulation of calcitonin to reach the market.”
Tarsa plans to submit a New Drug Application to the US Food and Drug Administration for the use of its oral calcitonin as a treatment for postmenopausal osteoporosis later this year, and a Marketing Authorization Application to the European Medicines Agency next year.
Calcitonin is currently approved for the treatment of postmenopausal osteoporosis, but its use has been limited by the fact that it is currently available only in intranasal and injectable forms. Tarsa’s oral calcitonin product has been shown in prior clinical studies to deliver the desired blood levels of calcitonin and reduce levels of biomarkers of bone resorption.
Dr. David Krause, Chief Medical Officer of Tarsa, commented, “Osteoporosis is a common condition that poses major health risks to individuals as they age, but it can be both treated and prevented. Calcitonin has a long history of safety and efficacy as an osteoporosis therapy, and we believe the availability of Tarsa’s easy-to-use, once-daily oral calcitonin tablet will be welcomed by the many health care providers and patients seeking additional treatment options, especially in view of continuing concerns about potential long-term safety issues with other popular classes of osteoporosis drugs.”
Tarsa’s Phase 2 prevention trial will also explore the optimal dosing regimen for oral calcitonin by administering the tablets either with the evening meal or at bedtime. Calcitonin helps maintain bone mass by acting on osteoclasts to limit bone resorption. Most bone resorption occurs while individuals are sleeping, therefore some researchers believe that nighttime administration would be ideal for an anti-resorptive agent such as calcitonin.
Date: February 14, 2011
Source: Tarsa Therapeutics, Inc.