Bosutinib, the better tyrosine kinase inhibitor of Bcr-Abl?

Bosutinib (SKI-606) is the third-generation tyrosine kinase inhibitor of Bcr-Abl, the constitutively active tyrosine kinase resulting from the Philadelphia chromosome abnormality in CML. Bosutinib also inhibits kinases in the Src family, including Src, Lyn, and Hck. According to many research reports, Bosutinib is active against many imatinib-resistant mutations (16 of 18 imatinib-resistant forms of Bcr-Abl in murine myeloid cell lines), but not active against the T315I and V299L mutations.

 

According to clinicaltrials.gov, there are 3 ongoing trials on Bosutinib.

 

▪          BELA: Bosutinib (BOS) versus imatinib (IM) in patients (pts) with newly diagnosed chronic phase chronic myeloid leukemia (CP CML)

 

▪          Study Evaluating SKI-606 (Bosutinib) In Philadelphia Chromosome Positive Leukemias

 

▪          Compare Bosutinib To Imatinib In Subjects With Newly Diagnosed Chronic Phase Philadelphia Chromosome Positive CML

Bortezomib (PS-341) may be a potential treatment for GRMD?

Golden retriever muscular dystrophy (GRMD) is a genetic myopathy corresponding to Duchenne muscular dystrophy (DMD) in humans. Muscle atrophy is known to be associated with degradation of the dystrophin-glycoprotein complex (DGC) via the ubiquitin-proteasome pathway.

In a recently published study, the investigators looked at the effect of bortezomib treatment on the muscle fibers of GRMD dogs. The Dogs treated with the proteasome inhibitor bortezomib (TD- Treated) were compared with control dogs (CD). Pharmacodynamics were evaluated by measuring the inhibition of 20S proteasome activity in whole blood after treatment.Immunohistochemical studies were performed on muscle biopsy specimens to evaluate the rescue of dystrophin and dystrophin-associated proteins in the muscles of GRMD dogs treated with bortezomib. Skeletal tissue from TD had lower levels of connective tissue deposition and inflammatory cell infiltration than CD as determined by histology, collagen morphometry and ultrastructural analysis. The CD showed higher expression of phospho-NFκB and TGF-β1, suggesting a more pronounced activation of anti-apoptotic factors and inflammatory molecules and greater connective tissue deposition, respectively. Immunohistochemical analysis demonstrated that dystrophin was not present in the sarcoplasmic membrane of either group. However, bortezomib-TD showed higher expression of α- and β-dystroglycan, indicating an improved disease histopathology phenotype. Significant inhibition of 20S proteasome activity was observed 1 hour after bortezomib administration in the last cycle when the dose was higher. Proteasome inhibitors may thus improve the appearance of GRMD muscle fibers, lessen connective tissue deposition and reduce the infiltration of inflammatory cells. In addition, proteasome inhibitors may rescue some dystrophin-associated proteins in the muscle fiber membrane.

Gilotrif TM (afatinib) has been approved as first-line treatment for lung cancer patients with EGFR mutations by FDA

Lung cancer is the biggest cancer killer in the world with incidence rates higher in men than in women, it accounts for 1.6 million new cancer cases annually. However, lung cancer isn’t just one disease; research has shown there are many different types requiring specific treatment approaches. One distinct subtype of lung cancer is defined by mutations in EGFR (a member of the ErbB Family of receptors). These are patients that in clinical trials have been shown to benefit most from afatinib treatment.

 

U.S. Food and Drug Administration (FDA) has approved afatinib tablets under the U.S. brand name GILOTRIFTM for oral use, as a new first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.

 

The approval of afatinib in the U.S. is based on data from the pivotal LUX-Lung 3 trial, comparing afatinib to chemotherapy with pemetrexed/cisplatin. Data from LUX-Lung 3 has shown that patients taking afatinib as a first-line treatment lived for almost one year without their tumour growing again (median progression-free survival (PFS) of 11.1 months) versus just over half a year (PFS of 6.9 months) for those treated with pemetrexed/cisplatin. In addition, NSCLC patients with tumours harbouring the two most common EGFR mutations (Del19 or L858R) taking afatinib lived for well over a year without tumour progression (PFS of 13.6 months) versus just over half a year (PFS of 6.9 months) for those in the comparator arm.

 

91. Bortezomib (PS-341) may be a potential treatment for GRMD?

 

Catgory: Drugs and clinical trails

 

Golden retriever muscular dystrophy (GRMD) is a genetic myopathy corresponding to Duchenne muscular dystrophy (DMD) in humans. Muscle atrophy is known to be associated with degradation of the dystrophin-glycoprotein complex (DGC) via the ubiquitin-proteasome pathway.

 

In a recently published study, the investigators looked at the effect of bortezomib treatment on the muscle fibers of GRMD dogs. The Dogs treated with the proteasome inhibitor bortezomib (TD- Treated) were compared with control dogs (CD). Pharmacodynamics were evaluated by measuring the inhibition of 20S proteasome activity in whole blood after treatment.Immunohistochemical studies were performed on muscle biopsy specimens to evaluate the rescue of dystrophin and dystrophin-associated proteins in the muscles of GRMD dogs treated with bortezomib. Skeletal tissue from TD had lower levels of connective tissue deposition and inflammatory cell infiltration than CD as determined by histology, collagen morphometry and ultrastructural analysis. The CD showed higher expression of phospho-NFκB and TGF-β1, suggesting a more pronounced activation of anti-apoptotic factors and inflammatory molecules and greater connective tissue deposition, respectively. Immunohistochemical analysis demonstrated that dystrophin was not present in the sarcoplasmic membrane of either group. However, bortezomib-TD showed higher expression of α- and β-dystroglycan, indicating an improved disease histopathology phenotype. Significant inhibition of 20S proteasome activity was observed 1 hour after bortezomib administration in the last cycle when the dose was higher. Proteasome inhibitors may thus improve the appearance of GRMD muscle fibers, lessen connective tissue deposition and reduce the infiltration of inflammatory cells. In addition, proteasome inhibitors may rescue some dystrophin-associated proteins in the muscle fiber membrane.

Nintedanib (BIBF 1120), a TOMORROW’s medicine for idiopathic pulmonary fibrosis (IVF)? Part II

Patients aged at least 40 years with a predefined IPF diagnosis of less than 5 years prior to the study screening were included in the study. Eligible patients had a FVC≥50% and a DLCOpred 30-79% and a PaO2 ≥55mmHg. Concomitant oral therapy with prednisone (or equivalents) of ≤15 mg if stable during the 8 weeks previous to the study enrollment.

The primary efficacy endpoint was represented by the FVC decline rate and the secondary endpoints included changes from baseline in FVC, DLco, SpO2, TLC, exercise capacity, SGRQ (St. George respiratory questionnaire) scores, the incidence of acute exacerbations, overall mortality, and that due to respiratory causes.

The highest BIBF 1120 dose was associated with the most significant therapeutic effect on the lung function decline compared to placebo, the drug reducing the annual rate of lung function decline by 68.4% compared to placebo group.

The highest dose of BIBF 1120 therapy was also associated with a lower percentage of patients exhibiting a significant reduction of the FVC (of >10% or of >200ml) compared to placebo (23.8% versus 44%, p=0.004). Unlike placebo BIBF 1120 preserved the total lung capacity (−0.24 liters vs. 0.12 liters, p<0.001).

Mean change from baseline in the SpO2 was −0.2% with BIBF 1120 and −1.3% with placebo (p = 0.02). The highest dose therapy was also associated with a lower percentage of significant desaturation (>4% reduction from baseline in resting SpO2) over the study period 3.6% respectively 11.0%, p = 0.03). BIBF 1120 didn’t exert a significant therapeutic benefit on the DLCO and in the exercise capacity as compared to placebo.

 

Health Related Quality-of-Life (HRQoL) evaluated with SGRQ was found to be significantly improved with the BIBF highest dose as compared to placebo the difference being also clinically significant: mean change −0.66 points with the active treatment compared to 5.46 points with placebo p = 0.007.

Overall, there were comparable incidences of adverse events among all groups with comparable rates of severe/life-threatening effects as well. The adverse events which most commonly led to treatment discontinuation were diarrhea, nausea, and vomiting and were reported in the group receiving 150 mg twice a day.

 

The TOMORROW trial is planned to be followed by an open-label continuation phase in which efficacy and safety of BIBF-1120 are planned to be further studied.

Two phase III studies aimed at evaluating the efficacy and safety of BIBF 1120 150 mg×2/day over 52 weeks in patients with IPF are also planned. These two studies have similar endpoints which include the annual decline rate in FVC, quality of life and time to first exacerbation, overall survival.

Nintedanib (BIBF 1120), a TOMORROW’s medicine for idiopathic pulmonary fibrosis (IVF)? Part I

Idiopathic pulmonary fibrosis (IPF) is a rare life-threatening disease of the lungs characterized by a rapidly progressive fibrogenesis, limited survival and by limited therapeutic resources. The poor disease outcome is due not only to the fact that there are only few therapies available, but also to the rather modest antifibrotic effects of treatments such as corticosteroids, cyclophosphamide or azathioprine which are conventionally used as the first line approach in such patients.

 

BIBF 1120 (nintedanib), an oxindole derivative is a triple kinase inhibitor with potent suppressing effects on VEGFR, PDGFR and bFGFR. Nintedanib is currently in advanced clinical testing for various types of advanced solid cancers as a potential antiangiogenic therapy to be added to the cytotoxic agents to exert synergistic antitumour effects. The antiangiogenic effects of nintedanib were demonstrated in various preclinical studies such including inhibition of proliferation of HUVEC cell line or animal models of xenografttumour, as well as in clinical trials in subjects with advanced non-small cell lung cancer or gastrointestinal tumours.

 

BIBF 1120 was assessed in many clinical studies performed in a wide range of solid malignancies including non-small cell lung cancer (NSCLC) as an antiangiogenic therapy and in few clinical studies as a potential antifibrotic therapy in IPF.

The TOMORROW (To Improve Pulmonary Fibrosis with BIBF-1120) study was a 12 month, randomized, placebo controlled, phase II study evaluating the efficacy and safety of four nintedanib doses (50 mg once daily, 50 mg twice daily, 100 mg twice daily, 150 mg twice daily) in patients with idiopathic pulmonary fibrosis.

The dual PI3K/mTOR inhibitor NVP-BEZ235 induces tumor regression in a genetically engineered mouse model of PI3KCA wild-type colorectal cancer

A recent research study has reported the in vitro and in vivo efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in treatment of PIK3CA wild-type colorectal cancer (CRC). PIK3CA mutant and wild-type human CRC cell lines were treated in vitro with NVP-BEZ235, and the resulting effects on proliferation, apoptosis, and signaling were assessed. Colonic tumors from a genetically engineered mouse (GEM) model for sporadic wild-type PIK3CA CRC were treated in vivo with NVP-BEZ235. The resulting effects on macroscopic tumor growth/regression, proliferation, apoptosis, angiogenesis, and signaling were examined.In vitro treatment of CRC cell lines with NVP-BEZ235 resulted in transient PI3K blockade, sustained decreases in mTORC1/mTORC2 signaling, and a corresponding decrease in cell viability (median IC(50) = 9.0-14.3 nM). Similar effects were seen in paired isogenic CRC cell lines that differed only in the presence or absence of an activating PIK3CA mutant allele. In vivo treatment of colonic tumor-bearing mice with NVP-BEZ235 resulted in transient PI3K inhibition and sustained blockade of mTORC1/mTORC2 signaling. Longitudinal tumor surveillance by optical colonoscopy demonstrated a 97% increase in tumor size in control mice  vs. a 43% decrease in treated mice. Ex vivo analysis of the NVP-BEZ235-treated tumors demonstrated a 56% decrease in proliferation, no effects on apoptosis, and a 75% reduction in angiogenesis.These studies provide the preclinical rationale for studies examining the efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in treatment of PIK3CA wild-type CRC.

Sanofi (France), Medtronic, Inc. Team Up To Develop New Diabetes Devices Part II

“Diabetes is unfortunately rising in prevalence around the world, driving up system costs and, most importantly, adversely impacting the lives of millions of people. Like Sanofi, we believe there is tremendous opportunity to better align care across the diabetes care continuum through new and varied technologies and patient care management strategies,” said Omar Ishrak, Chairman and CEO, Medtronic. “Medtronic is committed to taking a broader approach, expanding beyond our core strength in Type 1 diabetes, to co-develop an array of technologies and patient services that will deliver superior clinical outcomes at an affordable price. We also know we can’t do it alone – so we are particularly excited to join in this effort with Sanofi who, like us, is committed to exploring new avenues and approaches to solving the challenges associated with diabetes.”

The alliance will pair Sanofi’s extensive insulin portfolio and drug development expertise with Medtronic’s expertise in insulin pumps and continuous glucose monitoring. One of the priorities of the alliance will be to deliver novel drug-device combinations, including new form factors that are affordable, convenient and easy to-use to increase therapy adherence and deliver better outcomes. These efforts will focus on improving the management of Type 2 diabetes, especially for people who cannot achieve glucose control even with multiple daily injections of insulin.

Care management services, another priority area for collaboration, will be delivered through a program designed to guide people with Type 2 diabetes who are failing to achieve disease control on oral therapies through the initiation phase of insulin treatment. Insulin initiation can be challenging as a high number of patients drop insulin treatment in this early phase.

As world leaders in complementary segments of diabetes care Sanofi and Medtronic already have an agreement in place serving specific Type 1 diabetes patients in Europe with an implantable insulin delivery system, and intend to add this project and additional innovative projects to the alliance. Implementation of the alliance is subject to the negotiation and execution of a definitive agreement between the companies.

Vintafolide, a new drug study for non-small cell lung cancer (NSCLC) PART2

Vintafolideis in a phase IIb study (TARGET) for the treatment of non-small cell lung cancer (NSCLC). Detailed data from this study is expected in late 2014. Endocyte announced that it has regained worldwide rights to oncology candidate, vintafolide, from Merck & Co. Inc. Endocyte received the rights to vintafolide as Merck decided to discontinue its investment in the development of vintafolide, after an extensive assessment of Merck’s portfolio.

In Apr 2012, Merck had acquired the rights for the development and commercialization of vintafolide for six separate cancer indications. Merck’s decision to discontinue the development of vintafolide does not come as a surprise considering the recent vintafolide-related setbacks. In May 2014, as recommended by the Data and Safety Monitoring Board (DSMB), Endocyte and Merck had stopped patient enrollment in a phase III study on vintafolide for the treatment of platinum resistant ovarian cancer (PROC) and withdrew their conditional marketing authorization applications in the EU for vintafolide and companion imaging components. Endocyte shares were down in pre-market trading on the news regarding the termination of the Merck partnership.

Currently, we have low visibility regarding the future of vintafolide. The market for NSCLC is becoming increasingly competitive. Currently approved drugs for the treatment of NSCLC include Xalkori and Alimta. AbbVie’s veliparib is in phase III studies for the same indication. A better-ranked stock in the biotech sector is ARIAD Pharmaceuticals, Inc.

Vintafolide, a new drug study for non-small cell lung cancer (NSCLC) PART1

A drug studied to improve chemotherapy may be effective in treating patients with cancers related to the BRCA 1 or 2 genetic mutations, as well as patients with BRCA-like breast cancers, according to a University of Pittsburgh Cancer Institute clinical trial.

The results of the phase I study were presented today at the 50th annual American Society of Clinical Oncology (ASCO) annual meeting in Chicago.

Veliparib (ABT-888), a PARP inhibitor, which means it lowers the resistance of cancer cells to treatment by targeting the polymerase (PARP) family of enzymes responsible for a wide variety of cellular processes in cancer cells.

Cancer cells have increased levels of PARP, which we believe may, in part, lead to resistance to chemotherapies and other cancer treatments. Tumor cells in patients with BRCA mutations are particularly sensitive to the effects of PARP inhibitors due to underlying DNA repair abnormalities caused by the BRCA mutation. Veliparib can act as personalized medicine for patients with tumors caused by an inherited BRCA mutation, due to this particular sensitivity.

The study enrolled 60 patients with a BRCA genetic mutation and 28 patients without a mutation. The objectives of the trial included determining how veliparib affected cancer cells and observing how patients responded to the drug. We found that veliparib is well-tolerated by patients, with fewer side effects than what can be seen with chemotherapies. In addition, anti-tumor activity was detected in both our BRCA-positive and our BRCA-negative patients.

A research team at UPCI have been investigating ABT-888 for five years. Their research began in the laboratory and progressed to human clinical trials. Dr. Puhalla currently is leading a phase II clinical trial with ABT-888. Many cancer patients with BRCA mutations end up exhausting their treatment options. Veliparib may give  another option.

Ramucirumab recently approved as Cyramza for stomach cancer

Lilly has taken its effort to expand the market range for its key cancer drug ramucirumab. Ramucirumab recently approved as Cyramza for stomach cancer.Investigators say that the drug failed to hit the goal line for overall survival among liver cancer patients. Lilly, ever optimistic about its chances in the clinic, highlighted a trend in favor of the drug and also noted some positive signs of efficacy in subpopulations. Although the REACH study did not achieve statistical significance for survival, they are encouraged by the efficacy seen overall, especially in specific subpopulations. We plan to discuss these results with regulatory authorities.

Ramucirumab has had a series of ups and downs in the clinic. The drug failed a big breast cancer study, setting up a roadblock for the drug in a key market. It also recently delivered a marginal benefit for patients suffering from advanced non-small cell lung cancer, reducing the risk of death.This latest failure highlights a long drought of major new approvals, which was only broken with ramucirumab’s OK at the FDA. Lilly’s numbers have been hit hard by patent losses on its top products, opening the door to generic competition that has eroded earnings and placed the company in a must-win position in the clinic.

Lilly promised investors that the company will see new approvals each year for the next few years. But it needs more than a slate of approvals to reverse the effects of a long string of trial failures. It needs major new drugs that can command blockbuster sales. Its top drug prospect in the late-stage pipeline is now dulaglutide, though Lilly will soon be forced to detail new data.