Author: [email protected]

Phenotypic and metabolic investigation of a CSF-1R kinase receptor inhibitor (BLZ945) and its pharmacologically active metabolite.

1. 4-[2((1R,2R)-2-Hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylic acid methylamide (BLZ945) is a small molecule inhibitor of CSF-1R kinase activity within osteoclasts designed to prevent skeletal related events in metastatic disease. Key metabolites were enzymatically and structurally characterized to understand the metabolic fate of BLZ945 and pharmacological implications. The relative intrinsic clearances for metabolites were derived from in vitro studies using human hepatocytes, microsomes and phenotyped with recombinant P450 enzymes. 2. Formation of a pharmacologically active metabolite (M9) was observed in human hepatocytes. The M9 metabolite is a structural isomer (diastereomer) of BLZ945 and is about 4-fold less potent. This isomer was enzymatically formed via P450 oxidation of the BLZ945 hydroxyl group, followed by aldo-keto reduction to the alcohol (M9). 3. Two reaction phenotyping approaches based on fractional clearances were applied to BLZ945 using hepatocytes and liver microsomes. The fraction metabolized (fm) or contribution ratio was determined for each metabolic reaction type (oxidation, glucuronidation or isomerization) as well as for each metabolite. The results quantitatively illustrate contribution ratios of the involved enzymes and pathways, e.g. the isomerization to metabolite M9 accounted for 24% intrinsic clearance in human hepatocytes. In summary, contribution ratios for the Phase I and Phase II pathways can be determined in hepatocytes.

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(Press release, Intensity Therapeutics, SEP 2, 2014, View Source [SID:1234503396])

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VentiRx Pharmaceuticals Announces Fast Track Designation Granted for Motolimod (VTX-2337), a Novel Immunotherapy for Women with Ovarian Cancer

On September 2, 2014 VentiRx Pharmaceuticals reported that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to the investigation of motolimod (VTX-2337) when administered in combination with pegylated liposomal doxorubicin (PLD) for the treatment of women with ovarian cancer whose disease has progressed on or recurred after platinum-based chemotherapy (Press release VentiRx Pharmaceuticals, SEP 2, 2014, View Source [SID:1234500744]).

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Motolimid is a novel TLR8 immunotherapy currently being evaluated in two randomized, placebo-controlled Phase 2 trials.
FDA Fast Track Designation is designed to facilitate frequent interactions with the FDA review team to expedite clinical development and submission of a New Drug Application (NDA) for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs.

"The Fast Track designation is an important regulatory milestone for the motolimod (VTX-2337) program and underscores the potential for this novel agent to address a significant unmet medical need for women with ovarian cancer who have progressed on or recurred after receiving platinum-based chemotherapy," said Robert Hershberg, MD, PhD, President and CEO of VentiRx. "We look forward to emerging clinical data and to the possibility of providing a meaningful treatment for women with ovarian cancer."

VentiRx has completed enrollment of over 290 patients in the GOG-3003 randomized, placebo-controlled Phase 2 trial of motolimod in combination with PLD in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancer who have failed prior platinum-based chemotherapy. The study is being performed in collaboration with the Gynecologic Oncology Group (GOG) Partners Program. The primary endpoint of the study is overall survival. In April 2014, the FDA granted Orphan Drug designation to motolimod (VTX-2337) for the treatment of ovarian cancer.

Amgen Submits Marketing Authorization Application For Talimogene Laherparepvec To The European Medicines Agency

On September 2, 2014 Amgen reported the submission of a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) via the centralized procedure for talimogene laherparepvec seeking approval for the treatment of adults with melanoma that is regionally or distantly metastatic (Press release Amgen, SEP 2, 2014, View Source [SID:1234500719]). Talimogene laherparepvec is an investigational oncolytic immunotherapy administered as an intralesional injection that is designed to initiate a systemic anti-tumor immune response. If approved, talimogene laherparepvec will represent the first in a class of novel agents known as oncolytic immunotherapies.

The MAA for talimogene laherparepvec contains data from more than 400 patients and is based on a global, randomized, open-label Phase 3 trial evaluating the safety and efficacy of talimogene laherparepvec in patients with stage IIIB, IIIC or IV melanoma when resection was not recommended compared to granulocyte-macrophage colony-stimulating factor (GM-CSF).

“The submission of the Marketing Authorization Application in Europe for talimogene laherparepvec brings us a step closer to helping address an unmet medical need for patients with metastatic melanoma,” said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. “This regulatory milestone, on the heels of our Biologics License Application submission to the U.S. FDA, represents an important step for our pipeline and we look forward to working with the European Medicines Agency as it conducts its review of talimogene laherparepvec.”

Melanoma is a type of skin cancer that is characterized by the uncontrolled growth of melanocytes, which are the cells responsible for providing the pigment to skin. Melanoma is the most aggressive and serious form of skin cancer. Currently, 132,000 melanoma cases occur globally each year. The number of people with melanoma is expected to rise considerably worldwide, with more than 279,000 projected new cases by the year 2020.3 Outcomes are substantially worse for people with regional and distantly metastatic disease, with high risk of recurrence for Stage IIIB, IIIC, and IV melanoma.

Melanoma is considered to be advanced when it has spread, or metastasized, from the origin site to deeper parts of the skin or other organs such as the lymph nodes, lungs or other parts of the body distant from the primary tumor site.

Ipsen announces acceptance of filings for Somatuline® in the treatment of GEP-NETs in the US with priority review and in Europe

On September 1, 2014 Ipsen reported that the U.S. Food and Drug Administration (FDA) has accepted and granted priority review of its supplemental New Drug Application (sNDA) for Somatuline Depot 120mg injection in the treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) (Press release Ipsen, SEP 1, 2014, View Source [SID:1234500724]). The FDA designates priority review status to drug candidates that have the potential to offer a significant improvement in treatment compared to currently approved options. Decision is expected in early Q1, 2015.

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In the European Union, the dossier of the national marketing authorization (MA) variations for Somatuline Autogel 120mg injection has been validated by all national 25 drug regulatory authorities. The first decisions are expected by Q2 2015.

The regulatory submissions and variations were supported by the results of the CLARINET Phase III study, which demonstrated the antitumor effect of Somatuline in the treatment of patients with GEP-NETs, and which was recently published in the July 17th issue of The New England Journal of Medicine.

Marc de Garidel, Chairman and Chief Executive Officer of Ipsen stated: "We are pleased that the US and European regulatory authorities have accepted the filing for Somatuline in the treatment of GEP-NETs and that the dossier in the US has been granted priority review. We are excited about the potential benefits Somatuline could bring to patients suffering from this debilitating disease".

The data from CLARINET is purely investigational, as Somatuline is not authorized for the indication of treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in any market. In many countries where it is marketed as Somatuline Autogel, Somatuline is approved for treatment of acromegaly and for the symptoms associated with neuroendocrine tumors, which can include the treatment of GEP-NET patients experiencing symptoms from carcinoid syndrome, and Somatuline is approved in many countries for the treatment of acromegaly. Somatuline Depot is approved in the US for the treatment of acromegaly but not for the treatment of GEP-NETs or the symptoms thereof.