On April 25 2016 Ipsen (Euronext: IPN; ADR: IPSEY) reported that its partner Exelixis, Inc. (NASDAQ:EXEL) received approval from the U.S. Food and Drug Administration (FDA) for CABOMETYX (cabozantinib) tablets earlier today for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy (Press release, Ipsen, APR 25, 2016, View Source [SID:1234511439]). On February 29, 2016, Exelixis and Ipsen jointly announced an exclusive licensing agreement for the commercialization and further development of cabozantinib indications outside of the United States, Canada and Japan.

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RCC is the most common form of kidney cancer in adults. The incidence of advanced RCC is estimated to be around 20,000 new patients per year in Ipsen’s territories.

CABOMETYX, which was granted Fast Track and Breakthrough Therapy designations by the FDA, is the first therapy to demonstrate in a large, randomized phase 3 trial for patients with advanced RCC, robust and clinically meaningful improvements in all three key efficacy parameters — overall survival, progression free survival and objective response rate.

Compared with everolimus, CABOMETYX is associated with a 42 percent reduction in the rate of disease progression or death and 34 percent reduction in the rate of death. Median progressionfree survival for CABOMETYX is 7.4 months versus 3.8 months for everolimus (HR=0.58, 95% CI 0.45-0.74, P<0.0001). Median overall survival is 21.4 months for patients receiving CABOMETYX versus 16.5 months for those receiving everolimus (HR=0.66, 95% CI 0.53-0.83, P=0.0003).

In Europe, the Marketing Authorization Application (MAA) for cabozantinib in advanced RCC has been accepted and granted accelerated assessment. With this designation, the MAA is eligible for a 150-day review, versus the standard 210 days (excluding clock stops when information is requested by the EMA).

Exelixis press release is available here: http://bit.ly/24gckfO

Phagocytosis is an initial step in innate immunity, which is also stimulated by signals via Toll-like receptors (TLRs); however, the cooperation of phagocytosis with signals through TLRs to establish acquired immunity is unknown. We found that phagocytosis is an essential process to induce an immune reaction against an insoluble TLR ligand. Cell-wall skeleton prepared from Mycobacterium bovis BCG (BCG-CWS), an insoluble TLR2 ligand, activated and matured murine splenic dendritic cell (DC) line BC-1 as well as a soluble TLR2 ligand, Pam3CSK4. Surprisingly, BC-1 maturation with BCG-CWS was completely suppressed by inhibiting phagocytosis, while that with Pam3CSK4 was not affected. Moreover, BCGCWS induced intense delayed-type hypersensitivity (DTH) reactions against mitomycin C-inactivated Lewis lung carcinoma cells but Pam3CSK4 did not. These results suggested that the phagocytosis process enables the insoluble TLR2 ligand to activate DCs via TLR2 comparable to a soluble TLR2 ligand in vitro, and stimulating TLR2 alone is not sufficient to establish T cell-mediated immunity in vivo. It is therefore conceivable that the process of phagocytosis induces additional effects on TLR2-stimulated DCs to activate cellmediated immunity in vivo.

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The androgen receptor (AR) is a member of the nuclear hormone receptor super family of transcription factors. Androgens play an essential role in the development, growth, and maintenance of male sex organs, as well as the musculoskeletal and central nervous systems. Yet with advancing age, androgens can drive the onset of prostate cancer, the second leading cause of cancer death in males within the United States. Androgen deprivation therapy (ADT) by pharmacologic and/or surgical castration induces apoptosis of prostate cells and subsequent shrinkage of the prostate and prostate tumors. However, ADT is associated with significant musculoskeletal and behavioral adverse effects. The unique pharmacological activity of selective androgen receptor modulator (SARM) MK-4541 recently has been reported as an AR antagonist with 5α-reductase inhibitor function. The molecule inhibits proliferation and induces apoptosis in AR positive, androgen dependent prostate cancer cells. Importantly, MK-4541 inhibited androgen-dependent prostate growth in male rats yet maintained lean body mass and bone formation following ovariectomy in female rats. In the present study, we evaluated the effects of SARM MK-4541 in the androgen-dependent Dunning R3327-G prostate carcinoma xenograft mouse model as well as on skeletal muscle mass and function, and AR-regulated behavior in mice. MK-4541 significantly inhibited the growth of R3327-G prostate tumors, exhibited anti-androgen effects on the seminal vesicles, reduced plasma testosterone concentrations in intact males, and inhibited Ki67 expression. MK-4541 treated xenografts appeared similar to xenografts in castrated mice. Importantly, we demonstrate that MK-4541 exhibited anabolic activity in androgen deficient conditions, increasing lean body mass and muscle function in adult castrated mice. Moreover, MK-4541 treatment restored general activity levels in castrated mice. Thus, MK-4541 exhibits an optimum profile as an adjuvant therapy to ADT which may provide potent anti-androgenic activity at the prostate yet protective activity on skeletal muscle and behavior in patients.
Copyright © 2016. Published by Elsevier Ltd.

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The objective of this study was to compare rates of nephrectomy (Nx) in, and characteristics of, patients with metastatic renal cell carcinoma (mRCC) enrolled in prospective clinical trials of tyrosine kinase inhibitors (TKIs) that were completed through (Group 1) versus after (Group 2) 2007.
Searching online databases, we retrospectively identified phase I to III trials with ≥ 15 patients with mRCC treated with first-line TKIs, alone or in combination with other agent(s).
Of 70 trials identified, 42 were included in the analysis (n = 6074 patients). Compared with Group 1, Group 2 patients had significantly less Nx (85.7% vs. 93.7%; P &amp;lt; .001) and prior cytokine therapy (11.1% vs. 46.8%; P &amp;lt; .001). Group 2 also had significantly fewer patients with good prognostic risk (based on Memorial Sloan-Kettering Cancer Center criteria) or performance status (both P &amp;lt; .001). Group 2 patients had a significantly greater objective response rate than Group 1 patients (intent-to-treat analysis: 28.6% vs. 23.1%, respectively; P &amp;lt; .001), whereas Group 1 patients had significantly more stable disease. Clinical benefit was similar in both groups (P = .157), and the means of median progression-free survival were comparable (8.2 and 9.0 months in Groups 1 and 2, respectively; P = .2528).
Use of Nx in mRCC patients participating in clinical trials has declined in the TKI era. More patients with worse prognostic risk profiles are participating in first-line TKI trials after 2007, but objective response rates are higher. Despite patient characteristics that favor the earlier group, progression-free survival is similar as TKIs have replaced cytokines as first-line therapy.
Copyright © 2016 Elsevier Inc. All rights reserved.

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Although a large number of pharmaceutical therapies are available to treat cardiovascular diseases like heart failure, in many medical conditions treatment is still not optimal and, therefore, the need for innovative, safe and efficacious drugs is still very high in this indication. Biomarkers are an important tool in the preclinical and clinical drug development process; they allow patient selection for clinical studies as well as therapy monitoring during studies. Biomarker concepts in cardiovascular indications differ very much from those in oncology and are very diverse. The present article gives an overview of the pathomechanisms of heart failure and describes the socioeconomic impact of the disease and the biomarker strategies being applied in the development of new heart failure drugs. The focus lies on protein biomarkers that can be measured in the blood and on functional biomarkers that can be derived from implanted and wearable medical devices.
© 2016 WILEY-VCH Verlag GmbH &amp;amp; Co. KGaA, Weinheim.

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