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A whole recombinant yeast-based therapeutic vaccine elicits HBV X, S and Core specific T cells in mice and activates human T cells recognizing epitopes linked to viral clearance.

Chronic hepatitis B infection (CHB) is characterized by sub-optimal T cell responses to viral antigens. A therapeutic vaccine capable of restoring these immune responses could potentially improve HBsAg seroconversion rates in the setting of direct acting antiviral therapies. A yeast-based immunotherapy (Tarmogen) platform was used to make a vaccine candidate expressing hepatitis B virus (HBV) X, surface (S), and Core antigens (X-S-Core). Murine and human immunogenicity models were used to evaluate the type and magnitude of HBV-Ag specific T cell responses elicited by the vaccine. C57BL/6J, BALB/c, and HLA-A*0201 transgenic mice immunized with yeast expressing X-S-Core showed T cell responses to X, S and Core when evaluated by lymphocyte proliferation assay, ELISpot, intracellular cytokine staining (ICS), or tumor challenge assays. Both CD4+ and CD8+ T cell responses were observed. Human T cells transduced with HBc18-27 and HBs183-91 specific T cell receptors (TCRs) produced interferon gamma (IFNγ following incubation with X-S-Core-pulsed dendritic cells (DCs). Furthermore, stimulation of peripheral blood mononuclear cells (PBMCs) isolated from CHB patients or from HBV vaccine recipients with autologous DCs pulsed with X-S-Core or a related product (S-Core) resulted in pronounced expansions of HBV Ag-specific T cells possessing a cytolytic phenotype. These data indicate that X-S-Core-expressing yeast elicit functional adaptive immune responses and supports the ongoing evaluation of this therapeutic vaccine in patients with CHB to enhance the induction of HBV-specific T cell responses.

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The clinical pharmacology and pharmacokinetics of ulipristal acetate for the treatment of uterine fibroids.

Uterine fibroids are benign hormone-sensitive tumors of uterine smooth muscle cells leading to heavy menstrual bleeding and pelvic pain. Ulipristal acetate (UPA) is an emerging medical treatment of fibroids with the potential to be used for long-term treatment. In this context, the present article summarizes UPA’s main clinical pharmacology and pharmacokinetic (PK) properties. Ulipristal acetate has good oral bioavailability and a half-life allowing one single oral administration per day for the management of fibroids. As a steroid, UPA is a substrate for cytochrome P450 (CYP) 3A4 but does not act as an inducer or inhibitor of the CYP system or transporter proteins. With the exception of drugs modulating CYP3A4 activity, risks of drug-drug interactions with UPA are unlikely. In conclusion, besides its pharmacodynamic characteristics, UPA shows favorable PK properties that contribute to a good efficacy-safety ratio for the long-term management of uterine fibroids in clinical practice.
© The Author(s) 2014.

Metabolite profiling of the multiple tyrosine kinase inhibitor lenvatinib: a cross-species comparison.

Lenvatinib is an oral, multiple receptor tyrosine kinase inhibitor. Preclinical drug metabolism studies showed unique metabolic pathways for lenvatinib in monkeys and rats. A human mass balance study demonstrated that lenvatinib related material is mainly excreted via feces with a small fraction as unchanged parent drug, but little is reported about its metabolic fate. The objective of the current study was to further elucidate the metabolic pathways of lenvatinib in humans and to compare these results to the metabolism in rats and monkeys. To this end, we used plasma, urine and feces collected in a human mass balance study after a single 24 mg (100 μCi) oral dose of (14)C-lenvatinib. Metabolites of (14)C-lenvatinib were identified using liquid chromatography (high resolution) mass spectrometry with off-line radioactivity detection. Close to 50 lenvatinib-related compounds were detected. In humans, unchanged lenvatinib accounted for 97 % of the radioactivity in plasma, and comprised 0.38 and 2.5 % of the administered dose excreted in urine and feces, respectively. The primary biotransformation pathways of lenvatinib were hydrolysis, oxidation and hydroxylation, N-oxidation, dealkylation and glucuronidation. Various combinations of these conversions with modifications, including hydrolysis, gluthathione/cysteine conjugation, intramolecular rearrangement and dimerization, were observed. Some metabolites seem to be unique to the investigated species (human, rat, monkey). Because all lenvatinib metabolites in human plasma were at very low levels compared to lenvatinib, only lenvatinib is expected to contribute to the pharmacological effects in humans.

Enzalutamide in Japanese patients with chemotherapy-naïve, metastatic castration-resistant prostate cancer: A post-hoc analysis of the placebo-controlled PREVAIL trial.

To evaluate the treatment effects, safety and pharmacokinetics of enzalutamide in Japanese patients.
This was a post-hoc analysis of the phase 3, double-blind, placebo-controlled PREVAIL trial. Asymptomatic or mildly symptomatic chemotherapy-naïve patients with metastatic castration-resistant prostate cancer progressing on androgen deprivation therapy were randomized one-to-one to 160 mg/day oral enzalutamide or placebo until discontinuation on radiographic progression or skeletal-related event and initiation of subsequent antineoplastic therapy. Coprimary end-points were centrally assessed radiographic progression-free survival and overall survival. Secondary end-points were investigator-assessed radiographic progression-free survival, time to initiation of chemotherapy, time to prostate-specific antigen progression, prostate-specific antigen response (≥50% decline) and time to skeletal-related event.
Of 1717 patients, 61 were enrolled in Japan (enzalutamide, n = 28; placebo, n = 33); hazard ratios (95% confidence interval) of 0.30 for centrally assessed radiographic progression-free survival (0.03-2.95), 0.59 for overall survival (0.20-1.8), 0.46 for time to chemotherapy (0.22-0.96) and 0.36 for time to prostate-specific antigen progression (0.17-0.75) showed the treatment benefit of enzalutamide over the placebo. Prostate-specific antigen responses were observed in 60.7% of enzalutamide-treated men versus 21.2% of placebo-treated men. Plasma concentrations of enzalutamide were higher in Japanese patients: the geometric mean ratio of Japanese/non-Japanese patients was 1.126 (90% confidence interval 1.018-1.245) at 13 weeks. Treatment-related adverse events grade ≥3 occurred in 3.6% of enzalutamide- and 6.1% of placebo-treated Japanese patients.
Treatment effects and safety in Japanese patients were generally consistent with the overall results from PREVAIL.
© 2016 The Authors. International Journal of Urology published by John Wiley &amp; Sons Australia, Ltd on behalf of the Japanese Urological Association.

Boehringer Ingelheim Venture Fund invests in Amal Therapeutics to develop novel therapeutic colorectal cancer vaccine

On March 30, 2016 Amal Therapeutics (Amal) reported that they have completed CHF 3 million (EUR 2.75 million) Series A financing round with Boehringer Ingelheim Venture Fund (BIVF) as cornerstone investors (Press release, Boehringer Ingelheim, MAR 29, 2016, View Source [SID:1234510134]). VI Partners and High-Tech Gründerfonds also participated in the round which will help progress Amal’s cancer vaccines.

Amal Therapeutics is a Swiss biotech company developing and progressing therapeutic cancer vaccines. The company will use the funds to progress the preclinical development of its lead vaccine (ATP124) for colorectal cancer and to further develop its KISIMA technology platform for therapeutic tumor vaccination. This novel technology is able to generate potent long lasting anti-tumor immunity and avoid tumor immune escape.

Dr. Frank Kalkbrenner from the Boehringer Ingelheim Venture Fund and Dr. Frank Hensel from the High-Tech Gruenderfonds will join the Board as Board Observers. Dr. Diego Braguglia from VI Partners will also become a member of Amal’s Supervisory Board.

Dr. Madiha Derouazi, CEO and founder of Amal Therapeutics said: "This Series A investment recognizes the potential of the KISIMA technology platform and the value of our scientific assets. We are now in a position to rapidly progress our lead vaccine, ATP124, for colorectal cancer into the clinic and continue to develop our pipeline in other cancer indications. I look forward to working with the Board to make Amal Therapeutics a leading innovator in the field of immunotherapies".

Dr. Knut Elbers, Boehringer Ingelheim Venture Fund representative on Amal’s Board added: "Dr. Derouazi’s dedicated leadership and scientific expertise allowed us to assemble a group of outstanding scientists to show proof-of-principle in a series of pre-clinical tumor studies. We are confident that Amal’s KISIMA technology could revolutionize the peptide-based cancer vaccine field – bringing an exciting new technology to the patient".

Dr. Braguglia, VI Partners: "We believe that the KISIMA technology is superior to many other tumor vaccine technologies, both as a stand-alone treatment and in combination with other vaccines or immuno-oncology treatment modalities. I’m pleased to be joining the current seasoned investors and support the team of Amal in moving its technology into the clinic".

Amal’s vaccines combine a Cell Penetrating Peptide (CPP) with a multi-antigenic chimeric cargo with various CD8+ and CD4+ epitopes and a constitutive activator of dendritic cells, enabling them to simultaneously stimulate multi-epitopic cytotoxic T cell-mediated immunity, induce helper T (Th) cells and promote immunological memory.

About Amal Therapeutics SA