Author: [email protected]

Exposure to hypomethylating agent, 5-Azacytidine, may improve iCasp9 suicide gene therapy for treating GvHD in allografts.

Anti-tumor cellular immunotherapies that implement a suicide gene system can limit potential undesirable effects. In a haplo-identical bone marrow transplant clinical trial, over 90% of iCaspase-9-expressing cells were eradicated after AP1903 exposure, and signs of graft-versus-host disease disappeared. Nevertheless, low numbers of genetically-modified T cells survived this treatment. We studied genetically-modified cell lines (GMCL) that carried a dual iCaspase-9/ΔCD19 DNA construct (ΔCD19=truncated CD19). With AP1903 exposure, a low percentage of cells (1.47%±0.67%; n=5 replications) persisted in-vitro. Repeated exposures to increasing AP1903 doses generated low (GMCLLR) and high AP1903-responders (GMCLHR), which expressed different levels of surface ΔCD19and intracellular iCaspase-9. Compared to GMCLHR, GMCLLR exhibited higher methylation of 5′-long-terminal repeat (LTR) promoters, both in the number of sequences with at least one methylated CpG (16 vs 51.5%, respectively) and in the number of CpG islands (1.2 vs 8.9%, respectively). Four days of 5-azacytidine exposure reduced methylation and increased ΔCD19 and iCaspase-9 expression. Interestingly, LTR demethylation restored GMCLLR sensitivity to AP1903 by 24.3-fold (1.8 vs 43.8%) without affecting GMCLHR. We showed that 5’LTR-methylation inhibited transgene expression and caused AP1903 hypo-responsiveness. Treating with a hypomethylating agent restored AP1903 sensitivity. This approach can be applied in further clinical trials to improve iCaspase-9 response if low response is detected.Gene Therapy accepted article preview online, 25 April 2016. doi:10.1038/gt.2016.39.

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The percentage of prostate-specific antigen (PSA) isoform [-2]proPSA and the Prostate Health Index improve the diagnostic accuracy for clinically relevant prostate cancer at initial and repeat biopsy compared with total PSA and percentage free PSA in men aged ≤65 years.

To prospectively test the diagnostic accuracy of the percentage of prostate specific antigen (PSA) isoform [-2]proPSA (%p2PSA) and the Prostate Health Index (PHI), and to determine their role for discrimination between significant and insignificant prostate cancer at initial and repeat prostate biopsy in men aged ≤65 years.
The diagnostic performance of %p2PSA and PHI were evaluated in a multicentre study. In all, 769 men aged ≤65 years scheduled for initial or repeat prostate biopsy were recruited in four sites based on a total PSA (t-PSA) level of 1.6-8.0 ng/mL World Health Organization (WHO) calibrated (2-10 ng/mL Hybritech-calibrated). Serum samples were measured for the concentration of t-PSA, free PSA (f-PSA) and p2PSA with Beckman Coulter immunoassays on Access-2 or DxI800 instruments. PHI was calculated as (p2PSA/f-PSA × √t-PSA). Uni- and multivariable logistic regression models and an artificial neural network (ANN) were complemented by decision curve analysis (DCA).
In univariate analysis %p2PSA and PHI were the best predictors of prostate cancer detection in all patients (area under the curve [AUC] 0.72 and 0.73, respectively), at initial (AUC 0.67 and 0.69) and repeat biopsy (AUC 0.74 and 0.74). t-PSA and %f-PSA performed less accurately for all patients (AUC 0.54 and 0.62). For detection of significant prostate cancer (based on Prostate Cancer Research International Active Surveillance [PRIAS] criteria) the %p2PSA and PHI equally demonstrated best performance (AUC 0.70 and 0.73) compared with t-PSA and %f-PSA (AUC 0.54 and 0.59). In multivariate analysis PHI we added to a base model of age, prostate volume, digital rectal examination, t-PSA and %f-PSA. PHI was strongest in predicting prostate cancer in all patients, at initial and repeat biopsy and for significant prostate cancer (AUC 0.73, 0.68, 0.78 and 0.72, respectively). In DCA for all patients the ANN showed the broadest threshold probability and best net benefit. PHI as single parameter and the base model + PHI were equivalent with threshold probability and net benefit nearing those of the ANN. For significant cancers the ANN was the strongest parameter in DCA.
The present multicentre study showed that %p2PSA and PHI have a superior diagnostic performance for detecting prostate cancer in the PSA range of 1.6-8.0 ng/mL compared with t-PSA and %f-PSA at initial and repeat biopsy and for predicting significant prostate cancer in men aged ≤65 years. They are equally superior for counselling patients before biopsy.
© 2015 The Authors BJU International © 2015 BJU International Published by John Wiley & Sons Ltd.

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AP32788 is ARIAD’s most recent, internally-discovered drug candidate

AP32788 is a tyrosine kinase inhibitor (TKI) designed to address an unmet medical need in a subset of non-small cell lung cancers (Company Pipeline, Ariad, APR 26, 2016, View Source [SID:1234511400]). Using our targeted structure-based drug discovery methods, ARIAD’s research team worked to design and build this molecule and see it from concept to nomination in under a year –a testament to the process, science, and people involved in ARIAD’s drug discovery group.

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In December 2014, we nominated AP32788 for clinical development and are currently conducting studies necessary to support the filing of an investigational new drug (IND) application. We expect to file the IND by the end of 2015 and to commence a Phase 1/2 proof-of-concept clinical trial of AP32788 in 2016.

Bayer off to a successful start in 2016

On April 26, 2016 The Bayer Group reported that they got off to a successful start in the new fiscal year (Press release, Bayer, APR 26, 2016, View Source [SID:1234511411]).

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"All segments posted gains in their operating performance," said CEO Dr. Marijn Dekkers when he presented the interim report for the first quarter on Tuesday. At Pharmaceuticals, Bayer again benefited from the very good development of its recently launched products. The Consumer Health business also developed positively. Crop Science outperformed the prior-year quarter despite a weak market environment. Animal Health posted substantial gains. Thus the Life Science businesses showed encouraging development. Sales at Covestro declined as anticipated, while earnings rose significantly. Dekkers remains optimistic for the year as a whole: "We confirm our outlook for 2016."

Sales of the Bayer Group moved ahead in the first quarter of 2016 by 0.5 percent to EUR 11,941 million (Q1 2015: EUR 11,879 million). After adjusting for currency and portfolio effects (Fx & portfolio adj.), the increase was 3.2 percent. EBITDA before special items advanced by a substantial 15.7 percent to EUR 3,404 million (Q1 2015: EUR 2,941 million), despite higher research and development expenses at Pharmaceuticals and Crop Science and negative currency effects of around EUR 60 million. EBIT climbed by a robust 20.1 percent to EUR 2,335 million (Q1 2015: EUR 1,944 million) after special charges of EUR 272 million (Q1 2015: EUR 244 million). These mainly comprised impairment losses on intangible assets, costs for the integration of acquired businesses and costs associated with efficiency improvement measures. Net income grew 13.3 percent to EUR 1,511 million (Q1 2015: EUR 1,334 million). Core earnings per share from continuing operations advanced by 13.9 percent to EUR 2.37 (Q1 2015: EUR 2.08).

Gross cash flow from continuing operations advanced by 28.1 percent to EUR 2,576 million (Q1 2015: EUR 2,011 million), due mainly to the expansion of business. Net cash flow (total) was diminished by an increase in cash tied up in working capital but rose by 82.6 percent to EUR 1,322 million (Q1 2015: EUR 724 million), mainly because of the inflow from the divestiture of the Diabetes Care business. Net financial debt declined by EUR 1.1 billion against December 31, 2015, to EUR 16.3 billion on March 31, 2016.

Pharmaceuticals Division posts substantial sales and earnings growth

Sales of prescription medicines (Pharmaceuticals) rose in the first quarter by a very encouraging 12.2 percent (Fx & portfolio adj.) to EUR 3,889 million. "This was largely attributable to the continued strong development of the company’s recently launched products," said Dekkers. The anticoagulant Xarelto, the eye medicine Eylea, the cancer drugs Stivarga and Xofigo, and Adempas to treat pulmonary hypertension generated total combined sales of EUR 1,187 million (Q1 2015: EUR 898 million). Xarelto posted encouraging sales gains of 31.5 percent (Fx adj.), which were mainly attributable to volume increases in Europe and Japan. Business with Xarelto also developed positively in the United States, where it is marketed by a subsidiary of Johnson & Johnson. Bayer registered considerably higher sales (Fx adj. plus 48.9 percent) of the eye medicine Eylea in all regions, particularly in Europe, Canada and Japan.

Among the established products, the blood-clotting medicine Kogenate posted significant sales gains in comparison with a weak prior-year quarter. Bayer also began marketing the new hemophilia medicine Kovaltry in Europe and the United States in the first quarter of 2016. Sales of the Kogenate/Kovaltry product family climbed 13.7 percent (Fx adj.). Business with the hormone-releasing intrauterine devices of the Mirena product family rose by 7.2 percent (Fx adj.) overall, benefiting especially from expanded volumes in the United States. The cancer drug Nexavar achieved currency-adjusted growth of 10.8 percent, due particularly to considerable sales gains in the United States. Sales of the multiple sclerosis product Betaferon/Betaseron were down 7.9 percent (Fx adj.) overall, due partly to changes in sales phasing for tender businesses in Latin America. By contrast, sales rose in the United States. Overall, Bayer substantially expanded the Pharmaceuticals business (Fx adj.) in all regions.

EBITDA before special items of the division advanced by 16.2 percent to EUR 1,261 million. This substantial increase in earnings was due largely to very good business performance, more than offsetting higher investments in research and development and negative currency effects of around EUR 30 million.

Positive business development at Consumer Health

"Our business with self-care products also developed positively," said Dekkers. Sales of the Consumer Health Division rose by 2.2 percent (Fx & portfolio adj.) to EUR 1,520 million. The business posted significant gains in Latin America/Africa/Middle East and in Asia/Pacific, while sales were down in Europe due mainly to the macroeconomic situation in Russia. Sales declined slightly in the United States.

Significant gains of 10.4 percent (Fx adj.) were achieved with the Bepanthen/ Bepanthol wound and skin care products, while business with the antifungal Canesten advanced by 21.1 percent (Fx adj.). The multivitamin product Berocca also developed very positively (Fx adj. plus 31.6 percent). Sales of the antihistamine Claritin declined by 7.4 percent (Fx adj.) cycling over a strong prior-year quarter due to shifts in order volumes in China. The encouraging sales development in the United States was not sufficient to offset this effect. The Alka-Seltzer family of products to treat gastric complaints and cold symptoms registered a sales decline of 14.5 percent (Fx adj.), due particularly to a weaker cold season in the United States.

EBITDA before special items improved by 3.8 percent to EUR 383 million. Alongside earnings contributions from positive sales development, cost synergies had a favorable effect. By contrast, negative currency effects amounted to about EUR 20 million.

Ongoing weak market environment at Crop Science

First-quarter sales of the agricultural business (Crop Science) moved ahead by 1.2 percent (Fx & portfolio adj.) to EUR 3,023 million. "We slightly expanded business at Crop Protection/Seeds despite an ongoing weak market environment," explained Dekkers. In regional terms, the Crop Science business developed positively in North America in particular (Fx adj. plus 3.8 percent). In Latin America/Africa/Middle East, sales increased slightly by 1.0 percent (Fx adj.), whereas sales in Europe were level year on year (Fx adj. plus 0.7 percent). Business in the Asia/Pacific region declined by 2.5 percent (Fx adj.).

At Crop Protection, the SeedGrowth business grew by 5.4 percent (Fx. & portfolio adj.). The Fungicides business also developed positively (Fx & portfolio adj. plus 2.9 percent), whereas sales of Insecticides and Herbicides declined (Fx & portfolio adj. minus 12.2 percent and minus 3.8 percent, respectively). Sales of Seeds grew by a substantial 11.9 percent (Fx & portfolio adj.). Business at Environmental Science advanced by 3.0 percent (Fx & portfolio adj.).

EBITDA before special items of the Crop Science Division improved by 6.3 percent to EUR 1,106 million. Earnings contributions from higher selling prices and lower cost of goods sold stood against higher research and development spending and a negative currency effect of EUR 15 million.

Animal Health benefits from strong U.S. business

The Animal Health business grew sales by 8.8 percent (Fx & portfolio adj.) to EUR 408 million. This growth was chiefly attributable to increased demand in the United States. While sales of the Advantage family of flea, tick and worm control products rose by 3.5 percent (Fx adj.), sales of the Seresto flea and tick collar nearly doubled. EBITDA before special items of Animal Health climbed by 19.6 percent to EUR 122 million.

Substantial earnings growth at Covestro

Sales of the high-tech polymer materials business (Covestro) fell by 4.7 percent (Fx & portfolio adj.) to EUR 2,850 million. Selling prices were down significantly, due mainly to the raw material price development and primarily at Polyurethanes. Volumes were above the level of the prior-year quarter overall. EBITDA before special items improved by a considerable 18.9 percent to EUR 504 million. Higher volumes and decreased raw material prices outweighed the lower selling prices to deliver a net increase in earnings.

Outlook for 2016 confirmed

Bayer is confirming the forecast for the full year it published in February. According to this, sales of approximately EUR 35 billion are planned for the Life Science businesses, i.e. the Bayer Group excluding Covestro (2015 pro forma: EUR 34,342 million). This corresponds to a mid-single-digit percentage increase on a currency- and portfolio-adjusted basis. Bayer also plans to increase EBITDA before special items of the Life Science businesses by a mid-single-digit percentage (2015 pro forma: EUR 8,607 million). The company aims to increase core earnings per share from continuing operations including Covestro by a mid-single-digit percentage as well (2015: EUR 6.83). (See Chapter 18.2 of the Annual Report 2015 for the full forecast.)

Evotec and ex scientia announce partnership to discover bispecific small molecule immuno-oncology therapeutics

On April 26, 2016 Evotec AG (Frankfurt Stock Exchange: EVT, TecDAX, ISIN: DE0005664809) and ex scientia Ltd (Dundee, UK) reported a collaboration with the objective to discover and develop first-in-class bispecific small molecule immuno-oncology therapies (Press release, Evotec, APR 26, 2016, View Source [SID:1234511409]).

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Ex scientia will contribute its unique algorithmic design platform while Evotec, mainly through its Toulouse site, will be responsible for medicinal chemistry, in vitro and in vivo pharmacology as well as development capabilities and expertise.

Application of bispecific small molecules is an exciting strategy to significantly expand and enhance efficacy beyond conventional single target therapies. The initial focus will be cancer-related adenosine targets which are increasingly recognised to play important roles in immuno-oncology. Combining adenosine-based mechanisms with related targets holds great promise in boosting efficacy and addressing larger patient populations through a single small molecule drug.

Dr Cord Dohrmann, Chief Scientific Officer of Evotec, commented: "Polypharmacy is a widely used strategy to manage diseases more effectively. Ex scientia has built an outstanding platform to purposely design bispecific small molecules that can address multiple targets through a single molecule. Together we are well positioned to discover and develop a new generation of small molecule immuno-oncology therapies."

Commenting on the relationship, Andrew Hopkins, CEO, ex Scientia, said: "This is an ideal partnership to develop an innovative immuno-oncology portfolio where our focus is on delivering efficacious drug candidates to tackle the inherent challenges of the complex biology. Evotec have an excellent track record in project delivery and their proven track record in regarding efficiency gains in drug discovery chime with our own."

This is a co-owned, risk-shared-partnership, no further financial details were disclosed.