On March 29, 2016 Argos Therapeutics, Inc. (Nasdaq:ARGS), an immuno-oncology company focused on the development and commercialization of truly individualized immunotherapies for the treatment of cancer based on the Arcelis technology platform, reported financial results for the fourth quarter and full-year ended December 31, 2015 and provided an update on the Company’s clinical programs (Press release, Argos Therapeutics, MAR 29, 2016, View Source [SID:1234510104]).

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"In the past year we have achieved a number of important milestones, both from a clinical and a corporate perspective," said Jeff Abbey, president and chief executive officer. "In July, we successfully completed enrollment of our Phase 3 ADAPT trial of AGS-003 in metastatic renal cell carcinoma. The ADAPT trial also successfully navigated two data analyses, in June and December, by the Independent Data Monitoring Committee (IDMC). The next review of data by the IDMC is scheduled to take place in June of 2016. We expect a subsequent IDMC meeting and review of data to occur in late 2016 and anticipate having a sufficient number of events from the ADAPT trial to permit the primary analysis and assessment of overall survival to occur in the first half of 2017."

"We also successfully formed our Scientific Advisory Board in 2015. These highly-regarded individuals are a significant resource as we continue to advance our clinical development programs," said Mr. Abbey. "Additionally, we also saw the initiation of an early stage investigator-sponsored RCC trial of AGS-003 at Roswell Park Cancer Institute in Buffalo, NY. With this study, for the first time we will assess the effects of AGS-003 in patients with kidney cancer that has not spread to nearby lymph nodes or other parts of the body. As we have emphasized, this is an important opportunity to manufacture AGS-003 using a needle biopsy procedure for tumor collection prior to surgery, while directly studying immune changes within the primary tumor before and after administration of AGS-003."

Mr. Abbey continued, "With the accomplishments of 2015 and those we have already announced in 2016, including the hiring of Dr. Lee Allen as our chief medical officer, the initiation of an investigator-sponsored trial of AGS-003 in non-small cell lung cancer, and our recently announced financing of up to $60 million, which, if it is funded in full, should fund our operations into the second quarter of 2017 when we anticipate final data of the ADAPT trial, we believe we have taken many of the necessary steps to be successful."

2015 Operational Highlights:

In June and December 2015, following data reviews, the IDMC recommended continuation of the pivotal Phase 3 ADAPT clinical trial of AGS-003 in combination with standard targeted therapy for the treatment of mRCC
In July 2015, the ADAPT clinical trial reached its enrollment goal of at least 450 randomized patients
462 patients enrolled
The breakdown of patients enrolled in the ADAPT study is approximately 73% intermediate risk patients, meaning they present with 1 or 2 risk factors at diagnosis, and approximately 27% poor risk patients, meaning they present with either 3 or 4 risk factors at diagnosis
In July 2015, the Company established a Scientific Advisory Board (SAB)
Inaugural members include distinguished oncologists and immunologists to provide perspectives in further research and development of AGS-003
In July 2015, an investigator-initiated early stage RCC trial of AGS-003 commenced at Roswell Park Cancer Institute in Buffalo, NY
Preliminary data expected in the fourth quarter of 2015

Selected Third Quarter 2015 Financial Results

Net loss attributable to common stockholders for the three months ended December 31, 2015 was $17.6 million, or $0.84 per share, compared to a net loss attributable to common stockholders of $16.2 million, or $0.83 per share, for the same period in 2014. Net loss attributable to common stockholders for the full-year ended December 31, 2015 was $74.8 million, or $3.66 per share, compared to a net loss attributable to common stockholders of $54.2 million, or $3.12 per share, for the same period in 2014.

Revenue for the three months ended December 31, 2015 totaled $0.1 million compared to $0.3 million for the same period in 2014. Revenue for the full-year ended December 31, 2015 totaled $0.5 million compared to $2.0 million for the same period in 2014.

Research and development expense for the three months ended December 31, 2015 totaled $14.0 million compared to $13.5 million for the same period in 2014. Research and development expense for the full-year ended December 31, 2015 totaled $62.1 million compared to $45.5 million for the same period in 2014.

General and administrative expense for the three months ended December 31, 2015 totaled $3.0 million compared to $2.5 million for the same period in 2014. General and administrative expense for the full-year ended December 31, 2015 totaled $11.0 million compared to $8.6 million for the same period in 2014.

As of December 31, 2015, Argos’ cash, cash equivalents and short-term investments totaled $7.2 million compared to $56.2 million as of December 31, 2014.

About the Arcelis Technology Platform
Arcelis is a truly personalized immunotherapy technology that captures mutated and variant antigens that are specific to each patient’s disease. It is designed to overcome immunosuppression by producing a durable memory T-cell response without adjuvants that may be associated with toxicity. The technology is potentially applicable to a wide range of different cancers, and is designed to overcome many of the manufacturing and commercialization challenges that have impeded other personalized cancer immunotherapies. The Arcelis process uses only a small tumor or blood sample and the patient’s own dendritic cells, which are optimized from cells collected by a single leukapheresis procedure. The proprietary process uses RNA isolated from the patient’s disease sample to program dendritic cells to target disease specific antigens. The activated, antigen-loaded dendritic cells are then formulated with the patient’s plasma and administered via intradermal injection.

On March 29, 2016 AstraZeneca reported that the Japanese Ministry of Health, Labour and Welfare (MHLW) has approved Tagrisso (osimertinib, AZD9291) 80mg once-daily tablets for the treatment of patients with epidermal growth factor receptor (EGFR) T790M mutation-positive inoperable or recurrent non-small cell lung cancer (NSCLC) that is resistant to EGFR tyrosine kinase inhibitor (TKI) therapy (Filing, 6-K, AstraZeneca, MAR 29, 2016, View Source [SID:1234510105]).

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: "We continue to move at an unprecedented pace with osimertinib, with the full approval in Japan following closely the recent US and EU approvals. As first-in-class lung cancer treatment directed at the T790M mutation, we are delighted that this targeted medicine is now available to patients in Japan to address the existing unmet medical need."

Dr. Tetsuya Mitsudomi, Division of Thoracic Surgery, Department of Surgery, Kinki University Faculty of Medicine said: "A significant proportion of Japanese patients with lung cancer have the EGFR mutation and about 60% of them are likely to develop the T790M resistance mutation following initial TKI treatment. Osimertinib enables us to respond to this disease progression in a precise and logical way as clearly demonstrated in clinical trials, with potential to make a meaningful difference to the lives of Japanese patients."

Approximately 30-40% of Asian patients with NSCLC have the EGFR mutation at diagnosis. Nearly two out of three patients with NSCLC whose disease progresses after treatment with an EGFR-TKI develop the T790M mutation, for which treatment options are currently limited. Osimertinib targets both the EGFR mutation involved in cancer development and T790M, a mutation that makes tumours resistant to existing treatment with EGFR-TKIs. Patients with EGFRm NSCLC, who experience disease progression, should be tested for their mutation status through a validated diagnostic test. AstraZeneca has collaborated with Roche to develop the cobas EGFR Mutation Test v2 as the companion diagnostic for osimertinib.

The Japanese approval is based on data from the two multinational AURA Phase II trials (AURA extension and AURA2), with 22% of patients enrolled from Japan. The studies demonstrated efficacy in patients who had progressed on or after treatment with an EGFR-TKI and whose tumours tested positive for the EGFR T790M mutation. The overall objective response rate (ORR, a measurement of tumour shrinkage) was 61.3% (95% CI: 54.2% to 68.1%) in AURA extension (n=199), and 70.9% (95% CI: 64.0% to 77.1%) in AURA2 (n=199) (1 May 2015 cut-off).

In the two AURA Phase II studies (n=411), the most commonly reported adverse events assessed by the investigator were rash/acne (37.7%), diarrhoea (36.5%), dry skin/eczema, etc. (28.5%), nail disorder including paronychia, etc (23.4%). In Japanese patients (n=80), the incidence of interstitial lung disease (ILD; including pneumonitis etc.), as assessed by the investigator, for all grades was 6.3% (1 May 2015 cut-off). Warnings and precautions include ILD, QT interval prolongation, hepatic impairment and haematological changes.

AstraZeneca has agreed a Risk Management Plan with the Japanese Health Authority.

The full Japanese approval was granted seven months after the New Drug Application submission in August 2015. The Japanese approval for osimertinib was granted under the Priority Review mechanism of the MHLW, in recognition of the submitted data and the life-threatening nature of the disease. The Japanese approval follows US FDA Accelerated Approval in November 2015 and European Commission conditional marketing authorisation in February 2016. Interactions with regulatory authorities in the rest of the world are ongoing.

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On March 29, 2016 Asterias Biotherapeutics, Inc. (NYSE MKT: AST), a biotechnology company focused on the emerging field of regenerative medicine, reported financial results for the fourth quarter and year ended December 31, 2015, as well as key corporate highlights (Press release, BioTime, MAR 29, 2016, View Source;p=RssLanding&cat=news&id=2151544 [SID:1234510107]).

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"Asterias has three promising clinical-stage therapeutic programs based on our immunotherapy and pluripotent stem cell platform technologies. These pioneering cell therapy programs have the potential to address areas of very high unmet medical need in the fields of oncology and neurology. We are focused on continuing to advance all three therapeutic programs through clinical development," said Steve Cartt, President and Chief Executive Officer of Asterias.

The Company recently completed the End-of-Phase 2 meeting with the U.S. Food and Drug Administration (FDA) for AST-VAC1, the company’s lead clinical program targeting maintenance of relapse-free-survival in acute myeloid leukemia (AML) patients. Asterias is planning for the initiation of a single pivotal Phase 3 trial that could support an accelerated development pathway towards a potential future biologic license application (BLA) filing.

The company’s second clinical-stage program, AST-VAC2, will be investigated in a planned Phase 1/2 trial in non-small cell lung cancer that will be sponsored, managed and funded by the company’s development partner, Cancer Research UK (CRUK). This study is expected to begin enrollment in early 2017.

The company’s third clinical program, AST-OPC1, has successfully completed the initial 2 million cell safety cohort and is currently enrolling patients for the 10 million cell second cohort in a Phase 1/2a clinical trial in complete cervical spinal cord injury. This trial is being funded in part by a $14.3 million grant from the California Institute of Regenerative Medicine.

"We look forward to achieving further progress on these pioneering cell therapy clinical programs, including important clinical and other development milestones, during the remainder of 2016 and into 2017," Mr. Cartt concluded.

Research and Development Highlights:

Since Asterias released third quarter results in November 2015, the Company has reported the following progress:

AST-VAC1 (antigen-presenting autologous dendritic cells)

Asterias successfully completed an End-of-Phase 2 meeting with the U.S. FDA for AST-VAC1, its investigational cancer immunotherapy targeting AML. During the meeting, the FDA indicated general agreement with Asterias’ proposed development plan for registration of AST-VAC1 through a single Phase 3 trial to support an accelerated development pathway and BLA filing. In this study, Asterias will assess the impact of AST-VAC1 compared to placebo on the duration of relapse-free-survival as the primary endpoint, and on overall survival as the secondary endpoint in patients who have achieved complete remission using standard therapies. The Company currently plans to submit a request for a Special Protocol Assessment to the FDA to confirm the primary endpoint and other design elements of this pivotal Phase 3 trial.

The Phase 2 clinical trial data discussed with FDA was previously presented at the 2015 ASCO (Free ASCO Whitepaper) annual meeting. Nineteen AML patients in complete remission (16 CR1 and 3 CR2) received AST-VAC1. The duration of relapse-free survival was greater after AST-VAC1 treatment as compared to that of historical controls. Eleven of 19 (58%) patients (median follow-up 52 mos.) remained in remission as of last follow-up. Of the 19 CR patients, seven were ≥ 60 years old at the time of AST-VAC1 immunotherapy and were at high-risk for recurrence. Four of the seven (57%) patients ≥ 60 years old remained relapse free 52 to 59 months post AST-VAC1 immunotherapy. The results suggest that immunotherapy with AST-VAC1 is safe and may extend relapse-free survival even in patients with high risk AML.
AST-VAC2 (antigen-presenting allogeneic dendritic cells)

Asterias completed the transfer of its manufacturing processes for production of AST-VAC2, the company’s innovative immunotherapy product that contains mature dendritic cells derived from pluripotent stem cells, to Cancer Research UK (CRUK). To accelerate clinical development of AST-VAC2, Asterias has an ongoing partnership with CRUK and Cancer Research Technology, the charity’s development and commercialization arm, to execute the first clinical trial of AST-VAC2. As part of this partnership, CRUK will perform cGMP manufacture of AST-VAC2 at its Biotherapeutics Development Unit, and will submit a Clinical Trial Authorisation application to the UK regulatory authorities for a Phase 1/2 clinical trial in non-small cell lung cancer. The trial will be sponsored, managed and funded by CRUK’s Centre for Drug Development. The clinical trial will examine the safety, immunogenicity and activity of AST-VAC2 and may position the immunotherapy to be tested for numerous clinical indications.
AST-OPC1 (oligodendrocyte progenitor cells)

The FDA granted Orphan Drug Designation for AST-OPC1, Asterias’ product development candidate based on its pluripotent stem cell technology platform, for the treatment of acute spinal cord injury. Orphan Drug designation is a special status that the FDA may grant a drug intended to treat a rare disease or condition. Orphan Drug Designation qualifies the sponsor of the drug certain benefits and incentives, including seven years of marketing exclusivity following regulatory approval, and financial incentives such as potential tax credits for certain activities and waiver of certain administrative fees.
Corporate Highlights

In February, pharmaceutical industry veteran Stephen L. Cartt was appointed as President and Chief Executive Officer of Asterias, and member of the company’s Board of Directors. Mr. Cartt previously served as Chief Operating Officer of Questcor Pharmaceuticals Inc. until its sale in 2014 to Mallinckrodt, plc. In addition, Don M. Bailey was appointed to Asterias’ Board of Directors and named Chairman of the Board of Directors. Mr. Bailey previously served as President and Chief Executive Officer of Questcor until its sale in 2014 to Mallinckrodt, plc.

In February, Asterias simplified its capital structure through an asset swap with BioTime, Inc. BioTime acquired from Asterias shares of capital stock of BioTime subsidiaries Cell Cure Neurosciences Ltd and OrthoCyte Corporation. Asterias acquired from BioTime warrants to purchase 3,150,000 shares of Asterias Series A Common Stock. In addition, the companies entered into a patent cross-license agreement for pluripotent stem cell-derived cell therapies and other potential uses, which allows both companies the freedom to leverage a large patent estate covering the therapeutic uses of pluripotent stem cell technology.
Fourth Quarter and Full Year 2015 Financial Results

Cash Position and Usage: Asterias had cash and cash equivalents of $11.2 million as of December 31, 2015, compared to $3.1 million as of December 31, 2014. At December 31, 2015, Asterias held approximately $17 million in available-for-sale securities. For the fourth quarter, net cash used in operating activities was $4.0 million.

Revenues: Total revenues were $608,000 for the fourth quarter and $3.6 million for the full year ended December 31, 2015. Revenues are comprised of grant income as well as royalty revenues on product sales by licensees. Grant income in 2015 was entirely from the California Institute for Regenerative Medicine (CIRM). CIRM is disbursing funds under the grant award to Asterias over four years through 2018 in accordance with a quarterly disbursement schedule, subject to attainment of certain progress and safety milestones.

R&D Expenses: Research and development expenses were $5.4 million for the fourth quarter and $17.3 million for the full year ended December 31, 2015, compared to $5.4 million and $13.3 million for the comparable periods in 2014.

G&A Expenses: General and administrative expenses were $2.8 million for the fourth quarter and $7.9 million for the full year of 2015, compared to $1.2 million and $5.3 million for the comparable periods in 2014.

Net Loss: Net loss was $4.9 million for the three months ended December 31, 2015, or $0.13 per share, including deferred income tax benefits of $2.9 million. For the full year ended December 31, 2015, net loss was $15.0 million or $0.42 per share, including deferred income tax benefits of $7.3 million. For the comparable periods in 2014, fourth quarter net loss was $3.3 million, or $0.11 per share, including deferred income tax benefits of $2.2 million, and full year net loss was $10.1 million or $0.33 per share, including deferred income tax benefits of $7.4 million.

DNA structural lesions are prevalent in sporadic colorectal cancer. Therefore, we proposed that gene variants that predispose to DNA double-strand breaks (DSBs) would be found in patients with familial colorectal carcinomas of an undefined genetic basis (UFCRC).
We collected primary T cells from 25 patients with UFCRC and matched patients without colorectal cancer (controls) and assayed for DSBs. We performed exome sequence analyses of germline DNA from 20 patients with UFCRC and 5 undiagnosed patients with polyposis. The prevalence of identified variants in genes linked to DNA integrity was compared with that of individuals without a family history of cancer. The effects of representative variants found to be associated with UFCRC was confirmed in functional assays with HCT116 cells.
Primary T cells from most patients with UFCRC had increased levels of the DSB marker γ(phosphorylated)histone2AX (γH2AX) after treatment with DNA damaging agents, compared with T cells from controls (P < .001). Exome sequence analysis identified a mean 1.4 rare variants per patient that were predicted to disrupt functions of genes relevant to DSBs. Controls (from public databases) had a much lower frequency of variants in the same genes (P < .001). Knockdown of representative variant genes in HCT116 CRC cells increased γH2AX. A detailed analysis of immortalized patient-derived B cells that contained variants in the Werner syndrome, RecQ helicase-like gene (WRN, encoding T705I), and excision repair cross-complementation group 6 (ERCC6, encoding N180Y) showed reduced levels of these proteins and increased DSBs, compared with B cells from controls. This phenotype was rescued by exogenous expression of WRN or ERCC6. Direct analysis of the recombinant variant proteins confirmed defective enzymatic activities.
These results provide evidence that defects in suppression of DSBs underlie some cases of UFCRC; these can be identified by assays of circulating lymphocytes. We specifically associated UFCRC with variants in WRN and ERCC6 that reduce the capacity for repair of DNA DSBs. These observations could lead to a simple screening strategy for UFCRC, and provide insight into the pathogenic mechanisms of colorectal carcinogenesis.
Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

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Controversy exists as to whether erectile response to phosphodiesterase type 5 inhibitors is compromised in men with low total testosterone (TT) levels. This is amplified by reports of improved response to phosphodiesterase type 5 inhibitor therapy after coadministration of testosterone replacement therapy in hypogonadal men unresponsive to phosphodiesterase type 5 inhibitors.
To determine whether TT and luteinizing hormone levels influence efficacy of tadalafil for erectile dysfunction in men with concomitant lower urinary tract symptoms and benign prostatic hyperplasia.
This integrated analysis included 1,075 men randomized to once-daily tadalafil 5 mg (n = 540) or placebo (n = 535) for 12 weeks in three prospective clinical trials who had not received concomitant testosterone replacement therapy. Subjects were categorized at baseline by low vs normal TT levels (n = 1,049; <300 vs ≥300 ng/dL) and normal vs high luteinizing hormone levels (n = 1,058; ≤9.4 vs >9.4 mIU/mL). Treatment-group differences in International Index of Erectile Function (IIEF) by hormone subgroups were assessed using analysis of covariance.
Changes in IIEF erectile function domain and other domain scores.
The overall study population was comprised primarily of white men (>86%) with a mean age range of 64 to 70 years. Median baseline TT level in the integrated population was 355 ng/dL; levels were lower than 300 ng/dL (cutoff for normal) in 32.4% of men. Men with low TT levels reported diabetes (21.8%), cardiovascular disease (54.1%), and hypertension (49.1%) numerically more often than men with normal TT levels (10.6%, 43.2%, and 36.7%, respectively). Low TT and high luteinizing hormone levels were associated with numerically, but not statistically significantly, lower 12-week IIEF domain scores compared with those with normal levels. Changes in most 12-week IIEF domain scores showed that tadalafil was significantly more effective than placebo (P < .02).
Low TT levels at baseline did not negatively influence response to tadalafil in men of advancing age with concomitant lower urinary tract symptoms and benign prostatic hyperplasia and erectile dysfunction.
Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

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