TECOS, Merck's Cardiovascular Safety Trial of JANUVIA, Met Primary Endpoint; FDA Agrees with OncoGenex' Phase 3 AFFINITY Protocol Amendment Print
By William Kent   
Wednesday, 10 June 2015 20:09
Below is a look at some of the headlines for companies that made news in the healthcare sector on June 10, 2015.
Merck (NYSE: MRK), announced the primary results of the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), a placebo-controlled study of the cardiovascular (CV) safety of Merck’s DPP-4 inhibitor, JANUVIA® (sitagliptin), added to usual care in more than 14,000 patients. The study achieved its primary composite CV endpoint of non-inferiority (defined as the time to the first confirmed event of any of the following: CV-related death, nonfatal myocardial infarction (MI), nonfatal stroke, or hospitalization for unstable angina) compared to usual care without sitagliptin. Overall, the primary endpoint occurred in 11.4 percent (n=839) of sitagliptin-treated patients compared with 11.6 percent (n=851) of placebo-treated patients in the Intention-to-Treat (ITT) analysis (HR=0.98; 95% CI [0.89-1.08]), and in 9.6 percent of patients (n=695) in both the sitagliptin and placebo groups in the Per Protocol (PP) analysis (HR=0.98; 95% CI [0.88-1.09]; p<0.001 for non-inferiority).1 In addition, there was no increase in hospitalization for heart failure and rates of all-cause mortality were similar in both treatment groups, which were two key secondary endpoints. These data were presented today at the 75th Scientific Sessions of the American Diabetes Association and were also published in the New England Journal of Medicine.
  
Indications and Limitations of Use for JANUVIA® (sitagliptin) 25 mg, 50 mg and 100 mg tablets -- JANUVIA is indicated, as an adjunct to diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus. JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. JANUVIA has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while taking JANUVIA.
  
Selected Important Risk Information about JANUVIA -- JANUVIA is contraindicated in patients with a history of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.
  
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUVIA or with any other antidiabetic drug.
  
“Patients with type 2 diabetes need antihyperglycemic medicines to help control their blood sugar. Because these patients are at increased risk for cardiovascular complications, understanding the cardiovascular safety of these medicines is important,” said study co-chair, Rury Holman, Professor of Diabetic Medicine and
Diabetes Trials Unit Director, University of Oxford. “The results from TECOS showed that sitagliptin did not increase the risk of cardiovascular events in a diverse group of patients with type 2 diabetes at high cardiovascular risk.”
   
Additional Findings from the TECOS CV Safety Trial -- TECOS was an event-driven study designed to assess the long-term CV safety of the addition of sitagliptin to usual care, compared to usual care without sitagliptin, in patients with type 2 diabetes and

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established CV disease. In addition to showing no increased risk for the primary composite CV endpoint, sitagliptin also met the secondary composite CV endpoint (defined as the time to the first confirmed event of any of the following: CV-related death, nonfatal MI, or nonfatal stroke), showing non-inferiority compared to usual care without sitagliptin (HR=0.99; 95% CI [0.89-1.11]; p<0.001 for non-inferiority).
   
In additional secondary endpoints assessing time to first confirmed event, hospitalization for heart failure was reported in 3.1 percent (n=228) of sitagliptin-treated patients and
3.1 percent (n=229) of placebo-treated patients (HR=1.00; 95% CI [0.83-1.20]). All-cause mortality was similar in both treatment groups, occurring in 7.5 percent (n=547) of patients in the sitagliptin group and 7.3 percent (n=537) in the placebo group (HR=1.01; 95% CI [0.90-1.14]).
   
Acute pancreatitis was uncommon, occurring in 0.3 percent of patients in the sitagliptin group (n=23) and 0.2 percent of patients in the placebo group (n=12); the difference was not statistically different between groups (p=0.065). Pancreatic cancer was also uncommon, occurring in 0.1 percent of patients in the sitagliptin group (n=9) and 0.2 percent of patients in the placebo group (n=14), and was not statistically different between groups (p=0.322).
   
In additional secondary analyses of the composite of time to first hospitalization for heart failure or CV death, the first confirmed hospitalization for heart failure or CV death occurred in 7.3 percent (n=538) in the sitagliptin group compared with 7.2 percent (n=525) for placebo (HR=1.01; 95% CI [0.90-1.14]). The proportion of patients with CV death was 5.2 percent (n=380) in the sitagliptin group compared with 5.0 percent (n=366) in the placebo group (HR 1.03; 95% CI [0.89-1.19]).
   
The proportion of patients with non-CV death was 2.3 percent in both treatment groups. Death due to infection was 0.6 percent and 0.7 percent in the sitagliptin and placebo groups, respectively. A slight reduction in eGFR (estimated glomerular filtration rate), a measure of renal function, was observed in both treatment groups during the study: at month 48, mean change from baseline in eGFR was -4.0 ± 18.4 mL/min/1.73m2 in the sitagliptin group compared to -2.8 ± 18.3 mL/min/1.73m2 for placebo.
   
“We believe the results of TECOS provide important clinical information about the cardiovascular safety profile of sitagliptin,” said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. “The TECOS CV safety trial reflects the best efforts of clinical scientists at the University of Oxford, the Duke Clinical Research Institute and Merck on behalf of patients around the world who suffer from type 2 diabetes.”
   
To minimize any potential effect that differences in glucose control might have on CV outcomes, the study aimed to achieve similar glucose control (glycemic equipoise) between treatment groups. At four months, mean HbA1c level was 0.4 percent lower in the sitagliptin group compared with placebo, and this narrowed to 0.1 percent lower during patient follow-up. This resulted in an overall difference of -0.29 percent in patients treated with sitagliptin versus placebo. Compared with patients treated with placebo, fewer patients treated with sitagliptin received additional antihyperglycemic agents during the study period (1,591 vs. 2,046 patients, respectively; p<0.001) and were less likely to start chronic insulin therapy (542 vs. 744 patients, respectively; p<0.001).
   
Study Methods and Design -- TECOS was led by an independent academic research collaboration between the University of Oxford Diabetes Trials Unit (DTU) and the Duke University Clinical Research Institute (DCRI), and was sponsored by Merck. A total of 14,735 patients from 38 countries were randomized between December 2008 and July 2012. Of these, 14,671 were included in the ITT analysis population, with 7,332 assigned to sitagliptin and 7,339 to placebo, in addition to existing therapy. The median patient follow-up was three years, with a maximum follow-up of 5.7 years.
   
Patients enrolled in the trial had type 2 diabetes with established CV disease in the coronary, cerebral, or peripheral arteries. Patients were at least 50 years of age, had a baseline HbA1c between 6.5 and 8.0 percent, and were dose-stable for at least three months on either: monotherapy or dual combination therapy with metformin, pioglitazone or a sulfonylurea; or insulin as monotherapy or in combination with a stable dose of metformin. Participants were randomly assigned to treatment with sitagliptin 100 mg daily (50 mg daily if baseline eGFR was ≥30 and <50 mL/min/1.73m2) or matching placebo.
   
The primary non-inferiority hypothesis was assessed by determining whether the upper bound of the 95 percent confidence interval around the hazard ratio for the risk of the primary composite CV endpoint (time to first event) between the sitagliptin and placebo groups in the PP population did not exceed 1.3, with a key supporting analysis in the ITT population. If non-inferiority on the primary composite CV endpoint was met, superiority was to be evaluated in the ITT population.
   
There have been postmarketing reports of acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, in patients taking JANUVIA. After initiating JANUVIA, observe patients carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue JANUVIA and initiate appropriate management.
   
Assessment of renal function is recommended prior to initiating JANUVIA and periodically thereafter. A dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with end-stage renal disease requiring hemodialysis or peritoneal dialysis. Caution should be used to ensure that the correct dose of JANUVIA is prescribed.
   
There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis. A subset of these reports involved patients with renal insufficiency, some of whom were prescribed inappropriate doses of sitagliptin.
   
When JANUVIA was used in combination with a sulfonylurea or insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo. Therefore, a lower dose of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.
   
The incidence (and rate) of hypoglycemia based on all reports of symptomatic hypoglycemia were: 12.2 percent (0.59 episodes per patient-year) for JANUVIA 100 mg in combination with glimepiride (with or without metformin), 1.8 percent (0.24 episodes per patient-year) for placebo in combination with glimepiride (with or without metformin), 15.5 percent (1.06 episodes per patient-year) for JANUVIA (sitagliptin) 100 mg in combination with insulin (with or without metformin), and 7.8 percent (0.51 episodes per patient-year) for placebo in combination with insulin (with or without metformin).
    
There have been postmarketing reports of serious hypersensitivity reactions in patients treated with JANUVIA® (sitagliptin), such as anaphylaxis, angioedema and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment with JANUVIA, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUVIA, assess for other potential causes for the event, and institute alternative treatment for diabetes.
    
Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with JANUVIA.
   
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUVIA or with any other antidiabetic drug. In clinical studies, the adverse reactions reported, regardless of investigator assessment of causality, in greater than or equal to 5 percent of patients treated with JANUVIA as monotherapy and in combination therapy, and more commonly than in patients treated with placebo, were upper respiratory tract infection, nasopharyngitis and headache.
  
  
   
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OncoGenex Pharmaceuticals, Inc. (NASDAQ: OGXI) announced the U.S. Food and Drug Administration has agreed to the Company's proposed amendment to the Phase 3 AFFINITY protocol and statistical analysis plan. The amendment includes the addition of a co-primary endpoint designed to prospectively evaluate the survival benefit of custirsen in men who are at increased risk for poor outcomes when treated with cabazitaxel for metastatic castrate-resistant prostate cancer (CRPC).
  
"There are limited effective treatment options for men with metastatic CRPC who have risk factors for poor outcomes and who fall into a poor prognosis category. Recent findings from the SYNERGY trial showed a significant survival benefit in this group of patients," said Cindy Jacobs, PhD, MD, Chief Medical Officer and Executive Vice President of OncoGenex. "We have applied this key insight from the SYNERGY trial to the AFFINITY protocol to better evaluate this vulnerable subpopulation of men who have poor prognosis and shorter survival time."
   
The FDA is in agreement with plans for prospectively defining a poor prognostic subpopulation in the Phase 3 AFFINITY trial. OncoGenex, in collaboration with study investigators, has defined a simple 5-criteria characterization for poor prognosis in prostate cancer based on the Phase 3 SYNERGY trial, which includes: poor performance status, elevated prostate specific antigen (PSA), elevated lactate dehyrdogenase (LDH), decreased hemoglobin, and the presence of liver metastasis. Patients with poor prognosis will be identified as having 2 or more of these 5 well-recognized high-risk criteria. The proposed change for AFFINITY is also consistent with custirsen's mechanism of action, since custirsen was designed to address treatment resistance which may be more prevalent in this subpopulation.
   
In the revised statistical analysis plan for the AFFINITY trial, the hypothesized hazard ratio (HR) for the poor prognosis subpopulation is specified to be 0.69 with the critical HR ≤ 0.778. The hypothesized HR for the intent-to-treat patients (ITT population) remains unchanged as 0.75 with the critical HR ≤ 0.820.
    
Timing for the final analysis of the poor prognosis subpopulation is projected to occur by the end of 2015, while the final analysis for the ITT population is projected to occur in the second half of 2016. FDA and OncoGenex have further agreed that an interim analysis will occur for the ITT population when the final analysis for the poor prognosis subpopulation occurs. This interim analysis will have both futility and early efficacy criteria defined for the ITT population. If the earlier final analysis on the poor prognostic subpopulation shows a survival benefit for custirsen, OncoGenex could initiate a regulatory submission. The entire trial could also be stopped early due to efficacy based on the interim assessment for the ITT population by the Independent Data Monitoring Committee (IDMC).
    
"Findings from the SYNERGY trial recently presented at ASCO have provided important insight into the patient population in whom custirsen treatment is most relevant," said Scott Cormack, President and CEO of OncoGenex. "We are pleased that the FDA has agreed with our amendment and look forward to announcing top-line results at the end of this year and in 2016."
   
OncoGenex has also initiated a review with the European Medicines Agency (EMA) for the proposed amendment to the Phase 3 AFFINITY protocol and statistical analysis plan, and expects to have this completed in the second half of 2015.
   
A retrospective analysis of data from the Phase 3 SYNERGY trial recently presented at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) showed a benefit with custirsen therapy when added to first-line docetaxel chemotherapy in men with metastatic CRPC who had a poor prognosis. The analysis showed that over 40 percent of men in the trial had at least 2 of the 5 common risk factors for poor prognosis as stated above. In these men, the analysis found a 27 percent lower risk of death when custirsen was used in combination with first-line docetaxel compared to docetaxel alone.
   
AFFINITY is being conducted at 95 global clinical trial sites and earlier this year, the IDMC recommended the trial continue following the completion of an interim futility analysis. The trial is fully accrued, and the protocol amendment does not affect the conduct of the study.
   
   
   
   
Also Wednesday:
  
  
  
  
ALK (ALKB:DC / OMX: ALK B / AKABY / AKBLF) today announced that its partner, MSD, known as Merck (NYSE:MRK) in the USA and Canada, has published positive results from a Phase II environmental exposure chamber trial evaluating the onset and dose-related efficacy of the  house dust mite (HDM) sublingual allergy immunotherapy tablet (SLIT-tablet). 
  
Amarantus BioScience Holdings, Inc. (OTCQB:AMBS), a biotechnology company focused on developing therapeutic and diagnostic products for neurological disorders and orphan indications, announced it has completed its capital restructuring in preparation for a national exchange listing via a 1-for-150 reverse split of its common stock effective at the close of trading on Tuesday, June 9, 2015. 
  
Amarantus BioScience Holdings, Inc. (OTCQB:AMBSD), a biotechnology company focused on developing therapeutic and diagnostic products for neurological disorders and orphan indications, announced that it will be presenting at the BIO International Convention being held June 15-18, 2015, in Philadelphia, PA.
  
Cara Therapeutics, Inc. (Nasdaq:CARA), a biotechnology company focused on developing and commercializing new chemical entities designed to alleviate pain and pruritus by selectively targeting kappa opioid receptors, today announced that it will sponsor a symposium titled "New Analgesic and Abuse Deterrent Approaches: Kappa Opioid Receptor Agonists (KORAs)" at the College on Problems of Drug Dependence (CPDD) 77th Annual Meeting in Phoenix, Arizona. 
  
Curis, Inc. (Nasdaq:CRIS), a biotechnology company focused on the development and commercialization of innovative drug candidates for the treatment of human cancers, today announced that data for CUDC-907 will be presented at the 20th Congress of the European Hematology Association (EHA), being held from June 11 - June 14, 2015 in Vienna, Austria as well as at the 13th International Congress on Malignant Lymphoma (ICML), being held from June 17 – June 20, 2015 in Lugano, Switzerland.
  
EPIRUS Biopharmaceuticals, Inc. (Nasdaq:EPRS), a Boston-based biopharmaceutical company focused on the global development and commercialization of biosimilar monoclonal antibodies, today announced the presentation of new BOW015 (infliximab, reference biologic Remicade®) data at the European League Against Rheumatism Annual Congress (EULAR 2015) in Rome, Italy on June 10 – 13, 2015. 
  
HTG Molecular Diagnostics, Inc. (Nasdaq:HTGM), a provider of instruments and reagents for molecular profiling applications, today announced that its management will be presenting at the JMP Securities Life Sciences Conference on Tuesday, June 23, 2015 in New York City.
  
INC Research Holdings, Inc. (Nasdaq:INCR), a leading global Phase I to IV contract research organization, will demonstrate its focus on clinical innovation and continued commitment to clinical research sites with an extensive presence at the DIA 2015 51st Annual Meeting June 14-18 at the Walter E. Washington Convention Center in Washington, D.C. 
  
K2M Group Holdings, Inc. (Nasdaq:KTWO), a global medical device company focused on designing, developing and commercializing innovative and proprietary complex spine and minimally invasive technologies and techniques, today announced that the Company's Chief Financial Officer, Greg Cole, will participate in the JMP Securities Life Sciences Conference 2015 at the St. Regis New York. Mr. Cole will host a presentation with investors on Tuesday, June 23, 2015 at 4:30 p.m. Eastern Time.
  
Lion Biotechnologies, Inc. (Nasdaq:LBIO), a biotechnology company that is developing novel cancer immunotherapies based on tumor-infiltrating lymphocytes (TIL), today announced that the FDA has granted orphan status to the company's lead product candidate, LN-144, for the treatment of stage 2b to stage 4 malignant melanoma.
  
Matinas BioPharma Holdings, Inc. (OTCQB:MTNB), a clinical-stage biopharmaceutical company, today announced that it will be presenting at the BIO International Convention being held June 15-18, 2015, in Philadelphia, PA.
  
Medigus Ltd. (Nasdaq:MDGS) (TASE:MDGS), a medical device company developing minimally invasive endosurgical tools and a leader in direct visualization technology, announced that the first ever live Medigus Ultrasonic Surgical Endostapler (MUSE) procedure in the Unites States was performed by leading gastroenterologists, Drs. Glen Lehman and William Kessler, at Winthrop-University Hospital in Mineola, NY in late March.
  
Medgenics, Inc. (NYSE MKT:MDGN), the developer of a proprietary platform for the sustained production and delivery of therapeutic proteins and peptides in patients using ex vivo gene therapy and their own tissue for the treatment of rare and orphan diseases, today announced the appointment of Barbara Duncan to the Company's Board of Directors effective July 22, 2015.
  
Nexvet Biopharma (Nasdaq:NVET), a veterinary biologic therapy developer, today announced that Dr. Mark Heffernan, Nexvet's Chief Executive Officer, is scheduled to present at the JMP Securities Life Sciences Conference 2015 in New York on Tuesday, June 23 at 11:00AM EDT. 
  
Prothena Corporation plc (Nasdaq:PRTA), a late-stage clinical biotechnology company focused on the discovery, development and commercialization of novel protein immunotherapy programs, today announced the successful first human dosing in a Phase 1 clinical trial of its proprietary protein immunotherapy, PRX003. PRX003 is a monoclonal antibody targeting melanoma cell adhesion molecule (MCAM) for the potential treatment of psoriasis and other inflammatory diseases.
  
ScripsAmerica Inc. (OTCBB:SCRC) today announced today that the final phase of the auditing process for its 10K for 2014 and 10Q for Q1 2015 is scheduled to commence on June 22, 2015. 
  
Vericel Corporation (Nasdaq:VCEL), a leading developer of patient-specific expanded cellular therapies for the treatment of severe diseases and conditions, today announced that following discussions with the U.S. Food and Drug Administration (FDA) the company plans to submit a Biologics License Application (BLA) to the FDA by the end of 2015 for MACI™ for the treatment of focal chondral cartilage defects in the knee.
  
Zafgen, Inc. (Nasdaq:ZFGN), a biopharmaceutical company dedicated to significantly improving the health and well-being of patients affected by obesity and complex metabolic disorders, today announced that Thomas Hughes, Ph.D., Chief Executive Officer, is scheduled to present a company overview at the 2015 BIO International Convention. 
  
Ziarco Group Ltd., a biopharmaceutical company focusing on inflammatory skin diseases, today announced that it has dosed the first patient in its Phase 2a proof-of-concept clinical trial of ZPL-389 in patients with moderate to severe atopic dermatitis at MAC Clinical Research in Manchester, UK.



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