Apixaban effective in polypharmacy setting

In continuation of my update on Apixaban

The superiority of apixaban over warfarin in patients with atrial fibrillation is maintained in those taking multiple medications, shows further analysis of the ARISTOTLE trial.

 Apixaban

The researchers found superior efficacy of apixaban against the primary thromboembolic endpoint (stroke or systemic embolism) regardless of the number of drugs patients were taking.

By contrast, the advantage of apixaban over warfarin in terms of major bleeding tended to decline in line with the number of drugs patients were taking. The absolute rate reduction per 100 patient-years with apixaban versus warfarin was 1.28 for patients taking up to five medications, falling to 0.82 and 0.66 for those taking six to eight and more than nine drugs, respectively.

"Importantly, the risk reduction of intracranial bleeding did not diminish with an increasing number of concomitant drugs", write the researchers in The BMJ.

"Therefore, the fact that the relative benefit of apixaban over warfarin appears to diminish across groups is due to other types of major bleeding."

They give the example of major gastrointestinal bleeding, which was significantly reduced with apixaban versus warfarin in patients taking up to five drugs, but not in those taking nine or more drugs.

Polypharmacy was common among the 18,201 ARISTOTLE participants, with 76.5% taking at least five concomitant drugs. Patients' average age rose in line with the number of drugs used, as did their stroke and bleeding risk. Patients taking more drugs also had more cardiovascular comorbidities, and also more neurological, renal, endocrine, musculoskeletal, pulmonary, gastrointestinal and haematological comorbidities.

Rates of the primary thromboembolic and bleeding endpoints rose with the number of drugs taken for patients in the apixaban group as well as those in the warfarin group.

Jeroen Jaspers Focks (Radboud University Nijmegen Medical Centre, the Netherlands) and study co-authors stress that "this increased risk of adverse outcomes should be placed in the context of the association between the number of drug treatments and comorbidities present at baseline, indicating a more frail status of patients with polypharmacy."

The researchers suggest that adjusting for these differences would abolish the relationship between the number of drugs used and safety outcomes, but add that the purpose of the study was to use polypharmacy as a marker of patient frailty.

Moreover, increasing frailty did not significantly influence the efficacy of apixaban against stroke or systemic embolism, with the relative risk versus warfarin being 14% among those taking up to five drugs and 24% in those taking more.

Espero Pharmaceuticals Receives FDA Approval for GoNitro (nitroglycerin) Sublingual Powder

Espero Pharmaceuticals, Inc., a privately held specialty pharmaceutical company, announced that the U.S. Food and Drug Administration (FDA) has approved GoNitro (nitroglycerin) sublingual powder for acute relief of an attack or prophylaxis of angina pectoris due to coronary artery disease. With this approval, GoNitro is the first and only short-acting nitrate in a stabilized crystal granule form available in single dose packets.

“The FDA’s approval of GoNitro enhances the treatment options available to the more than 8 million U.S. patients suffering with stable angina due to coronary artery disease (CAD), the most common type of heart disease,” commented Quang Pham, Founder and CEO of Espero Pharmaceuticals. “GoNitro is a sublingual nitrate and as this class of drug therapy is a Class I recommendation according to the 2012 Stable Ischemic Heart Disease (SIHD) Guidelines, it should be prescribed to all patients with known SIHD.”

“Short-acting nitrates are the current standard of care for acute relief of an angina attack. The novel features of a sublingual powder in a portable single dose packet make GoNitro attractive to angina patients who need fast relief and want to continue to live an active lifestyle,” said Dr. A. Allen Seals, Fellow of the American College of Cardiology (FACC).

Each individual packet of GoNitro contains 400 mcg of nitroglycerin. The clinical data indicate that the sublingual absorption of nitroglycerin is higher following the administration of GoNitro compared to Nitrolingual® Pumpspray (nitroglycerin lingual spray) which was launched in 1997 and is currently marketed by Espero in the U.S. GoNitro was approved by the FDA via the 505(b) regulatory pathway.

Espero will promote and distribute GoNitro nitroglycerin sublingual powder in the U.S. market under an exclusive licensing agreement with G. Pohl-Boskamp GmbH & Co. KG, (Pohl Boskamp), an established global leader in the short-acting nitrate market. The United States Patent and Trademark Office awarded Pohl Boskamp Patent No. 9,101,592 B2 for stabilized granules containing glyceryl trinitrate (GTN or nitroglycerin) in August 2015.

“GoNitro is the first new dosage form in the short-acting nitrate category in nearly 20 years and we intend to educate healthcare providers and patients about our exciting new product immediately,” remarked Jeff Cole, President & CFO of Espero Pharmaceuticals.

GoNitro will be available in the second half of 2016 and promoted by Espero’s specialty sales force at launch.




Cabozantinib extends advanced RCC overall survival

In continuation of my update on Cabozantinib

Patients with advanced or metastatic renal cell carcinoma (RCC) derive a significant overall survival (OS) benefit from second-line treatment with the multi-tyrosine kinase inhibitor (TKI) cabozantinib relative to everolimus.

These findings come from the final analysis of the phase III METEOR trial in which 330 participants were randomly assigned to receive cabozantinib 60 mg/day and 328 allocated to the mammalian target of rapamycin inhibitor everolimus at a dose of 10 mg/day. All patients had received at least one previous vascular endothelial growth factor receptor TKI.

After a median follow-up of 18.7 and 18.8 months in the cabozantinib and everolimus arms, respectively, the corresponding median OS times were 21.4 and 16.5 months, a significant difference equating to a hazard ratio for death of 0.66.

Progression-free survival was also significantly improved in the cabozantinib arm, as was the objective response rate - findings that were consistent with the previously reported results for the first 375 randomly assigned patients, report Toni Choueiri (Dana-Farber Cancer Institute, Boston, Massachusetts, USA) and team.

They conclude in The Lancet Oncology: "Based on these results, cabozantinib should be considered as a new standard-of-care treatment option for previously treated patients with advanced renal cell carcinoma."

Licensed from medwireNews with permission from Springer Healthcare Ltd. ©Springer Healthcare Ltd. All rights reserved. Neither of these parties endorse or recommend any commercial products, services, or equipment.

Ref : http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2816%2930107-3/abstract

Carfilzomib therapy shows promise for pre-kidney transplant patients

In continuation of my update on carfilzomib,

Early findings by researchers at the University of Cincinnati (UC) College of Medicine suggest that the use of a second generation cancer drug, carfilzomib, may provide an improved approach for the reduction of antibodies in potential kidney transplant candidates. The research team includes members from UC Transplant Clinical Research, UC's Division of Hematology Oncology and the Cincinnati Children's Hospital Medical Center's Biomedical Informatics division.

 carfilzomib

This pre-transplant drug therapy approach is aimed at reducing antibodies in kidney transplant candidates with greater success than with traditional methods and with reduced side effects.

Antibodies are Y-shaped proteins that in most instances are good because they help fight infection, but people can also make antibodies that work against other humans, which is often a major barrier to transplantation.

"Carfilzomib has been well tolerated by the first group of six study patients who experienced antibody reductions between 31 to 100 percent," says the study's lead author Simon Tremblay, PharmD, research associate in the UC College of Medicine's transplant research programs.

The study's preliminary findings will be presented at the annual American Transplant Congress on June 13, in Boston, Mass., where Tremblay will be awarded the American Transplant Society's Young Investigator award.

Since 2008, the UC research team has been developing therapies that target plasma cells—the cells that make antibodies. The first generation of drug therapy studied was the cancer drug bortezomib, a proteasome inhibitor that, like carfilzomib, is already approved by the Food and Drug Administration for treatment of multiple myeloma. In that 50 person study, which was published in 2015, a significant decrease in antibodies was observed. Furthermore, transplanted patients had low rejection rates and the chances of developing a new antibody against their kidney was also low. In addition, in some patients, antibodies remained suppressed for several months—something that has not previously been described with other approaches.

In the same scientific session, James Driscoll, MD, PhD, assistant professor in the UC College of Medicine's Division of Hematology Oncology, will present the results of translational research studies in the carfilzomib-treated patients. Driscoll will present new genomic data on plasma cells isolated from patients prior to and after receiving carfilzomib therapy.

"Our gene expression profiling studies in normal human plasma cells are giving us a detailed, comprehensive view of how plasma cells survive and avoid the death inducing effects of carfilzomib," says Driscoll. These studies, he says, were performed in collaboration with Bruce Aronow, PhD, at Cincinnati Children's.

Carfilzomib is one of four new regimens—described as "second-generation plasma cell targeted therapies that are being evaluated by the UC transplant Clinical Research Team, " says the principal investigator on both studies, E. Steve Woodle, MD, UC Health transplant surgeon and director of the division of transplantation at the UC College of Medicine.

New experimental antibiotic can help combat MRSA infections

A new experimental antibiotic developed by a team of scientists at Rutgers University successfully treats the deadly MRSA infection and restores the efficacy of a commonly prescribed antibiotic that has become ineffective against MRSA.

In research published in the July issue of Antimicrobial Agents and Chemotherapy, Rutgers scientists say that the combination of their newly developed antibiotic, TXA709, with cefdinir, an antibiotic that has been on the market for almost two decades, successfully treated the MRSA infection in animals.

"This is important because even though TXA709 is effective on its own in treating MRSA, combining it with cefdinir - used to treat a wide range of bacterial infections like strep throat, pneumonia, bronchitis and middle ear and sinus infections - makes it even more efficacious, while also significantly reducing the potential for the MRSA bacteria to become resistant in the future," said Daniel Pilch, associate professor in the Department of Pharmacology at Robert Wood Johnson Medical School.

Pilch and fellow scientists are racing to develop a new class of antibiotics to treat methicillin-resistant Staphylococcus aureus (MRSA) infections, which are responsible for 19,000 deaths annually and represent $3 billion in annual health care costs.

The threat of MRSA and other antibiotic-resistant infections has become so severe that the World Health Organization predicts that common infections and minor injuries could become life-threatening because of a lack of drug treatments available to destroy these bacterial infections. Last month the first case in the United States of a patient with an infection resistant to all known antibiotics was reported by the U.S. Centers for Disease Control and Prevention.

"Current standard-of-care drugs for the treatment of MRSA infections are limited," said Pilch. "Furthermore, resistance to these drugs is on the rise, and their clinical effectiveness is likely to diminish in the future."

Pilch said that TXA709 kills MRSA bacteria in a unique manner unlike any other antibiotic in current clinical use, inhibiting the function of a protein, FtsZ, essential for the bacteria to divide and survive. By combining TXA709 with cefdinir, a cephalosporin antibiotic that acts much like penicillin, scientists were able to lower the dosage of the new antibiotic required to eradicate the MRSA infection.

This is significant, Rutgers scientists say, because it decreases the potential for any drug-induced toxicity and side effects that might occur from a higher dosage.

"What is also good about this experimental treatment is that both drugs can be taken orally, which means they can be administered on an outpatient basis," said Pilch, who collaborated with Edmond LaVoie, professor and chair of the Department of Medicinal Chemistry at the Ernest Mario School of Pharmacy at Rutgers. "All but two of the current antibiotics being used clinically to treat MRSA need to be administered intravenously," he said.

Researchers say Phase I clinical trials on the new antibiotic, which will assess and evaluate its safety and effectiveness in humans, are expected to begin next spring.

Ref : http://aac.asm.org/content/59/8/4845.full?sid=949e5603-f4b2-4eec-8e5f-f79d0c758e44

Empagliflozin offers long-term renal protection in Type 2 diabetes

The sodium-glucose cotransporter 2 inhibitor empagliflozin slows renal progression and averts clinical events, shows further analysis of the EMPA-REG OUTCOME trial.

 empagliflozin 

The previously reported primary analysis showed a reduced risk of major cardiovascular events in patients randomly assigned to take empagliflozin 10 or 25 mg daily, compared with placebo, in addition to their existing medication.

As now reported in The New England Journal of Medicine, the researchers found that microvascular events were also significantly less common in the 4132 patients taking either empagliflozin dose than in the 2068 taking placebo, at 14.0% versus 20.5%.

This was driven almost entirely by renal outcomes, report Christoph Wanner (Würzburg University Clinic, Germany) and team.

Incident or worsening nephropathy occurred in 12.7% of the empagliflozin group versus 18.8% of the placebo group, a significant 39% relative reduction. And 11.2% of patients taking empagliflozin versus 16.2% of those taking placebo progressed to macroalbuminuria, equating to a significant 38% risk reduction.

Patients in the empagliflozin group also had a significantly reduced risk of having a doubling of their serum creatinine level and requiring initiation of renal-replacement therapy.

During the first 4 weeks of treatment, patients taking empagliflozin had a reduction in their average estimated glomerular filtration rate (eGFR) of 0.62 and 0.82 mL/min per 1.73 m2 in the 10 and 25 mg dose groups, respectively. After this, however, eGFR in both groups remained relatively stable, with an annual decline of just 0.19 mL/min per 1.73 m2, compared with 1.67 mL/min per 1.73 m2 in the placebo group.

In an editorial that also refers to the just published LEADER trial, Julie Ingelfinger (Massachusetts General Hospital, Boston, USA) and Clifford Rosen (Maine Medical Center Research Institute, Scarborough, USA) agree with the LEADER investigators' view that differences in trial design and participant characteristics do not account for diabetes medications being cardioprotective in some studies but not others.

"We are left with differences that appear encouraging, yet are not a 'home run' with regard to the management of diabetes", they write.

The editorialists hope that, in the future, head-to-head trials of older and newer diabetes therapies "may help to delineate an even more effective treatment plan for the millions of people whose lives are affected by type 2 diabetes."

Ref : http://www.nejm.org/doi/full/10.1056/NEJMoa1515920#t=abstract

Cranberries can reduce symptomatic UTIs and avoid chronic suppressive antibiotics

 In continuation of my update on craneberries

According to the study, recently published by the American Journal of Clinical Nutrition, drinking an 8-ounce (240 ml) glass of cranberry juice a day reduces symptomatic UTIs by nearly 40 percent in women with recurrent UTIs - reducing the burden of UTIs and reducing the antibiotic use associated with treating recurrent UTIs.

"Currently the primary approach to reducing symptomatic events of UTI is the use of chronic antibiotics for suppression, an approach associated with side effects and development of antibiotic resistance. This study shows that consuming one 8-ounce (240 ml) glass of cranberry juice a day reduces the number of times women suffer from repeat episodes of symptomatic UTI and avoids chronic suppressive antibiotics," said Dr. Kalpana Gupta, infectious disease specialist and Professor of Medicine at Boston University's School of Medicine.

An author on the study and panelist at today's session, Dr. Gupta believes that cranberries can help to reduce the worldwide use of antibiotics and significantly improve the quality of life for women who suffer from recurrent UTI symptoms.

Single Largest Clinical Trial on Cranberries of its Kind

The 24-week study of 373 women, conducted by researchers at Boston University, Biofortis Innovation Services (a division of Merieux Nutrisciences) and 18 clinical sites throughout the US and France, is the largest clinical trial of its kind examining the effects of cranberry juice consumption on UTIs. This trial adds to more than 50 years of cranberry research and supports the cranberry's ability to support urinary tract health and reduce symptomatic UTIs among chronic UTI sufferers.

Researchers set out to find whether recurrent (or repeat) UTI sufferers could be protected from repeat infections by drinking cranberry juice. Participants were all healthy women, with an average age of 40, who had experienced at least two UTIs within the past year. During the study, participants were randomly chosen to drink a daily dose of eight ounces (240 ml) of either cranberry juice or a "placebo" beverage without cranberries.

The rate of UTIs decreased significantly among the cranberry drinkers, with just 39 diagnoses during the six-month study compared with 67 in the placebo group.

Compared to some other studies, this trial had greater statistical power to detect differences than others due to its larger sample, use of incidence density to account for the tendency of clinical UTIs to cluster in time within an individual, a high average level of compliance (98%), and a comparatively large percentage of subjects in each group completing the treatment period (86%).

How Cranberries Work

Luckily, cranberries contain a unique combination of compounds including Type-A PACs (or proanthocyanidins) that prevent bacteria from sticking and causing infection. In addition to PACs, new studies have revealed a new class of compounds, xyloglucan oligosaccharides, which have similar anti-bacterial properties against E. coli as PACs. This means there are multiple, unique elements within cranberries working hard for your health.

These unique compounds can be found in a variety of products, including cranberry juice cocktail, 100% cranberry juice, light cranberry juice, dried cranberries and cranberry extract; however most of the research surrounding cranberries and UTIs has been conducted using juice.

Cranberries, a Natural Approach to Better Health

The suggestion that a nutritional approach like cranberry juice could reduce antibiotic use is welcome news given the alarming challenge it presents to public health, one that the WHO refers to as one of the greatest challenges to public health today, and that the UK Chancellor of the Exchequer said could become a threat 'greater than cancer'.

According to Gupta, those who suffer from UTIs can feel confident that this nutritional approach is a potential solution - further validating more than 50 years of well-documented cranberry research.

Long-term dasatinib findings support first-line use in CML

In continuation of my update on dasatinib

Final DASISION study findings confirm dasatinib to be an effective, long-term treatment for patients with a new diagnosis of chronic phase-chronic myeloid leukaemia (CP-CML).

 dasatinib

After 5 years, 61% of 259 patients randomly assigned to receive dasatinib 100 mg/day were still taking the tyrosine kinase inhibitor (TKI), while 63% of the 260 patients started on imatinib 400 mg/day continued with their treatment, the investigators report in the Journal of Clinical Oncology.

The primary endpoint of complete cytogenetic response (CCyR) at 5 years had been achieved by 28% of dasatinib-treated patients and 26% of their imatinib-treated counterparts, although the researchers note that these values may have been higher if bone marrow samples had been tested in the patients at the end of the study.

Cumulative 5-year rates of major molecular response (MMR) and molecular responses with a 4.5-log (MR4.5) reduction in BCR-ABL1 transcripts from baseline were also comparable in the dasatinib and imatinib treatment arms, at 76% versus 64%, and 42% versus 33%, respectively, say Jorge Cortes, from the University of Texas MD Anderson Cancer Center in Houston, USA, and co-authors.

Five-year estimated overall survival was 91.0% for the dasatinib group and 90.0% for those given imatinib. And estimated progression-free survival was a corresponding 85.0% and 86.0% with 4.6% and 7.3% of patients transforming to accelerated or blast phase CML during a period of follow-up that continued beyond TKI discontinuation.

In all, 84% of dasatinib-treated patients and 64% of imatinib-treated patients achievedBCR-ABL1 of 10% or less within 3 months of treatment. Compared with patients who did not reach this target, these individuals were more likely to achieve CCyR, MMR and MR4.5over 5 years, had higher rates of overall and progression-free survival, and were less likely to have transformation.

Cortes et al note that no new adverse effects were reported for dasatinib or imatinib by the end of the 5-year study period and just 15% and 11% of adverse effects were grade 3 or 4 in the groups, respectively.

Patients given dasatinib had higher rates of grade 3 or 4 neutropenia (29 vs 24%), anaemia (13 vs 9%) and thrombocytopenia (22 vs 14%) but lower rates of other nonhaematological side effects, except for any grade of pleural effusion (28.0 vs 0.8%). Discontinuation for drug-related side effects occurred in 16% and 7% of dasatinib- and imatinib-treated patients, respectively.

Pulmonary hypertension was reported in 5.0% and 0.4% of the dasatinib and imatinib groups, respectively, with 12 of the 14 diagnoses deemed to be drug related. Arterial ischaemic events were "uncommon" in both groups, affecting 5.0% and 2.0%, respectively.

However, there was a "disproportionate number" of deaths from infection in the dasatinib versus imatinib groups (11 vs 1), with seven deaths reported between 69 days and 4.5 years after dasatinib discontinuation.

"It will be important to prospectively and intentionally look at a possible imbalance in the occurrence of infections and, if present, determine a possible mechanism(s) for dasatinib-related infectious complications", the investigators comment.

"These results suggest that first-line dasatinib should continue to be considered a standard first-line therapy for patients with newly diagnosed CML-CP", the researchers conclude.

While patients given dasatinib were more likely to achieve early treatment milestones, the authors explain that the high rates of CCyR and overall survival in both treatment arms mean a longer follow-up period and larger study population are likely needed to demonstrate any significant difference in survival between the TKIs.

Diabetes Drug Victoza May Help the Heart: Study

In continuation of my update on liraglutide

The blood sugar-lowering drug Victoza (liraglutide) cuts the risk of heart attack and stroke in type 2 diabetes patients, a new study finds.

Heart disease is the leading cause of death among people with type 2 diabetes, the researchers noted.

The study was funded by the drug's maker, Novo Nordisk, and the U.S. National Institutes of Health. It included more than 9,300 adults from 32 countries who have type 2 diabetes and a high risk of heart disease.

About half took Victoza, while the other half took an inactive placebo. Both groups also took other medications for health problems, such as high blood pressure and high cholesterol, the study authors said.

Tracking patients for three years, the researchers found that compared with patients in the placebo group, people who took Victoza had a 13 percent lower risk of heart attack or stroke. They also had a 22 percent lower risk of death from heart disease; a 15 percent lower risk of death from any cause; and a 22 percent lower risk of new evidence of advanced kidney disease.

Some patients did discontinue the drug due to "gastrointestinal events," according to the report.

The study was presented June 13 at the American Diabetes Association's annual meeting, in New Orleans. It was also published simultaneously in the New England Journal of Medicine.

"I've been excited about liraglutide for a long time because I think it's unique," said study senior author Dr. John Buse. He directs the Diabetes Care Center at the University of North Carolina, Chapel Hill.

"This is the first diabetes drug that has shown across-the-board benefits for cardiovascular diseases, and this suggests it plays a role in treating atherosclerosis [hardening of the arteries], which is what leads to heart attacks and strokes," Buse said in a university news release.

One diabetes expert called the study "encouraging."

Victoza "is a relatively new medication, given by daily injection," said Dr. Allison Reiss, who runs the inflammation laboratory at Winthrop-University Hospital in Mineola, N.Y.

Still, the long-term effectiveness of the drug is unknown, Reiss added. "It will be important to follow these patients over the next few years to see whether [Victoza] benefits continue and to investigate how it is working," she said.

The researchers explained that Victoza is from a newer class of diabetes drugs known as GLP-1 agonists. These medications work in the pancreas to cut the production of an anti-insulin hormone called glucagon. The drugs boost insulin production and help control blood sugar levels.

As a secondary mechanism, Victoza also works on the brain to help lower appetite and boost feelings of "fullness" when eating, Buse's team explained.

Reiss noted that because of this activity, Victoza can help spur weight loss -- and that might be the prime factor driving the improvements in heart health.

Dr. Gerald Bernstein coordinates the Friedman Diabetes Program at Lenox Hill Hospital in New York City. He said that Victoza -- and other drugs in its class -- are being increasingly used, so "decreased cardiovascular risk is an important finding."

FDA Issues Complete Response Letter for Mycapssa New Drug Application

Chiasma, Inc. , a late-stage biopharmaceutical company focused on improving the lives of patients with rare and serious chronic diseases, today announced that it received a Complete Response Letter (CRL) from the United States (U.S.) Food and Drug Administration (FDA) regarding the company’s New Drug Application for Mycapssa (octreotide) capsules for the maintenance treatment of U.S. adult patients with acromegaly. The FDA issues CRLs to indicate that the review cycle for an application is complete and that the application is not ready for approval in its present form. 

Mycapssa, octreotide (RG3806) (formerly Octreolin)

About Mycapssa

Mycapssa is an investigational new oral drug proposed for the maintenance therapy of adult patients with acromegaly. If approved, octreotide capsules may be the first oral somatostatin analog approved for acromegaly. Octreotide capsules have been granted orphan designation in the United States and the European Union for the potential treatment of acromegaly.

Octreotide capsules are an investigational drug that has not been approved for use in any jurisdiction.

About Chiasma

Chiasma is a late-stage biopharmaceutical company focused on improving the lives of patients suffering from orphan diseases by developing and commercializing novel oral forms of therapies that are available today only by injection. The company’s lead product candidate is Mycapssa (octreotide) capsules, an investigational new drug developed with Chiasma’s Transient Permeability Enhancer (TPE®) technology to facilitate gastrointestinal absorption of unmodified drug into the bloodstream safely. Mycapssa is a proposed tradename, and this investigational new drug has not been approved for use in any jurisdiction. Using TPE® technology, Chiasma is evaluating additional proteins, peptides and small molecule drugs that are currently only available by injection but could potentially be converted to oral delivery. TPE® technology is potentially well suited for drugs with chronic indications, where frequent dosing is required and the need for an oral alternative is greatest. Chiasma is a Delaware corporation with a wholly-owned Israeli subsidiary. Mycapssa and TPE® are trademarks of Chiasma.

Cempra Completes NDA Submissions for Solithromycin in the Treatment of Community-Acquired Bacterial Pneumonia

Cempra, Inc.  , a clinical-stage pharmaceutical company focused on developing antibiotics to meet critical medical needs in the treatment of bacterial infectious diseases, announced the completion of its rolling submission of the New Drug Applications (NDA) for solithromycin to the U.S. Food and Drug Administration (FDA) for the treatment of community-acquired bacterial pneumonia (CABP). Based on the Qualified Infectious Disease Product (QIDP) designation by the FDA of solithromycin, Cempra has Priority Review and has been granted Fast Track for both the oral capsule and intravenous formulations for the treatment of CABP, which could result in an FDA decision on solithromycin's NDA within eight months, or by the end of 2016, based on the Prescription Drug User Fee Act (PDUFA) performance goals.

 Solithromycin

"Completion of the rolling submission of our first NDAs during Cempra's ten year anniversary year represents a major milestone for the company and a significant step toward our goal of developing antibiotics to meet the critical medical needs of patients in the treatment of bacterial infectious diseases," stated Prabhavathi Fernandes, Ph.D., president and chief executive officer of Cempra. "We believe the intravenous and capsule formulations will provide dosing flexibility that could lead to fewer hospital admissions, earlier discharge if admitted, and increased treatment of CABP on an outpatient basis. We are confident we have a strong data package for solithromycin."

"The management of CABP remains a challenge to healthcare professionals and I firmly believe that solithromycin has the potential to be a significant part of the treatment of this life threatening illness, given its published clinical efficacy and potential for multiple formulations," stated Thomas M. File, M.D., principal investigator for solithromycin clinical trials, Northeast Ohio Medical University. "Solithromycin's potency, spectrum of activity and tolerability could help to offset the rising problem of bacterial resistance, and it is gratifying to note that patients could be closer to benefiting from this potential new treatment."

The FDA has a 60-day filing review period to determine whether the NDAs are complete and acceptable for filing, and to confirm that Priority Review has been granted. Cempra expects to communicate the agency's decision regarding acceptance of the NDAs and its PDUFA date when it is known. Cempra's submissions in the EU remain on track for completion by the end of June 2016.

About Solithromycin

Solithromycin is a highly potent next-generation macrolide, the first fluoroketolide, which has potent activity against most macrolide-resistant strains. In vitro and in vivo studies have shown potent activity against S. pneumoniae as well as an extended spectrum of activity against CA-MRSA, streptococci, Haemophilus, enterococci, Mycobacterium avium and in animal models of malaria. It is also active against atypical bacteria, such as legionella, chlamydia, mycoplasma and ureaplasma, and against gonococci and other organisms that cause genitourinary tract infections. It is 8-16 times more potent than azithromycin against many bacteria and is active against azithromycin-resistant strains. Solithromycin's activity against resistant strains is driven by its ability to interact with three sites on the bacterial ribosome, compared to one for current macrolides. The binding to bacterial ribosomes and interaction with three ribosomal sites is expected to limit the development of bacterial resistance to solithromycin.

FDA Grants Soligenix “Fast Track” Designation for SGX943 for the Treatment of Melioidosis

Soligenix, Inc. (Soligenix or the Company), a late-stage biopharmaceutical company focused on developing and commercializing products to treat rare diseases where there is an unmet medical need, announced today that its SGX943 (dusquetide) development program has received “Fast Track” designation from the US Food and Drug Administration (FDA) as adjunctive therapy with other antibacterial drugs, for the treatment of melioidosis, a serious and potentially life-threatening condition.

 SGX943 (dusquetide)

Fast track is a designation that the FDA reserves for a drug intended to treat a serious or life- threatening condition and one that demonstrates the potential to address an unmet medical need for the condition. Fast track designation is designed to facilitate the development and expedite the review of new drugs. For instance, should events warrant, Soligenix will be eligible to submit a new drug application (NDA) for SGX943 on a rolling basis, permitting the FDA to review sections of the NDA prior to receiving the complete submission. Additionally, NDAs for fast track development programs ordinarily will be eligible for priority review, which imparts an abbreviated review time of approximately six months.

“We are very pleased to have been granted fast track designation from the FDA,” stated Christopher J. Schaber, PhD, President and Chief Executive Officer of Soligenix. “We believe that the FDA’s action in granting fast track designation validates the unmet medical need that currently exists for the treatment of melioidosis and for the potential key role SGX943 can serve as a therapy in this rare, life-threatening disease. We look forward to working with the federal government to advance this biodefense development program.”

About Melioidosis

Melioidosis is a potentially fatal infection caused by the Gram-negative bacillus, Burkholderia pseudomallei(Bps). Highly resistant to many antibiotics, Bps can cause an acute disease characterized by a fulminant pneumonia and a chronic condition that can recrudesce. There is no preventive vaccine or effective immunotherapy for melioidosis. Therefore, there is a significant medical need for improved prevention and therapy.

Bps and the closely related Burkholderia mallei (Bm) are considered possible biological warfare agents by the Department of Health and Human Services (DHHS) because of the potential for widespread dissemination through aerosol. Bps is classified as a Tier 1 biothreat and a category B priority pathogen by the NIAID and is a top 5 priority in the most recent Public Health Emergency Medical Countermeasure Enterprise (PHEMCE) Strategy document.

Bps infection (melioidosis) is a major public health concern in the endemic regions of Southeast Asia and Northern Australia. Moreover, the organism has a worldwide distribution and the full extent of global spread is likely underestimated. Bps activity is seen in Southeast Asia, South America, Africa, the Middle East, India, and Northern Australia. The highest pockets of disease activity occur in Northern Australia and Northeast Thailand, Burma and Vietnam, and is likely under-reported in China. In Northeast Thailand, the mortality rate associated with Bps infection is over 40%, making it the third most common cause of death from infectious disease in that region after HIV/AIDS and tuberculosis.

About SGX943

SGX943 is the drug product designation for the active ingredient dusquetide in the treatment of melioidosis. Dusquetide is an IDR, a new class of short, synthetic peptides that has a novel mechanism of action in that it has simultaneous anti-inflammatory and anti-infective activity. IDRs have no direct antibiotic activity but modulate host responses, increasing survival after infections with a broad range of bacterial Gram-negative and Gram-positive pathogens, as well as accelerating resolution of tissue damage following exposure to a variety of agents including bacterial pathogens, trauma and chemo- and/or radiation-therapy. Dusquetide has demonstrated safety in a Phase 1 clinical study in 84 healthy human volunteers and preliminary efficacy and safety in an exploratory Phase 2 clinical study in 111 patients with oral mucositis due to chemoradiation therapy for head and neck cancer. Dusquetide has also previously demonstrated efficacy in numerous animal disease models including melioidosis, mucositis, colitis, skin infection and other bacterial infections. Dusquetide and related analogs have a strong intellectual property position, including composition of matter. Dusquetide was developed pursuant to discoveries made by Professors B. Brett Finlay, PhD and Robert Hancock, PhD of the University of British Columbia.

Charleston Laboratories, Inc. and Daiichi Sankyo, Inc. Announce FDA Acceptance of New Drug Application (NDA) for CL-108

In continuation of my updates on hydrocodone, Promethazine & acetaminophen

Charleston Laboratories, Inc. and Daiichi Sankyo, Inc.  announced that the U.S. Food and Drug Administration (FDA) has accepted for review the New Drug Application (NDA) for CL-108   (is a novel bi-layered tablet containing 12.5mg of immediate release promethazine with a modified release of 7.5 mg of hydrocodone and 325mg of acetaminophen) for the relief of moderate to severe pain while preventing or reducing the associated opioid-induced nausea and vomiting (OINV). CL-108 is a fixed-dose, immediate-release bi-layered tablet with a rapid release layer containing 12.5 mg of promethazine and a second layer containing 7.5 mg of hydrocodone and 325 mg of acetaminophen. The FDA has set a target action date under the Prescription Drug User Fee Act (PDUFA) of January 31, 2017.

 promethazine

"With this NDA acceptance, patients are one step closer to being able to have an option for relieving pain while also preventing or minimizing the nausea and vomiting side effects of opioid treatment," said Paul Bosse, President and Chief Executive Officer of Charleston Laboratories, Inc. "At Charleston Laboratories, a key part of our mission is to develop and commercialize products that provide patients with novel solutions for improving their pain management. This acceptance represents an important contractual milestone under our relationship with Daiichi Sankyo."

"Daiichi Sankyo is dedicated to bringing innovative medicines to patients with unmet medical needs in the area of pain management," said Mahmoud Ghazzi, MD, PhD, President and Global Head of Development for Daiichi Sankyo. "We look forward to working closely with the FDA during the review process for CL-108 and support the Agency's efforts to foster the safe and responsible use of opioid medications."

The NDA for CL-108 is supported by two pivotal randomized, double-blind, placebo- and active-controlled Phase 3 clinical studies, one following oral surgery (molar removal) and the other after bunionectomy surgery (removal of bunions from the foot), as well as by an additional Phase 3 open-label, actual use safety study in patients with moderate-to-severe acute pain, or "flares," associated with osteoarthritis of the knee or hip. More than 1,000 patients have been enrolled in the CL-108 Phase 3 clinical trial program. A human abuse liability study has also been conducted.

Shionogi Announces Acceptance of NDA for Naldemedine for the Treatment of Opioid-Induced Constipation

Shionogi announced that the New Drug Application (NDA) submitted in the U.S. for naldemedine, a once-daily, oral 0.2 mg tablet, has been accepted for review. In the U.S., the proposed indication is for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain (CNCP). The target action date under the Prescription Drug User Fee Act (PDUFA) is March 23, 2017. The company also submitted an NDA in Japan on March 30, 2016 for the proposed indication of the treatment of OIC in adult patients.

Naldemedine is an investigational peripherally-acting mu-opioid receptor antagonist (PAMORA) being studied in the US for the treatment of OIC in adult patients with CNCP. Opioid-induced constipation is characterized by any of the following: reduced bowel movement frequency, development or worsening of straining to pass bowel movements, a sense of incomplete rectal evacuation, or harder stool consistency after initiating opioid therapy.

"If approved, naldemedine will offer a new therapeutic option for chronic non-cancer pain patients living with opioid-induced constipation, a common and often debilitating condition," said Dr. John Keller, President and CEO, Shionogi Inc. "Shionogi is committed to developing new treatments to improve the lives of patients around the world. We look forward to working with U.S. and Japanese health authorities to bring naldemedine to market for their respective indications."

The NDA submissions include data supporting the efficacy and safety of naldemedine from the Phase III COMPOSE program.

About COMPOSE

The COMPOSE program is a global comprehensive development program comprised of seven clinical studies being conducted in patients with OIC and cancer or chronic non-cancer pain.

COMPOSE I and II were 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies. Both studies were designed to evaluate the efficacy and safety of naldemedine therapy versus placebo in patients on opioid therapy for at least three months and on a stable dose of opioids for at least four weeks, and who experience chronic non-cancer pain accompanied by OIC. The sample population for COMPOSE I and II included 547 and 553 patients, respectively.

Shionogi previously announced that naldemedine met its primary and key secondary endpoints in COMPOSE I, II and IV. COMPOSE IV was conducted in Japan.

In the studies, a bowel movement occurring within 24 hours after rescue laxative therapy was not considered a spontaneous bowel movement (SBM).

About Opioid-Induced Constipation (OIC)

Opioid-induced constipation (OIC) is characterized by any of the following after initiating opioid therapy: reduced bowel movement frequency, development or worsening of straining to pass bowel movements, a sense of incomplete rectal evacuation, or harder stool consistency.1 Approximately half of all chronic non-cancer pain patients who have OIC are dissatisfied with laxatives.2 Managing OIC and its clinical consequences places a significant burden on the healthcare system and the patient.

Shionogi Announces Acceptance of NDA for Naldemedine for the Treatment of Opioid-Induced Constipation

FDA Issues Complete Response Letter for Apadaz New Drug Application

KemPharm, Inc.  a clinical-stage specialty pharmaceutical company engaged in the discovery and development of proprietary prodrugs,  announced that the U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) regarding the New Drug Application (NDA) for Apadaz™ (benzhydrocodone and acetaminophen), KemPharm’s investigational abuse-deterrent product candidate for the short-term management of acute pain.

 benzhydrocodone         acetaminophen

The FDA issues CRLs to indicate that the Agency considers the review cycle for an application is complete and that the application is not ready for approval in its present form. Included in the CRL is guidance that describes all specific deficiencies that the FDA has identified in the application. When possible, the FDA recommends actions that the applicant may take to place the application in condition for approval.

“After last week’s amendment request, a Complete Response Letter from the FDA was received for the Apadaz NDA,” said Travis C. Mickle, Ph.D., President and CEO of KemPharm. “We are currently evaluating the points raised in the CRL and intend to request an End of Review meeting with the Agency to determine the pathway forward for Apadaz.”