Alkermes Announces FDA Acceptance for Review of New Drug Application for ALKS 5461 for the Adjunctive Treatment of Major Depressive Disorder

In continuation of my update on ALKS-5461  .................

We know that, Buprenorphine/samidorphan (developmental code name ALKS-5461) is a combination drug formulation of buprenorphine and samidorphan acting as a μ-opioid receptor antagonist which is under development by Alkermes as an adjunct to antidepressant therapy in treatment-resistant depression (TRD).

Buprenorphine 

 Samidorphan

Alkermes plc (Nasdaq: ALKS)announced that the U.S. Food and Drug Administration (FDA) has accepted for review the New Drug Application (NDA) for ALKS 5461, a novel, once-daily, oral investigational medicine for the adjunctive treatment of major depressive disorder (MDD) in patients with an inadequate response to standard antidepressant therapies. FDA's target action date for the ALKS 5461 NDA is Jan. 31, 2019.

FDA's acceptance of the ALKS 5461 NDA and rescission of the Refusal to File letter issued March 30, 2018 follows productive interactions with the Agency in which Alkermes clarified certain aspects of the NDA submission. No additional data or analyses were submitted by Alkermes to FDA.

"FDA's filing of the ALKS 5461 application is a positive step forward for patients suffering from major depressive disorder, a serious disease where inadequate response to existing antidepressants remains a well-known and significant treatment limitation, and where there have been no new pharmacological treatment approaches in 30 years," stated Craig Hopkinson, M.D., Chief Medical Officer and Senior Vice President of Medicines Development and Medical Affairs at Alkermes. "We will continue to engage with the FDA throughout the review process, as we work to bring this important medicine to patients."

The NDA filing for ALKS 5461 is based on results from a clinical efficacy and safety package with data from more than 30 clinical trials and more than 1,500 patients with MDD. Throughout the clinical development program, ALKS 5461 demonstrated a consistent profile of antidepressant activity, safety and tolerability in the adjunctive treatment of MDD.

Achaogen Announces FDA Advisory Committee Voted Unanimously in Favor of Plazomicin for Treatment of Adults with Complicated Urinary Tract Infections

Achaogen, Inc. (NASDAQ:AKAO), a late-stage biopharmaceutical company developing innovative antibacterials addressing multi-drug resistant (MDR) gram-negative infections, announced that the U.S. Food and Drug Administration's (FDA) Antimicrobial Drugs Advisory Committee voted on the two points for Advisory Committee consideration as follows:

1. Has the applicant provided substantial evidence of the safety and effectiveness of plazomicin for the treatment of complicated urinary tract infections?

Result: (15-0-0) There were 15 yes votes and zero no votes. No members of the panel abstained.

2. Has the applicant provided substantial evidence of the safety and effectiveness of plazomicin for the treatment of bloodstream infections in patients with limited or no treatment options?

Result: (4-11-0) There were four yes votes and 11 no votes. No members of the panel abstained.

There were 16 panel members at the meeting, one of whom departed prior to the vote and was therefore not present for the voting.

"We are encouraged by the Committee's unanimous vote in favor of plazomicin for complicated urinary tract infections (cUTI). The discussion underscored the real-world challenges that healthcare providers face every day given limited or inadequate treatment options for certain pathogens," said Blake Wise, Achaogen's Chief Executive Officer. "Regarding bloodstream infections, the Limited-Population Antibacterial Drug pathway, or LPAD, is a novel approach that enables the FDA to consider the benefits and risks for the sickest patients who have few or no available treatment options, and to approve antibiotics like plazomicin that we believe, have the potential to address these limited patient populations."

The FDA is not bound by the Committee's votes but takes its input into consideration when reviewing marketing applications. Plazomicin has a Prescription Drug User Fee Act (PDUFA) date of June 25, 2018. If the FDA approves plazomicin by this target action date, Achaogen expects to launch plazomicin in the U.S. soon thereafter.

http://investors.achaogen.com/releasedetail.cfm?ReleaseID=1066053

FDA Advisory Committee Votes in Favor of Waylivra (volanesorsen) for Treatment of Familial Chylomicronemia Syndrome

Akcea Therapeutics, Inc. (NASDAQ:AKCA), an affiliate of Ionis Pharmaceuticals, Inc., and Ionis Pharmaceuticals, Inc. (NASDAQ:IONS)   announced that the U.S. Food and Drug Administration’s (FDA) Division of Metabolism and Endocrinology Products Advisory Committee voted 12-8 to support approval of Waylivra (volanesorsen) for the treatment of people with familial chylomicronemia syndrome (FCS). The committee’s non-binding recommendation will be considered by the FDA in its review of Akcea’s New Drug Application for Waylivra. The PDUFA date for completion of the review of Waylivra is August 30, 2018.

3’—A*—G*—mC*—T*—T*—dmC—dT—dT—dG—dT—dmC—dmC—dA—dG—dmC—T*—T*—T*—A*—T*—5’




* = 2’-O-(2-methoxyethyl)

m = 5-methyl

d = 2’-deoxy

“We thank the committee members for their time and their comments today. The Committee’s majority vote in favor of approval is an important positive step to bring Waylivra to people with FCS who have no adequate treatment options,” said Paula Soteropoulos, chief executive officer of Akcea Therapeutics. “We look forward to working with the FDA to complete the final stages of regulatory review for Waylivra. We are committed to the FCS community and will continue to focus on bringing Waylivra, potentially the first and only treatment, to people living with this serious and potentially fatal disease.”

“Given the severity of FCS and the burden it places on patients, the need for a therapy is critical. The progress in development of a potential first-ever treatment is very encouraging. The planned efforts in monitoring and education are designed to achieve the highest levels of patient adherence, compliance and safety,” said Dr. Seth Baum, president, American Society for Preventive Cardiology. “The medical community is eager to have a medicine to treat our patients with FCS.”

The Advisory Committee reviewed data from two Phase 3 clinical trials, APPROACH and COMPASS, as well as the ongoing APPROACH Open Label study for Waylivra. Results from the phase 3 APPROACH trial, the largest study ever conducted in patients with FCS, show that patients with FCS treated with Waylivra achieved a statistically significant mean reduction in triglycerides of 77% from baseline and decreased risk of pancreatitis. The most common adverse events in the APPROACH study were injection site reactions and platelet declines. The Committee's input will be considered by the FDA in its review of the New Drug Application for Waylivra. The FDA is not bound by the Committee's guidance, but takes its advice into consideration when reviewing investigational medicines. Waylivra is also under regulatory review in the European Union and Canada.

“People with FCS have severely elevated triglycerides, which lead to multiple severe daily and chronic symptoms, such as abdominal pain and increased risk for pancreatitis, which can be fatal. Waylivra is the first drug to demonstrate substantial triglyceride lowering in clinical trials in people with FCS,” said Brett P. Monia, chief operating officer at Ionis. “Waylivra illustrates how our antisense technology can create targeted drugs for people living with severe diseases who currently have no available therapeutic options.”

Ref : http://ir.akceatx.com/news-releases/news-release-details/fda-advisory-committee-votes-favor-waylivra-treatment-familial

AcelRx Announces FDA Acceptance of NDA for DSUVIA

In continuation of my update on  sufentanil

AcelRx Pharmaceuticals, Inc. (Nasdaq: ACRX), (AcelRx or the Company), a specialty pharmaceutical company focused on innovative therapies for use in medically supervised settings, today announced the acceptance of its New Drug Application (NDA) resubmission for DSUVIA™ by the U.S. Food and Drug Administration (FDA). The FDA considers the DSUVIA NDA resubmission a complete class 2 response to their October 2017 action letter. Therefore, the FDA has assigned a PDUFA (Prescription Drug User Fee Act) goal date of November 3, 2018.

The acceptance of the DSUVIA NDA resubmission is yet another important milestone achieved by the Company this year," stated Vince Angotti, Chief Executive Officer of AcelRx. "We are one step closer to potentially delivering a new, non-invasive treatment option for the management of moderate-to-severe acute pain for adult patients in medically supervised settings. We believe DSUVIA, if approved, also has the opportunity to help U.S. hospitals manage through the intravenous opioid shortage1 they are currently experiencing in their facilities," continued Angotti.

About DSUVIA™ (sufentanil sublingual tablet), 30 mcg

DSUVIA™ (sufentanil sublingual tablet, 30 microgram), known as DZUVEO™ outside the United States, has a proposed indication for the management of moderate-to-severe acute pain in medically supervised settings, in adult patients and was designed to eliminate dosing errors associated with IV administration via its non-invasive single-dose applicator (SDA) administered by health care professionals. Sufentanil is an opioid analgesic currently marketed for intravenous (IV) and epidural anesthesia and analgesia. The sufentanil pharmacokinetic profile when delivered sublingually avoids the high peak plasma levels and short duration of action observed with IV administration. In Europe, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion, recommending approval of DZUVEO. A decision by the European Commission on whether to grant the marketing authorization is expected in the third quarter of 2018.

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AcelRx Announces FDA Acceptance of NDA for DSUVIA

FDA to Review Zynquista (sotagliflozin) as Potential Treatment for Type 1 Diabetes

The U.S. Food and Drug Administration (FDA) has accepted Sanofi's regulatory filing for Zynquista (sotagliflozin). The investigational oral treatment would be used in addition to insulin therapy to improve blood sugar control in adults with type 1 diabetes.

"If approved, Zynquista would be the first oral antidiabetic drug approved in the U.S. for use by adults with type 1 diabetes, in combination with insulin." says Jorge Insuasty, Senior-Vice President, Global Head of Development, Sanofi. "We look forward to working with the FDA through the review process with a view towards bringing this investigational medicine to adults with type 1 diabetes in the U.S."

Developed in partnership with Lexicon Pharmaceuticals, Inc., Zynquista is an investigational oral dual inhibitor of SGLT-1 and SGLT-2, proteins that influence how the intestines and kidneys absorb and eliminate sugar (glucose) resulting in improved glucose control and additional clinical benefits.

"After decades of little change and innovation, the treatment of type 1 diabetes has begun to shift significantly and, if approved, our dual SGLT-1 and SGLT-2 inhibitor, Zynquista, would be the first approved oral therapy used in combination with insulin to improve glycemic control and patient outcomes for adults in the United States who are living with type 1 diabetes," said Pablo Lapuerta, M.D., executive vice president and chief medical officer, Lexicon. "The acceptance of the NDA filing moves us closer to providing a meaningful option for people with type 1 diabetes and we look forward to continuing to work closely with the FDA during the review process."

The FDA New Drug Application for sotagliflozin is based on data from the inTandem clinical trial program which includes three Phase 3 clinical trials assessing the safety and efficacy of Zynquista in approximately 3,000 adults with inadequately controlled type 1 diabetes.1–3 The safety and efficacy data have not yet been evaluated by any regulatory authority.

The target FDA action date under the Prescription Drug User Fee Act (PDUFA) is anticipated to be March 22, 2019. Sanofi also submitted a regulatory application to the European Medicines Agency earlier this year.

TherapeuticsMD Announces FDA Approval of Imvexxy (estradiol vaginal inserts) for the Treatment of Dyspareunia Due to Menopause

In continuation of my update on estradiol

TherapeuticsMD, Inc., an innovative women's healthcare company,  announced that the United States Food and Drug Administration (FDA) has approved Imvexxy (estradiol vaginal inserts) for the treatment of moderate-to-severe dyspareunia (vaginal pain associated with sexual activity), a symptom of vulvar and vaginal atrophy (VVA), due to menopause. Imvexxy is the only product in its therapeutic class to offer a 4 mcg and 10 mcg dose, the 4 mcg representing the lowest approved dose of vaginal estradiol available.

"Imvexxy is a bio-identical vaginal estrogen product that offers a fraction of the estrogen contained in the average doses of many existing products currently on the market," said Brian Bernick, MD, Chief Clinical Officer of TherapeuticsMD. "Imvexxy is the only product specifically designed to be applicator-free. It dissolves completely without mess or additional clean-up, and can be used anytime of day. It allows women the freedom to immediately return to their normal daily activities. Studies showed that, in patients who used Imvexxy, systemic absorption of estradiol remained within postmenopausal range."

"We are excited to bring Imvexxy to market as TherapeuticsMD's first FDA-approved drug as we strive to be the premier Women's Health Company," said Robert Finizio, Chief Executive Officer of TherapeuticsMD. "Imvexxy reflects our long-standing corporate mission and commitment to health solutions that women want, based on the concepts of medical need, efficacy, safety, simplicity, and affordability. Imvexxy will be offered at a price in parity with other products that have been on the market for 10 to 30 years. By ensuring patients can access Imvexxy at an affordable price, TherapeuticsMD is doing the right thing for women."

Pfizer Announces U.S. FDA Approves Xeljanz (tofacitinib) for the Treatment of Moderately to Severely Active Ulcerative Colitis

In continuation of my update on tofacitinib

Pfizer Inc. announced that the United States (U.S.) Food and Drug Administration (FDA) approved Xeljanz (tofacitinib) 10 mg twice-daily (BID) for at least eight weeks, followed by Xeljanz 5 mg BID or 10 mg BID, for the treatment of adult patients in the U.S. with moderately to severely active ulcerative colitis (UC).“Ulcerative colitis is a chronic inflammatory bowel disease that can significantly impact the lives of patients and has limited therapeutic options available,” said Michael Goettler, Global President, Inflammation and Immunology, Pfizer. “With the FDA approval of Xeljanz, adults living with moderately to severely active UC now have an oral option that may help achieve and maintain steroid-free remission.”

Xeljanz is indicated for the treatment of adult patients with moderately to severely active UC. Use of Xeljanz in combination with biological therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.1

This approval was based on data from three pivotal Phase 3 studies from the Oral Clinical Trials for tofAcitinib in ulceratiVE colitis global clinical development program (OCTAVE Induction 1, OCTAVE Induction 2 and OCTAVE Sustain), and OCTAVE Open, an ongoing open label long-term extension study. Data from all three pivotal Phase 3 studies met their respective primary endpoints, showing a statistically significant, greater proportion of patients in remission at week 8 in the induction studies and in remission at week 52 in the maintenance study in patients with moderately to severely active UC treated with tofacitinib compared to placebo. Remission was defined as a Mayo score of 2 points or lower, with no individual subscore exceeding 1 point, and a rectal bleeding subscore of 0.i Full results from OCTAVE Induction 1, OCTAVE Induction 2 and OCTAVE Sustain were published in the New England Journal of Medicine in May 2017.

“The FDA approval of Xeljanz is positive news for the ulcerative colitis community, a patient population that can often encounter frequent and debilitating disruptions to their daily lives,” said William J. Sandborn, MD, Chief, Division of Gastroenterology, Professor of Medicine at the University of California San Diego School of Medicine and OCTAVE study investigator. “Xeljanz provides people living with ulcerative colitis and their prescribing physicians with a new oral treatment option.”

Risks observed in the UC clinical program include serious infection, including herpes zoster and opportunistic infections, malignancies (including non-melanoma skin cancer [NMSC] and lymphoproliferative disorders), gastrointestinal perforation and laboratory abnormalities. There was no discernable difference in frequency of gastrointestinal perforation between the placebo and Xeljanz arms in clinical trials of patients with UC, and many of the trial participants were receiving background corticosteroids.

Dose-dependent adverse reactions seen in patients treated with 10 mg BID, in comparison to 5 mg BID, include the following: herpes zoster infections, serious infections, and NMSC.

“What works for one ulcerative colitis patient may not work for another and some struggle with ongoing symptoms. That is why it is so critical that our patients have different treatment options available to them,” said Michael Osso, President & CEO of the Crohn’s & Colitis Foundation. “We are thrilled to have this new treatment option available to ulcerative colitis patients. Every new treatment provides new hope to our community.”

Pfizer Announces U.S. FDA Approves Xeljanz (tofacitinib) for the Treatment of Moderately to Severely Active Ulcerative Colitis

Researchers find leukemia and lymphoma drug may benefit glioblastoma patients

In continuation of my update on ibrutinib

New Cleveland Clinic research shows for the first time that ibrutinib, an FDA-approved drug for lymphoma and leukemia, may also help treat the most common—and deadliest—type of brain tumor. The findings, published in Science Translational Medicine, offer hope that the drug may one day be used in patients with glioblastoma and improve poor survival rates.

The team of researchers, led by Shideng Bao, Ph.D., of Cleveland Clinic's Lerner Research Institute found that ibrutinib slowed brain tumor growth in a preclinical model and extended survival more than 10-times the rate of the current standard-of-care chemotherapy drug.

They found in human glioblastoma cells that ibrutinib works by inhibiting glioma stem cells—an aggressive type of brain cancer cell that tends to resist treatment and spread. Furthermore, they showed that combining ibrutinib with radiation therapy prevents glioblastoma cells from developing this resistance. Combination therapy overcame resistance and extended lifespan more effectively than either radiation or ibrutinib treatment alone.

According to the American Brain Tumor Association, glioblastoma survival is very poor—median survival in patients undergoing standard treatment is less than 15 months.

"Glioblastoma is the most lethal primary brain tumor and is highly resistant to current therapies," said Bao. "There is an urgent need to get new treatments to these patients as quickly as possible."

In earlier studies, Bao and colleagues found that glioma stem cells have high levels of a protein called BMX (bone marrow and X-linked non-receptor tyrosine kinase). BMX activates a protein called STAT3 (signal transducer and activator of transcription 3), which is responsible for the aggressive, pro-cancer qualities of glioma stem cells. In this new study, the researchers found that ibrutinib works by inhibiting both proteins.

"Additional research is important to understand the effects of ibrutinib in patients, but these early findings are promising," said Bao. "Using an FDA-approved drug would allow us to surpass many of the lengthy regulatory studies needed when developing a new treatment, and we could potentially begin clinical trials very soon."

Ibrutinib (Imbruvica) has been approved by the U.S. Food & Drug Administration to treat certain types of leukemia and lymphoma, as well as chronic graft versus host disease.

Mouse study links triclosan, a common antimicrobial, to colonic inflammation

A large research team led by senior author Guodong Zhang at the University of Massachusetts Amherst reports that the antimicrobial ingredient triclosan, found in hand soaps and toothpastes among other products, could have adverse effects on colonic inflammation and colon cancer by altering gut microbiota, the microbes found in our intestines.

The study reported in Science Translational Medicine suggests that short-time treatment with low-dose triclosan caused low-grade colonic inflammation, and exaggerated disease development of colitis and colitis-associated colon cancer in mice, Zhang says. "These results, for the first time, suggest that triclosan could have adverse effects on gut health," he notes.

Co-first authors Haixia Yang and Weicang Wang, both from the Zhang laboratory in the food science department at UMass Amherst, point out that triclosan is among the most widely used antimicrobial ingredients and is found in more than 2,000 consumer products. They note that a National Health and Nutrition Examination Survey showed that triclosan was detected in about 75 percent of the urine samples of individuals tested in the United States and it is among the top ten pollutants found in U.S. rivers.

"Because this compound is so widely used, our study suggests that there is an urgent need to further evaluate the impact of triclosan exposure on gut health in preparation for the potential establishment of further regulatory policies," says Yang, a postdoctoral fellow in Zhang laboratory.

In this study, the 21-member team that included 12 UMass Amherst researchers, investigated the effects of triclosan on colonic inflammation and colon cancer using several mouse models. In all mouse models tested, triclosan promoted colonic inflammation and colon tumorigenesis, Zhang reports.

His co-author, food scientist Hang Xiao, adds, "In particular, we used a genetically engineered mouse model which develops spontaneous inflammatory bowel disease or IBD. Also, treatment with triclosan significantly increased disease development of IBD in the mice, suggesting that IBD patients may need to reduce exposure to this compound."

In a series of experiments designed to explore mechanisms, the research team found that gut microbiota is critical for the observed adverse effects of triclosan. Feeding triclosan to mice reduced the diversity and changed the composition of the gut microbiome, a result similar to what was observed in a human study conducted by others, Zhang says.

Also, triclosan had no effect in a germ-free mouse model where there is no gut microbiome present, nor in a genetically engineered mouse model where there is no Toll-like receptor 4 (TLR4) - an important mediator for host-microbiota communications. "This is strong evidence that gut microbiota is required for the biological effects of triclosan" Zhang points out.

In an editorial note accompanying the article, the journal says, "Triclosan exposure is practically unavoidable in the United States, but little is known how ingestion may affect our health." This study observed that triclosan altered mouse gut microbiota, increased inflammation, increased the severity of colitis symptoms and spurred colitis-associated colon cancer cell growth. Though limited to mouse models, "this work suggests that the effects of triclosan on human health should be examined more closely," editors noted.

Ref : http://www.umass.edu/newsoffice/article/triclosan-common-antimicrobial-ingredient

http://stm.sciencemag.org/content/10/443/eaan4116

Mini-dose glucagon may halt post-exercise hypoglycemia

Mini-dose glucagon (MDG) is an effective approach for preventing exercise-induced hypoglycemia in patients with type 1 diabetes, according to a study published online May 18 in Diabetes Care.

Michael R. Rickels, M.D., from the University of Pennsylvania in Philadelphia, and colleagues aimed to determine whether MDG given subcutaneously pre-exercise could prevent glucose lowering and compared the glycemic response to current approaches for mitigating exercise-associated hypoglycemia. The authors performed a four-session, randomized crossover trial in which 15 adults with type 1 diabetes treated with continuous subcutaneous insulin infusion exercised fasting in the morning at approximately 55 percent VO_2max with no intervention (control), 50 percent basal insulin reduction, 40-g oral glucose tablets, or 150-µg subcutaneous MDG.

The researchers found that during exercise and early recovery from exercise, plasma glucose increased slightly with MDG and decreased with control and insulin reduction, and there was a greater increase with glucose tablets. There were no differences in insulin levels among sessions; glucagon increased with MDG administration. Six participants experienced hypoglycemia (plasma glucose <70 mg/dL) during control sessions, five subjects during insulin reduction, and none with glucose tablets or MDG. However, five participants experienced hyperglycemia (plasma glucose ≥250 mg/dL) with glucose tablets and one with MDG.

"MDG may be more effective than insulin reduction for preventing exercise-induced hypoglycemia and may result in less post-intervention hyperglycemia than ingestion of carbohydrate," the authors write.

Several authors disclosed financial ties to medical device and pharmaceutical companies, including Xeris Pharmaceuticals, which provided the MDG product for the study.

Ref : http://care.diabetesjournals.org/content/early/2018/05/17/dc18-0051