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

Drugs that suppress immune system may protect against Parkinson's

The findings, published May 31 in Annals of Clinical and Translational Neurology, suggest that a person's own immune system helps nudge him or her down the path toward Parkinson's. Restraining the immune system with drugs potentially could prevent the neurological disorder, which is characterized by tremors, slow movements, stiffness and difficulty walking.

"The idea that a person's immune system could be contributing to neurologic damage has been suggested for quite some time," said Brad Racette, MD, the Robert Allan Finke Professor of Neurology and the study's senior author. "We've found that taking certain classes of immunosuppressant drugs reduces the risk of developing Parkinson's. One group of drugs in particular looks really promising and warrants further investigation to determine whether it can slow disease progression."

Parkinson's, a neurodegenerative disease, affects about a million people in the United States. Its causes are not well-understood.

Last year, Racette and colleagues analyzed millions of medical records and developed an algorithm to predict which people would be diagnosed with the disease. As they mined the data, they discovered that people with several types of autoimmune diseases, including ulcerative colitis, were less likely to be diagnosed with Parkinson's than the general population. The autoimmune diseases were a mixed bag, linked to myriad glitches in the immune system and affecting a variety of organ systems. It was hard to see how such a hodgepodge of immune system malfunctions all could end up having the same beneficial effect.

The researchers noted, however, that many autoimmune diseases do have one thing in common: They are treated with drugs that dampen immune activity. Having an autoimmune disease may not be a good thing, but being treated for one might be, they decided.

Racette and colleagues analyzed Medicare Part D prescription drug data on 48,295 people diagnosed with Parkinson's in 2009 and 52,324 people never diagnosed with Parkinson's. They identified 26 commonly prescribed immunosuppressant drugs, representing six classes of medications. The researchers determined which people in the data set had been prescribed any of the drugs a year or more before the date of diagnosis or by a pre-set cutoff date. Prescriptions written in the 12 months before diagnosis or by the cutoff were excluded to rule out any chance that the prescriptions might have been linked to early signs of the disease.

The researchers found that people taking drugs in either of two classes were significantly less likely to develop Parkinson's than those taking no immunosuppressants. People taking corticosteroids such as prednisone were 20 percent less likely to be diagnosed with Parkinson's, while those on inosine monophosphate dehydrogenase (IMDH) inhibitors were about one-third less likely.

When the researchers included specific autoimmune diseases in their analysis, the calculated risks didn't change, suggesting that the difference was due to use of the drugs, not the underlying diseases they were treating.

The findings suggest that tamping down immunity with drugs may keep Parkinson's disease at bay. But doing so also makes people more susceptible to infectious diseases and cancer. The benefits of immunosuppressive drugs outweigh the costs for people with serious autoimmune diseases like rheumatoid arthritis. But doctors probably would hesitate to prescribe risky drugs to healthy people to stave off Parkinson's, especially since there is no reliable way to predict who is on track to develop the disease.

"What we really need is a drug for people who are newly diagnosed, to prevent the disease from worsening," Racette said. "It's a reasonable assumption that if a drug reduces the risk of getting Parkinson's, it also will slow disease progression, and we're exploring that now."

Corticosteroids have many side effects, and doctors already try to minimize their use, so Racette and colleagues have turned their attention to IMDH inhibitors.

"Our next step is to conduct a proof-of-concept study with people newly diagnosed with Parkinson's disease to see whether these drugs have the effect on the immune system that we'd expect," Racette said. "It's too early to be thinking about clinical trials to see whether it modifies the disease, but the potential is intriguing."

Ref:  https://onlinelibrary.wiley.com/doi/full/10.1002/acn3.580

Antifungal drug eliminates sleeping bowel cancer cells in mice

In continuation of my update on  itraconazole 

An antifungal medication, commonly prescribed for toenail infections, could help eliminate dormant cells within bowel tumours, according to new research funded by Cancer Research UK and published in the Journal of Experimental Medicinetoday.

Researchers at the Cancer Research UK Cambridge Institute have shown in laboratory studies in mice, that itraconazole effectively halts the growth and progression of certain types of bowel cancer. The next step will be to see if this holds true in patients with the disease.

Dr. Simon Buczacki, co-lead author and Cancer Research UK clinician scientist, said: "One of the biggest challenges in treating any cancer is the diversity of different cells within the same tumour. We've targeted a type of cell that lies asleep within bowel tumours, remaining unresponsive to treatment and putting the patient at risk of their cancer coming back."

The Cambridge team characterised the molecular nature of dormant bowel cancer cells. These 'sleeping' cells are resistant to drugs, including chemotherapy, which work by targeting cells that are actively growing. So even if it looks like a treatment has worked, some of these dormant cells can later awaken after treatment has finished and lead to the tumour re-growing.

The scientists identified two key pathways involved in cell dormancy and used miniature bowel tumours grown from the cells of mice with cancer, to test different drugs targeting these pathways.

They found, for the first time, that itraconazole blocked signals from a pathway called Wnt, which is implicated in the growth and spread of many different cancers. This led to the tumours collapsing in the mice—dormant cells disappeared and the tumour stopped growing.

"What's interesting is that this drug seems to kick both dormant and non-dormant cells into action," added Dr. Simon Buczacki. "It forces cells back into a short cycle of growth before slamming on an irreversible 'stop' button, entering a permanent standstill that's known as senescence."

The next stage will be to test this drug in people. The researchers hope to set up a clinical trial where they can test its effect on patients with hard to treat advanced bowel cancer. They also intend to investigate whether this drug could be more effective in combination with other treatments like chemotherapy.

Professor Greg Hannon, director of the Cancer Research UK Cambridge Institute, said: "This innovative study has taken a step toward addressing one of the biggest challenges in cancer research. Tumours are made up of many different types of cancer cells, which can evolve separately and respond to treatments differently.

"The presence of drug-resistant, dormant tumour cells is a problem in many types of cancer. If we find ways to target these cells in bowel cancer, it might provide insights into tackling the problem of dormant tumour cells more broadly."

Ref : http://jem.rupress.org/content/early/2018/05/30/jem.20171385