US FDA Accepts Regulatory Submissions for Review of Tafamidis to Treat Transthyretin Amyloid Cardiomyopathy

In continuation of my update on Tafamidis

Pfizer Inc. (NYSE: PFE) announced today that the US Food and Drug Administration (FDA) accepted for filing the company’s New Drug Applications (NDAs) for tafamidis for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM). Pfizer has submitted two NDAs based on two forms of tafamidis: meglumine salt and free acid. Tafamidis is the only product to complete a Phase 3 trial evaluating its efficacy, safety, and tolerability in patients with ATTR-CM, a rare, fatal, and underdiagnosed condition.1,2

The tafamidis meglumine form (20 mg capsule) has been granted Priority Review. The FDA grants Priority Review to medicines that may offer significant advances in treatment or may provide a treatment where no adequate therapy exists. The target Prescription Drug User Fee Act (PDUFA) action date for a decision by the FDA is in July 2019.

The tafamidis free acid form (61 mg capsule) will be under Standard Review. This form is bioequivalent to the 80 mg tafamidis meglumine dose, which was administered as four 20 mg capsules in the pivotal trial; it was developed for patient convenience to enable a single capsule for daily administration. The target PDUFA action date for a decision by the FDA is in November 2019.

“The diagnosis of ATTR-CM is often delayed, primarily because disease awareness is low and patients often present with symptoms similar to more common causes of heart failure. In fact, we believe less than one percent of patients living with this disease are currently diagnosed,” said Brenda Cooperstone MD, Senior Vice President and Chief Development Officer, Rare Disease, Pfizer Global Product Development. “The FDA’s filing acceptance is an encouraging step toward our goal of further raising awareness and providing a treatment option for ATTR-CM patients who are in desperate need of an approved pharmacologic therapy. We look forward to working with the FDA to bring the first treatment for this deadly disease to patients.”

The submission is based on findings from the pivotal Phase 3 Transthyretin Amyloid Cardiomyopathy (ATTR-ACT) study, which evaluated the efficacy, safety, and tolerability of tafamidis meglumine compared to placebo for the treatment of patients with ATTR-CM. In the primary analysis of the study, tafamidis met the primary endpoint, demonstrating a significant reduction in the hierarchical combination of all-cause mortality and frequency of cardiovascular-related hospitalizations compared to placebo over a 30-month period in patients with wild-type or hereditary ATTR-CM (P=0.0006). Tafamidis was well tolerated, with an observed safety profile comparable to placebo.3 The primary results were presented in a Hot Line session at the ESC Congress 2018 in Munich, Germany, and simultaneously published online in the New England Journal of Medicine (NEJM) in August 2018. Results from additional sub-group analyses were presented during the Late Breaking Clinical Trials session at the Heart Failure Society of America 22nd Annual Scientific Meeting in Nashville, TN, in September 2018. For more information on the ATTR-ACT trial, go to www.clinicaltrials.gov.

https://en.wikipedia.org/wiki/Tafamidis

US FDA Accepts Regulatory Submissions for Review of Tafamidis to Treat Transthyretin Amyloid Cardiomyopathy

Sprycel (dasatinib) Tablets Now Approved in Combination with Chemotherapy in Certain Pediatric Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

In continuation of my update on Dasatinib

Bristol-Myers Squibb Company (NYSE:BMY)  announced the U.S. Food and Drug Administration (FDA) has expanded the indication for Sprycel ® (dasatinib) tablets to include the treatment of pediatric patients one year of age and older with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in combination with chemotherapy.1 Sprycel is the only second-generation tyrosine kinase inhibitor approved for this patient population. The approval, which was granted following priority review by the FDA, is based on data from the Phase 2 study, CA180-372 (NCT01460160).

“We recognize the urgency around developing and delivering therapies for children and young adults living with cancer, and today’s approval is an important example of our commitment to pediatric oncology,” said Jeffrey Jackson, Ph.D., development lead, hematology, Bristol-Myers Squibb. “Building on our previous indication for children with Ph+ chronic myeloid leukemia in chronic phase, we’re pleased to bring Sprycel tablets to a second type of pediatric leukemia. This approval will give physicians another treatment option to offer appropriate pediatric patients with Ph+ ALL.”

Sprycel is associated with the following Warnings and Precautions: myelosuppression, bleeding-related events, fluid retention, cardiovascular events, pulmonary arterial hypertension, QT prolongation, severe dermatologic reactions, tumor lysis syndrome, embryo-fetal toxicity and effects on growth and development in pediatric patients.1 Please see detailed Important Safety Information below.

The efficacy of Sprycel tablets in combination with chemotherapy was evaluated in a single cohort of the Phase 2, multicenter, single-arm CA180-372 study, which included 78 pediatric patients with newly diagnosed B-cell precursor Ph+ ALL.1,2 At three years, the study demonstrated an event-free survival (EFS) binary rate of 64.1% (95% confidence interval [CI]: 52.4 to 74.7).1 Event-free survival is defined as the time from the start of Sprycel to lack of complete response at the end of the third high-risk block, relapse, secondary malignancy or death from any cause.

Of the 81 patients evaluated for safety, fatal adverse reactions occurred in three patients (4%), and eight (10%) experienced adverse reactions leading to treatment discontinuation, including fungal sepsis, hepatotoxicity of graft versus host disease, thrombocytopenia, CMV infection, pneumonia, nausea, enteritis and drug hypersensitivity.1 The most common serious adverse reactions (incidence ≥10%) were pyrexia, febrile neutropenia, mucositis, diarrhea, sepsis, hypotension, infections (bacterial, viral and fungal), hypersensitivity, vomiting, renal insufficiency, abdominal pain and musculoskeletal pain.1

“As treatments have advanced in recent years, we’ve seen improvements in outcomes for pediatric patients with Ph+ ALL overall, but there remains a need for additional options,”3 said Stephen Hunger, MD, lead study author, chief of the division of oncology and director of the Center for Childhood Cancer Research at Children’s Hospital of Philadelphia. “The Phase 2 CA180-372 trial was particularly informative because it was designed to limit the use of cranial irradiation and stem cell transplant. In the study, Sprycel plus chemotherapy demonstrated a three-year event-free survival benefit. These results show that Sprycel is an effective medication for physicians to consider for children and adolescents with Ph+ ALL.”1,4

Acute lymphoblastic leukemia is characterized by chromosomal abnormalities and genetic alterations involved in the differentiation and proliferation of lymphoid precursor cells.5 The most common childhood cancer in the United States, ALL represents 20% of all cancers diagnosed in persons aged less than 20 years, or more than 3,000 new cases each year.6 Three percent of children who have ALL have the Ph+ subtype, which means they have a chromosome alteration that results in a specific mutation of the BCR-ABL gene.3

“Coping with a pediatric cancer diagnosis, including searching for and identifying the right treatment regimen, can take a physical and emotional toll on patients and their families,” said Vickie Buenger, president of the Coalition Against Childhood Cancer (CAC2). “The availability of another option is a welcome step forward for those affected by this disease.”

In addition to this pediatric approval, Sprycel is approved for use in children one year of age and older with Ph+ chronic myeloid leukemia (CML) in chronic phase (CP).

New Drug Application for Insomnia Disorder Treatment Lemborexant Submitted in the United States

Eisai Co., Ltd. (CEO: Haruo Naito, “Eisai”) and Purdue Pharma L.P. (President and CEO: Craig Landau, MD, “Purdue Pharma”) today announced that a new drug application has been submitted to the U.S. Food and Drug Administration (FDA) for lemborexant, an investigational agent for sleep-wake regulation, seeking approval for the treatment of insomnia, a sleep-wake disorder.

This application was based on the results of two pivotal Phase 3 clinical studies in patients with insomnia, SUNRISE 1 (Study 304) and SUNRISE 2 (Study 303), enrolling approximately 2,000 patients, as well as important safety studies, including assessment of postural stability after middle-of-the-night awakening and a next-morning driving study. SUNRISE 1, a one-month, double-blind, placebo-controlled study, included the first ever Phase 3 head-to-head comparison versus zolpidem ER and objectively assessed sleep parameters (time to sleep onset, sleep efficiency, and wake after sleep onset) resulting in the largest (objective) polysomnography dataset collected to date in patients with insomnia. SUNRISE 2 was a 12-month study and subjectively assessed for ability to fall asleep and stay asleep based on patient self reports (sleep diaries).

Lemborexant, which acts on the orexin neurotransmitter system and is believed to regulate sleep and wake by dampening wakefulness without impeding the ability to awaken to external stimuli, is being jointly developed by Eisai and Purdue Pharma for the treatment of multiple sleep-wake disorders, including insomnia disorder. In addition to the treatment of insomnia disorder, a Phase 2 clinical study of lemborexant in patients with irregular sleep-wake rhythm disorder and mild to moderate Alzheimer's dementia is underway. Information about ongoing clinical studies is available at clinicaltrials.gov.

Eisai and Purdue Pharma are striving to address new unmet medical needs and to improve the lives of patients and their families.

This release discusses investigational uses of an agent in development and is not intended to convey conclusions about efficacy or safety. There is no guarantee that such an investigational agent will successfully complete clinical development or gain health authority approval.

https://en.wikipedia.org/wiki/Lemborexant







New Drug Application for Insomnia Disorder Treatment Lemborexant Submitted in the United States

FDA Advisory Committee Votes on Zynquista (sotagliflozin) as Treatment for Adults with Type 1 Diabetes

In continuation of my update on sotagliflozin

The Endocrinologic and Metabolic Drugs Advisory Committee of the U.S. Food and Drug Administration (FDA) today voted eight to eight on the question of whether the overall benefits of Zynquista™* (sotagliflozin) outweighed the risks to support approval. Sotagliflozin is an investigational oral dual SGLT1 and SGLT2 inhibitor under regulatory review as an adjunct to insulin for the treatment of adults with type 1 diabetes (T1D). While the FDA is not required to follow the committee’s vote, the agency considers the committee’s recommendations when making its decision, which is anticipated by March 22, 2019.

Sotagliflozin, developed by Sanofi and Lexicon, has the potential to be the first oral antidiabetic drug approved in the United States together with insulin therapy to improve glycemic (blood sugar) control in adults with T1D.

“We believe in the overall benefit-risk profile of sotagliflozin for adults with type 1 diabetes who lack adequate glycemic control using insulin alone,” said Rachele Berria, MD, PhD, Global Vice President and Head of Diabetes Medical Affairs, Sanofi. “We will continue to work with the FDA through its review process to hopefully bring to patients a new treatment that can help people living with type 1 diabetes control their blood sugar and address some of the challenges of insulin-only therapy.”

Sotagliflozin is an investigational oral dual inhibitor of two proteins responsible for glucose regulation known as sodium-dependent glucose co-transporter types 1 and 2 (SGLT1 and SGLT2). SGLT1 is responsible for glucose absorption in the gastrointestinal tract, and SGLT2 is responsible for glucose reabsorption by the kidney. About 1.3 million Americans have T1D and an estimated 40,000 people will be newly diagnosed each year in the U.S., according to the American Diabetes Association.

“In clinical trials, when used in combination with insulin therapy, sotagliflozin significantly improved glycemic control without increasing hypoglycemia,” said Pablo Lapuerta, MD, Executive Vice President and Chief Medical Officer, Lexicon. “These results could not be achieved with insulin alone. Diabetic ketoacidosis is an inherent risk of type 1 diabetes and an increase was seen with sotagliflozin compared to insulin alone. We believe this can potentially be addressed with proper education and monitoring.” 

The New Drug Application for sotagliflozin included data from the inTandem clinical trial program, which included three Phase 3 clinical trials assessing the safety and efficacy of sotagliflozin in approximately 3,000 adults with inadequately controlled T1D. The safety and efficacy data have not yet been fully evaluated by any regulatory authority.

Sanofi also submitted a regulatory application to the European Medicines Agency (EMA) in 2018. An EMA approval decision is expected in the first half of 2019.

https://www.drugbank.ca/drugs/DB12713

https://pubchem.ncbi.nlm.nih.gov/compound/lx-4211#section=2D-Structure

FDA Advisory Committee Votes on Zynquista (sotagliflozin) as Treatment for Adults with Type 1 Diabetes

Exelixis Announces U.S. FDA Approval of Cabometyx (cabozantinib) Tablets for Previously Treated Hepatocellular Carcinoma

In continuation of my update on Cabometyx (cabozantinib)

Exelixis, Inc. announced that the U.S. Food and Drug Administration (FDA) approved Cabometyx (cabozantinib) tablets for patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. HCC is the most common form of liver cancer and the fastest-rising cause of cancer-related death in the U.S. 

“This new indication for Cabometyx is an important treatment advance for patients with this aggressive form of liver cancer, a community in need of new therapeutic options,” said Michael M. Morrissey, Ph.D., President and Chief Executive Officer of Exelixis. “This approval is an important milestone as we continue to explore how Cabometyx may benefit people with difficult-to-treat-cancers beyond renal cell carcinoma. We would like to thank the patients and clinicians who participated in CELESTIAL and to acknowledge the team at the FDA for their continued collaboration during the review of our application.”

The FDA’s approval of Cabometyx was based on results from the CELESTIAL phase 3 pivotal trial of Cabometyx for patients with advanced HCC who received prior sorafenib. Cabometyx demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) versus placebo. On November 15, 2018, Exelixis’ partner Ipsen received approval from the European Commission for Cabometyx tablets as a monotherapy for HCC in adults who have previously been treated with sorafenib.

“Patients with this form of advanced liver cancer have few treatment options, particularly once their disease progresses following treatment with sorafenib,” said Ghassan K. Abou-Alfa, M.D., Memorial Sloan Kettering Cancer Center, New York and lead investigator on CELESTIAL. “Physicians are eager for new options for these patients, and the results of the CELESTIAL trial demonstrate that Cabometyx has the efficacy and safety profile to become an important new therapy in our efforts to slow disease progression and improve treatment outcomes.”

In the pivotal CELESTIAL trial, median OS was 10.2 months with cabozantinib versus 8.0 months with placebo (HR 0.76, 95 percent CI 0.63-0.92; p=0.0049). Median progression-free survival (PFS) was more than doubled, at 5.2 months with cabozantinib and 1.9 months with placebo (HR 0.44, 95 percent CI 0.36-0.52; p<0.0001). Objective response rates per RECIST 1.1 were 4 percent with cabozantinib and 0.4 percent with placebo (p=0.0086). Disease control (partial response or stable disease) was achieved by 64 percent of patients in the cabozantinib group compared with 33 percent of patients in the placebo group.

Adverse events in CELESTIAL were consistent with the known safety profile of cabozantinib. The most common (≥10 percent) grade 3 or 4 adverse events in the cabozantinib group compared to the placebo group were palmar-plantar erythrodysesthesia (17 percent vs. 0 percent), hypertension (16 percent vs. 2 percent), increased aspartate aminotransferase (12 percent vs. 7 percent), fatigue (10 percent vs. 4 percent) and diarrhea (10 percent vs. 2 percent). Treatment-related grade 5 adverse events occurred in six patients in the cabozantinib group (hepatic failure, esophagobronchial fistula, portal vein thrombosis, upper gastrointestinal hemorrhage, pulmonary embolism and hepatorenal syndrome) and in one patient in the placebo group (hepatic failure). Sixteen percent of patients in the cabozantinib arm and three percent of patients in the placebo arm discontinued treatment due to treatment-related adverse events.

“While we’ve seen some progress in the treatment of primary liver cancer in recent years, the patient community still needs new and better options,” said Andrea Wilson, President and Founder of Blue Faery: The Adrienne Wilson Liver Cancer Association. “The approval of Cabometyx has been eagerly anticipated, making this an important day for patients diagnosed with this devastating disease.”

In December 2018, Exelixis and its partner Ipsen announced the initiation of COSMIC-312, a phase 3 pivotal trial of cabozantinib in combination with atezolizumab versus sorafenib in previously untreated advanced HCC. The trial will also explore single-agent activity of cabozantinib in the first-line setting. For more information about the trial, visit ClinicalTrials.gov.

https://en.wikipedia.org/wiki/Cabozantinib



Exelixis Announces U.S. FDA Approval of Cabometyx (cabozantinib) Tablets for Previously Treated Hepatocellular Carcinoma

FDA Approves Tosymra (sumatriptan) Nasal Spray for Acute Treatment of Migraine

In continuation of my update on Tosymra (sumatriptan)

Dr. Reddy’s Laboratories Ltd. and its subsidiary, Promius Pharma, LLC today announced the approval of Tosymra (previously known as DFN-02) by the U.S. Food and Drug Administration (FDA). Tosymra is indicated for the acute treatment of migraine with or without aura in adults. Tosymra is the latest product to join the Promius Pharma acute migraine treatment portfolio. The company is working toward commercialization of this product.

“We are excited about the approval of Tosymra. This approval affirms our ability to develop well-differentiated products to meet the unmet needs of patients with migraine and HCPs treating them,” said G.V. Prasad, Co-Chairman and CEO, Dr. Reddy’s Laboratories.

According to Dr. Anil Namboodiripad, PhD, President, Promius Pharma, “Tosymra nasal spray is formulated using a proprietary novel excipient known as Intravail [®] to achieve blood levels similar to a 4-mg sumatriptan subcutaneous injection, resulting in rapid onset of action. Independent research shows that 26% to 40% of migraine patients are not optimally controlled with their current treatment.  For patients who suffer from the debilitating and disruptive effects of migraine, there continues to be a need for reliable and efficacious treatment options. At Promius, we are committed to developing new ways of improving patient experiences. Tosymra is a mist-like nasal spray that acts rapidly and is well tolerated.”

https://en.wikipedia.org/wiki/Sumatriptan

FDA Approves Tosymra (sumatriptan) Nasal Spray for Acute Treatment of Migraine

FDA Approves Imbruvica (ibrutinib) Plus Obinutuzumab as First Non-Chemotherapy Combination Regimen for Treatment-Naïve Patients with Chronic Lymphocytic Leukemia

In continuation of my update on  ibrutinib

The Janssen Pharmaceutical Companies of Johnson & Johnson announced  the U.S. Food and Drug Administration (FDA) approval of Imbruvica (ibrutinib) in combination with obinutuzumab in treatment-naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), the most common form of leukemia in adults.1 This is the first approval for a non-chemotherapy combination regimen for treatment-naïve patients with CLL/SLL, and marks the tenth FDA approval for Imbruvica since its U.S. launch in November 2013. The approval expands the label for Imbruvica in frontline CLL/SLL beyond its use as a monotherapy to include combination use with obinutuzumab. Imbruvica, a Bruton's tyrosine kinase (BTK) inhibitor, is jointly developed and commercialized by Janssen Biotech, Inc. and Pharmacyclics LLC, an AbbVie company.

"In just a few years, Imbruvica has become an important treatment for chronic lymphocytic leukemia. Imbruvica as a single agent – and now as a combination with obinutuzumab – provides patients with CLL with an alternative to frontline treatment with chemoimmunotherapy," said Carol Moreno, M.D., Ph.D., Consultant Hematologist, Hospital de la Santa Creu Sant Pau, Autonomous University of Barcelona, Barcelona, Spain, and lead investigator of the iLLUMINATE study.

This approval is based on results from the Phase 3 iLLUMINATE study (PCYC-1130). At a median follow-up of 31 months, Imbruvica plus obinutuzumab showed a significant improvement in Independent Review Committee (IRC)-evaluated progression-free survival compared with chlorambucil plus obinutuzumab (median not evaluable [NE] vs. 19 months; hazard ratio [HR] 0.23; 95 percent confidence interval [CI]: 0.15-0.37; P<0.0001), with a 77 percent reduction in risk of progression or death. Patients with high-risk disease (17p deletion/TP53 mutation, 11q deletion, or unmutated IGHV) treated with Imbruvica plus obinutuzumab experienced an 85 percent reduction in risk of progression or death (HR 0.15; 95 percent CI: 0.09-0.27). The IRC-evaluated overall response rate was 89 percent in the Imbruvica plus obinutuzumab arm versus 73 percent in the chlorambucil plus obinutuzumab arm. The data were recently presented in an oral session at the 2018 American Society of Hematology (ASH) Annual Meeting and simultaneously published in The Lancet Oncology.

"This label update builds upon the established efficacy and safety of Imbruvica in the frontline treatment of patients with CLL/SLL, as a monotherapy or in combination with other treatments," said Craig Tendler, M.D., Vice President, Clinical Development and Global Medical Affairs, Janssen Research & Development, LLC. "This milestone represents our continued commitment to develop Imbruvica-based, non-chemotherapy regimens to address the clinical needs of patients living with CLL/SLL."

The FDA also updated the Imbruvica label to include additional long-term efficacy data supporting its use as a monotherapy in CLL/SLL, with approximately five years of follow-up from the Phase 3 RESONATE™ (PCYC-1112) and RESONATE™-2 (PCYC-1115, PCYC-1116) international studies.

Warnings and Precautions include hemorrhage, infections, cytopenias, cardiac arrhythmias, hypertension, second primary malignancies, tumor lysis syndrome, and embryo-fetal toxicity. The most common adverse reactions (occurring in 20 percent or more of patients) of all grades in patients treated with Imbruvica plus obinutuzumab in the iLLUMINATE study were neutropenia (48 percent), thrombocytopenia (36 percent), rash (36 percent), diarrhea (34 percent), musculoskeletal pain (33 percent), bruising (32 percent), cough (27 percent), infusion related reaction (25 percent), hemorrhage (25 percent), and arthralgia (22 percent).

The recommended dose of Imbruvica for CLL/SLL is 420 mg orally once daily until disease progression or unacceptable toxicity as a single agent or in combination with obinutuzumab or bendamustine and rituximab (BR). When administering Imbruvica in combination with rituximab or obinutuzumab, doctors should consider administering Imbruvica prior to rituximab or obinutuzumab when given on the same day.

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FDA Approves Imbruvica (ibrutinib) Plus Obinutuzumab as First Non-Chemotherapy Combination  Regimen for Treatment-Naïve Patients with Chronic Lymphocytic Leukemia

FDA Approves Osphena (ospemifene) for Moderate to Severe Vaginal Dryness Due to Menopause

Duchesnay Inc., a pharmaceutical company specializing in women’s health, announced   that the FDA has approved its supplemental New Drug Application (sNDA) seeking to add moderate to severe vaginal dryness, a symptom of vulvar and vaginal atrophy (VVA), due to menopause, to the indication of Osphena (ospemifene).

The sNDA was based on new safety and efficacy data acquired through a confirmatory phase 3 randomized, double blind, placebo-controlled multicenter study evaluating the efficacy and safety of ospemifene in patients with moderate to severe vaginal dryness. Osphena is non-hormonal and helps improve specific vaginal tissues by increasing superficial cells, decreasing parabasal cells and reducing vaginal pH.

Prior to this approval, Osphena was indicated only for the treatment of moderate to severe dyspareunia (painful intercourse), also a symptom of VVA, due to menopause.

“Many menopausal women are not aware that vaginal dryness is one of the two most common and most bothersome symptoms (MBS) of vulvovaginal atrophy due to menopause. FDA’s approval of this additional indication affirms Osphena’s safety and effectiveness for treating moderate to severe vaginal dryness, broadening its benefits to a larger number of menopausal women,” affirmed Dr. James A. Simon, Clinical Professor of Obstetrics and Gynecology at George Washington University.

Before menopause, estrogen helps maintain the thickness, elasticity and lubrication of vaginal tissues. However, as women age, estrogen levels drop, causing changes in these tissues, which can lead to dryness, itching, burning and painful intercourse.

“With the addition of moderate to severe vaginal dryness to Osphena’s indication, Duchesnay USA can now help postmenopausal women suffering from this symptom of VVA”, explained Dean Hopkins, General Manager of Duchesnay USA. “With this new indication, Osphena now provides an oral option for women who prefer a non-hormonal treatment alternative.”

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FDA Approves Osphena (ospemifene) for Moderate to Severe Vaginal Dryness Due to Menopause

New One-Dose Flu Drug Shows Promise

An experimental single-dose flu drug shows promise as a new way to alleviate the misery of influenza, researchers say. 

The drug  called baloxavir (structre)  worked better than no treatment in one phase of a new study. The study also found it as effective as the current standard drug, oseltamivir (Tamiflu), at controlling symptoms such as coughing, sore throat, headache, fever, muscle and joint pain, and fatigue.

Moreover, in light of concerns about flu-drug resistance, most patients treated with baloxavir responded as expected, the study authors said.

"There are few approved influenza antivirals, and current treatments have limitations," said study lead author Dr. Frederick Hayden, of the University of Virginia School of Medicine.

"For example, currently circulating influenza viruses are resistant to the older class of antivirals," he said. These include the drugs amantadine (brand name Symmetrel) and rimantadine (Flumadine).

Resistance is also growing to the class of drugs including widely used Tamiflu and Relenza (zanamivir), Hayden said. "Consequently, there are medical needs for new anti-influenza agents with different mechanisms of action and greater potency," he added.

Hayden, professor emeritus of clinical virology and medicine, said the new study indicates that baloxavir resolves flu symptoms as quickly, effectively and safely as current options, without yet raising concerns about resistance. It also demonstrated "significantly greater antiviral effects," he added.

Also, while Tamiflu must be taken twice a day for five days, baloxavir requires just one dose.

The investigation was funded by the drug company Shionogi, Inc., which developed and manufactures baloxavir.

Baloxavir is approved for use in Japan. In the United States, it remains an "investigational drug," with the U.S. Food and Drug Administration expected to decide on approval by the end of this year.

The new study, which was published Sept. 6 in the New England Journal of Medicine, unfolded in two trials, both involving otherwise healthy flu patients at low risk for influenza complications.

One trial was conducted during the 2015-2016 flu season. About 400 patients, aged 20 to 64, received one of three doses of baloxavir (ranging from 10 to 40 milligrams) or a placebo. Flu symptoms eased notably faster among all three baloxavir groups, compared with placebo (untreated) patients, the findings showed.

The following flu season, nearly 1,100 patients, aged 12 to 64, were treated with baloxavir or Tamiflu. The drugs relieved symptoms in roughly the same time period, with similar side-effect risk.

However, about 10 percent of the baloxavir patients had a less than robust response to the drug. Hayden acknowledged that "the clinical and public health implications of reduced susceptibility to baloxavir are not fully understood."

Dr. Timothy Uyeki, author of an accompanying journal editorial, heads the influenza division at the U.S. Centers for Disease Control and Prevention's National Center for Immunization and Respiratory Diseases.

"There is a need for antiviral drugs with new mechanisms of action," he agreed.Uyeki highlighted the benefit of baloxavir's single-dose regimen. Besides its convenience, it "avoids concerns about compliance with a five-day treatment course of oseltamivir," he said.

But he also stressed the need for further testing.

It remains unclear what benefits might accrue from combining baloxavir with Tamiflu, Uyeki noted.

Also, he cautioned, the current research only included otherwise healthy people aged 12 to 64 who were not at high risk for flu complications. Whether baloxavir will benefit high-risk groups -- young children, the elderly, pregnant women and others with underlying chronic medical conditions -- remains unknown, Uyeki said.

"A lot more studies are needed of the clinical benefit of baloxavir treatment of influenza in high-risk outpatients," he added.

FDA Approves New Indication for Envarsus XR (tacrolimus extended-release tablets)

In continuation of my update on Tacrolimus

Veloxis Pharmaceuticals announced today that the U.S. Food & Drug Administration (FDA) approved a new indication for Envarsus XR (tacrolimus extended-release tablets) to prevent organ rejection in de novo kidney transplant patients in combination with other immunosuppressants. This indication is commonly referred to as the de novo indication.

Envarsus XR was approved for the prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations in 2015 and has already been used in the conversion setting in more than 90% of the transplant centers in the U.S.  The approval for de novo use provides an important new treatment option for kidney transplant patients and providers, where significant unmet need currently exists.

"Today marks the beginning of an exciting new chapter in immunosuppression.  Kidney transplant patients will now be able to receive a refined and simplified gold standard treatment regimen from the beginning of the kidney transplant journey," said Ulf Meier-Kriesche, M.D. Chief Scientific Officer at Veloxis Pharmaceuticals, Inc.

The FDA's approval is based on the Phase 3 clinical development program which was a randomized, double-blind, double-dummy, Phase III study in 543 de novo kidney transplant patients that demonstrated comparable efficacy and safety compared to twice-daily tacrolimus (Prograf®).

The primary endpoint of the study was a composite endpoint of treatment failure (biopsy-proven acute rejection or BPAR, graft failure, loss to follow up or death) that was evaluated after a 12-month treatment period to demonstrate the non-inferiority of Envarsus® compared to Prograf®. The treatment failure rate for Envarsus® was 18.3% compared to 19.6% for Prograf®.    

"There are approximately 200,000 patients living with a kidney transplant today and we have seen a significant number of them convert to Envarsus XR since our launch in December 2015.  With the addition of the de novo indication, the roughly 16,000 adult patients who receive a kidney transplant each year will now have access to Envarsus XR following surgery. This approval is another example of Veloxis's commitment to transplant and the patients, donors and providers that make it all possible," said Craig A. Collard, Chief Executive Officer of Veloxis Pharmaceuticals A/S.

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FDA Approves New Indication for Envarsus XR (tacrolimus extended-release tablets)

FDA Approves Motegrity (prucalopride) for Adults with Chronic Idiopathic Constipation (CIC)

SHPG) has announced that the U.S. Food and Drug Administration (FDA) has approved Motegrity (prucalopride), a once-daily, oral treatment option for adults with Chronic Idiopathic Constipation (CIC).

Motegrity, a selective serotonin-4 (5-HT4) receptor agonist, provides a different class of treatment for CIC that works by enhancing colonic peristalsis to increase bowel motility. Motegrity is expected to launch in 2019 in the United States, where an estimated 35 million adults are living with CIC.  While not all patients may be right for treatment, Motegrity represents an important new option.

“The approval of Motegrity marks a new day in the treatment of CIC,” said Howard Mayer, M.D., Senior Vice President and Chief Medical Officer, Shire. “This significant milestone reinforces our continued commitment to the GI community and advances our goal of addressing the unmet need of patients suffering from rare, specialized and common GI conditions.”

The efficacy of once-daily treatment with Motegrity was evaluated in six double-blind, placebo-controlled, randomized, multicenter clinical studies lasting 12 weeks (studies 1-5) or 24 weeks (study 6) Of the 2,484 patients, most were female (76%) and Caucasian (76%), with an average age of 47 (+/- 16 years).

“As a gastroenterologist, it’s important for me to help patients with CIC find a treatment that works well for them,” said Brooks Cash, M.D., Chief of the Division of Gastroenterology, Hepatology, and Nutrition at the University of Texas Health Science Center at Houston. “It’s exciting to be able to now offer my patients a new treatment option that addresses colonic peristalsis.”

 During studies, significantly more patients taking Motegrity achieved the primary endpoint (an average of ≥3 complete spontaneous bowel movements [CSBMs] per week over 12 weeks, considered normalization of BM frequency) than those in the placebo group (19-38% Motegrity ≤2 mg vs. 10-20% placebo) across five of six trials. A rapid response was seen with Motegrity as early as week 1, with improvements maintained throughout 12 weeks of treatment.1 The FDA has requested that Shire conduct five post-marketing studies evaluating the pharmacokinetics, efficacy, and safety of Motegrity in pediatric patients with CIC (6 months old to less than 18 years of age) and pregnant and lactating women with CIC treated with Motegrity.

Motegrity is contraindicated in patients with a history of hypersensitivity to Motegrity. Reactions include dyspnea, rash, pruritus, urticaria, and facial edema have been observed. Motegrity is also contraindicated in patients with intestinal perforation or obstruction due to structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory conditions of the intestinal tract such as Crohn’s disease, ulcerative colitis, and toxic megacolon/megarectum.

In clinical trials, suicides, suicide attempts, and suicidal ideation have been reported. A causal association between treatment with Motegrity and an increased risk of suicidal ideation and behavior has not been established. Monitor all patients treated with Motegrity for persistent worsening of depression or the emergence of suicidal thoughts and behaviors. Counsel patients, their caregivers, and family members of patients to be aware of any unusual changes in mood or behavior and alert the healthcare provider. Instruct patients to discontinue Motegrity immediately and contact their healthcare provider if they experience any of these symptoms.

Most common adverse reactions (≥2%) are headache, abdominal pain, nausea, diarrhea, abdominal distension, dizziness, vomiting, flatulence and fatigue. Overall, discontinuation due to adverse events was low (5% Motegrity 2 mg once daily; 3% placebo). If reported, adverse events of diarrhea or headache typically resolved within a few days.1 In addition, cardiovascular safety was evaluated in a MACE† (major adverse cardiovascular events) analysis of the double-blind, placebo-controlled and open-label studies. It was also assessed in a retrospective observational study, which demonstrated no increase in the risk of MACE with Motegrity relative to polyethylene glycol (PEG).

CIC is a common condition affecting roughly 14% of the adult population. Symptoms can range from straining and bloating, to infrequent, or incomplete bowel movements. While “idiopathic” by definition (meaning the exact cause is not known), it is believed that CIC may be caused by insufficient movement of the colon muscle

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FDA Approves Motegrity (prucalopride) for Adults with Chronic Idiopathic Constipation (CIC)

FDA Grants Priority Review Designation for Heron Therapeutics' NDA for HTX-011, a Non-Opioid for Postoperative Pain Management

      

Heron Therapeutics, Inc. (Nasdaq: HRTX), a commercial-stage biotechnology company, announced that the U.S. Food and Drug Administration (FDA) has accepted the new drug application (NDA) for Heron's investigational agent, HTX-011, and has granted it a Priority Review designation. HTX-011 is a long-acting, extended-release formulation of the local anesthetic bupivacaine in a fixed-dose combination with the anti-inflammatory meloxicam for the management of postoperative pain. HTX-011 is the first and only dual-action fixed-combination product specifically designed to address both postoperative pain and inflammation in a single administration at the surgical site. The NDA for HTX-011, which was submitted on October 30, 2018, comprises data from five Phase 2 clinical trials and two Phase 3 clinical trials that included over 1,000 patients undergoing five different surgical procedures. The FDA also indicated that it is not currently planning to hold an advisory committee meeting to discuss this application. The FDA set a Prescription Drug User Fee Act goal date of April 30, 2019."We are pleased to receive Priority Review designation for the HTX-011 NDA," said Barry D. Quart, Pharm.D., Chief Executive Officer of Heron. "We believe that HTX-011 could have a considerable impact on the lives of patients by significantly reducing the proportion of patients who experience severe pain and receive opioids after surgery, especially at discharge. We look forward to continuing to work closely with the FDA during the review process with the goal of bringing this important product to patients in 2019."

The FDA had previously granted Breakthrough Therapy designation for HTX-011 based on the results of Phase 2 studies and two completed Phase 3 studies, which showed that HTX-011 produced significant reductions in both pain intensity and the need for opioids through 72 hours post-surgery compared to placebo and bupivacaine solution, the standard-of-care. The FDA has now granted Priority Review designation to the NDA for HTX-011. Priority Review designation is for drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment or prevention of serious conditions. HTX-011 is the first and only non-opioid, long acting local anesthetic to demonstrate in Phase 3 studies a statistically significant reduction in severe pain and an increase in the number of patients who require no opioids for 72 hours postoperatively versus bupivacaine solution, the standard-of-care. The overall safety profile of HTX-011, administered locally into the surgical site without a needle, was similar to that of the well-established safety profile of bupivacaine solution, without evidence of meloxicam-related toxicities.

"Despite ongoing efforts to prevent opioid abuse, patients continue to receive large quantities of opioids for postsurgical pain," said Jay Redan, M.D., FACS, Medical Director of Minimally-Invasive General Surgery at Florida Hospital Celebration Health. "There is a significant need for safe, effective and non-addictive options that can decrease opioid exposure and improve the patient recovery experience, as well as make an impact on the opioid epidemic by significantly reducing the amount of opioids necessary to take home for pain management."

About HTX-011 for Postoperative Pain

HTX-011, which utilizes Heron's proprietary Biochronomer® drug delivery technology, is an investigational, long-acting, extended-release formulation of the local anesthetic bupivacaine in a fixed-dose combination with the anti-inflammatory meloxicam for the management of postoperative pain. By delivering sustained levels of both a potent anesthetic and a local anti-inflammatory agent directly to the site of tissue injury, HTX-011 was designed to deliver superior pain relief while reducing the need for systemically administered pain medications such as opioids, which carry the risk of harmful side effects, abuse and addiction. HTX-011 has been shown to reduce pain significantly better than placebo or bupivacaine alone in five diverse surgical models: hernia repair, abdominoplasty, bunionectomy, total knee arthroplasty and breast augmentation. HTX-011 was granted Fast Track designation from the FDA in the fourth quarter of 2017 and Breakthrough Therapy designation in the second quarter of 2018. Heron submitted an NDA to the FDA for HTX-011 in October of 2018 and received Priority Review designation in December 2018. The FDA set a Prescription Drug User Fee Act goal date of April 30, 2019.

Ref: https://en.wikipedia.org/wiki/Bupivacaine

Lynparza (olaparib) Approved by US FDA for First-Line Maintenance Therapy in BRCA-Mutated Advanced Ovarian Cancer

In continuation of my update on olaparib

AstraZeneca and Merck & Co., Inc., (Merck: known as MSD outside the US and Canada)  announced that the US Food and Drug Administration (FDA) has approved Lynparza for use as maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to 1st-line platinum-based chemotherapy. Patients with gBRCAm advanced epithelial ovarian, fallopian tube or primary peritoneal cancer are selected for therapy based on an FDA-approved companion diagnostic for Lynparza.

This is the first regulatory approval for a PARP inhibitor in the 1st-line maintenance setting for BRCAm advanced ovarian cancer. The approval was based on positive results from the pivotal Phase III SOLO-1 trial  in which Lynparza reduced the risk of disease progression or death by 70% in patients with BRCAm advanced ovarian cancer who were in complete or partial response to platinum-based chemotherapy (HR 0.30 [95% CI 0.23-0.41], p<0.0001) compared to placebo.

Dave Fredrickson, Executive Vice President, Head of the Oncology Business Unit, AstraZeneca, said: “Women with ovarian cancer are often first diagnosed with advanced disease, which is associated with poor outcomes. In SOLO-1, Lynparza in the first-line maintenance setting reduced the risk of disease progression or death by 70 percent for patients with BRCAm advanced ovarian cancer. Today’s approval is a critical advancement and brings us closer to our goal of helping these patients achieve long-term remission.”

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, Merck Research Laboratories, said: “The expanded approval of Lynparza based upon the SOLO-1 trial has the potential to change medical practice and reinforces the importance of knowing a woman’s BRCA status at diagnosis. We continue to work in collaboration with AstraZeneca on our overall goal of improving outcomes for patients.”

In the SOLO-1 trial, with median 41 months of follow-up, the median progression-free survival (PFS) for patients treated with Lynparza (n=260) was not reached compared to 13.8 months for patients treated with placebo (n=131). In the trial, 60% of patients receiving Lynparza remained progression-free at 3 years compared to 27% of patients receiving placebo. The data from the SOLO-1 trial can be found in the October 21, 2018, online issue of the New England Journal of Medicine.

The most common adverse reactions (ARs) in ≥10% of patients taking Lynparza in the SOLO-1 trial were nausea (77%), fatigue (67%), abdominal pain (45%), vomiting (40%), anemia (38%), diarrhea (37%), constipation (28%), upper respiratory tract infection/influenza/nasopharyngitis/bronchitis (28%), dysgeusia (26%), dizziness (20%), decreased appetite (20%), neutropenia (17%), dyspepsia (17%), dyspnea (15%), leukopenia (13%), UTI (13%), thrombocytopenia (11%) and stomatitis (11%). The most common Grade ≥3 ARs were anemia (21%) and neutropenia (6%). Dose interruptions due to an AR of any grade occurred in 52% of patients receiving Lynparza and 17% of those receiving placebo. Seventy-two percent (n=186) of patients on Lynparza remained on the recommended starting dose of 300 mg (two 150 mg tablets twice daily) versus 97% (n=126) on placebo. Adverse reactions that most frequently led to discontinuation in patients treated with Lynparza were fatigue (3.1%), anemia (2.3%), and nausea (2.3%). Eighty-eight percent (n=230) of patients on Lynparza continued treatment without an AR-related discontinuation versus 98% (n=127) on placebo.

Kathleen Moore, Co-Principal Investigator of the SOLO-1 trial and Associate Director for Clinical Research, Stephenson Cancer Center at The University of Oklahoma, Oklahoma City, Oklahoma, said: “SOLO-1 is truly a landmark trial in gynecologic cancer. This approval will likely change the way we treat women with BRCA-mutated advanced ovarian cancer. The ability to offer this important first-line maintenance treatment option to eligible patients may slow down or even stop the natural course of disease progression.”

AstraZeneca and Merck are exploring additional trials in ovarian cancer, including the ongoing GINECO/ENGOTov25 Phase III trial, PAOLA-1. This trial is testing the effect of Lynparza in combination with bevacizumab as a maintenance treatment for patients with newly-diagnosed advanced ovarian cancer, regardless of their BRCA status. Results are expected during the second half of 2019.

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Lynparza (olaparib) Approved by US FDA for First-Line Maintenance Therapy in BRCA-Mutated Advanced Ovarian Cancer

Nabriva Therapeutics Announces Acceptance of the New Drug Application for Intravenous Contepo to Treat Complicated Urinary Tract Infections by FDA

Nabriva Therapeutics plc (NASDAQ: NBRV), a clinical-stage biopharmaceutical company announced that the U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) and granted a priority review for Contepo™ (fosfomycin for injection) to treat complicated urinary tract infections (cUTIs), including acute pyelonephritis. The acceptance of the NDA indicates that the FDA has deemed the application sufficiently complete to allow a substantive review. The PDUFA (Prescription Drug User Fee Act) goal date for the completion of the FDA’s review of the Contepo NDA is June 30, 2019. In addition to priority review, Contepo has been granted Qualified Infectious Disease Product (QIDP) and Fast Track designations by the FDA for the treatment of several serious infections, including cUTI.

“The acceptance of the Contepo NDA marks another major milestone for Nabriva Therapeutics, demonstrating our commitment to bring novel anti-infective agents that address the urgent, unmet medical need in patients with serious infections,” said Dr. Jennifer Schranz, chief medical officer of Nabriva Therapeutics. “Contepo, if approved in the United States, represents a first-in-class intravenous antibiotic with broad spectrum activity against Gram-negative and Gram-positive organisms, including ESBL-producing Enterobacteriaceae and other contemporary multi-drug resistant (MDR) organisms.”

The NDA submission is utilizing the 505(b)(2) regulatory pathway and is supported by a robust data package, including a pivotal Phase 2/3 clinical trial (known as ZEUS™), which met its primary endpoint of statistical non-inferiority to piperacillin/tazobactam in patients with cUTI, including acute pyelonephritis.

In the NDA acceptance letter, the FDA stated that no filing or potential review issues were identified. In addition, the Agency stated that it has not referred Contepo to an advisory committee meeting at this time.

Ref: https://www.rxlist.com/monurol-drug.htm#indications

Experimental drug can protect against Ebola in a single dose

Dr. Thomas Geisbert, a world-renowned Ebola researcher at The University of Texas Medical Branch, said that previous therapeutics typically were of the "one bug, one drug" variety. But because of the unpredictable nature and variety of the Ebola virus, scientists have been seeking a way to protect against different strains of the virus.

Our experimental drug can protect against all forms of Ebola known to harm people, suggesting that it will continue to protect people if the Ebola viruses evolve over time," said Geisbert, who is a professor of microbiology and immunology at UTMB.

The team of scientists demonstrated that a two-antibody cocktail called MBP134 could fully protect nonhuman primates and ferrets against lethal Ebola virus infections of caused by the Bundibugyo and Sudan strain as well as the deadliest Zaire strain that caused the 2013-16 epidemic in West Africa and the current outbreak in the Democratic Republic of Congo.

"We were able to protect the nonhuman primates against all the Ebola species plaguing people at a single low dose," said Larry Zeitlin, president of Mapp Biopharmaceutical Inc. "Further studies exploring even lower doses could open the door to treatment via auto-injectors like the kind used for allergic reactions. The ability to quickly and efficiently provide protection against all Ebola viruses in a single dose would reduce the burden on health care workers in the field during outbreaks, especially in regions that have a less-developed infrastructure."

Ref: https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(18)30632-2