FDA Approves Libervant (diazepam) Buccal Film for the Treatment of Seizure Clusters in Pediatric Patients Ages 2-5 Years

Aquestive Therapeutics, Inc. (NASDAQ: AQST) (“Aquestive” or the “Company”), a pharmaceutical company advancing medicines to bring meaningful improvement to patients' lives through innovative science and delivery technologies, today announced the U.S. Food and Drug Administration (FDA) has approved Libervant™ (diazepam) Buccal Film for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy between 2 to 5 years of age.

“We are thrilled to have received FDA approval for Libervant™ in patients between the ages of two and five,” said Daniel Barber, Chief Executive Officer of Aquestive. “Patients have been waiting years for Libervant, the first and only FDA approved orally-administered rescue product for the treatment of seizure clusters. Our first priority is to provide and maintain availability of Libervant to the intended patient population. I am pleased to announce that we are currently able to accept and fill non-Medicaid prescriptions. We expect to expand our distribution capabilities over the coming weeks and months. I am also pleased with our continued track record of success with the FDA. We respect the FDA’s mission to protect public health and we will always seek to partner with the FDA wherever possible.”

“Libervant provides a new way to deliver diazepam for the treatment of acute repetitive seizure emergencies in children aged two to five,” said Michael Rogawski, M.D., Ph.D, distinguished professor of neurology and pharmacology, University of California, Davis, “The film is placed onto the buccal mucosa inside the cheek where it adheres firmly and dissolves quickly, delivering a consistent dose of diazepam. Studies show that the film is easy to administer and performs reliably in children as young as 2 years of age. Libervant is packaged in a compact foil pouch that is convenient to carry so that the treatment can be available wherever these children may be.”

In 2023, over 55,000 prescriptions were filled for patients between the ages of 2 and 5. This was an increase of 10.8% over the previous year and an average increase of 9.3% over the last three years for this patient population. Over 90% of filled prescriptions in 2023 for this patient population were for diazepam rectal gel. Prescription writing for this indication is highly concentrated among pediatric epileptologists and pediatric neurologists.

REF: https://en.wikipedia.org/wiki/Diazepam

FDA Approves Libervant (diazepam) Buccal Film for the Treatment of Seizure Clusters in Pediatric Patients Ages 2-5 Years

FDA Approves Vafseo (vadadustat) for the Treatment of Anemia due to Chronic Kidney Disease in Adult Patients on Dialysis

Akebia Therapeutics, Inc. (Nasdaq: AKBA), a biopharmaceutical company with the purpose to better the lives of people impacted by kidney disease, today announced that the U.S. Food and Drug Administration (FDA) has approved Vafseo® (vadadustat) Tablets for the treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least three months. Vafseo is a once-daily oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor that activates the physiologic response to hypoxia to stimulate endogenous production of erythropoietin to manage anemia. Vafseo is now approved in 37 countries.

"With the approval of Vafseo in the U.S., we're proud to deliver an alternative treatment option for the hundreds of thousands of Americans on dialysis who are diagnosed with anemia due to CKD," said John P. Butler, Chief Executive Officer of Akebia. "At Akebia we are committed to kidney patients, a dedication that has driven our team to achieve this milestone. We believe this commitment uniquely positions the company to execute a successful launch designed to drive toward a potential new oral standard of care for dialysis patients."

The approval of Vafseo for the treatment of anemia due to CKD in adults who have been receiving dialysis for at least three months is based on efficacy and safety data from the INNO2VATE program and an assessment of post marketing safety data from Japan where VAFSEO was launched in August 2020. Results from the INNO2VATE program were published in the New England Journal of Medicine: (N Engl J Med 2021; 384:1601-1612); (N Engl J Med 2021; 384:1589-1600). See the Important Safety Information section below, including BOXED WARNING regarding increased risk of death, myocardial infarction, stroke, venous thromboembolism and thrombosis of vascular access.

Approximately 500,000 adult patients in the U.S. on dialysis suffer from anemia due to CKD1, which may be associated with many adverse clinical outcomes. The burden of managing uncontrolled anemia in CKD patients can be substantial, both in terms of healthcare costs and the impact on patients, healthcare providers and caregivers. Today, most CKD patients are treated for anemia with injectable erythropoiesis-stimulating agents mostly administered at dialysis centers. "Patients receiving maintenance dialysis would benefit from additional therapeutic options that can effectively increase and maintain hemoglobin concentrations within guideline-recommended target ranges," said Glenn M. Chertow, M.D., M.P.H., Professor of Medicine, Division of Nephrology at Stanford University and Co-Chair of the independent Executive Steering Committee for PRO2TECT and INNO2VATE, the global Phase 3 clinical development programs for Vafseo.

Lori Hartwell, who has had kidney disease since she was a young child, is the Founder and President of the Renal Support Network. She expressed her support of this new therapy for adults with anemia due to chronic kidney disease on dialysis by stating, "Anemia is a debilitating condition that significantly impacts our daily lives. It is promising to see the introduction of innovative treatment options for people fighting anemia."

Akebia intends to commercialize Vafseo in the U.S. with its established commercial team that has deep renal experience and by leveraging its relationship with CSL Vifor, an industry leader in bringing innovative therapies to U.S. dialysis organizations. In line with the approved label, Akebia will execute a launch strategy to drive Vafseo toward the goal of becoming a new oral standard of care for adult dialysis patients.

Mr. Butler added, "We are tremendously grateful for the patients, physicians, investigators, and site coordinators who participated in our clinical trials that led to this important approval. This milestone is the culmination of years of perseverance by Akebia employees and partners committed to bettering the lives of people impacted by kidney disease."

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

FDA Approves Vafseo (vadadustat) for the Treatment of Anemia due to Chronic Kidney Disease in Adult Patients on Dialysis

FDA Approves Duvyzat (givinostat) for Duchenne Muscular Dystrophy

Italfarmaco S.p.A. announced today that the U.S. Food and Drug Administration (FDA) has approved Duvyzat™ (givinostat), a novel histone deacetylase (HDAC) inhibitor, for the treatment of patients 6 years or older with Duchenne muscular dystrophy (DMD), a rare X-linked progressive and life-limiting neuromuscular condition with symptoms from early childhood.

“The FDA’s approval of Duvyzat for DMD, based on our robust and successful clinical development program, reflects Italfarmaco’s commitment to providing a safe and proven-effective therapy that can have a meaningful impact for people living with DMD,” said Paolo Bettica, MD, PhD, Chief Medical Officer at Italfarmaco Group. “We are grateful for the support of those living with DMD and their dedicated caregivers, which played a central role in helping us reach this landmark FDA approval. Our focus now is to make Duvyzat available as a treatment for DMD management in the U.S. as quickly as possible.”

Dr Francesco De Santis, President of Italfarmaco Holding and Chairman of Italfarmaco Group added, “Duchenne muscular dystrophy is a disease with significant unmet medical need and Duvyzat has the potential to benefit a broad DMD patient population independent of the underlying gene mutation that causes the disease. The FDA approval highlights the dedication of Italfarmaco’s research and clinical teams to achieve this milestone for the company.”

The approval is based on the results of the pivotal multicentre, randomised, double-blind, placebo-controlled phase 3 EPIDYS trial (NCT02851797). In the EPIDYS study, a total of 179 ambulant boys six years of age or older received either Duvyzat twice daily or placebo, in addition to glucocorticosteroid treatment. The EPIDYS study met its primary endpoint demonstrating that patients on Duvyzat showed a statistically significant and clinically meaningful difference in time to complete the four-stair climb assessment. Duvyzat also showed favourable results on key secondary endpoints including North Star Ambulatory Assessment (NSAA), and fat infiltration evaluation by magnetic resonance imaging. The majority of adverse effects observed with Duvyzat were mild to moderate in severity. Results from this study were published in The Lancet Neurology in March 2024.

“There is a tremendous unmet need for novel therapies in DMD that can achieve meaningful benefits for a broad range of patients. Duvyzat’s unique mechanism of action has shown a positive risk/benefit profile and the ability to delay disease progression, supporting its potential to become a key component of the standard of care for people living with DMD,” added Craig M. McDonald, MD, Professor at the Department of Pediatrics and Physical Medicine Rehabilitation at the University of California Davis Health and investigator for the EPIDYS trial. “I would like to thank all patients and their families for participating in the clinical trials and for making this approval possible.”

“We are thrilled with the FDA’s approval of Duvyzat, a new therapy for DMD. It is an oral medication that will be available to every person 6 years and older with DMD. This brings great hope for the Duchenne community, and we believe this will be a key therapy to prevent disease progression in Duchenne,” said Pat Furlong, Founding President & CEO at Parent Project Muscular Dystropy (PPMD).

Italfarmaco has significantly expanded its U.S. presence through the formation of a new fully owned subsidiary, ITF Therapeutics LLC. ITF Therapeutics will be responsible for the commercialisation of Duvyzat in the U.S. and the company is working closely with healthcare providers, patient advocacy groups and payors to make Duvyzat available to patients.

Duvyzat received priority review, orphan drug and rare pediatric disease designations from the FDA. A Marketing Authorisation Application (MAA) for givinostat as a potential treatment for DMD has been submitted to the European Medicine Agency (EMA) and is currently under review. Italfarmaco has a global presence and is also working with other regulatory agencies.

Ref: https://www.drugs.com/pro/duvyzat.html

FDA Approves Duvyzat (givinostat) for Duchenne Muscular Dystrophy

FDA Approves Opsynvi (macitentan and tadalafil) for Adults with Pulmonary Arterial Hypertension

Johnson & Johnson today announced that the U.S. Food and Drug Administration (FDA) has approved Opsynvi® – a single-tablet combination of macitentan, an endothelin receptor antagonist (ERA), and tadalafil, a phosphodiesterase 5 (PDE5) inhibitor – for the chronic treatment of adults with pulmonary arterial hypertension (PAH, World Health Organization [WHO] Group I) and WHO functional class (FC) II-III.1 Opsynvi® may be used in patients with PAH who are treatment-naïve or who are already on an ERA, PDE5 inhibitor or both. Opsynvi® may be used in patients who are currently treated concomitantly with stable doses of macitentan 10 mg and tadalafil 40 mg (20 mg x 2) as separate tablets.

PAH is a rare, progressive, and life-threatening blood vessel disorder characterized by the constriction of small pulmonary arteries and elevated blood pressure in the pulmonary circulation that eventually leads to right heart failure.2 An estimated 500 to 1,000 new cases of PAH are diagnosed each year in the U.S., classifying the disease as a rare condition.3

The 2022 European Society of Cardiology (ESC) / European Respiratory Society (ERS) clinical guidelines recommend initial combination therapy of an ERA and a PDE5 inhibitor for patients with idiopathic PAH, heritable drug-associated PAH, or PAH-associated with connective tissue disease without cardiopulmonary comorbidities at low or intermediate risk.2

“Clinical guidelines recommend treating patients with initial and sequential dual-combination therapy, regardless of risk at initial diagnosis and follow-up. Historically, this required patients to take multiple pills because no single-tablet combination therapy targeting two or more pathways was available,” said Kelly Chin, M.D., Professor of Internal Medicine and Director of the Pulmonary Hypertension Program at UT Southwestern Medical Center, and an investigator in the A DUE study.* “As administration of macitentan and tadalafil together are commonly prescribed for initial therapy for PAH, the introduction of a single tablet combining both is promising for clinicians treating patients as it may help bridge the gap between clinical guidelines and everyday clinical practice, while offering a patient-friendly approach to support initial combination therapy and rapid escalation for the appropriate patients.”

The FDA’s approval of Opsynvi® is based on the results from the pivotal Phase 3 A DUE study, in which Opsynvi® demonstrated greater reduction in Pulmonary Vascular Resistance (PVR) after 16 weeks versus tadalafil or macitentan monotherapy. Opsynvi® has a Boxed Warning due to the risk of embryo-fetal toxicity and requires female patients to enroll in the Macitentan-Containing Products Risk Evaluation and Mitigation Strategy (REMS) program.1

With the approval, Johnson & Johnson now offers a PAH portfolio addressing all three foundational and guideline-recommended pathways – nitric oxide, endothelin, and prostacyclin.

“People with PAH often live with the burden of taking many pills each day, which can pose challenges,” said James F. List, M.D., Ph.D., Global Therapeutic Area Head, whose team oversees a portfolio of programs including Pulmonary Hypertension at Johnson & Johnson. “We’re thrilled to bring this single tablet combination therapy to patients, as it has the potential to optimize disease management and fulfill a significant unmet need in supporting recently updated treatment guidelines that call for initial or early combination treatment.”

Ref:

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

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

FDA Approves Opsynvi (macitentan and tadalafil) for Adults with Pulmonary Arterial Hypertension

FDA Approves Rezenopy (naloxone hydrochloride) Nasal Spray for the Emergency Treatment of Opioid Overdose

The U.S. Food and Drug Administration has approved Rezenopy (naloxone hydrochloride) nasal spray 10 mg for emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression in adult and pediatric patients.

Drug overdose, including most commonly opioid overdose, is one of the leading causes of accidental death in the United States.

Rezenopy nasal spray is intended for immediate administration as emergency therapy in settings where opioids may be present.

Naloxone hydrochloride is an opioid antagonist that works to reverse the effects of opioids during an overdose, including respiratory depression, sedation and hypotension.

Rezenopy is a high-dose naloxone hydrochloride nasal spray formulation containing 10 mg of naloxone per spray available on prescription. There are a number of naloxone hydrochloride nasal spray products available that contain a lower dose of naloxone, including Kloxxado (8 mg/spray) and Rextovy (4 mg/spray) which are available on prescription, and Narcan (4 mg/spray) and ReVive (3 mg/spray) which are available over-the-counter.

Common adverse reactions reported with Rezenopy include upper abdominal pain, nasopharyngitis, and dysgeusia.

REF: https://en.wikipedia.org/wiki/Naloxone

FDA Approves Rezenopy (naloxone hydrochloride) Nasal Spray for the Emergency Treatment of Opioid Overdose

FDA Approves Tryvio (aprocitentan) for the Combination Treatment of Resistant Hypertension

Idorsia Pharmaceuticals U.S. Inc. announced the US Food and Drug Administration (FDA) approval of  Tryvio™ (aprocitentan) for the treatment of hypertension in combination with other antihypertensive drugs, to lower blood pressure in adult patients who are not adequately controlled on other drugs.1 Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions.1 The recommended dosage of Tryvio is 12.5 mg orally once daily, with or without food. 

Jean-Paul Clozel, MD and Chief Executive Officer of Idorsia commented:

"Today, there are millions of Americans whose blood pressure is not well-controlled despite existing therapies. This is a major public health issue leading to a high incidence of cardio- and cerebrovascular events. In order to help address this issue, Idorsia developed aprocitentan, an endothelin receptor antagonist suited to the treatment of these patients. Idorsia conducted an ambitious clinical program in patients remaining hypertensive despite a minimum of three drugs at their optimal dose and sometimes up to four, five, or even six antihypertensives. I'm very proud of the Idorsia team and very happy that physicians will have a new treatment option to treat patients whose blood pressure is not controlled."

Tryvio (aprocitentan) is an endothelin receptor antagonist that inhibits the binding of endothelin (ET)-1 to ETA and ETB receptors.1,2 The effects of ET-1 bear many similarities with the pathophysiology of hypertension,3 and ET-1 is a major driver of aldosterone production.4 Until the approval of Tryvio, no systemic antihypertensive medications targeted the ET pathway,5 as approved antihypertensive therapies focus on the regulation of salt and water (diuretics), antagonism of the renin–angiotensin–aldosterone (RAAS) system, reduction of influx of extracellular calcium into the cell (calcium channel blockers), sympatholytic activity (beta blockers, central alpha-agonist agents), or non-selective vasodilatory effects.6,7

Tryvio was evaluated as a monotherapy in a Phase 2 study in patients with hypertension,8 and as an add-on therapy in a Phase 3 study called PRECISION in patients with confirmed resistant hypertension.9 In PRECISION, aprocitentan was well tolerated and superior to placebo in lowering blood pressure at week 4, with a sustained effect at week 40.10

Martine Clozel, MD and Chief Scientific Officer of Idorsia, commented:

"Early on, we realized that endothelin was involved in patients with hypertension, especially in those remaining uncontrolled despite other anti-hypertensive drugs. Since the endothelin pathway was not yet tackled in these patients, we selected aprocitentan, an endothelin receptor antagonist with the ideal properties for use in this condition. We were delighted when we saw the safety and efficacy data with Tryvio, even on top of multiple antihypertensives, in patients whose hypertension is not adequately controlled. The recognition of its potential with today's FDA approval is great news for prescribers and patients."

Michael A. Weber, MD, Professor of Medicine, Division of Cardiovascular Medicine State University of New York, and an investigator in the PRECISION study commented:

"Today, we are not able to reduce blood pressure below recommended levels in at least 10% of the hypertensive patients we treat. As well, it is often patients at high risk of adverse cardiovascular outcomes and typically with comorbidities who pose this challenge. We have had to wait for over 30 years to see the approval of an oral anti-hypertensive agent that works on a new therapeutic pathway, so Tryvio provides transformational progress in the field of systemic hypertension. It is taken as a single daily oral dose that works in combination with whatever other drugs are being prescribed and without drug-drug interactions in patients with the burden of uncontrolled hypertension. Tryvio is easy for physicians to prescribe and easy for patients to use."

Phase 3 clinical study1,9,10

The efficacy of Tryvio (aprocitentan) was evaluated in a multipart, Phase 3 multicenter study (PRECISION, NCT03541174) in adults with systolic blood pressure (SBP) ≥140 mmHg who were prescribed at least three antihypertensive medications. The trial included a placebo run-in period, which was followed by three parts as described below. Prior to the placebo run-in period, all patients were switched to standard background antihypertensive therapy consisting of an angiotensin receptor blocker, a calcium channel blocker, and a diuretic, which was continued throughout the study. Patients with concomitant use of beta‑blockers continued this treatment throughout the study.

Following the 4-week placebo run-in period, 730 patients were randomized equally to aprocitentan at either 12.5 mg, 25 mg, or placebo once daily during the initial 4-week double-blind (DB) treatment period (part 1). At the end of 4 weeks, all patients entered the single-blind treatment period (part 2) where they received 25 mg aprocitentan once daily for 32 weeks. At the end of the 32 weeks, patients were re-randomized to receive either 25 mg aprocitentan or placebo, once daily, during a 12-week DB-withdrawal period (part 3).

The primary efficacy endpoint was the change in sitting SBP (SiSBP) from baseline to Week 4 during part 1, measured at trough by unattended automated office blood pressure (uAOBP).

The key secondary endpoint was the change in SiSBP measured at trough by uAOBP from Week 36 (i.e., prior to randomized withdrawal to 25 mg aprocitentan or placebo in part 3) to Week 40.

Patients had a mean age of 62 years (range 24 to 84 years) and 60% were male. Patients were White (83%), African American (11%) or Asian (5%). Approximately 10% were Hispanic. The mean body mass index (BMI) was 34 kg/m2 (range 18 to 64 kg/m2). At baseline, 19% of patients had an eGFR 30–59 mL/min/1.73 m2 and 3% had an eGFR 15–29 mL/min/1.73 m2. At baseline, 24% of patients had a urine albumin-to-creatinine ratio (UACR) of 30–300 mg/g and 13% had a UACR >300 mg/g. Approximately 54% of patients had a medical history of diabetes mellitus, 31% ischemic heart disease, and 20% congestive heart failure. At baseline, 63% of patients reported taking four or more antihypertensive medications.

Tryvio 12.5 mg was statistically superior to placebo in reducing SiSBP at Week 4 (part 1). The treatment effect was consistent for sitting diastolic BP (SiDBP).

The persistence of the BP-lowering effect of Tryvio was demonstrated in part 3 of the trial, in which patients on aprocitentan were re-randomized to placebo or 25 mg aprocitentan following a period during which all patients were treated with 25 mg. In patients re-randomized to placebo, the mean SiSBP increased, whereas in patients re-randomized to 25 mg aprocitentan the mean effect on SiSBP was maintained and was statistically superior to placebo at Week 40. The treatment effect was consistent for SiDBP.

Most of the BP-lowering effect occurred within the first two weeks of treatment with Tryvio. Tryvio is not approved for use at a 25 mg dose. The efficacy for the 25 mg aprocitentan dose as measured in the primary end point of change in sitting SBP (SiSBP) from baseline to Week 4 in part 1, was similar to the 12.5 mg dose and thus aprocitentan 12.5 mg is the approved dose.

Tryvio's BP-lowering effect appeared consistent among subgroups defined by age, sex, race, BMI, baseline eGFR, baseline UACR, medical history of diabetes, and between BP measurement methodologies (uAOBP and ambulatory BP measurements).

The most frequently reported adverse reactions to Tryvio during the 4-week double-blind placebo-controlled treatment period (part 1) of the PRECISION study were edema/fluid retention and anemia. During the initial 4-week double-blind placebo-controlled treatment period (part 1), 0.8% of patients experienced an adverse reaction of hypersensitivity (i.e., rash, erythema, allergic edema) on Tryvio compared to no reports in patients treated with placebo. One patient experienced allergic dermatitis requiring hospitalization while receiving aprocitentan 25 mg. Tryvio is contraindicated in patients who are hypersensitive to aprocitentan or any of its excipients. Use of Tryvio is contraindicated in pregnancy.

Lowering BP reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes. There are no controlled trials demonstrating reduction of risk of these events with Tryvio.

Alberto Gimona, MD and Head of Global Clinical Development of Idorsia, commented:

"When designing PRECISION, we did not shy away from including patients who are most at risk of the serious negative consequences of hypertension. In addition, while all patients needed to be on three antihypertensives to join the study, 63 percent of patients were on four or more anti-hypertensives. The study was therefore truly reflective of the real-world patient population whose blood pressure is not adequately controlled on other drugs. Tryvio demonstrated a clear and consistent effect across all endpoints of blood pressure measurement and in key sub-populations. As a result, Tryvio brings hope as a novel, effective and well-tolerated treatment option for patients with hypertension not adequately controlled."

Tosh Butt, President and General Manager of Idorsia US commented:

"The approval of Tryvio in the US marks another major milestone for Idorsia. With Tryvio, we've got an innovative medicine with a unique mode of action in systemic hypertension. The team at Idorsia has a deep understanding and rich history in the field of endothelin receptor antagonism. We are eager to provide physicians and patients with a novel medicine working in a new pathway in uncontrolled hypertension that can provide additional blood pressure control. We recognize that the resources required to reach the entire prescribing community could be substantial, so we will carefully craft the Tryvio launch strategy in the coming months, while preparing to make Tryvio available during the second half of 2024."

The team at Idorsia has been working on the research and development of endothelin receptor antagonists for more than 30 years, successfully bringing three other molecules from this class to patients in different indications. ET-1, via its receptors (ETA and ETB), mediates a variety of deleterious effects such as vasoconstriction, fibrosis, cell proliferation, and inflammation. In hypertension, ET-1 can cause endothelial dysfunction, vascular hypertrophy and remodeling, sympathetic activation, and increased aldosterone synthesis.1

Martine Clozel, MD and Chief Scientific Officer of Idorsia, concluded:

"After more than 30 years working in the field of endothelin science, our research has brought about changes in the treatment paradigm of several cardiovascular diseases. Now we are bringing significant medical progress for patients with systemic hypertension. I am convinced that with the data we have seen, the approval of Tryvio heralds a new era of endothelin research beyond hypertension, where we intend to investigate the utility of aprocitentan for first-in-class applications in new indications."

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

FDA Approves Tryvio (aprocitentan) for the Combination Treatment of Resistant Hypertension

FDA Approves Xolremdi (mavorixafor) for Use in Patients with WHIM Syndrome

X4 Pharmaceuticals (Nasdaq: XFOR), a company driven to improve the lives of people with rare diseases of the immune system, today announced that the U.S. Food and Drug Administration (FDA) has approved Xolremdi™ (mavorixafor) capsules for use in patients 12 years of age and older with WHIM syndrome (warts, hypogammaglobulinemia, infections and myelokathexis) to increase the number of circulating mature neutrophils and lymphocytes.

Xolremdi, a selective CXC chemokine receptor 4 (CXCR4) antagonist, is the first therapy specifically indicated in patients with WHIM syndrome, a rare, combined primary immunodeficiency and chronic neutropenic disorder caused by CXCR4 pathway dysfunction. People with WHIM syndrome characteristically have low blood levels of neutrophils (neutropenia) and lymphocytes (lymphopenia) and experience serious and/or frequent infections. The FDA granted Breakthrough Therapy Designation to mavorixafor in WHIM syndrome and evaluated the New Drug Application (NDA) under Priority Review, a designation for therapies that have the potential to provide significant improvement in the treatment, diagnosis, or prevention of serious conditions.

“The approval of Xolremdi is a transformational milestone both for X4 and, more importantly, for the WHIM syndrome community,” said Paula Ragan, Ph.D., President and Chief Executive Officer of X4 Pharmaceuticals. “We are incredibly grateful to the people living with WHIM syndrome, their families, and the investigators who took part in our clinical program, to U.S. regulators for their continued focus on rare-disease treatment development, and to our dedicated employees for making this targeted breakthrough therapy a reality.”

“Effective and innovative treatments are critical for those diagnosed with a primary immunodeficiency. The approval of Xolremdi marks an important advancement for people living with WHIM syndrome, who are susceptible to serious and frequent infections,” said Jorey Berry, President and Chief Executive Officer of the Immune Deficiency Foundation (IDF). “We are very pleased to have been a partner to X4 in their journey to bring this much-needed treatment to this underserved rare disease community.”

Teresa K. Tarrant, M.D., Associate Professor of Medicine, Rheumatology, and Immunology at Duke University School of Medicine and a principal investigator in the 4WHIM trial, commented on the news: “Until now, supportive care for people with WHIM syndrome has focused on symptom management and not the underlying cause of disease — the dysfunction of the CXCR4 pathway. I am thrilled that with the approval of Xolremdi, a therapy designed to address dysregulated CXCR4 pathway signaling, we now have a targeted treatment that has demonstrated the ability to elevate absolute neutrophil and lymphocyte counts, increasing WHIM patients’ ability to fight infections.”

The FDA approval of Xolremdi was based on results of the pivotal, 4WHIM Phase 3 clinical trial, a global, randomized, double-blind, placebo-controlled, 52-week multicenter study that evaluated the efficacy and safety of Xolremdi in 31 people aged 12 years and older diagnosed with WHIM syndrome. The efficacy of Xolremdi was determined by improvement in absolute neutrophil counts (ANC), improvement in absolute lymphocyte counts (ALC), and a reduction in infections. In the 4WHIM trial, Xolremdi treatment demonstrated increased time above threshold (≥500 cells/microliter) for absolute neutrophil count (TAT-ANC) vs. placebo (p<0.0001) and increased time above threshold (≥1000 cells/microliter) for absolute lymphocyte count (TAT-ALC) v. placebo (p<0.0001). The efficacy of Xolremdi was further assessed in a composite endpoint consisting of total infection score and total wart change score using a Win-Ratio method. Analyses of the individual components of this composite endpoint showed an approximate 40% reduction in total infection score, weighted by infection severity, in Xolremdi-treated patients compared with placebo-treated patients. There was no difference in total wart change scores between the Xolremdi and placebo treatment arms over the 52-week period. Treatment with Xolremdi also resulted in a 60% reduction in the annualized infection rate compared with placebo-treated patients. The most common adverse reactions reported in the 4WHIM trial (≥10% and more frequently reported than placebo) were: thrombocytopenia, pityriasis, rash, rhinitis, epistaxis, vomiting, and dizziness.

With the FDA approval of Xolremdi, X4 has received a Rare Pediatric Disease Priority Review Voucher that can be used to obtain priority review for a subsequent application or sold to another drug sponsor.

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

FDA Approves Xolremdi (mavorixafor) for Use in Patients with WHIM Syndrome

FDA Approves Exblifep (cefepime/enmetazobactam) for the Treatment of Complicated Urinary Tract Infections,

Allecra Therapeutics (“Allecra”), a biopharmaceutical company developing novel therapies to combat antibiotic resistance, announced today that the U.S. Food and Drug Administration (FDA) has approved Exblifep (cefepime/enmetazobactam), as a treatment for complicated urinary tract infections (cUTIs), including pyelonephritis, in patients 18 years and older. Allecra has also received a five-year marketing exclusivity extension from the FDA as part of the Generating Antibiotic Incentives Now Act (GAIN Act). The GAIN Act, enacted by the U.S. Congress, incentivizes the creation of new anti-infective therapeutics by providing benefits to manufacturers of Qualified Infectious Disease. Products (QIDPs).

"Receiving FDA approval is a tremendous achievement for Allecra and a testament to the hard work and dedication of a small, yet highly focused team of individuals. I extend my sincere congratulations to my colleagues Omar Lahlou and Patrick Velicitat for their leadership and oversight throughout this whole process,” said Iain Buchanan, Supervisory Board Member of Allecra Therapeutics. “As we continue our discussions with strategic partners for product launch in the U.S., we value the FDA’s positive decision on Exblifep’s ability to address a critical unmet medical need for patients.”

The FDA’s approval of Exblifep was supported by a totality of clinical data that demonstrated Exblifep effectiveness against antimicrobial resistance in gram-negative bacteria, especially resistance mediated by both ESBL (Extended Spectrum Beta Lactamases) and AmpC. This included results from Allecra’s Phase 3 ALLIUM trial, which met criteria for non-inferiority and superiority compared to piperacillin/tazobactam in the primary composite outcome of clinical cure and microbiological eradication in patients with cUTIs.

Allecra is the sole holder of a significant patent estate covering Exblifep in major territories with the GAIN Act extending Allecra’s market exclusivity until 2032. Enmetazobactam was first discovered by Orchid Pharma and all rights outside India were assigned to Allecra Therapeutics in 2013. The company has since taken the sole responsibility for the international clinical and regulatory development of Exblifep. Allecra was founded through a strategic partnership formed by Nicholas Benedict, Stuart Shapiro and Edward Currie in conjunction with Orchid Chemicals and Pharmaceuticals Ltd. and Allecra lead investors, Andera Partners, Forbion and EMBL Ventures. The company has concluded exclusive license agreements for Exblifep with Shanghai Haini Pharmaceutical in Greater China and ADVANZ PHARMA in Europe.

https://en.wikipedia.org/wiki/Cefepime/enmetazobactam

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

FDA Approves Exblifep (cefepime/enmetazobactam) for the Treatment of Complicated Urinary Tract Infections

UCLA-led research results in FDA approval of 4-drug combination for frontline treatment of metastatic pancreatic cancer

A four-drug chemotherapy regimen of irinotecan liposome (Onivyde) in combination with oxaliplatin, leucovorin, and fluorouracil—together referred to as NALIRIFOX—has been approved by the U.S. Food and Drug Administration (FDA) for the first-line treatment of metastatic pancreatic adenocarcinoma.

                                                                            Irinotecan

                                                                      Fluorouracil

                                                                    Folinic acid

                                                                Oxaliplatin

The FDA approval was based on results of the NAPOLI 3 trial, a study led by Dr. Zev Wainberg, co-director of the UCLA Health GI Oncology Program and a researcher at the UCLA Health Jonsson Comprehensive Cancer Center.

Findings from the NAPOLI 3 trial were first presented at the 2023 American Society of Clinical Oncology Gastrointestinal Cancers Symposium annual meeting and published in the Lancet in September of 2023. Wainberg, the global principal investigator for the trial, reported NALIRIFOX resulted in longer overall survival than a two-drug protocol comprised of nab-paclitaxel (Abraxane) and gemcitabine.

“The FDA approval is significant because of how difficult it is to treat metastatic pancreatic cancer,” said Wainberg, who is also a professor of medicine at the David Geffen School of Medicine at UCLA. “Metastatic pancreas cancer has long been recognized as a very difficult type of cancer to treat, but this study represents a possible new benchmark standard for current therapies and a promising avenue for ongoing research and drug development.”

The phase 3 study included 770 patients with pancreatic ductal adenocarcinoma, which makes up 95% of pancreatic cancers. Participants were from 250 sites in 25 countries and were randomly assigned to NALIRIFOX or the two-drug therapy.

Patients in the NALIRIFOX group had an overall survival of 11.1 months, compared with 9.2 months for those in the two-drug arm. Progression-free survival also increased with NALIRIFOX to 7.4 months versus 5.6 months with the two-drug regimen, which translates into a 30% reduction in the risk of disease progression or death.

The study is believed to be the first metastatic pancreatic cancer study in nearly a decade to have a positive endpoint for overall survival.

Most cases of pancreatic cancer are diagnosed at more advanced stages when the disease is more aggressive and has already started spreading to other parts of the body. There are also limited treatment options, which contributes to the high fatality rate of pancreatic cancer—Only about 13% of patients survive five or more years. In 2024 alone, the American Cancer Society estimates that around 35,000 people are anticipated to die from the disease.

The most common side effects people experienced in the trial included diarrhea, fatigue, nausea, vomiting, reduced appetite, abdominal pain, mucosal inflammation, constipation and decreased weight.

https://www.sciencedirect.com/science/article/pii/S0140673623013661?via%3Dihub

UCLA-led research results in FDA approval of 4-drug combination for frontline treatment of metastatic pancreatic cancer

FDA Approves Augtyro (repotrectinib) for the Treatment of Locally Advanced or Metastatic ROS1-Positive Non-Small Cell Lung Cancer (NSCLC)

Bristol Myers Squibb (NYSE: BMY) announced  the U.S. Food and Drug Administration (FDA) approval of  Augtyro (repotrectinib) for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC). Administered as an oral therapy, Augtyro is a tyrosine kinase inhibitor (TKI) targeting ROS1 oncogenic fusions.

The approval is based on the TRIDENT-1 study, an open-label, single-arm, Phase 1/2 trial that evaluated Augtyro in TKI-naïve and TKI-pretreated patients.2 In TKI-naïve patients (n=71), the primary endpoint of objective response rate (ORR), defined as the percentage of people treated within a certain period of time whose tumor size decreased (partial response) or who no longer have signs of cancer (complete response),was 79% (95% Confidence Interval [CI]: 68 to 88).1,3 The median duration of response (mDOR) was 34.1 months. Among patients pretreated with one prior ROS1 TKI and no prior chemotherapy (n=56), the ORR was 38% (95% CI: 25 to 52) and the mDOR was 14.8 months.1 Among those who had measurable central nervous system (CNS) metastases at baseline, responses in intracranial lesions were observed in 7 of 8 TKI-naïve patients (n=71) and 5 of 12 of those who were TKI-pretreated (n=56).

“New treatment options continue to be needed for patients with ROS1 fusion-positive NSCLC that support important clinical goals, including achieving durable therapeutic responses,” said Jessica J. Lin, MD, TRIDENT-1 primary investigator and attending physician at the Center for Thoracic Cancers at Massachusetts General Hospital and Assistant Professor of Medicine at Harvard Medical School.4,5,6,7 “Based on the data we have seen in the TRIDENT-1 trial, repotrectinib has the potential to become a new standard of care option for patients with locally advanced or metastatic ROS1 fusion-positive lung cancer.”1

Augtyro is associated with the following Warnings & Precautions: central nervous system (CNS) effects, interstitial lung disease (ILD)/pneumonitis, hepatotoxicity, myalgia with creatine phosphokinase elevation, hyperuricemia, skeletal fractures, and embryo-fetal toxicity.1 Please see Important Safety Information below.

“While progress has been made in the treatment of NSCLC over the past decade, there is still a need to address this particularly difficult-to-treat form of the disease with innovative science and a targeted approach,” said Samit Hirawat, MD, executive vice president, chief medical officer, Global Drug Development, Bristol Myers Squibb.6,7 “As the only approved next-generation TKI for ROS1-positiveNSCLCpatients, Augtyro builds on our legacy of delivering transformational therapies for patients with thoracic cancers.”6,8,9

“ROS1-positive NSCLC patients and their families face a stressful journey because our cancer can be difficult to treat, especially when it spreads to the brain,” said Janet Freeman-Daily, co-founder and president of The ROS1ders, a patient advocacy organization.10 “Today’s approval brings a new treatment option for the ROS1-positive patient community, which gives us hope for more time with loved ones.”

Augtyro is designed to minimize interactions that can lead to certain forms of treatment resistance in ROS1-positive metastatic NSCLC patients. Itis expected to be available to patients in the U.S. in mid-December 2023. Bristol Myers Squibb thanks the patients and investigators involved in the TRIDENT-1 clinical trial program.

ref ;https://en.wikipedia.org/wiki/Repotrectinib

FDA Approves Augtyro (repotrectinib) for the Treatment of Locally Advanced or Metastatic ROS1-Positive Non-Small Cell Lung Cancer (NSCLC)

FDA Approves Eohilia (budesonide oral suspension) for the Treatment of Eosinophilic Esophagitis

 Takeda (TSE:4502/NYSE: TAK)   announced the U.S. Food and Drug Administration (FDA)   approval of Eohilia (budesonide oral suspension), the first and only FDA-approved oral therapy for people 11 years and older with eosinophilic esophagitis (EoE).1 It will be available in 2 mg/10 mL convenient, single-dose stick packs by the end of February.

Eohilia is a corticosteroid indicated for 12 weeks of treatment in patients 11 years and older with EoE.1 Developed specifically for EoE, Eohilia’s novel formulation of budesonide confers thixotropic properties – flowing more freely when shaken and returning to a more viscous state when swallowed.1,2

“Various formulations of corticosteroids have been used in the past to manage EoE, but in an off-label capacity and using multiple delivery options. With Eohilia, it’s gratifying to now have an FDA-approved treatment specifically formulated for a consistent dose delivery with demonstrated ability to address esophageal inflammation and EoE dysphagia symptoms,” said Ikuo Hirano, MD, professor of medicine and director of the Kenneth C. Griffin Esophageal Center in the Division of Gastroenterology and Hepatology at Northwestern University Feinberg School of Medicine. “As the treatment needs and goals of patients with EoE can vary, I welcome the flexibility that Eohilia offers as an oral medication.”

The FDA approval of Eohilia 2 mg twice daily is based on efficacy and safety data from two multicenter, randomized, double-blind, parallel-group, placebo-controlled 12-week studies (Study 1 and Study 2) in patients (ages 11 to 56 and 11 to 42, respectively) with EoE.1 In both studies, patients received at least one dose of either Eohilia 2 mg twice daily or placebo orally twice daily. Efficacy endpoints included histologic remission (peak eosinophil count of ≤6 per high-powered field across all available esophageal levels) and the absolute change from baseline in patient-reported Dysphagia Symptom Questionnaire (DSQ) combined score after 12 weeks of treatment. The DSQ measures how often a patient with EoE has trouble swallowing and the behavioral adaptations they subsequently use, as reported directly by patients.3

Significantly more patients receiving Eohilia achieved histologic remission vs. placebo in Study 1 (53.1% vs. 1%).1 In Study 2, 38% of Eohilia patients achieved histologic remission vs. 2.4% of those in the placebo group. Absolute change from baseline in DSQ combined score in the Eohilia vs. placebo groups in Study 1 was -10.2 (1.5) vs. -6.5 (1.8) and in Study 2, -14.5 (1.8) vs. -5.9 (2.1). During the last two weeks of each study, more patients receiving Eohilia experienced no dysphagia or only experienced dysphagia that “got better or cleared up on its own” as compared to placebo, as measured by the DSQ. Eohilia has not been shown to be safe and effective for the treatment of EoE for longer than 12 weeks. The most common adverse reactions (≥2% of patients receiving Eohilia and at a rate greater than placebo) in Study 1 included: respiratory tract infection (13%), gastrointestinal mucosal candidiasis (8%), headache (5%), gastroenteritis (3%), throat irritation (3%), adrenal suppression (2%) and erosive esophagitis (2%). The safety profile of Eohilia in Study 2 was generally similar to Study 1.1

“For most of us, eating is a simple experience. But for people living with eosinophilic esophagitis, sitting down for a meal can include painful and difficult swallowing, chest pain and a choking sensation,” said Brandon Monk, senior vice president and head, U.S. Gastroenterology Business Unit, Takeda. “With Eohilia, patients and their physicians now have the first and only FDA-approved oral treatment option for EoE that was shown during two 12-week clinical studies to reduce esophageal inflammation and improve the ability to swallow.”

EoE is a chronic, immune-mediated, inflammatory disease localized in the esophagus.4 Although the exact cause is unknown, it is believed to be triggered by a variety of stimuli including certain foods and environmental allergens.5,6 The chronic inflammation of EoE can lead to a range of symptoms, which can vary by person and age, and include difficulty swallowing, vomiting and pain.7 Identifying EoE can be complex and delayed diagnosis is common among patients. If left untreated, the inflammation of EoE can worsen and narrow the esophagus, which can lead to food impaction (when food becomes stuck in the esophagus).8,9 In fact, EoE is the leading cause of emergency room visits for food impaction.10

Takeda is assessing the financial impacts of the approval, including a reversal of impairment loss for intangible assets, on the fiscal year ending on March 31, 2024 (FY2023), but does not anticipate the impact to be material.

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

FDA Approves Eohilia (budesonide oral suspension) for the Treatment of Eosinophilic Esophagitis

FDA Approves Airsupra (albuterol/budesonide) Metered-Dose Inhaler to Reduce the Risk of Asthma Exacerbations

Airsupra (albuterol/budesonide), formerly known as PT027, has been approved in the US for the as-needed treatment or prevention of bronchoconstriction and to reduce the risk of exacerbations in people with asthma aged 18 years and older.

The approval by the Food and Drug Administration (FDA) was based on results from the MANDALA and DENALI Phase III trials. In MANDALA, Airsupra significantly reduced the risk of severe exacerbations compared to albuterol in patients with moderate to severe asthma when used as an as-needed rescue medication in response to symptoms. Importantly, in the secondary endpoint of mean annualised total systemic corticosteroid exposure, Airsupra demonstrated a significant reduction compared to albuterol at the approved dose of 180mcg albuterol/160mcg budesonide. In DENALI, Airsupra significantly improved lung function compared to the individual components albuterol and budesonide in patients with mild to moderate asthma.

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Airsupra is a first-in-class, pressurised metered-dose inhaler (pMDI), fixed-dose combination rescue medication containing albuterol, a short-acting beta2-agonist (SABA), and budesonide, an anti-inflammatory inhaled corticosteroid (ICS) in the US. It is being developed by AstraZeneca and Avillion.

Bradley E. Chipps, Past President of the American College of Allergy, Asthma & Immunology and Medical Director of Capital Allergy & Respiratory Disease Center in Sacramento, US, said: “People with asthma are at risk of severe exacerbations regardless of their disease severity or level of control. Current albuterol rescue inhalers alleviate acute symptoms, but do not treat the underlying inflammation in asthma. The approval of Airsupra means that for the first time, adults with asthma in the US have a rescue treatment to manage both their symptoms and the inflammatory nature of their disease.”

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca, said: “With patients experiencing more than 10 million asthma exacerbations each year in the US and uncontrolled asthma expected to cost the US economy billions of dollars in direct medical costs alone over the next 20 years, today’s positive decision is good news for those adults with asthma who make up more than 80% of asthma patients in the US. Physicians will be able to offer their patients Airsupra, an important new rescue treatment that reduces the risk of asthma exacerbations.”

Asthma is a chronic, inflammatory respiratory disease with variable symptoms that affects as many as 262 million people worldwide.3 In the US over 21 million adults have asthma, representing more than 80% of the total number of people with asthma.4 Adults have 8.5 million exacerbations each year in the US.4 Uncontrolled asthma will cost the US economy an estimated $300 billion (in 2018 dollar values) in the next 20 years in direct medical costs alone.5

The safety and tolerability of Airsupra in both trials were consistent with the known profiles of the components,1,2 with the most common adverse events including headache, oral candidiasis, cough and dysphonia

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

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

FDA Approves Airsupra (albuterol/budesonide) Metered-Dose Inhaler to Reduce the Risk of Asthma Exacerbations