Drug turns cancer gene into 'eat me' flag for immune system

Sotorasib

The new therapy, described Sept. 12 in Cell Cancer, pulls a mutated version of the protein KRAS to the surface of cancer cells, where the drug-KRAS complex acts as an "eat me" flag. Then, an immunotherapy can coax the immune system to effectively eliminate all cells bearing this flag.

"The immune system already has the potential to recognize mutated KRAS, but it usually can't find it very well. When we put this marker on the protein, it becomes much easier for the immune system," said UCSF chemist and Howard Hughes Medical Institute Investigator Kevan Shokat, PhD, who helped lead the new work.

KRAS mutations are found in about one quarter of all tumors, making them one of the most common gene mutations in cancer. Mutated KRAS is also the target of sotorasib, which the Food and Drug Administration (FDA) has given preliminary approval for use in lung cancer, and the two approaches may eventually work well in combination.

"It's exciting to have a new strategy leveraging the immune system that we can combine with targeted KRAS drugs," said Charles Craik, PhD, a lead study author and professor of pharmaceutical chemistry at UCSF. "We suspect that this could lead to deeper and longer responses for cancer patients."

Turning Cancer Markers Inside Out

The immune system typically recognizes foreign cells because of unusual proteins that jut out of their surfaces. But when it comes to cancer cells, there are few unique proteins found on their outsides. Instead, most proteins that differentiate tumor cells from healthy cells are inside the cells, where the immune system can't detect them.

For many years, KRAS -- despite how common it is in cancers -- was considered undruggable. The mutated version of KRAS, which drives the growth of tumor cells, operates inside cells. It often has only one small change that differentiates it from normal KRAS and doesn't have a readily visible spot on its structure for a drug to bind. But over recent decades, Shokat carried out detailed analyses of the protein and discovered a hidden pocket in mutated KRAS that a drug could block. His work contributed to the development and approval of sotorasib.

Sotorasib, however, doesn't help all patients with KRAS mutations, and some of the tumors it does shrink become resistant and start growing again. Shokat, Craik and their colleagues wondered whether there was another way to target KRAS.

In the new work, the team shows that when ARS1620 -- a targeted KRAS drug similar to sotorasib -- binds to mutated KRAS, it doesn't just block KRAS from effecting tumor growth. It also coaxes the cell to recognize the ARS1620-KRAS complex as a foreign molecule.

"This mutated protein is usually flying under the radar because it's so similar to the healthy protein," says Craik. "But when you attach this drug to it, it gets spotted right away."

That means the cell processes the protein and moves it to its surface, as a signal to the immune system. The KRAS that was once hidden inside is now displayed as an "eat me" flag on the outside of the tumor cells.

A Promising Immunotherapy

With the shift of mutated KRAS from the inside to the outside of cells, the UCSF team was next able to screen a library of billions of human antibodies to identify those that could now recognize this KRAS flag. The researchers showed with studies on both isolated protein and human cells that the most promising antibody they had identified could bind tightly to the drug ARS1620 as well as the ARS1620-KRAS complex.

Then, the group engineered an immunotherapy around that antibody, coaxing the immune system's T cells to recognize the KRAS flag and target cells for destruction. They found that the new immunotherapy could kill tumor cells that had the mutated KRAS and were treated with ARS1620, including those that had already developed resistance to ARS1620.

"What we've shown here is proof of principle that a cell resistant to current drugs can be killed by our strategy," says Shokat.

More work is needed in animals and humans before the treatment could be used clinically.

The researchers say that the new approach could pave the way not only for combination treatments in cancers with KRAS mutations, but also other similar pairings of targeted drugs with immunotherapies.

"This is a platform technology," says Craik. "We'd like to go after other targets that might also move molecules to the cell surface and make them amenable to immunotherapy."

Ref : 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965201/

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

Smoking May Increase Odds of Meniere Disease in Men

For men, smoking is positively related and alcohol consumption is negatively related to the risk for Meniere disease (MD), according to a study published online Aug. 26 in the Journal of Clinical Medicine.

So Young Kim, Ph.D., from the CHA University in Seongnam, South Korea, and colleagues examined the association of smoking, alcohol consumption, and obesity with MD among the population older than 40 years of age in the Korean National Health Insurance Service-Health Screening Cohort from 2002 to 2019. A total of 15,208 MD patients were matched with 499,658 controls.

The researchers found that in the overall adult population, there was no association for smoking and alcohol consumption with MD. The odds of MD were lower in association with being underweight (adjusted odds ratio, 0.80; 95 percent confidence interval, 0.68 to 0.93; P = 0.004). Smoking was positively associated with MD in men, while there was a negative association observed for alcohol consumption with MD (adjusted odds ratios, 1.08 [95 percent confidence interval, 1.00 to 1.17; P = 0.043] and 0.87 [95 percent confidence interval, 0.81 to 0.94; P < 0.001], respectively).

"The current study improved previous knowledge on the associated factors of MD by concurrently assessing multiple lifestyle factors, including smoking, alcohol consumption, and obesity," the authors write. "As these are modifiable factors, lifestyle modifications can be clinically valuable management strategies for patients who suffer from MD."

Ref : For men, smoking is positively related and alcohol consumption is negatively related to the risk for Meniere disease (MD), according to a study published online Aug. 26 in the Journal of Clinical Medicine.

So Young Kim, Ph.D., from the CHA University in Seongnam, South Korea, and colleagues examined the association of smoking, alcohol consumption, and obesity with MD among the population older than 40 years of age in the Korean National Health Insurance Service-Health Screening Cohort from 2002 to 2019. A total of 15,208 MD patients were matched with 499,658 controls.

The researchers found that in the overall adult population, there was no association for smoking and alcohol consumption with MD. The odds of MD were lower in association with being underweight (adjusted odds ratio, 0.80; 95 percent confidence interval, 0.68 to 0.93; P = 0.004). Smoking was positively associated with MD in men, while there was a negative association observed for alcohol consumption with MD (adjusted odds ratios, 1.08 [95 percent confidence interval, 1.00 to 1.17; P = 0.043] and 0.87 [95 percent confidence interval, 0.81 to 0.94; P < 0.001], respectively).

"The current study improved previous knowledge on the associated factors of MD by concurrently assessing multiple lifestyle factors, including smoking, alcohol consumption, and obesity," the authors write. "As these are modifiable factors, lifestyle modifications can be clinically valuable management strategies for patients who suffer from MD."

Ref : Smoking May Increase Odds of Meniere Disease in Men 

Daily Multivitamin May Protect Against Cognitive Decline in Older Adults

In continuation of my update on Vitamin and their importance 

A daily multivitamin may provide cognitive benefits for older adults, according to a study published online Sept. 14 in Alzheimer’s & Dementia.

Laura D. Baker, Ph.D., from the Wake Forest University School of Medicine in Winston-Salem, North Carolina, and colleagues assessed whether daily use of cocoa extract (containing 500 mg/day flavanols) versus placebo and a commercial multivitamin-mineral (MVM) versus placebo improved cognition in 2,262 older women and men (mean age, 73 years).

The researchers found that cocoa extract had no effect on global cognition. However, compared with placebo, daily MVM supplementation resulted in a statistically significant benefit on global cognition, with a more pronounced effect seen in participants with a history of cardiovascular disease. Benefits of MVM were also seen for memory and executive function. There were no significant interactions observed between cocoa extract and MVM for any of the cognitive composites.

"Our study showed that although cocoa extract did not affect cognition, daily multivitamin-mineral supplementation resulted in statistically significant cognitive improvement. This is the first evidence of cognitive benefit in a large longer-term study of multivitamin supplementation in older adults," Baker said in a statement. "It's too early to recommend daily multivitamin supplementation to prevent cognitive decline. While these preliminary findings are promising, additional research is needed in a larger and more diverse group of people."

Ref : Daily Multivitamin May Protect Against Cognitive Decline in Older Adults 

FDA Approves Zoryve (roflumilast) Cream for the Treatment of Plaque Psoriasis

 

 

 

Arcutis Biotherapeutics, Inc.   an early commercial-stage biopharmaceutical company focused on developing meaningful innovations in immuno-dermatology, announced the U.S. Food and Drug Administration (FDA)   approval of the  the New Drug Application (NDA) for Zoryve (roflumilast) cream 0.3% for the treatment of plaque psoriasis, including intertriginous areas, in patients 12 years of age or older. The first and only topical phosphodiesterase-4 (PDE4) inhibitor approved for the treatment of plaque psoriasis, Zoryve provides rapid clearance of psoriasis plaques and reduces itch in all affected areas of the body. Zoryve — a once-daily, steroid-free cream in a safe and well tolerated, patient-friendly formulation — is uniquely formulated to simplify disease management for people living with plaque psoriasis.

“Today Arcutis has reached a major milestone, with our ability to offer this next generation topical PDE4 inhibitor to both adults and adolescents with plaque psoriasis. Zoryve’s combination of efficacy, safety, and tolerability, coupled with our proprietary HydroARQ Technology formulation, is designed to fit into patients’ everyday lives with no restrictions on duration of use,” said Frank Watanabe, President and CEO of Arcutis. “Additionally, Zoryve has been shown to rapidly clear plaques and reduce itch across all areas of the body. Zoryve is the only topical for which data focused on the treatment of intertriginous plaques — a common area affected by plaque psoriasis — have been specifically generated. This FDA approval is the fruition of our efforts, and we are excited to launch Zoryve, with expected product availability by mid-August.”

Topical therapies remain the primary treatment option for the vast majority of individuals with plaque psoriasis, a common immune-mediated skin disease that affects approximately nine million people in the U.S. and is the most frequent type of psoriasis occurring in both adults and adolescents. Severity can range between mild, moderate, and severe, with itch being the most burdensome and frequently reported symptom.

While the disease may affect any area of the body, plaques in certain areas, like the face, elbows and knees, genitalia, and intertriginous areas (areas of skin-to-skin contact), present unique treatment challenges. As a result, individuals with psoriasis are often prescribed multiple topical medications for different areas, which makes for a complicated treatment regimen.

“In multiple clinical trials, Zoryve was proven to be safe and effective, with improvements in disease clearance in hard-to-treat areas like knees and elbows, as well as in sensitive areas such as the face, genitalia, and intertriginous areas. Zoryve is very well tolerated, which is an important consideration for treating a chronic skin disease such as plaque psoriasis,” said Mark Lebwohl M.D., FAAD, principal investigator and Dean for Clinical Therapeutics and Chairman Emeritus of the Kimberly and Eric J. Waldman Department of Dermatology at the Icahn School of Medicine at Mount Sinai. “With this FDA approval, adults and adolescents with psoriasis and their dermatologists have a new steroid-free treatment option for use on all affected areas of the body.”

Zoryve features HydroARQ Technology™, a proprietary drug delivery formulation that creates a non-greasy moisturizing cream that spreads easily and absorbs quickly.

“Plaque psoriasis is a challenging disease and finding the right treatment option can be complicated, especially if individuals have to use multiple treatments for different parts of their body. We welcome a new treatment option that can make a meaningful difference for adults and adolescents with plaque psoriasis,” says Leah M. Howard, President and CEO of the National Psoriasis Foundation. “Our hope is that new treatments translate into improved outcomes and help alleviate the burdens of chronic disease for people impacted by psoriasis.”

Arcutis intends to make Zoryve widely available via key wholesaler and national dermatology pharmacy channels as a new treatment option by mid-August, and the Company is dedicated to affordable access to therapy. The Zoryve Direct patient support program will help commercially insured individuals with plaque psoriasis get access and start Zoryve treatment as prescribed by their healthcare provider quickly and easily by helping them navigate the payer process, lowering the out-of-pocket cost for eligible patients, and offering programs that support staying on therapy.^† Arcutis will also offer the Arcutis Cares patient assistance program (PAP) – the first of its kind for a topical psoriasis treatment – that will provide Zoryve at no cost for financially eligible patients who are uninsured or underinsured.^‡

With this approval, Arcutis has access to, and plans to draw, an additional $125 million tranche as part of the Company’s non-dilutive financing agreement with SLR Capital Partners. Combined with the Company’s cash, cash equivalents, restricted cash, and marketable securities as of June 30, 2022, this additional $125 million will provide for capital resources of over $400 million to support the launch and commercialization efforts for Zoryve, as well as continue to advance the Company’s pipeline development initiatives.

 

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

FDA Approves Auvelity (dextromethorphan and bupropion) for the Treatment of Major Depressive Disorder in Adults

 

        

dextromethorphan

 

Bupropion

In continuation of my updates on dextromethorphan and Bupropion, 

Axsome Therapeutics, Inc. , a biopharmaceutical company developing and delivering novel therapies for the management of central nervous system (CNS) disorders,  announced  the U.S. Food and Drug Administration (FDA)  approval of  Auvelity (dextromethorphan HBr -bupropion HCl) extended-release tablets for the treatment of major depressive disorder (MDD) in adults.¹ Auvelity is the first and only rapid-acting oral medicine approved for the treatment of MDD with labeling of statistically significant antidepressant efficacy compared to placebo starting at one week.  The rapid antidepressant effects of Auvelity were sustained at all subsequent timepoints. Auvelity is the first and only oral N-methyl D-aspartate (NMDA) receptor antagonist approved for the treatment of MDD.  Axsome anticipates Auvelity to be commercially available in the U.S. in the fourth quarter of 2022.

Maurizio Fava, MD, Psychiatrist-In-Chief, Department of Psychiatry, Massachusetts General Hospital, Executive Director, Clinical Trials Network & Institute, Associate Dean for Clinical & Translational Research, and Slater Family Professor of Psychiatry, Harvard Medical School said, “The approval of Auvelity represents a milestone in depression treatment based on its novel oral NMDA antagonist mechanism, its rapid antidepressant efficacy demonstrated in controlled trials, and a relatively favorable safety profile. Auvelity, which was granted Breakthrough Therapy designation by the FDA, represents the first new oral non-monoamine-based mechanism of action approved to treat major depressive disorder in over sixty years. Nearly two thirds of patients treated with currently available antidepressants do not adequately respond, and those that do may not achieve clinically meaningful responses for up to six to eight weeks. Given the debilitating nature of depression, the efficacy of Auvelity observed at one week and sustained thereafter may have a significant impact on the current treatment paradigm for this condition.”

Michael Pollock, Chief Executive Officer of the Depression and Bipolar Support Alliance (DBSA), a leading national patient advocacy organization focusing on depression and bipolar disorder said, “The mental health crisis in the United States is one of the most pressing health issues facing our country today. Over 20 million American adults experienced major depressive disorder each year prior to the COVID-19 pandemic. These numbers increased dramatically during the pandemic with approximately thirty percent of adults in the U.S. or more than 80 million Americans experiencing elevated symptoms of depression. The need for new treatment options, particularly those with new mechanisms of action, could not be clearer and more urgent for those living with, or impacted by, major depressive disorder.”

Dan V. Iosifescu, MD, Professor of Psychiatry at the New York University School of Medicine, and Director of the Clinical Research Division at the Nathan Kline Institute for Psychiatric Research said, “Major depressive disorder is disabling and potentially life-threatening, causes profound distress for patients and their families, and leads to substantial healthcare resource utilization. Auvelity’s oral NMDA receptor antagonist and sigma-1 receptor agonist activity, which targets glutamatergic neurotransmission, provides clinicians a long sought after new mechanistic approach which may benefit the millions of patients living with this serious condition. In clinical trials, Auvelity has demonstrated rapid and statistically significant improvement in depressive symptoms as early as Week 1, and increased rates of remission at Week 2 compared with placebo. This early benefit with Auvelity was maintained and increased with continued treatment, and was accompanied by a favorable safety and tolerability profile.”

Auvelity was studied in a comprehensive clinical program which included more than 1,100 patients with depression. The efficacy of Auvelity in the treatment of MDD was demonstrated in the GEMINI placebo-controlled study, and confirmatory evidence which included the ASCEND study comparing Auvelity to bupropion sustained-release tablets. In the GEMENI study, Auvelity was statistically significantly superior to placebo in improvement of depressive symptoms as measured by the change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 6, the study’s primary endpoint. To evaluate speed of onset of action, the change in MADRS total score from baseline to Week 1 and from baseline to Week 2 were pre-specified secondary efficacy endpoints. The difference between Auvelity and placebo in change from baseline in MADRS total score was statistically significant at Week 1 and at Week 2.¹ In the ASCEND study, Auvelity was statistically significantly superior to bupropion sustained-release tablets 105 mg twice daily on the primary outcome measure.⁵ The primary outcome measure of the ASCEND study was calculated by assessing the change from baseline in MADRS total scores from Week 1 to Week 6 and then taking the average of those scores.¹ In the placebo-controlled clinical study, the most common (incidence ≥5% for Auvelity and more than twice as frequently as placebo) adverse reactions were dizziness, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, and hyperhidrosis.¹

The FDA granted Breakthrough Therapy designation for Auvelity for the treatment of MDD in March 2019. This designation is granted to candidate drugs that show potential for benefit above that of available therapies based on preliminary clinical data, and it provides the sponsor with added focus from and greater interactions with FDA staff during the development of the candidate drug.⁶ The Auvelity New Drug Application (NDA) was evaluated by the FDA under Priority Review, which is granted by the FDA to applications for medicines that, if approved, would provide significant improvements in the effectiveness or safety of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications.

 

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

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

 

FDA Approves Konvomep (omeprazole and sodium bicarbonate for oral suspension) for Gastric Ulcer and Reduction of Risk of Gastrointestinal Bleeding in Critically Ill Patients

 

 

 In continuation of my update on omeprazole

Azurity Pharmaceuticals, Inc., a pharmaceutical company focused on developing innovative dose-forms and formulations of products to serve the needs of overlooked patients, announced the U.S. Food and Drug Administration (FDA)   approval of  Konvomep (omeprazole and sodium bicarbonate for oral suspension). Konvomep is approved for the treatment of active benign gastric ulcer and reduction of risk of upper gastrointestinal bleeding in critically ill patients.

“We are very pleased that patients will soon have access to this FDA-approved oral liquid formulation option of a commonly prescribed proton pump inhibitor¹,” said Richard Blackburn, CEO of Azurity Pharmaceuticals. “Patients are our priority, and our purpose is to bring them new formulations that help them benefit from established medicines. Konvomep™ may give patients, particularly patients with difficulty swallowing pills or capsules, an option for treatment tailored to their needs.”

“Patients who struggle with taking solid oral dosage forms may be overlooked and have historically had limited FDA-approved treatment options available as liquid formulations,” said Olga Hilas, PharmD, MPH, BCPS, BCGP, Professor, Clinical Health Professions, St. John’s University College of Pharmacy & Health Sciences, Queens, New York.

 

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

 

FDA Approves Sotyktu (deucravacitinib) for the Treatment of Adults with Moderate-to-Severe Plaque Psoriasis

 

Bristol Myers Squibb (NYSE: BMY)   announced   the U.S. Food and Drug Administration (FDA) approval of  Sotyktu™(deucravacitinib), a first-in-class, oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor, for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Sotyktu is not recommended for use in combination with other potent immunosuppressants.

 

 

The approval is based on results from the pivotal Phase 3 POETYK PSO-1 and POETYK PSO-2 clinical trials, which demonstrated superior efficacy of once-daily Sotyktu compared to placebo and twice-daily Otezla^® (apremilast) in 1,684 patients aged 18 years and older with moderate-to-severe plaque psoriasis.¹ The superior efficacy of Sotyktu compared to placebo and Otezla was demonstrated at both 16 and 24 weeks, and responses with Sotyktu persisted through 52 weeks. See below for more information.

“Sotyktu has the potential to become the new standard of care oral treatment for people with moderate-to-severe plaque psoriasis, given its profile in helping patients achieve clearer skin as demonstrated in the POETYK PSO clinical program,” said April Armstrong, MD, MPH, clinical investigator in the POETYK PSO-1 trial and Associate Dean and Professor of Dermatology at the University of Southern California. “People living with moderate-to-severe plaque psoriasis face significant burdens, and Sotyktu is a welcome first-line systemic treatment option.”

Psoriasis is a widely prevalent, chronic, systemic immune-mediated disease that affects approximately 7.5 million people in the U.S.³ Up to 90 percent of patients with psoriasis have plaque psoriasis, which is characterized by distinct, round or oval plaques typically covered by silvery white scales. Nearly one-quarter of people with psoriasis, or around two million in the U.S., have cases that are considered moderate-to-severe.

“The approval of Sotyktu represents an exciting day for patients suffering from moderate-to-severe plaque psoriasis who are not satisfied with topical and conventional treatments. This is another extraordinary achievement for Bristol Myers Squibb, as we bring forward a new mechanism of action, the first oral treatment approved in nearly 10 years, and the first orally dosed once-daily treatment for moderate-to-severe plaque psoriasis,” said Samit Hirawat, MD, Chief Medical Officer, Bristol Myers Squibb. “We believe Sotyktu is a breakthrough in the treatment of patients with this condition, and we’re excited about its potential in other immune-mediated diseases.”

In the POETYK PSO trials, at Week 16, the most common adverse reactions (≥1 percent and higher than placebo) in patients on Sotyktu were upper respiratory infections (19.2 percent), blood creatine phosphokinase increase (2.7 percent), herpes simplex (2.0 percent), mouth ulcers (1.9 percent), folliculitis (1.7 percent) and acne (1.4 percent).¹ In addition, 2.4 percent of patients on Sotyktu, 3.8 percent of patients on placebo, and 5.2 percent of patients on Otezla experienced adverse reactions leading to discontinuation.

“Despite the availability of therapies, many people living with plaque psoriasis in the United States are untreated or undertreated,^5,6” said Leah M. Howard, JD, President and CEO of the National Psoriasis Foundation. “The FDA approval of a new oral treatment is exciting news for the psoriasis community. We welcome this new treatment option.”

 

 

 

 

 

 

FDA Approves Sotyktu (deucravacitinib) for the Treatment of Adults with Moderate-to-Severe Plaque Psoriasis

FDA Approves Terlivaz (terlipressin) for the Treatment of Hepatorenal Syndrome (HRS)

Mallinckrodt plc (OTCMKTS: MNKPF), a global specialty pharmaceutical company,   announced  the U.S. Food and Drug Administration (FDA) approval of  Terlivaz (terlipressin) for injection. Terlivaz is the first and only FDA-approved product indicated to improve kidney function in adults with hepatorenal syndrome (HRS) with rapid reduction in kidney function, an acute and life-threatening condition requiring hospitalization.

 

 

Please see Limitation of Use and Important Safety Information, including Boxed Warning, below.

Siggi Olafsson, President and Chief Executive Officer, said, "The FDA approval of Terlivaz is a significant milestone for Mallinckrodt as it brings an important treatment option to these critically ill patients requiring hospitalization and to U.S. physicians who historically have had limited treatment interventions. We're excited to bring Terlivaz to U.S. patients and physicians and plan to launch the product in the coming weeks. This approval reflects Mallinckrodt's continued commitment to underserved patients and their caregivers through our demonstrated expertise and dedication to developing therapeutics for critical conditions."

Terlipressin is recommended by the American Association for the Study of Liver Diseases (AASLD) guidance and the American College of Gastroenterology (ACG) guidelines.*^, Terlipressin is one of the most studied pharmacological agents in HRS with more than 70 published manuscripts and presented abstracts on clinical data to date. It has been approved outside the U.S. for more than 30 years and is available on five continents for its indications in the countries where it is approved.

The FDA approval was based, in part, on results from the Phase 3 CONFIRM trial, the largest-ever prospective study (n=300) conducted to assess the safety and efficacy of terlipressin in patients with HRS type 1 (HRS-1) in the U.S. and Canada. The CONFIRM trial met its primary endpoint of Verified HRS Reversal, defined as renal function improvement, avoidance of dialysis and short-term survival (p=0.012).  To achieve Verified HRS Reversal, patients had to have two consecutive serum creatinine (SCr) values of ≤1.5 mg/dL, at least two hours apart by day 14 or hospital discharge. To be included in the primary efficacy endpoint analysis, patients had to be alive and without intervening renal replacement therapy (e.g., dialysis) at least 10 days after achieving Verified HRS Reversal. Initial results were presented in a late-breaking session at The Liver Meeting^® 2019, the annual meeting of AASLD. Results were also published in the New England Journal of Medicine in March of 2021. The CONFIRM trial was completed prior to the updated diagnostic criteria and terminology published in the 2021 AASLD guidance on hepatorenal syndrome.

Steven Romano, M.D., Executive Vice President and Chief Scientific Officer at Mallinckrodt said, "Diagnosing and treating HRS can be challenging, and every minute counts when managing patients who have it. Terlivaz gives U.S. physicians the first FDA-approved option for treating HRS patients with rapid reduction in kidney function¹ that may help them improve kidney function and lessen the associated need for renal replacement therapy, such as dialysis."

The most commonly observed adverse reactions in at least 4 percent of patients treated with Terlivaz compared to placebo were abdominal pain reported in 19.5 percent (n=39) of patients (vs. 6.1%; n=6), nausea reported in 16 percent (n=32) of patients (vs. 10.1%; n=10), respiratory failure reported in 15.5 percent (n=31) of patients (vs. 7.1%; n=7) diarrhea reported in 13 percent (n=26) of patients (vs. 7.1%; n=7) and dyspnea reported in 12.5 percent (n=25) of patients (vs. 5.1%; n=5).¹

 

FDA Approves Aponvie (aprepitant) for the Prevention of Postoperative Nausea and Vomiting (PONV)

In continuation of my update on aprepitant

 

 

 

Heron Therapeutics, Inc., a commercial-stage biotechnology company focused on improving the lives of patients by developing best-in-class treatments to address some of the most important unmet patient needs,  announced  the U.S. Food and Drug Administration (FDA)   approval of  Aponvie (aprepitant) injectable emulsion, for intravenous use for the prevention of postoperative nausea and vomiting (PONV) in adults. 

Aponvie is the first and only IV formulation of aprepitant for PONV prevention. Administered via a single 30-second IV injection, Aponvie reaches drug levels associated with ≥97% receptor occupancy in the brain within five minutes and maintains therapeutic plasma concentrations for at least 48 hours. Aponvie is provided in a single-dose vial that delivers the full 32 mg dose approved for PONV. This ready-to-use, easy to administer, innovative IV formulation ensures rapid and consistent exposure in patients undergoing surgery.

An important component of the FDA approval of Aponvie were results from two multicenter, randomized, double-blind clinical studies comparing oral aprepitant to current standard of care, IV ondansetron, for the prevention of PONV in patients during the 48 hours following open abdominal surgery demonstrating that aprepitant was more effective than ondansetron in preventing vomiting. Treatment with aprepitant resulted in approximately 50% fewer patients vomiting in the first 24 and 48 hours compared to ondansetron. In clinical studies, Aponvie was well-tolerated and presented a safety profile comparable to oral aprepitant.

In a 2020 Cochrane meta-analysis, aprepitant was ranked as the most effective drug approved for PONV prophylaxis, being the most effective for the prevention of vomiting in the first 24 hours post-surgery and the drug with the fewest adverse events.

"With the approval of Aponvie our acute care portfolio now addresses the two most common concerns of patients and clinicians after surgery, postoperative pain and postoperative nausea and vomiting. This marks an important milestone for our expanding acute care portfolio and is a testament to our ongoing commitment to developing innovative solutions to help improve the overall patient experience after surgery," said Barry Quart, Pharm.D., Chairman and Chief Executive Officer of Heron. "With approximately 36 million procedures in the U.S. each year in patients with high to moderate risk for PONV, the approval of Aponvie provides an easy to use, highly effective option for these patients that fits seamlessly into our acute care franchise."

PONV are common adverse effects of anesthesia and surgery, with an estimated 30 percent of patients receiving general anesthesia and up to 80 percent of high-risk patients experiencing these symptoms, necessitating more effective preventative agents. PONV is a major cause of patient dissatisfaction after surgery, with patients frequently ranking vomiting as the most undesirable outcome of anesthesia. Additionally, PONV presents a significant risk in outpatient surgeries as patients are often discharged within hours after surgery and no longer have access to highly effective antiemetics.

"PONV is commonly experienced after surgery and may result in increased hospital stays, prolonged recovery time, and decreased patient satisfaction" said Ashraf Habib, MBBCh, MSc, MHSc, FRCA, Chief, Division of Women's Anesthesia at Duke University Hospital. "Oral aprepitant has been used to prevent postoperative nausea and vomiting for more than 16 years and it is exciting to see that, with the approval of Aponvie, physicians can now offer patients a more convenient IV injection that delivers the same effective treatment, with a 48-hour duration of effect, in a rapid, consistent and reliable way, ensuring a better experience for patients postoperatively."
 
 

Acadia Pharmaceuticals Announces Trofinetide New Drug Application for the Treatment of Rett Syndrome has been Accepted for Filing and Review by U.S. FDA

About Rett Syndrome

Rett syndrome is a rare genetic neurodevelopmental disorder that occurs primarily in females following a near normal development in the first two years of life.  It is caused by mutations on the X chromosome on a gene called MECP2.  Occurring worldwide in approximately one of every 10,000 to 15,000 female births and in the United States impacts 6,000 to 9,000 patients.  Children with Rett syndrome experience a period of developmental regression between 18-30 months of age, which is typically followed by a plateau period lasting years to decades. Rett syndrome is diagnosed based on clinical evaluation, typically by about three years of age

A complex and multisystem disorder, Rett syndrome causes profound impairment to central nervous system (CNS) function, including loss of communication skills, purposeful hand use, gait abnormalities, and stereotypic hand movements such as hand wringing/squeezing, clapping/tapping, mouthing and washing/rubbing automatisms.   People living with Rett syndrome may also experience a range of additional symptoms, such as gastrointestinal complications, skeletal abnormalities, neuroendocrine abnormalities, disruptive and anxiety-like behaviors, as well as mood dysregulation and sleep disturbances. Currently, there are no FDA-approved medicines for the treatment of Rett syndrome.

About Trofinetide

Trofinetide is an investigational drug. It is a novel synthetic analog of the amino‐terminal tripeptide of IGF-1 designed to treat the core symptoms of Rett syndrome by potentially reducing neuroinflammation and supporting synaptic function. Trofinetide is thought to stimulate synaptic maturation and overcome the synaptic and neuronal immaturities that are characteristic of Rett syndrome pathophysiology. In the central nervous system, IGF-1 is produced by both of the major types of brain cells – neurons and glia. IGF-1 in the brain is critical for both normal development and for response to injury and disease. Trofinetide has been shown to inhibit the production of inflammatory cytokines, inhibit the overactivation of microglia and astrocytes, and increase the amount of available IGF-1 that can bind to IGF-1 receptors.

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

Acadia Pharmaceuticals Inc.  announced   the U.S. Food and Drug Administration (FDA)  acceptance  for filing its New Drug Application (NDA) of trofinetide for the treatment of Rett syndrome. The FDA has granted a priority review and assigned a PDUFA (Prescription Drug User Fee Act) action date of March 12, 2023. The FDA has also informed the company that at this time they are not planning to hold an Advisory Committee meeting.

“We’re pleased that the FDA has accepted our NDA filing and we will be working closely with them to facilitate completion of the review in a timely manner,” said Steve Davis, Acadia’s Chief Executive Officer. “If approved, trofinetide will be the first drug available for the treatment of Rett syndrome, a rare and devastating condition for patients and their families. This milestone reinforces Acadia’s ongoing commitment to advancing research into high unmet needs in disorders affecting the central nervous system.”

Rett syndrome is a complex, multisystem neurodevelopmental disorder that includes a period of normal development followed by significant developmental regression with loss of language and hand function skills, impaired gait and development of hand stereotypes.1,2 It occurs worldwide in approximately one of every 10,000 to 15,000 female births.3

“Rett is a complex disease that can present with a diverse array of symptoms. In clinical trials, trofinetide demonstrated a significant improvement in a range of Rett syndrome symptoms,” said Jeffrey L. Neul, M.D., Ph.D., Annette Schaffer Eskind Chair and Director, Vanderbilt Kennedy Center, Professor of Pediatrics, Division of Neurology, Pharmacology, and Special Education, Vanderbilt University Medical Center and Phase 3 Lavender™ study investigator. “We look forward to the FDA’s review of this submission and the prospect of having access to the first approved treatment for Rett syndrome.”

The NDA is supported by results from the pivotal Phase 3 Lavender study evaluating the efficacy and safety of trofinetide versus placebo in 187 girls and young women aged 5-20 years with Rett syndrome. The study demonstrated a statistically significant improvement over placebo on the co-primary endpoints, the Rett Syndrome Behaviour Questionnaire (RSBQ) total score change from baseline to 12 weeks (p=0.0175; effect size=0.37) and the Clinical Global Impression-Improvement (CGI-I) scale score (p=0.0030; effect size=0.47). The RSBQ is a caregiver assessment of the core symptoms of Rett syndrome, and the CGI-I is a global physician assessment of worsening or improving of Rett syndrome. In addition, the study also met its key secondary endpoint, the Communication and Symbolic Behavior Scales Developmental Profile™ Infant-Toddler Checklist–Social Composite Score (CSBS-DP-IT–Social) change from baseline to week 12 (p=0.0064; effect size=0.43), a caregiver assessment of ability to communicate.

In 2018, Acadia entered into an exclusive license agreement with Neuren Pharmaceuticals Limited (ASX: NEU) for the development and commercialization of trofinetide for the treatment of Rett syndrome and other indications in North America. In addition to receiving priority review by the FDA, trofinetide has been granted Fast Track Status and Orphan Drug Designation for the treatment of Rett syndrome in the U.S. and has been granted Rare Pediatric Disease (RPD) designation by the FDA. Upon FDA approval of a product with RPD designation, the sponsor can receive a Priority Review Voucher, which can be used to obtain priority review for a subsequent application.