FDA Approves Daybue (trofinetide) for the Treatment of Rett Syndrome

In continuation of my update on trofinetide

Acadia Pharmaceuticals Inc. (Nasdaq: ACAD)  announced  the U.S. Food and Drug Administration (FDA)  approval of  Daybue (trofinetide) for the treatment of Rett syndrome in adult and pediatric patients two years of age and older. Daybue is the first and only drug approved for the treatment of Rett syndrome.

“Today marks an important milestone for the Rett community and Acadia. As the first FDA-approved drug for the treatment of Rett syndrome, Daybue now offers the potential to make meaningful differences in the lives of patients and their families who have lacked options to treat the diverse and debilitating array of symptoms caused by Rett syndrome,” said Steve Davis, Acadia’s Chief Executive Officer. “We are grateful to all of the Rett syndrome patients, caregivers, clinical investigators and our employees who have contributed to making today a reality and look forward to getting Daybue to patients as quickly as possible.”

“Rett syndrome is a profoundly debilitating and complex, rare, neurodevelopmental disorder that presents differently across patients and can lead to an array of unpredictable symptoms throughout the course of a patient’s life,” 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. “Now, for the first time after decades of clinical research, healthcare providers finally have a treatment option to address a range of core behavioral, communication and physical symptoms for their patients living with Rett syndrome.”

Rett syndrome is a complex, rare, neurodevelopmental disorder typically caused by a genetic mutation on the MECP2 gene.2,3 It is characterized by a period of normal development until six to 18 months of age, followed by significant developmental regression with loss of acquired communication skills and purposeful hand use. Symptoms of Rett syndrome may also include development of hand stereotypies, such as hand wringing and clapping, and gait abnormalities. Rett syndrome is believed to affect 6,000 to 9,000 patients in the U.S., with a diagnosed population of approximately 4,500 U.S. patients.

The FDA approval of Daybue was supported by results from the pivotal Phase 3 LAVENDER study evaluating the efficacy and safety of trofinetide versus placebo in 187 female patients with Rett syndrome five to 20 years of age. In the study, treatment with Daybue demonstrated statistically significant improvement compared to placebo on both co-primary efficacy endpoints, as measured by the change from baseline in Rett Syndrome Behaviour Questionnaire (RSBQ) total score (p=0.018) and the Clinical Global Impression-Improvement (CGI-I) scale score (p=0.003) at week 12. The RSBQ is a caregiver assessment that evaluates a range of symptoms of Rett syndrome including vocalizations, facial expressions, eye gaze, hand movements (or stereotypies), repetitive behaviors, breathing, night-time behaviors and mood. The CGI-I is a global physician assessment of whether a patient has improved or worsened. In the study, the most common side effects were diarrhea (82%) and vomiting (29%).

“This is a historic day for the Rett syndrome community and a meaningful moment for the patients and caregivers who have eagerly awaited the arrival of an approved treatment for this condition,” said Melissa Kennedy, Chief Executive Officer of the International Rett Syndrome Foundation. “Rett syndrome is a complicated, devastating disease that affects not only the individual patient, but whole families. With today’s FDA decision, those impacted by Rett have a promising new treatment option that has demonstrated benefit across a variety of Rett symptoms, including those that impact the daily lives of those living with Rett and their loved ones.”

FDA Approves Daybue (trofinetide) for the Treatment of Rett Syndrome

FDA Approves Zavzpret (zavegepant) Nasal Spray for the Acute Treatment of Migraine

Pfizer Inc. (NYSE: PFE)  announced the U.S. Food and Drug Administration (FDA)  approval of Zavzpret (zavegepant), the first and only calcitonin gene-related peptide (CGRP) receptor antagonist nasal spray for the acute treatment of migraine with or without aura in adults. In its pivotal Phase 3 study, Zavzpret was statistically superior to placebo on the co-primary endpoints of pain freedom and freedom from most bothersome symptom at two hours post-dose. The pivotal study also demonstrated pain relief as early as 15 minutes in a prespecified secondary endpoint versus placebo.

“The FDA approval of Zavzpret marks a significant breakthrough for people with migraine who need freedom from pain and prefer alternative options to oral medications,” said Angela Hwang, Chief Commercial Officer, President, Global Biopharmaceuticals Business, Pfizer. “Zavzpret underscores Pfizer’s commitment to delivering an additional treatment option to help people with migraine gain relief and get back to their daily lives. Pfizer will continue to build its migraine franchise to further support the billions of people worldwide impacted by this debilitating disease.”

The FDA approval is based on two pivotal randomized, double-blind, placebo-controlled studies that established the efficacy, tolerability and safety profiles of Zavzpret for the acute treatment of migraine. In these studies, Zavzpret was statistically superior to placebo on the co-primary endpoints of pain freedom (defined as a reduction of moderate or severe headache pain to no headache pain) and freedom from most bothersome symptom at two hours post-dose (defined as the absence of the self-identified most bothersome symptom). The pivotal Phase 3 study published in The Lancet Neurology found Zavzpret showed broad efficacy by also demonstrating statistically significant superiority to placebo across 13 of 17 prespecified secondary outcome measures, including early time point endpoints (e.g., 15 and 30-minute pain relief and return to normal function at 30 minutes), return to normal function at 2 hours, and durable efficacy endpoints (e.g., 2-24 and 2-48 hour sustained pain freedom and sustained pain relief). On the 14th endpoint, return to normal function at 15 minutes post-dose, the difference between Zavzpret and placebo was not significant. Consequently, in keeping with the trial’s statistical analysis plan, the remaining secondary endpoints were not formally tested.

“When a migraine hits, it has a significant negative impact on a person’s daily life,” said Kathleen Mullin, M.D., Associate Medical Director at New England Institute for Neurology & Headache. “Among my migraine patients, one of the most important attributes of an acute treatment option is how quickly it works. As a nasal spray with rapid drug absorption, Zavzpret offers an alternative treatment option for people who need pain relief or cannot take oral medications due to nausea or vomiting, so they can get back to normal function quickly.”

Zavzpret was well tolerated in clinical trials. The most common adverse reactions reported in at least 2% of patients treated with Zavzpret and at a frequency greater than placebo were taste disorders (includes dysgeusia and ageusia), nausea, nasal discomfort and vomiting. Zavzpret is contraindicated in patients with a history of hypersensitivity to zavegepant or to any of its components. Hypersensitivity reactions, including facial swelling and urticaria, have occurred with Zavzpret in clinical studies. 

 https://en.wikipedia.org/wiki/Zavegepant#/media/File:Zavegepant.svg

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

FDA Approves Zavzpret (zavegepant) Nasal Spray for the Acute Treatment of Migraine

FDA Approves Skyclarys (omaveloxolone) for the Treatment of Friedreich’s Ataxia

In continuation of my update on omaveloxolone

Reata Pharmaceuticals, Inc. (Nasdaq: RETA) announced   the U.S. Food and Drug Administration (“FDA”) approval of  Skyclarys™ (omaveloxolone) for the treatment of Friedreich’s ataxia in adults and adolescents aged 16 years and older. With this approval, the FDA granted a rare pediatric disease priority review voucher.

"The approval of Skyclarys, the first therapy specifically indicated for the treatment of Friedreich’s ataxia, is an important milestone for patients affected by this disease as well as their families and caregivers," said Warren Huff, Reata's Chief Executive Officer. "We are grateful to Friedreich’s ataxia patients, investigators, U.S. regulators, and our scientists and employees who made this approval possible. As a company, this is a transformative milestone that highlights our commitment to developing and commercializing novel therapies for patients with severe diseases with few or no approved therapies. We look forward to delivering Skyclarys to eligible patients as quickly as possible."

Friedreich’s ataxia is an ultra-rare, inherited neurodegenerative disorder that is typically diagnosed during adolescence. Patients with Friedreich’s ataxia experience progressive loss of coordination, muscle weakness, and fatigue, which commonly progresses to motor incapacitation and wheelchair reliance by their teens or early twenties, and eventually death. Friedreich’s ataxia affects approximately 5,000 diagnosed patients in the U.S.

“Friedreich's ataxia is a debilitating neuromuscular disease that progressively robs patients of their mobility and independence,” said Susan Perlman, MD, Clinical Professor, Department of Neurology, David Geffen School of Medicine, UCLA. “The approval of Skyclarys represents an important step forward in the treatment of Friedreich's ataxia, providing physicians with the first disease-specific treatment option approved for patients living with this ultra-rare and progressive disease.”

"Today’s approval of Skyclarys represents a significant milestone in our effort to advance research and achieve treatments for Friedreich’s ataxia," said Jen Farmer, Chief Executive Officer at Friedreich's Ataxia Research Alliance. "The entire Friedreich's ataxia community including patients, clinicians, scientists, pharmaceutical companies, government agencies, and others have worked collaboratively for decades to enable therapeutic development for this debilitating disease. Today, we celebrate the impact of an engaged patient community, and we are grateful to the FDA and Reata for working together on the approval of Skyclarys, the first therapy approved in the United States for adult and adolescent patients aged 16 years and older with Friedreich's ataxia.”

The approval of Skyclarys is supported by the efficacy and safety data from the MOXIe Part 2 trial and a post hoc Propensity-Matched Analysis of the open-label MOXIe Extension trial.

MOXIe Part 2 was a randomized, double-blind, placebo-controlled study. Patients with genetically confirmed Friedreich’s ataxia and baseline modified Friedreich’s Ataxia Rating Scale (“mFARS”) scores between 20 and 80 were randomized 1:1 to receive placebo or 150 mg of Skyclarys daily. The primary endpoint was change from baseline in mFARS score compared to placebo at Week 48 in the Full Analysis Population of patients without severe pes cavus (n=82). The mFARS is a clinical assessment tool to assess patient function and is used in clinical trials to assess the efficacy of investigational products for use in Friedreich’s ataxia. Treatment with Skyclarys resulted in statistically significant lower mFARS scores (less impairment) relative to placebo at Week 48. The placebo-corrected difference between the two groups was -2.41 points with a p-value of 0.0138. The most common adverse reactions in MOXIe Part 2 (≥20% and greater than placebo) were elevated liver enzymes (AST/ALT), headache, nausea, abdominal pain, fatigue, diarrhea, and musculoskeletal pain.

Further, in a post hoc Propensity-Matched Analysis, mFARS progression of patients treated with 150 mg of Skyclarys daily in the open-label MOXIe Extension trial was compared to the progression of propensity score-matched untreated patients in the largest natural history study of Friedreich’s ataxia, Clinical Outcome Measures in Friedreich’s ataxia (“FA-COMS”). All patients enrolled in the MOXIe Extension study with at least one post-baseline assessment (n=136) were matched one to one with patients from the FA-COMS study (n=136). Lower (improved) mFARS scores were observed in patients treated with Skyclarys after 3 years relative to the matched set of untreated patients from the FA-COMS natural history study. These exploratory analyses should be interpreted cautiously given the limitations of data collected outside of a controlled study, which may be subject to confounding.

FDA Approves Skyclarys (omaveloxolone) for the Treatment of Friedreich’s Ataxia

FDA Approves Rezzayo (rezafungin for injection) for the Treatment of Candidemia and Invasive Candidiasis

In continuation of my update on rezafungin

Cidara Therapeutics, Inc.   and Melinta Therapeutics, LLC  announced   the U.S. Food and Drug Administration (FDA) approval of  Rezzayo (rezafungin for injection) for the treatment of candidemia and invasive candidiasis in adults with limited or no alternative treatment options. Rezzayo is the first new treatment option approved for patients with candidemia and invasive candidiasis in over a decade.

“The FDA approval of Rezzayo represents a significant milestone for Cidara, and for patients confronted with difficult-to-treat and often deadly candidemia and invasive candidiasis,” said Jeffrey Stein, Ph.D., president and chief executive officer of Cidara. “I am extremely proud of all of the Cidara employees who collectively advanced Rezzayo from preclinical development to NDA approval and am grateful to the many patients and healthcare teams who have participated in the clinical studies.”

George Thompson, M.D., principal investigator in the ReSTORE trial and professor of clinical medicine at the University of California, Davis, School of Medicine, added, “The FDA approval of Rezzayo is tremendous news for those of us who have been hoping for a new option to treat our patients with these deadly fungal infections. Based on the totality of clinical data generated, Rezzayo has the potential to simplify the management of invasive candidiasis and enhance the continuity of echinocandin care.”

The FDA approval of once-weekly Rezzayo was based on clinical data from Cidara’s global ReSTORE Phase 3 trial and supported by the STRIVE Phase 2 clinical trial and extensive non-clinical development program. In clinical studies, Rezzayo, dosed once-weekly, met the FDA and EMA primary endpoints, demonstrating statistical non-inferiority versus caspofungin, a current once-daily standard of care. In addition, overall rates of adverse events and serious adverse events were comparable in patients receiving Rezzayo and caspofungin, while rates of adverse events leading to study drug discontinuation were also similar for Rezzayo and caspofungin. Based on Qualified Infectious Disease Product (QIDP) designation, Rezzayo was approved under Priority Review.

Christine Ann Miller, president and chief executive officer of Melinta Therapeutics, added, “We are thrilled that the FDA has approved Rezzayo, and are firmly committed to offering this innovative therapy to address unmet medical needs and simplify the treatment for patients suffering from invasive Candida infections. We intend to leverage our expansive commercial infrastructure and experience launching anti-infective drugs into acute care settings. We are working closely with Cidara and anticipate bringing Rezzayo, a differentiated once-weekly treatment to patients, this summer.”

Last year, Melinta announced that it had acquired the exclusive rights to commercialize Rezzayo in the U.S. from Cidara. Cidara retains the rights to rezafungin in Japan and has licensed the commercial rights to Melinta Therapeutics in the U.S. and Mundipharma in all other geographies. The European Medicines Agency (EMA) accepted the marketing authorization application (MAA) for rezafungin in August 2022 and it is currently under review.

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

FDA Approves Rezzayo (rezafungin for injection) for the Treatment of Candidemia and Invasive Candidiasis

FDA Approves Brenzavvy (bexagliflozin) for the Treatment of Adults with Type 2 Diabetes

TheracosBio  announced  the U.S. Food and Drug Administration (FDA)   approval of  Brenzavvy (bexagliflozin), an oral sodium-glucose cotransporter 2 (SGLT2) inhibitor. Brenzavvy is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Brenzavvy is not recommended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Brenzavvy is contraindicated in patients who are hypersensitive to bexagliflozin or any tablet ingredient and is not indicated for the treatment of type 2 diabetes in patients with end stage renal disease or who are receiving dialysis.

The FDA approval is based on results from a clinical program that evaluated the safety and efficacy of Brenzavvy in 23 clinical trials enrolling more than 5,000 adults with type 2 diabetes mellitus. Phase 3 studies showed Brenzavvy significantly reduced hemoglobin A1c and fasting blood sugar after 24 weeks, either as a monotherapy, in combination with metformin, or as an add-on to standard-of-care treatment consisting of a variety of regimens, including metformin, sulfonylureas, insulin, DPP4 inhibitors, or combinations of these agents. Although Brenzavvy is not approved for weight or blood pressure reduction, modest decreases in both weight and systolic blood pressure have been observed in the clinical program.

“As a class of drugs, SGLT2 inhibitors have shown tremendous benefit in treating adults with type 2 diabetes,” said Dr. Mason Freeman, M.D., Director of the Translational Research Center at Massachusetts General Hospital. “Being involved in all of the clinical trials for Brenzavvy, I am greatly impressed with the efficacy of the drug in reducing blood glucose levels and I believe it is an important addition to the SGLT2 inhibitor class of drugs.”

Brenzavvy treatment can be initiated in adults with type 2 diabetes with an estimated glomerular filtration rate (eGFR) greater than 30 mL/min/1.73 m2. Patients with eGFR less than 60 and greater than 30 mL/min/1.73 m2 are said to be in stage 3 chronic kidney disease, and for these patients metformin is often avoided due to the risk of lactic acidosis.

“Today's FDA approval represents a significant milestone for TheracosBio and provides an important treatment option to patients who suffer from type 2 diabetes. We look forward to bringing Brenzavvy to market,” said Albert R. Collinson, Ph.D., President and CEO of TheracosBio. “The approval of the Brenzavvy NDA is a result of the tireless work of the TheracosBio team and investigators. I want to thank all of the patients who took part in our clinical trials.”

According to the U.S. Centers for Disease Control and Prevention, more than 33 million Americans have type 2 diabetes, which means their bodies don’t use insulin correctly and as a result their blood sugar levels are too high. While some people can control their blood sugar levels with exercise and a healthy diet, others may need additional help to achieve good blood sugar (glycemic) control.

SGLT2 inhibitors are a class of prescription medicines that lower blood sugar by causing the kidneys to remove sugar from the body through urine.

Brenzavvy is available as 20 mg oral tablets recommended to be taken once daily, in the morning with or without food.

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

FDA Approves Brenzavvy (bexagliflozin) for the Treatment of Adults with Type 2 Diabetes

FDA Approves Jaypirca (pirtobrutinib) for Adult Patients with Relapsed or Refractory Mantle Cell Lymphoma

Loxo@Lilly, the oncology unit of Eli Lilly and Company (NYSE: LLY),  announced the U.S. Food and Drug Administration (FDA) approved Jaypirca™ (pirtobrutinib, 100 mg & 50 mg tablets) for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a Bruton's tyrosine kinase (BTK) inhibitor. Jaypirca was approved under the FDA's Accelerated Approval pathway based on response rate from the open-label, single-arm, international, Phase 1/2 study, called the BRUIN trial.1 Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Jaypirca, a highly selective kinase inhibitor, utilizes a novel binding mechanism and is the first and only FDA approved non-covalent (reversible) BTK inhibitor. Jaypirca can reestablish BTK inhibition in MCL patients previously treated with a covalent BTK inhibitor (ibrutinib, acalabrutinib, or zanubrutinib) and extend the benefit of targeting the BTK pathway.

"The approval of Jaypirca represents an important advance for patients with relapsed or refractory MCL, who currently have limited options and historically have had a poor prognosis following discontinuation of treatment with a covalent BTK inhibitor," said Michael Wang, M.D., Puddin Clarke Endowed Professor of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center. "These data indicate that Jaypirca can provide efficacy in patients previously treated with a covalent BTK inhibitor, potentially extending the time patients may benefit from BTK inhibition therapy. Jaypirca offers a new approach to targeting the BTK pathway following treatment with a covalent BTK inhibitor and has the potential to meaningfully impact the treatment paradigm for relapsed and refractory MCL patients."

The labeling for Jaypirca contains warnings and precautions for infections, hemorrhage, cytopenias, atrial fibrillation and flutter, second primary malignancies, and embryo-fetal toxicity. See Important Safety Information below and full Prescribing Information for additional information, including dosing modifications.

"We are pleased to bring a meaningful new therapeutic option to patients with MCL that can reestablish the benefit of targeting the BTK pathway after receiving multiple prior therapies, including a covalent BTK inhibitor," said Jacob Van Naarden, chief executive officer, Loxo@Lilly. "We are grateful to the patients, investigators, and other members of the clinical care teams for their contributions. Our team has been committed to rapidly advancing the development of Jaypirca for patients with MCL, and we look forward to building on this milestone by continuing to bring forward important new treatments for people with hematologic malignancies."

The FDA approval is based on data from a subset of patients in the BRUIN Phase 1/2 trial. The assessment of efficacy was based on 120 patients with MCL treated with Jaypirca 200 mg once daily until disease progression or unacceptable toxicity. Patients with active central nervous system lymphoma or allogeneic hematopoietic stem cell transplantation or CAR T-cell therapy within 60 days were excluded. Patients had received a median of three prior lines of therapy (range: 1 to 9), with 93% having two or more prior lines; all patients received one or more prior lines of therapy containing a covalent BTK inhibitor. Eighty-three percent (83%) of patients discontinued their last BTK inhibitor due to refractory or progressive disease. Efficacy was based on overall response rate (ORR) and duration of response (DOR) as assessed by an independent review committee (IRC) using 2014 Lugano criteria.

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https://en.wikipedia.org/wiki/Pirtobrutinib#/media/File:Pirtobrutinib.svg

FDA Approves Jaypirca (pirtobrutinib) for Adult Patients with Relapsed or Refractory Mantle Cell Lymphoma