Axsome Therapeutics Announces FDA Acceptance of New Drug Application for AXS-07 (meloxicam-rizatriptan) for the Acute Treatment of Migraine

 

In continuation of my update on meloxicam, 

Axsome Therapeutics, Inc.   that the U.S. Food and Drug Administration (FDA) has accepted for filing the Company’s New Drug Application (NDA) for AXS-07 for the acute treatment of migraine, and has set a Prescription Drug User Fee Act (PDUFA) target action date of April 30, 2022 for the NDA. AXS-07 (MoSEIC™ meloxicam-rizatriptan) is a novel, oral, rapidly absorbed, multi-mechanistic, investigational medicine for migraine.

  

meloxicam

 

Rizatriptan

  “The FDA’s acceptance of the NDA for AXS-07 is an important milestone for Axsome as it brings us closer to potentially making this multi-mechanistic treatment available to migraine patients in need,” said Herriot Tabuteau, MD, Chief Executive Officer of Axsome. “We look forward to continued interactions with the FDA during the review process.”

The NDA is supported by results from two Phase 3 randomized, double-blind, controlled trials of AXS-07 in the acute treatment of migraine, the MOMENTUM and INTERCEPT trials, which demonstrated statistically significant elimination of migraine pain with AXS-07 compared to placebo and active controls.

AXS-07 is a novel, oral, rapidly absorbed, multi-mechanistic investigational medicine for the acute treatment of migraine, consisting of MoSEIC™ meloxicam and rizatriptan. Meloxicam is a new molecular entity for migraine enabled by Axsome’s MoSEIC (Molecular Solubility Enhanced Inclusion Complex) technology, which results in rapid absorption of meloxicam while maintaining a long plasma half-life. Meloxicam is a COX-2 preferential non-steroidal anti-inflammatory drug and rizatriptan is a 5-HT1B/1D agonist. AXS-07 is designed to provide rapid, enhanced and consistent relief of migraine, with reduced symptom recurrence. AXS-07 is covered by more than 80 issued U.S. and international patents which provide protection out to 2036. AXS-07 is not approved by the FDA.

https://pubchem.ncbi.nlm.nih.gov/compound/Rizatriptan

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

Marinus Announces FDA Acceptance for New Drug Application for Ganaxolone in CDKL5 Deficiency Disorder

       

Marinus Pharmaceuticals, Inc.  announced  the U.S. FDA acceptance for filing the company’s New Drug Application (NDA) for the use of ganaxolone in the treatment of seizures associated with CDKL5 deficiency disorder (CDD), a rare, genetic epilepsy. The NDA was granted Priority Review designation and the FDA assigned a Prescription Drug User Fee Act (PDUFA) action date of March 20, 2022. Priority Review designation is given to an investigational medicine that, if approved, would be a significant improvement in the safety or effectiveness of the treatment of a serious condition and accelerates the timing of the FDA review of the application compared to a standard review.

“The FDA’s acceptance of our NDA submission is an important step toward potentially bringing the first approved therapy specifically for treatment of seizures associated with CDD—a devastating disorder with high unmet medical need—to families and healthcare providers,” said Scott Braunstein, M.D., Chief Executive Officer of Marinus Pharmaceuticals. “We believe that ganaxolone has the potential to provide meaningful clinical benefit for patients and we look forward to working closely with the FDA during the review process.”

Ganaxolone received orphan drug designation and Rare Pediatric Disease (RPD) designation for CDD in June 2017 and July 2020, respectively. If the NDA is approved, Marinus is eligible to receive a RPD Priority Review Voucher that may be sold or transferred.

In its acceptance letter, the FDA indicated that it is not currently planning to hold an advisory committee meeting to discuss the application.

The acceptance of the NDA for filing enables the company to draw $30 million of additional cash under its May 11, 2021 credit financing agreement with Oaktree Capital Management, L.P., subject to the satisfaction of certain customary conditions described in the credit agreement. If the NDA is approved by December 31, 2022, the company may draw an additional $30 million under the agreement, subject to the satisfaction of certain customary conditions described in the credit agreement.

The NDA is supported by data from the Marigold study, a Phase 3, double-blind placebo-controlled trial in 101 patients. Patients treated with ganaxolone showed a 30.7% median reduction in 28-day major motor seizure frequency, compared to a 6.9% reduction for those receiving placebo, achieving the trial’s primary endpoint (p=0.0036). Patients in the open-label extension study treated with ganaxolone for at least 12 months (n=48) experienced a median 49.6% reduction in major motor seizure frequency. In the Marigold trial, ganaxolone was generally well-tolerated and showed a safety profile consistent with previous clinical trials, with the most frequent adverse event being somnolence. 

Marinus has established an Expanded Access Program (EAP) (NCT04678479) for patients in the U.S. who may be eligible to receive access to ganaxolone during the review of the NDA. Additional information about Marinus’ EAP is available here.

More...

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

 

Arcutis Submits Topical Roflumilast Cream New Drug Application for the Treatment of Adults and Adolescents with Plaque Psoriasis

Arcutis Biotherapeutics, Inc. In continuation of my update on  roflumilast has submitted a new drug application (NDA) to the U.S. Food and Drug Administration (FDA) for roflumilast cream for the treatment of mild-to-severe plaque psoriasis.

 

 

Roflumilast cream (ARQ-151) is a once-daily topical formulation of roflumilast, a highly potent and selective inhibitor of phosphodiesterase type 4 (PDE4), an enzyme that drives overactive immune responses. In clinical trials, roflumilast cream demonstrated robust efficacy coupled with favorable safety and tolerability that, if approved, would enable chronic use across the body, without many of the local tolerability issues associated with alternative treatments.

“Today is a critical milestone for Arcutis in our efforts to bring innovative treatments to dermatologists and their patients, and is a reflection of our deep dermatology expertise,” said Frank Watanabe, President and CEO of Arcutis. “Individuals with plaque psoriasis currently do not have topical treatment options that offer a combination of good tolerability and the ability to be used for long periods of time, and that can be used on all parts of the body. If approved, roflumilast cream will be the first and only topical PDE4 inhibitor approved for psoriasis and an important non-steroidal treatment option for the millions of individuals struggling with plaque psoriasis. I want to thank the Arcutis team, as well as the clinical investigators, patients, and partners, for helping us reach this important milestone.”

Psoriasis is a common, non-contagious, immune-mediated skin disease that affects more than 3% of the U.S. population. The majority of patients develop “plaques,” or raised, red areas of skin covered with a silver or white layer of dead skin cells. Psoriatic plaques are often itchy and sometimes painful, and can appear on any area of the body. Plaques in certain anatomical areas present particular treatment challenges, including the face, elbows and knees, scalp, and areas where two skin areas may touch or rub together.

Topical treatments are the mainstay of therapy for the vast majority of psoriasis patients, particularly those with mild-to-moderate disease, as well as many moderate-to-severe patients who use topicals in combination with other treatments. However, existing topical treatments often force physicians and patients to make difficult trade-offs between tolerability and long-term use, requiring the use of multiple products or complicated treatment schedules. Roflumilast cream has been designed to address the challenges posed to dermatologists and patients by existing topical therapies and aims to simplify the overall management of plaque psoriasis.

Arcutis’ submission is supported by positive data from Arcutis’ pivotal Phase 3 program. The DERMIS 1 and DERMIS 2 (Trials of PDE4 inhibition with Roflumilast for the Management of plaque PsoriasIS” One and Two) were identical Phase 3 randomized, parallel, double-blind, vehicle-controlled, multi-national, multi-center studies to evaluate the safety and efficacy of roflumilast cream 0.3%. Roflumilast met its primary endpoint and had an ‘IGA Success’ rate of 42.4% compared to a vehicle rate of 6.1% (P<0.0001), and 37.5% compared to a vehicle rate of 6.9% (P<0.0001), in DERMIS 1 and 2 respectively. Roflumilast cream 0.3% also demonstrated statistically significant improvements over vehicle on key secondary endpoints, including on Intertriginous IGA (I-IGA) Success, Psoriasis Area Severity Index-75 (PASI-75), reductions in itch as measured by the Worst Itch-Numerical Rating Scale (WI-NRS), and patient perceptions of symptoms as measured by the Psoriasis Symptoms Diary (PSD). In trials, roflumilast cream was generally well-tolerated with a favorable safety and tolerability profile.

More..

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

 

Spero Therapeutics Submits New Drug Application for Tebipenem HBr for the Treatment of Complicated Urinary Tract Infections including Pyelonephritis

   

Spero Therapeutics, Inc. announced the submission of a new drug application (NDA) to the U.S. Food and Drug Administration (FDA), seeking approval for tebipenem HBr tablets for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis, caused by susceptible microorganisms. If approved, tebipenem HBr would be the only oral carbapenem antibiotic available for use in cUTI.

“With the submission of this NDA, we have taken a major step towards potentially providing a substantial number of appropriate cUTI patients with an oral treatment option that could replace historical use of intravenous (IV) therapy,” said Ankit Mahadevia, M.D., Chief Executive Officer of Spero Therapeutics. “If approved, we believe tebipenem HBr could help patients significantly, and the avoidance of IV administration could lead to reduced healthcare resource utilization. We look forward to working with the FDA during the NDA review process as we prepare for tebipenem HBr’s anticipated launch in the second half of 2022.”

The NDA submission includes previously communicated positive data from the Phase 3 ADAPT-PO trial. This data showed that ADAPT-PO met its primary endpoint by demonstrating that oral tebipenem HBr was statistically non-inferior to IV ertapenem in the treatment of patients with cUTI and patients with acute pyelonephritis (AP).

More...

https://pubchem.ncbi.nlm.nih.gov/compound/Tebipenem-pivoxil-hydrobromide

Incyte Announces Acceptance of NDA for Parsaclisib for Refractory Non-Hodgkin Lymphomas

 

 

 

Incyte (Nasdaq:INCY)  announced,  that the U.S. Food and Drug Administration (FDA) has accepted its New Drug Application (NDA) for parsaclisib, an investigational novel potent, highly selective, next-generation oral inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ), for the treatment of patients with relapsed or refractory follicular lymphoma (FL), marginal zone lymphoma (MZL) and mantle cell lymphoma (MCL).

The submission is based on data from several Phase 2 studies (CITADEL-203, -204 and -205) evaluating parsaclisib as a treatment for relapsed or refractory non-Hodgkin lymphomas (NHLs) (FL, MZL and MCL). Parsaclisib was generally well-tolerated in all studies with a manageable safety profile.

“Non-Hodgkin lymphomas are some of the most common cancers in the United States, and the FDA’s acceptance of this NDA represents an important milestone for Incyte and for NHL patients who have not responded to or who have progressed on initial therapies,” said Peter Langmuir, M.D., Group Vice President, Oncology Targeted Therapies, Incyte. “We look forward to working with the FDA to bring this innovative therapy to patients who may benefit.”

Parsaclisib has been granted Priority Review by the FDA for the treatment of adult patients with relapsed or refractory MZL who have received at least one prior anti-CD20-based regimen and for the treatment of adult patients with MCL who have received at least one prior therapy. The FDA grants Priority Review to medicines that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis or prevention of serious conditions when compared to standard applications. This designation shortens the review period by four months as compared to Standard Review so the Prescription Drug User Fee Act (PDUFA) target action date for these indications is April 30, 2022. The NDA for use of parsaclisib in adult patients with relapsed or refractory follicular lymphoma (FL) who have received at least two prior systemic therapies will have a Standard Review and a PDUFA target action date of August 30, 2022.

Confirmatory phase 3 studies are in preparation for parsaclisib in patients with MCL (CITADEL-310) and relapsed or refractory FL and MZL (CITADEL-302).

 More

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

Amylyx Pharmaceuticals Submits New Drug Application (NDA) for AMX0035 for the Treatment of ALS

 

Sodium phenylbutyrate

          

 

 

Taurursodiol

 

 

 

Amylyx Pharmaceuticals, Inc.  announced that, it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for AMX0035 (sodium phenylbutyrate (PB) and taurursodiol (TURSO; also known as ursodoxicoltaurine)) for the treatment of amyotrophic lateral sclerosis (ALS).

“We are excited to share with the ALS community the exciting milestone that we have submitted our NDA to the FDA for review,” said Justin Klee, Co-CEO, Director and Co-Founder of Amylyx. Joshua Cohen, Co-CEO, Chairman and Co-Founder of Amylyx added, “Our team has worked and continues to work around the clock as we know time is of the essence for people living with ALS and their families. We will continue to keep the community closely updated on our progress.”

“We will continue to work closely with the FDA throughout the review process to move AMX0035 toward a potential regulatory approval as quickly and efficiently as possible,” said Tammy Sarnelli, Global Head of Regulatory Affairs of Amylyx. “We are so inspired by the people who participated in CENTAUR, the trial investigators, the ALS community and our partners and team, and we will continue to work tirelessly on behalf of you all.”

The NDA submission to the FDA is based on data from the CENTAUR trial, a placebo-controlled study evaluating 137 people with ALS. In this study, participants receiving AMX0035 had statistically significant slowing of functional decline at the end of the 6-month randomized phase as measured by the Revised ALS Functional Rating Scale (ALSFRS-R), the most commonly used scale in clinics worldwide to measure function in ALS. In an interim survival analysis conducted in all randomized participants from CENTAUR who were followed for up to three years, which included participants who continued to receive AMX0035 in an open-label extension phase during the follow-up period, participants who started on AMX0035 during the placebo-controlled phase of CENTAUR showed a 44% lower risk of death compared to those who started on placebo during the placebo-controlled phase (HR 0.56; 95% CI, 0.34-0.92). Median survival duration through the open-label long-term follow-up phase was 25.0 months (95% CI, 19.0-33.6 months) in the group that started on AMX0035 and 18.5 months (95% CI, 13.5-23.2 months) in the group that started on placebo, a 6.5-month difference. Overall, reported rates of adverse events and discontinuations were substantially similar between AMX0035 and placebo groups during the 24-week randomized phase; however, gastrointestinal events occurred with greater frequency (≥2%) in the AMX0035 group. Detailed data from CENTAUR is published in the New England Journal of Medicine (NEJM) and Muscle and Nerve.

“This submission brings hope to people living with ALS and their families and caregivers,” said Merit Cudkowicz, M.D., co-principal investigator of the CENTAUR trial and co-founder of the Northeast ALS Consortium, Director of the Healey & AMG Center for ALS and Chair of Neurology at Massachusetts General Hospital and the Julieanne Dorn Professor of Neurology at Harvard Medical School. “We are honored to have led the collaboration between the Healey & AMG Center for ALS, ALS Finding a Cure, the ALS Association, and NEALS that made the CENTAUR trial a reality, the efforts and results of which made this NDA submission possible.”

“For people living with ALS and their physicians, this is a significant development offering hope of a potential new treatment option that has been shown to slow ALS disease progression and extend the time families that face this life-threatening disease have together,” said Sabrina Paganoni, M.D., Ph.D., principal investigator of the CENTAUR trial, investigator at the Healey & AMG Center for ALS at Massachusetts General Hospital and Assistant Professor of PM&R at Harvard Medical School and Spaulding Rehabilitation Hospital.

As previously reported, Amylyx filed a New Drug Submission (NDS) for AMX0035 for the treatment of ALS with Health Canada in June 2021. Amylyx also intends to submit a Marketing Authorization Application (MAA) for AMX0035 to the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) by approximately the end of 2021 and to initiate a global Phase 3 clinical trial with sites in Europe and the United States in the fourth quarter of 2021. The Phase 3 PHOENIX trial of AMX0035 for the treatment of people with ALS will assess the safety and efficacy of AMX0035 in an international population of approximately 600 participants and build upon findings from the CENTAUR trial. Amylyx is currently exploring the possibility of an Expanded Access Program (EAP) in the United States. If implemented, the EAP would run in parallel with the ongoing Phase 3 PHOENIX trial and marketing application reviews. Further information about the EAP is expected in the fourth quarter of 2021.

 More

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

https://www.kegg.jp/entry/D11836

FDA Grants Tentative Approval for Liquidia’s Yutrepia (treprostinil) Inhalation Powder

 In continuation of my update on treprostinil

 

Liquidia Corporation  announced that, the U.S. Food and Drug Administration (FDA) has granted tentative approval for Yutrepia™ (treprostinil) inhalation powder, previously referred to as LIQ861. Yutrepia is indicated for the treatment of pulmonary arterial hypertension (PAH) to improve exercise ability in adult patients with New York Heart Association (NYHA) Functional Class II-III symptoms. Tentative approval indicates that Yutrepia has met all regulatory standards for quality, safety and efficacy required for approval in the United States.

 

Dr. Tushar Shah, Chief Medical Officer of Liquidia, said: “We would like to take the opportunity to thank the patients and investigators who participated in the clinical development of Yutrepia. The tentative approval for Yutrepia is another step toward providing an important option for patients with PAH in the U.S. We believe Yutrepia can improve the limitations of current nebulized therapies by allowing the administration of an expanded dose range of inhaled treprostinil using a proven, convenient, palm-sized device.”

The addressable market for inhaled treprostinil is significant and expected to grow. In 2020, United Therapeutics reported that its nebulized formulation of treprostinil indicated for PAH achieved sales of more than $480 million. The attributes of Yutrepia including ease-of-use, convenience, direct lung delivery, and higher dosage range may not only make Yutrepia a preference to nebulized therapy, but also an alternative to oral treatments, and possibly a treatment option to delay the use of parenteral therapies in PAH. There may also be future expansion opportunities for inhaled treprostinil into additional indications.

Damian deGoa, Chief Executive Officer of Liquidia added: “This is a significant milestone for Liquidia. We are really proud of our team. Not only does the tentative approval establish the safety and efficacy of Yutrepia for PAH patients but, in the process, we have validated our proprietary PRINT® technology to engineer discrete drug particles with uniform composition, size, and shape. There is more work to be done. We will now focus our efforts on pre-commercial launch activities and the growing market opportunity for Yutrepia in PAH and potential new indications.”

Due to a regulatory stay pursuant to the Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman Act), Yutrepia cannot yet be marketed in the United States. In June 2020, United Therapeutics filed a lawsuit against Liquidia for alleged infringement of three patents related to Tyvaso®. As a result, the FDA cannot give final approval of Yutrepia until the expiration of the regulatory stay on October 27, 2022, or earlier resolution or settlement of the ongoing litigation.

About Yutrepia™(treprostinil) inhalation powder
Yutrepia is an investigational, inhaled dry powder formulation of treprostinil delivered through a proven, convenient, palm-sized device. On November 5, 2021, the FDA issued a tentative approval for Yutrepia, which is indicated for the treatment of pulmonary arterial hypertension (PAH) to improve exercise ability in adult patients with New York Heart Association (NYHA) Functional Class II-III symptoms. Yutrepia was designed using Liquidia’s PRINT® technology, which enables the development of drug particles that are precise and uniform in size, shape, and composition, and that are engineered for optimal deposition in the lung following oral inhalation. Liquidia has completed INSPIRE, or Investigation of the Safety and Pharmacology of Dry Powder Inhalation of Treprostinil, an open-label, multi-center phase 3 clinical study of Yutrepia in patients diagnosed with PAH who are naïve to inhaled treprostinil or who are transitioning from Tyvaso (nebulized treprostinil). Yutrepia was previously referred to as LIQ861 in investigational studies.

Submission of HTX-019 (aprepitant) NDA for the Prevention of Postoperative Nausea and Vomiting to FDA

 

 

 

 

Heron Therapeutics, Inc.  announced the submission of its New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for HTX-019 (aprepitant) injectable emulsion for the prevention of postoperative nausea and vomiting (PONV) in adults. HTX-019 is a proprietary intravenous (IV) formulation of aprepitant, a substance P/neurokinin-1 (NK₁) receptor antagonist (RA) that is approved for PONV prevention.

The NDA filing includes data demonstrating the bioequivalence of HTX-019 32 mg as a 30-second IV injection to oral aprepitant 40 mg, supporting its efficacy for the prevention of PONV. Results also showed HTX-019 was well-tolerated with a similar safety profile compared to oral aprepitant. Because HTX-019 is administered as an IV injection, it provides convenient, rapid, consistent, and reliable exposure in all patients and overcomes the need to take the oral formulation 1 to 3 hours before anesthesia. The HTX-019 injectable emulsion formulation intended for PONV prevention is identical to the approved CINVANTI^® (aprepitant) injectable emulsion formulation for prevention of chemotherapy-induced nausea and vomiting (CINV).

Despite advances in postoperative care, nausea and vomiting has remained a challenge for many patients undergoing surgery. There are approximately 65 million diagnostic and surgical procedures at risk of resulting in PONV in the U.S. each year. More than half of these patients are at moderate to high risk of developing PONV. Recent data has also shown that PONV can lead to increases in medical costs and delays in discharge and recovery following procedures. Aprepitant is the first and only NK₁ RA to be approved for prevention of PONV based on showing superiority to ondansetron, the current standard of care.

"In a recent Cochrane Meta-Analysis, aprepitant was found to be the most effective agent for PONV prevention with activity similar to two-drug combinations. In fact, the use of oral aprepitant has grown by almost 80% in the past three years without any promotional efforts. Our IV formulation is designed to directly deliver the active form of the drug, aprepitant, to patients over 30 seconds so it can take effect much more quickly than when taken orally," said Barry Quart, Pharm.D., Chairman and Chief Executive Officer of Heron. "The HTX-019 NDA was filed with the same FDA division that previously approved CINVANTI without delays."

"There remains an important unmet need for effective and convenient products for PONV prevention," said Ashraf Habib, MBBCh, MSc, MHSc, FRCA, Chief, Division of Women's Anesthesia at Duke University Hospital. "If approved, this innovative IV formulation of aprepitant, with rapid achievement of therapeutic drug levels, will enable physicians to provide patients with a well-established agent that effectively prevents nausea and vomiting after surgery, using a route of administration that fits well in the perioperative workflow."

About HTX-019 for PONV

HTX-019 is an IV injectable emulsion formulation designed to directly deliver aprepitant, the active ingredient in EMEND^® (aprepitant) capsules, which is the only substance P/neurokinin-1 receptor antagonist to be approved in the U.S. for the prevention of postoperative nausea and vomiting (PONV) in adults. The FDA-approved dose of oral EMEND is 40 mg for PONV prevention, which is given within 3 hours prior to induction of anesthesia for surgery. In a Phase 1 clinical trial, 32 mg of HTX-019 as a 30-second IV injection was demonstrated to be bioequivalent to oral aprepitant 40 mg. The NDA for HTX-019 for PONV was submitted in November 2021.

 More

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