Madrigal Pharmaceuticals' Rezdiffra (resmetirom, THR-β agonist) becomes the first US FDA approved drug for the treatment of NASH (MASH)

Madrigal Pharmaceuticals' Rezdiffra (resmetirom, THR-β agonist) becomes the first US FDA approved drug for the treatment of NASH (MASH) 

 

US FDA have granted accelerated approval for Rezdiffra in conjunction with diet and exercise for the treatment of adults with noncirrhotic NASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). 

 

Approval is based on Phase 3 MAESTRO-NASH trial that evaluated 80 or 100 mg of MGL-3196 vs. Placebo in pts. with NASH and Fibrosis  

 

Primary endpoints:  

• NASH resolution (including a reduction in the nonalcoholic fatty liver disease [NAFLD] activity score by ≥2 points) with no worsening of fibrosis An improvement in fibrosis by at least one stage with no worsening of the NAFLD activity score 

 

Results published in NEJM showed that NASH resolution with no worsening of fibrosis was achieved in 25.9% of the pts. in the 80-mg group and 29.9% of those in the 100-mg group vs. 9.7% of those in the placebo group  

 

Rezdiffra is expected to be available to patients in the U.S. in April and will be distributed through a limited specialty pharmacy network.  

Focus on 315,000 U.S. Patients seen by ~14K target specialists 

• Comes at an annual WAC price of $47,400.  
• Co-pay support: $10 co-pays for Commercial patients 
• Patient Assistance Program also available for pts. with no insurance or no coverage for Rezdiffra 

 

MAESTRO-NASH remains ongoing as an outcomes study designed to generate confirmatory data that, if positive, will help verify clinical benefit and may support full approval 

 

A second ongoing outcomes trial (MAESTRO-NASH OUTCOMES) is evaluating progression to liver decompensation events in patients with well-compensated NASH cirrhosis treated with Rezdiffra vs. placebo.

TAGRISSO Plus Chemotherapy Granted Priority Review in the US for Patients with EGFR-Mutated Advanced Lung Cancer

 AstraZeneca's supplemental New Drug Application (sNDA) for TAGRISSO (osimertinib) combined with chemotherapy has been accepted and granted Priority Review by the US Food and Drug Administration (FDA).

This application aims to treat adult patients with locally advanced or metastatic epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC). The Food and Drug Administration (FDA) grants Priority Review to applications for medicines that have the potential to offer significant improvements over existing options. 

This can be demonstrated through safety or efficacy enhancements, prevention of serious conditions, or improved patient compliance. The anticipated FDA action date for their regulatory decision, known as the Prescription Drug User Fee Act date, is expected during the first quarter of 2024. 

 Each year, approximately 2.2 million people diagnosed with lung cancer globally Out of these, about 70% are diagnosed with advanced NSCLC. In the US and Europe, approximately 10-15% of NSCLC patients 

The basis for the sNDA lies in data from the FLAURA2 Phase III trial, which was presented at the International Association for the Study of Lung Cancer (IASLC) 2023 World Conference on Lung Cancer (WCLC) in a Presidential Symposium. 

In this trial, combining TAGRISSO with chemotherapy demonstrated a 38% reduction in the risk of disease progression or death Median progression-free survival (PFS) was extended by 8.8 months according to investigator assessment. 

Results from blinded independent central review showed a 9.5-month extension in median PFS. The combination showed a clinically meaningful PFS benefit across various subgroups, including patients with central nervous system metastasis 

The trial continues to assess overall survival (OS) as a key secondary endpoint. Regarding safety, the combination of TAGRISSO plus chemotherapy had a generally manageable profile consistent with the established profiles of the individual medicines. 

Adverse event rates were higher in the combination arm due to known chemotherapy-related adverse events. 

In August 2023, TAGRISSO in combination with chemotherapy received Breakthrough Therapy Designation by the FDA for the 1st-line treatment of adult patients with locally advanced or metastatic EGFRm NSCLC. TAGRISSO is already approved as monotherapy in over 100 countries, including the US, EU, China, and Japan, for various indications related to EGFRm NSCLC

Pfizer's VELSIPITY Granted FDA Approval for Moderate to Severe Active Ulcerative Colitis in Adults

Pfizer has received the green light from the U.S. Food and Drug Administration (FDA) for VELSIPITY, also known as etrasimod, an oral medication that is taken once daily and selectively modulates the sphingosine-1-phosphate (S1P) receptor.

 This approval is specifically for adults who are dealing with moderately to severely active ulcerative colitis (UC), a chronic and often disabling condition affecting an estimated 1.25 million individuals in the United States. 

The recommended dose for 2 mg Symptoms of UC can be distressing and encompass chronic diarrhea with blood and mucus, abdominal pain, and a compelling sense of urgency, and the impact goes beyond the physical aspect due to the chronic and unpredictable nature of the symptoms. 

 The FDA approval was grounded on the promising outcomes of the ELEVATE UC Phase 3 registrational program, specifically the ELEVATE UC 52 and ELEVATE UC 12 trials. These trials evaluated the safety and efficacy of VELSIPITY 2 mg once daily in inducing clinical remission among UC patients who had previously failed or were intolerant to at least one conventional treatment, biologic, or Janus kinase (JAK) inhibitor therapy. Notably, a significant proportion of patients in these trials were treatment-naïve to biologic or JAK inhibitor therapy. 

The studies achieved all primary and key secondary efficacy endpoints, while maintaining a safety profile consistent with previous VELSIPITY studies. 

 In the ELEVATE UC 52 trial, patients treated with VELSIPITY demonstrated a substantial increase in clinical remission rates compared to those on placebo at both week 12 and week 52. at both week 12 and week 52 Similarly, in the ELEVATE UC 12 trial, a noteworthy proportion of patients on VELSIPITY achieved clinical remission compared to the placebo group at week 12. These findings, along with positive outcomes in key secondary endpoints like endoscopic improvement and mucosal healing, substantiated the efficacy of VELSIPITY in treating UC. VELSIPITY represents a significant advancement as a once-daily, oral medication that selectively binds with specific S1P receptor subtypes. 

Regulatory applications for VELSIPITY's approval in treating ulcerative colitis have been submitted in various countries worldwide, including Canada, Australia, Mexico, Russia, Switzerland, and Singapore. The European Medicines Agency (EMA) has accepted the Marketing Authorization Application (MAA) for VELSIPITY, and a decision from EMA is expected in the early months of 2024. 

The pivotal ELEVATE UC 52 trial was designed with a 12-week induction period followed by a 40-week maintenance period, employing a randomized, double-blind, placebo-controlled approach. The primary goal was to assess the safety and efficacy of etrasimod 2 mg once daily on clinical remission after both 12 and 52 weeks. The trial demonstrated significant improvements in primary and key secondary endpoints, including endoscopic improvement and mucosal healing. 

 Similarly, the ELEVATE UC 12 trial, which was also randomized and placebo-controlled, focused on assessing the efficacy and safety of etrasimod 2 mg once daily in subjects with moderately to severely active UC. The trial achieved its primary objective, showcasing a noteworthy proportion of patients achieving clinical remission with etrasimod compared to the placebo group at week 12 at week 12 

Importantly, the safety profile of VELSIPITY was consistent across both trials, with common adverse reactions being manageable and not unexpected. These trials affirm that initiating VELSIPITY treatment does not necessitate a complex up-titration regimen, enhancing its practicality and ease of use for patients

FDA approves encorafenib with binimetinib for metastatic non-small cell lung cancer with a BRAF V600E mutation

On October 11, 2023, the Food and Drug Administration (FDA) granted approval for the use of encorafenib (Braftovi, developed by Array BioPharma Inc., a subsidiary of Pfizer) in combination with binimetinib (Mektovi, also by Array BioPharma Inc.) for adult patients dealing with metastatic non-small cell lung cancer (NSCLC) characterized by a BRAF V600E mutation, as confirmed by an FDA-endorsed diagnostic test.

In conjunction with this approval, the FDA also sanctioned the utilization of FoundationOne CDx (tissue) and FoundationOne Liquid CDx (plasma) as companion diagnostics for encorafenib with binimetinib. It was emphasized that in cases where no mutation is detected in a plasma sample, a test should be conducted on tumor tissue.

The assessment of efficacy encompassed 98 patients grappling with metastatic NSCLC and possessing the BRAF V600E mutation. These patients were enrolled in the PHAROS study (NCT03915951), which was an open-label, multicenter, single-arm study. Notably, patients were not allowed to have had prior exposure to BRAF or MEK inhibitors. Patients received a regimen of encorafenib and binimetinib until either their disease progressed or they experienced unacceptable levels of toxicity.

The primary efficacy outcomes were gauged by the objective response rate (ORR) per RECIST v1.1 and the duration of response (DoR), as evaluated by an independent review committee. Out of 59 patients who were new to treatment, an ORR of 75% was observed (95% CI: 62, 85), with an indeterminate median DoR (NE) (95% CI: 23.1, NE). Among the 39 patients who had previously undergone treatment, an ORR of 46% was noted (95% CI: 30, 63) along with a median DoR of 16.7 months (95% CI: 7.4, NE).

The adverse reactions most frequently reported (≥25%) were fatigue, nausea, diarrhea, musculoskeletal pain, vomiting, abdominal pain, visual impairment, constipation, dyspnea, rash, and cough.

In terms of recommended doses for NSCLC patients positive for the BRAF V600E mutation, the guidance stipulates an oral administration of encorafenib at 450 mg once daily and binimetinib at 45 mg orally twice daily.

This comprehensive review of the application incorporated the Assessment Aid, a voluntary submission from the applicant intended to streamline the FDA's evaluation. Additionally, the application was granted orphan drug designation, underlining the significance and unique status of this therapeutic approach.

Vertex Announces U.S. FDA Approval for KALYDECO (ivacaftor) to Treat Eligible Infants With CF Ages 1 Month and Older

On 3 May 2023, Vertex Pharmaceuticals have announced the U.S.Food and Drug Administration (FDA) approved KALYDECO (ivacaftor) for use in children with cystic fibrosis (CF) ages 1 month to less than four months old who have at least one mutation in their cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to KALYDECO based on clinical and/or in vitro assay data.

KALYDECO is already approved in the U.S. and EU for the treatment of CF in patients ages four months and older.

The approval was supported by a cohort in the Phase 3, 24-week, open-label study to evaluate the safety, pharmacokinetics and pharmacodynamics of ivacaftor in subjects with CF who are less than 24 months of age and have an ivacaftor-responsive CFTR mutation.

This cohort demonstrated a safety profile similar to that observed in older children and adults.

FDA programs to expedite drug development

 The FDA has several programs aimed at streamlining and accelerating the development and review of new drugs for the treatment of serious or life-threatening conditions, particularly where there is an unmet medical need.

These expedited programs ensure that treatments for such conditions are available as soon as possible, provided that the benefits of the therapy outweigh its risks, taking into account the severity of the condition and availability of other treatment options.

The programs include:

breakthrough therapy designation,

fast track designation,

accelerated approval, and

priority review

 

Fast Track Designation

Fast track designation is a program designed to accelerate the development and review of drugs that address serious medical conditions with an unmet need.

The designation may be granted based on preclinical data. Sponsors of drugs that receive fast track designation can expect more frequent interactions with the FDA during the drug development process.

Additionally, drugs that have received fast track designation can benefit from rolling review, allowing for the submission of completed sections of the New Drug Application (NDA) on a rolling basis rather than waiting for the entire application to be completed before submission.

 

Accelerated Approval

Accelerated approval program expedites the development and approval of drugs for serious or life-threatening conditions

Allows approval of drugs that show an effect on surrogate or clinical endpoints that can predict clinical benefit

Useful when disease course is lengthy and takes time to measure clinical benefit

Post-marketing trials may be required to confirm clinical benefit, and approval may be withdrawn if trials fail to verify predicted benefit

 

Priority Review

The Program applies to new molecular entity NDAs and original BLAs submitted from Oct 1, 2012, through Sep 30, 2017, including resubmissions following Refuse-to-File actions

For applications filed under the Program, the PDUFA review clock begins after the 60-day filing review period that starts from FDA receipt of the original submission

Any drug, including those with other designations like fast track or breakthrough therapy, can be granted priority review if relevant criteria are met

 

Differences between the criteria for breakthrough therapy designation and fast track designation?

Breakthrough therapy and fast track designation programs aim to accelerate drug development and review for serious or life-threatening conditions.

A breakthrough therapy designation requires preliminary clinical evidence that the drug can substantially improve a significant clinical endpoint over available therapies, while a fast track designation requires nonclinical or clinical data demonstrating the potential to address unmet medical needs for the serious condition.

FDA Approves First Respiratory Syncytial Virus (RSV) Vaccine - Arexvy from GSK

On 3 May 2023, the U.S. Food and Drug Administration approved Arexvy, the first respiratory syncytial virus (RSV) vaccine approved for use in the United States.

Arexvy is approved for the prevention of lower respiratory tract disease caused by RSV in individuals 60 years of age and older.

RSV is a highly contagious virus that causes infections of the lungs and breathing passages in individuals of all age groups.

RSV circulation is seasonal, typically starting during the fall and peaking in the winter.

In older adults, RSV is a common cause of lower respiratory tract disease (LRTD), which affects the lungs and can cause life-threatening pneumonia and bronchiolitis (swelling of the small airway passages in the lungs).

According to the U.S.Centers for Disease Control and Prevention, each year in the U.S., RSV leads to approximately 60,000-120,000 hospitalizations and 6,000-10,000 deaths among adults 65 years of age and older.

The safety and effectiveness of Arexvy is based on the FDA’s analysis of data from an ongoing, randomized, placebo-controlled clinical study conducted in the U.S. and internationally in individuals 60 years of age and older.

The main clinical study of Arexvy was designed to assess the safety and effectiveness of a single dose administered to individuals 60 years of age and older.

Participants will remain in the study through three RSV seasons to assess the duration of effectiveness and the safety and effectiveness of repeat vaccination.

Data for a single dose of Arexvy from the first RSV season of the study were available for the FDA’s analysis.

In this study, approximately 12,500 participants have received Arexvy and 12,500 participants have received a placebo.

Among the participants who have received Arexvy and the participants who have received a placebo, the vaccine significantly reduced the risk of developing RSV-associated LRTD by 82.6% and reduced the risk of developing severe RSV-associated LRTD by 94.1%.

Among a subset of these clinical trial participants, the most commonly reported side effects by individuals who received Arexvy were injection site pain, fatigue, muscle pain, headache and joint stiffness/pain.

Among all clinical trial participants, atrial fibrillation within 30 days of vaccination was reported in 10 participants who received Arexvy and 4 participants who received placebo.

The FDA is requiring the company to conduct a postmarketing study to assess the signals of serious risks for Guillain-Barré syndrome and ADEM.

In addition, although not an FDA requirement, the company has committed to assess atrial fibrillation in the postmarketing study