▎Edited by the WuXi AppTec content team

According to the anticipated PDUFA goal date, the U.S. FDA is expected to make regulatory decisions on the approval of eight innovative drugs in April. This article will provide relevant introductions to these therapies.

Active Ingredient：Ceftobiprole

Indications：Staphylococcus aureus bacteremia,Acute Bacterial Skin and Skin Structure Infections,Community-Acquired Bacterial Pneumonia

Company Name：Basilea Pharmaceutica

Ceftobiprole is a new-generation cephalosporin antibiotic administered intravenously, which can rapidly kill a variety of Gram-positive bacteria (such as Staphylococcus aureus, including methicillin-resistant strains) and Gram-negative bacteria.It has been approved for marketing in Europe and China. The US FDA has granted it Qualified Infectious Disease Product (QIDP) designation.

In October 2023, Basilea Pharmaceutica announced that the U.S. FDA had accepted its New Drug Application (NDA) for ceftobiprole, intended for the treatment of three indications: Staphylococcus aureus bacteremia (SAB), acute bacterial skin and skin structure infections (ABSSSI), and community-acquired bacterial pneumonia (CABP). The FDA is expected to make a review decision by April 3.

This application is supported by data from three Phase 3 clinical trials: ERADICATE for the treatment of SAB, TARGET for the treatment of ABSSSI, and a Phase 3 clinical trial for the treatment of CABP.CEftobiprole met the non-inferiority criteria compared to the active control group in the trial.

▲Ceftobiprole Molecular Structure (Image Source: PubChem)

Active Ingredient：Anktiva

Indications：Non-Muscle-Invasive Bladder Cancer with Poor Response to BCG

Company Name：ImmunityBio

Anktiva is an interleukin-15 (IL-15) superagonist.IL-15 plays a crucial role in the immune system by influencing the development, maintenance, and function of natural killer (NK) cells and T cells. Anktiva consists of an IL-15 mutant (IL-15N72D) bound to an IL-15 receptor α/IgG1 Fc fusion protein. It binds to the βγ T-cell receptor, directly and specifically stimulating CD8-positive T cells and NK cells while avoiding stimulation of regulatory T cells (Tregs).Compared with natural, non-complex IL-15, Anktiva exhibits superior pharmacokinetic properties in patients, persists longer in lymphoid tissues, and demonstrates enhanced anti-tumor activity.When combined with Bacillus Calmette-Guérin (BCG) in a Phase 2/3 clinical trial for the treatment of non-muscle-invasive bladder cancer (NMIBC) that responds poorly to BCG, the therapy met the primary endpoint for treating patients with the papillary subtype.57% of patients achieved a 12-month disease-free survival (DFS).

In October 2023, the FDA accepted ImmunityBio'sAnktiva Resubmitted BLA, in Combination with BCG, for the TreatmentNon-muscle-invasive bladder cancer with poor response to BCG.

▲Mechanism of Action of Anktiva (Image Source: ImmunityBio Official Website)

Active Ingredient：Pivmecillinam

Indications: Non-complicated urinary tract infection

Company Name：Utility Therapeutics

Pivmecillinam is a β-lactam antibiotic with a unique mechanism of action., Over the past 40 years, it has been used in many countries and regions to treat urinary tract infections. In in vitro and in vivo studies, it has shown activity against the most common bacteria in urinary tract infections, including drug-resistant strains.

In January this year, UTILITY Therapeutics announced in the United StatesFDA Grants Priority Review to New Drug Application for Pivmecillinam for the Treatment of Uncomplicated Urinary Tract InfectionsThe company's press release noted that this antibiotic demonstrated95% Clinical Cure Rate, recommended as a first-line treatment for urinary tract infections in many countries and regions.

Pivmecillinam and its intravenous form, mecillinam, have both been granted Qualified Infectious Disease Product (QIDP) designation by the FDA. The NDA submission includes six clinical studies supporting the efficacy of pivmecillinam and twelve studies supporting its safety.

Active Ingredient：Mavorixafor

Indications：WHIM Syndrome

Company Name：X4 Pharmaceuticals

Mavorixafor is an investigational novel small molecule antagonist targeting the CXCR4 receptor.It is a once-daily oral therapy specifically developed for WHIM syndrome and certain types of chronic neutropenia. Mavorixafor has received Breakthrough Therapy designation, Fast Track status, Orphan Drug designation, and Rare Pediatric Disease designation from the FDA.

The submission of the NDA was supported by a global pivotal Phase 3 clinical trial.4WHIMThe support. This trial evaluates the efficacy and safety of once-daily oral mavorixafor in patients with WHIM syndrome. The results are encouraging,4WHIM Trial Meets Primary and Key Secondary Endpoints, with Patients in the Drug Group Maintaining Clinically Significant Thresholds of Absolute Neutrophil and Lymphocyte Counts for a Longer Duration Compared to the Placebo Group (p<0.0001).

The U.S. FDA has granted Priority Review status to the NDA for mavorixafor, and if approved,Mavorixafor has the potential to become the first therapy for patients with WHIM syndrome.

▲Pharmacological Mechanism of CXCR4 Antagonist (Image Source: X4 Pharmaceuticals Official Website)

Active Ingredient：Tovorafenib

Indications：Recurrent or Progressive Pediatric Low-Grade Glioma

Company Name：Day One Biopharmaceuticals

Tovorafenib is a highly specific pan-RAF kinase inhibitor that can inhibitBRAFFusion or BRAF V600 mutation-driven tumor growth, with brain penetrance.It has been granted Breakthrough Therapy Designation and Rare Pediatric Disease designation by the U.S. FDA for the treatment of patients with activatingRAFVariant Pediatric Low-Grade Glioma (pLGG).

The NDA submission is primarily based on the pivotal Phase 2 trial data, which included 137 patients.The Overall Response Rate (ORR) for recurrent or progressive pLGG patients treated with tovorafenib reached 67%.(Including complete response [CR] and partial response [PR]), as well as a 93% clinical benefit rate (CBR, which includes CR, PR, and stable disease [SD]).

Analysis showed that 17% (n=12) of the evaluable patients achieved complete response, 49% (n=34) achieved partial response, and 26% (n=18) had stable disease. The median duration of response based on RANO-HGG criteria was 16.6 months (95% CI: 11.6 months to not estimable).

▲Introduction to Tovorafenib (Image Source: Day One Biopharmaceuticals, Inc. official website)

Active Ingredient：mRNA-1345

Indications: Prevention of respiratory syncytial virus (RSV)-related lower respiratory tract diseases and acute respiratory diseases

Company Name：Moderna

mRNA-1345 is an mRNA vaccine that encodes the stabilized prefusion F glycoprotein of the RSV virus, which induces a superior neutralizing antibody response compared to the post-fusion state.It uses the same lipid nanoparticle (LNP) delivery system as Moderna's COVID-19 vaccine and contains optimized protein and codon sequences. The key trial met two primary efficacy endpoints, with vaccine effectiveness against RSV-associated lower respiratory tract disease (RSV-LRTD), defined by two or more symptoms, being83.7%, the vaccine effectiveness for RSV-LRTD defined by three or more symptoms is82.4%The U.S. FDA has granted mRNA-1345 Fast Track designation and Breakthrough Therapy designation to help prevent RSV-LRTD and Acute Respiratory Disease (ARD) in adults aged 60 years or older.

Active Ingredient：Fidanacogene elaparvovec

Indications: Hemophilia B

Company Name：Pfizer

Fidanacogene elaparvovec is a novel investigational gene therapy containing a bioengineered AAV capsid and a transgene encoding a high-activity variant of FIX.For patients with hemophilia B, the goal of this gene therapy is to enable them to produce their own FIX protein through a one-time treatment, rather than requiring regular intravenous infusions of FIX as is currently the standard treatment.

The submission of the marketing application is based on the efficacy and safety data from the Phase 3 BENEGENE-2 trial, which enrolled a total of 45 patients. The analysis showed that the BENEGENE-2 trial met its primary endpoint, namelyCompared with FIX prophylactic treatment, patients who received fidanacogene elaparvovec infusion achieved non-inferiority and superiority in the annualized bleeding rate (ABR) of total bleeding events.

In January this year,Health Canada has approved fidanacogene elaparvovec for marketing (brand nameBeqvez）, for the treatment of adult patients aged 18 years or older with moderate to severe or severe hemophilia B who do not have neutralizing antibodies targeting the AAV serotype Rh74 subtype.

Indications：Paroxysmal Nocturnal Hemoglobinuria (PNH)

Company Name：AstraZeneca

DanicopanIt is an oral complement factor D inhibitor, designed as an add-on therapy to complement C5 inhibitor treatment for PNH patients.These patients exhibit clinically significant extravascular hemolysis symptoms.DanicopanIt can selectively inhibit the key complement factor D in the alternative pathway, block the production of C3 convertase, and suppress the activity of the alternative pathway. Unlike C5 inhibitors, danicopanInhibit the deposition of C3b fragments on patients' erythrocytes, control the hemolysis of red blood cells and extravascular hemolysis in PNH patients, and thereby improve the therapeutic outcomes.

The submission of the NDA was primarily based on a randomized, double-blind, pivotal Phase 3 trial.ALPHAThe positive results. The trial evaluateddanicopanAs an add-on therapy to Ultomiris or Soliris, for patients experiencing clinically significantExtravascular HemolysisThe efficacy and safety of PNH patients. The results showed,dAnicopanPrimary endpoint of hemoglobin change from baseline to Week 12, as well as all key secondary endpoints, including avoidance of transfusions and changes in the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-Fatigue) score, were reached.

In January this year, AstraZeneca announced that danicopan had been approved by Japan's Ministry of Health, Labour and Welfare (MHLW) (brand nameVoydeya）, as an add-on therapy to the standard-of-care C5 complement inhibitors Ultomiris or Soliris, for the subset of patients with paroxysmal nocturnal hemoglobinuria who experience significant extravascular hemolysis while on C5 inhibitor therapy.

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[1] Basilea announces FDA acceptance of New Drug Application for antibiotic ceftobiprole. Retrieved March 29, 2024, from https://www.basilea.com/news#news_1448

[2] FDA to review European-approved oral antibiotic for urinary tract infections. Retrieved March 29, 2024, from https://www.cidrap.umn.edu/antimicrobial-stewardship/fda-review-european-approved-oral-antibiotic-urinary-tract-infections