Manufactured from pooled human plasma from US donors, Alyglo supplies a broad spectrum of neutralizing IgG antibodies to bacterial and viral pathogens, and their toxins. The product is manufactured using cation exchange chromatography, which removes coagulation factor XIa and reduces procoagulant activity. 

The approval was based on data from an open-label, single-arm, phase 3 study (ClinicalTrials.gov Identifier: NCT02783482) that evaluated the efficacy and safety of Alyglo in patients 17 years of age and older with PI. Study participants (N=33) received Alyglo infusion every 21 or 28 days for 12 months. The primary endpoint was the annualized rate of acute serious bacterial infections (SBIs).

The acute SBI rate was reported to be 0.03 during the 12-month study period, which met the predefined success rate of less than 1 acute SBI per patient per year. One patient experienced an acute SBI (1 episode of bacterial pneumonia). 

As for safety, the proportion of infusions with temporally associated adverse events occurring during or within 72 hours after infusion was 0.22. This result met the FDA-required prespecified endpoint of less than 0.40.

The most common adverse reactions reported with treatment were headache, nausea/vomiting, fatigue, nasal/sinus congestion, rash, arthralgia, diarrhea, muscle pain/aches, infusion site pain/swelling, abdominal pain/discomfort, cough, and dizziness. As with other IGIV products, the prescribing information for Alyglo includes a Boxed Warning regarding the risk of thrombosis, renal dysfunction, and acute renal failure. 

Alyglo is supplied in a single-dose vial in the following presentations: 5g in 50mL; 10g in 100mL; 20g in 200mL. 

The expanded approval was supported by data from a prospective, open-label, single-arm study (ClinicalTrials.gov Identifier: NCT03164967) conducted in 16 pediatric participants 2 to 16 years of age with primary immune deficiency disorders associated with defects in humoral immunity. Study participants received a Bivigam infusion every 3 or 4 weeks for approximately 5 months.

Efficacy was based on the incidence of acute serious bacterial infections (SBIs). Findings showed no acute SBIs occurred during the mean observation period of 152 days. There were no hospitalizations due to infection reported during this time period and none of the patients required IV antibiotics. Throughout the study, trough total IgG levels were maintained above 500mg/dL in all patients.

Bivigam was also evaluated in a second open-label, single-arm trial that included 63 participants, 9 of whom were children. The pharmacokinetics, safety, and efficacy of Bivigam were found to be similar between pediatric and adult patients. During the 12 month study period, there were 2 SBIs reported in 2 participants (both bacterial pneumonia); the mean rate of SBIs per year was 0.037. 

Bivigam is supplied as a liquid solution containing 10% IgG (100mg/mL) in a 50mL and 100mL single-use vial. It is administered as an intravenous infusion.

The Food and Drug Administration (FDA) has approved a new 50mL/10gm prefilled syringe for Hizentra^® (immune globulin subcutaneous [human] 20% liquid).

Hizentra is indicated:

• As replacement therapy for primary immunodeficiency (PI) in adults and pediatric patients 2 years of age and older (eg, congenital or X-linked agammaglobulinemia, common variable immunodeficiency, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies). 
• As maintenance therapy to prevent relapse of neuromuscular disability and impairment in adults with chronic inflammatory demyelinating polyneuropathy (CIDP).

The new 50mL/10gm prefilled syringe is expected to be available in early 2024. Hizentra is currently available in 5mL/1gm, 10mL/2gm, and 20mL/4gm prefilled syringes as well as in 5mL/1gm, 10mL/2gm, 20mL/4gm, and 50mL/10gm vials.

“As part of our promise to meet the needs of people who rely on our life-saving therapies, we recognize the important value of offering people with PI or CIDP a larger prefilled syringe size option to effectively manage their condition,” said Bob Lojewski, Senior Vice President and General Manager, North America, CSL Behring. “We are proud to be at the forefront of delivering effective treatment options that also provide flexibility by allowing those with PI or CIDP to self-administer their treatments based on their specific needs and lifestyles.”

Ceftobiprole for the Treatment of Serious Bacterial Infections

PDUFA date: April 3, 2024

Ceftobiprole is a broad spectrum cephalosporin antibiotic for intravenous administration. The drug has been shown to have rapid bactericidal activity against Gram positive bacteria such as Staphylococcus aureus, including methicillin-resistant strains (MRSA), and Gram negative bacteria. Basilea is seeking approval for 3 indications: S. aureus bacteremia (SAB), including right-sided infective endocarditis, acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). The application is supported by data from three phase 3 studies: ERADICATE (ClinicalTrials.gov Identifier: NCT03138733), TARGET (ClinicalTrials.gov Identifier: NCT03137173), and a phase 3 study in CABP (ClinicalTrials.gov Identifier: NCT00326287). Findings from these trials supported the effectiveness of ceftobiprole in the treatment of SAB, ABSSSI, and CABP vs a comparator antibiotic.

SPN-830 for Continuous Treatment of Motor Fluctuations in Parkinson Disease

PDUFA date: April 5, 2024

SPN-830 is an apomorphine infusion device that provides continuous treatment of motor fluctuations (off episodes) in adults with Parkinson disease. The drug/device combo had originally been submitted to the FDA for review in September 2020. The application included data from the phase 3 TOLEDO study (ClinicalTrials.gov Identifier: NCT02006121) and a supportive open-label study (ClinicalTrials.gov Identifier: NCT02339064). Results from TOLEDO showed that SPN-830 was associated with a statistically significant reduction in mean daily off time compared with placebo. The FDA subsequently issued a Refuse to File letter, and then a Complete Response Letter, which required Supernus to provide additional analysis for review. Apomorphine, a non-ergoline dopamine agonist, is currently available as a solution for subcutaneous injection and as a sublingual film.

N-803 plus BCG for High-Risk Non-Muscle-Invasive Bladder Cancer

PDUFA date: April 23, 2024

N-803 (Anktiva^®) is an interleukin-15 (IL-15) superagonist complex consisting of an IL-15 mutant (IL-15N72D) bound to an IL-15 receptor α/IgG1 Fc fusion protein. The investigational agent is being reviewed in combination with Bacillus Calmette-Guérin (BCG) for the treatment of BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC) carcinoma in situ (CIS) with or without Ta or T1 disease. The BLA is supported by data from the phase 2/3, open-label QUILT-3.032 study (ClinicalTrials.gov Identifier: NCT03022825). Findings showed 71% of patients with BCG-unresponsive NMIBC CIS and papillary disease treated with intravesical BCG plus N-803 achieved a complete response (primary endpoint), with median duration of response of 26.6 months. Among patients with CR, the Kaplan-Meier-estimated probability of avoiding cystectomy and of bladder cancer-specific survival was 89.2% and 100%, respectively, at 24 months. 

Tovorafenib for Relapsed or Progressive Pediatric Low-Grade Glioma

PDUFA date: April 30, 2024

Tovorafenib is an oral, brain-penetrant, highly-selective type II RAF kinase inhibitor designed to target a key enzyme in the MAPK signaling pathway. It is being reviewed for the treatment of relapsed or progressive pediatric low-grade glioma (pLGG). The NDA includes efficacy and safety data from the open-label, phase 2 FIREFLY-1 study (ClinicalTrials.gov Identifier: NCT04775485), which included 77 patients 6 months to 25 years of age with relapsed or progressive pLGG. Findings showed that among the 69 evaluable patients, the overall response rate (by Response Assessment for Neuro-Oncology High Grade Glioma criteria) was 67%, with median duration of response of 16.6 months. Tovorafenib was granted Rare Pediatric Disease Designation for relapsed or progressive pLGG.

Mavorixafor for the Treatment of WHIM Syndrome

PDUFA date: April 30, 2024

Mavorixafor is an investigational oral small-molecule antagonist of the CXCR4 receptor. It is being reviewed for the treatment of patients 12 years of age and older with WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome, a rare, primary immunodeficiency. The application includes data from the phase 3, double-blind, placebo-controlled 4WHIM study (ClinicalTrials.gov Identifier: NCT03995108), which evaluated oral, once-daily mavorixafor vs placebo in patients with genetically confirmed WHIM syndrome (N=31). Findings showed mavorixafor was associated with statistically significant and clinically relevant longer times above threshold levels for both absolute neutrophil (P <.0001) and absolute lymphocyte counts (P <.0001) compared with placebo. Treatment with mavorixafor also resulted in reductions in the rate, severity, and duration of infections vs placebo.

Previously, these storage conditions were only approved during the first 24 months of shelf life. The approval for extended ambient storage conditions for Asceniv and Bivigam is immediately effective, and applies to all existing lots currently in the commercial supply chain and to future production.

Asceniv and Bivigam are indicated for the treatment of primary humoral immunodeficiency in adults and adolescents (12 to 17 years of age). Primary immunodeficiency includes, but is not limited to, the humoral immune defect in common variable immunodeficiency, X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies. 

Asceniv is supplied as a liquid solution containing 10% IgG (100mg/mL) in a 50mL single-use vial. Bivigam is supplied as a liquid solution containing 10% IgG (100mg/mL) in a 50mL and 100mL single-use vial. 

“With the FDA-approved extension of room temperature storage conditions, the Company expects to reach more customers who were previously inaccessible due to limited refrigeration space and cold chain capacity constraints,” said Adam Grossman, President and CEO of ADMA. “We believe that this added storage flexibility for both Asceniv and Bivigam will meaningfully enhance our products’ market offerings, enabling more versatile utilization and better inventory management for providers.”

The Food and Drug Administration (FDA) has expanded the approval of HyQvia^® (immune globulin [IG] infusion 10% [human] with recombinant human hyaluronidase) to include children 2 to 16 years of age with primary immunodeficiency (PI). Previously, the treatment was only approved for adults.

HyQvia is a subcutaneous immune globulin treatment that can be administered once a month (every 3 or 4 weeks). The IG component is prepared from large pools of human plasma consisting of at least 98% IgG, and contains a broad spectrum of antibodies that provides the therapeutic effect. The recombinant human hyaluronidase component increases dispersion and absorption of the IG component.

The approval in pediatric patients was based on data from a prospective, open-label, non-controlled phase 3 trial (ClinicalTrials.gov Identifier: NCT03277313) that evaluated the efficacy and safety of HyQvia in 44 patients 2 to 16 years of age with PI who had received intravenous immunoglobulin or subcutaneous immunoglobulin treatment prior to enrollment. Data were analyzed when all patients completed 12 months of participation in the trial. The median number of infusions per month was 1.1 (range, 1.0 to 1.5) and was comparable across the age groups. 

The primary analysis for efficacy was based on the rate of acute serious bacterial infections (aSBIs), defined as bacteremia/sepsis, bacterial meningitis, osteomyelitis/septic arthritis, bacterial pneumonia, and visceral abscess, per patient per year. 

Results showed that the mean aSBI rate per year was 0.04 (upper 1-sided 99% CI of 0.21; P <.001), which met the predefined success rate of less than 1 aSBI per patient per year. The mean rate of all infections per patient-year was 3.20, with an upper limit of the 95% CI of 4.05. The overall rate of infections per patient was consistent with results obtained in the pivotal clinical study. Pediatric patients missed a mean of 5 days of work/school/daycare.  

HyQvia is available in a dual vial unit of 2 single-use vials containing the active IG 10% and recombinant human hyaluronidase: 2.5g/200U, 5g/400U, 10g/800U, 20g/1600U, and 30g/2400U.

Immune Globulins

The Food and Drug Administration (FDA) has accepted the resubmitted Biologics License Application (BLA) for GC5107B (immune globulin intravenous [human]) for patients with primary humoral immunodeficiency (PI).

GC5107B is a liquid solution containing 10% immunoglobulin G (100mg/mL) for intravenous infusion, manufactured from pooled human plasma from US donors. The application includes data from an open-label, single-arm, historically controlled, multicenter phase 3 study (ClinicalTrials.gov Identifier: NCT02783482) that evaluated the efficacy and safety of GC5107B in 49 patients aged 3 to 70 years with a confirmed diagnosis of PI. The primary endpoint of the study was the incidence of acute serious bacterial infections (aSBI).

Findings showed an incidence of 0.02 aSBI events per patient-year (FDA’s efficacy requirement is <1 aSBI per patient-year). Moreover, the study met all secondary efficacy endpoints, which were comprised of the number of days absent from work or school due to an infection (mean of 7.1 days), hospitalization due to infection (mean of 0.1 days), and days of unscheduled visits to a physician (mean 2.3 days). All were considered low and comparable to results seen with other IVIG products. The most common treatment-related adverse events reported were headache, fatigue, and nausea.

A Prescription Drug User Fee Act target date of January 13, 2024 has been set for the application.