Gazyva

Infusion-Related Reactions

Premedication to reduce the risk of IRRs is outlined in Table 7 [see Warnings and Precautions (5.3)].

Hypotension may occur during GAZYVA intravenous infusions. Consider withholding antihypertensive treatments for 12 hours prior to and throughout each GAZYVA infusion and for the first hour after administration [see Warnings and Precautions (5.3)].

Tumor Lysis Syndrome Prophylaxis

Patients with high tumor burden, high circulating absolute lymphocyte counts (greater than 25 × 10⁹/L) or renal impairment are considered at risk of tumor lysis syndrome and should receive prophylaxis. Premedicate with anti-hyperuricemics (e.g., allopurinol or rasburicase) and ensure adequate hydration prior to start of GAZYVA therapy. Continue prophylaxis prior to each subsequent GAZYVA infusion, as needed [see Warnings and Precautions (5.5)].

Antimicrobial Prophylaxis

Patients with Grade 3 to 4 neutropenia lasting more than one week are strongly recommended to receive antimicrobial prophylaxis until resolution of neutropenia to Grade 1 or 2. Consider antiviral and antifungal prophylaxis for patients with severe and long lasting (> 1 week) neutropenia.

Infusion-Related Reactions

If a patient experiences an IRR, adjust the infusion as follows [see Warnings and Precautions (5.3)]:

• Grade 4 (life-threatening): Stop infusion immediately and permanently discontinue GAZYVA.
• Grade 3 (severe): Interrupt infusion and manage symptoms.
  • For patients who experience Grade 3 IRRs during standard infusion, upon resolution of symptoms, consider restarting GAZYVA infusion at no more than half the previous rate (the rate being used at the time that the IRR occurred) for 30 minutes, and if patients do not experience any further IRR symptoms, the infusion rate escalation may resume at the increments and intervals as appropriate for the treatment cycle dose. Permanently discontinue treatment if patients experience a Grade 3 or higher IRR at rechallenge.
  • For patients with FL who experience Grade 3 IRRs during the approximately 90-minute infusion, upon resolution of symptoms, the infusion can be restarted at no more than half the previous rate (the rate being used at the time that the IRR occurred) and not greater than 400 mg/hr. Administer subsequent infusions at the standard rate. Permanently discontinue treatment if patients experience a Grade 3 or higher IRR at rechallenge.
  • For patients with CLL only, the Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour but not increased further.
• Grade 1–2 (mild to moderate): Reduce infusion rate or interrupt infusion and manage symptoms. Upon resolution of symptoms, continue or resume GAZYVA infusion, and if patient does not experience any further IRR symptoms, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment cycle dose.
  • For patients with CLL only, the Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour but not increased further.
  • For patients with LN or childhood-onset INS, reduce infusion rate to half the rate that was used at the time of the reaction and treat symptoms. Upon resolution of symptoms, the infusion should be kept at the reduced rate for an additional 30 minutes. If no further symptoms of IRR, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment dose.

Other Adverse Reactions

Consider treatment interruption if patients experience an infection, Grade 3 or 4 cytopenia, or Grade 2 or higher non-hematologic toxicity.

Preparation

Prepare the solution for infusion, using aseptic technique, as follows:

• Inspect visually for any particulate matter and discoloration prior to administration.
• Use a sterile needle and syringe to prepare GAZYVA.
• Dilute into a 0.9% Sodium Chloride Injection, USP PVC or non-PVC polyolefin infusion bag.
  Chronic Lymphocytic Leukemia
  • Preparation of solution for infusion on day 1 (100 mg) and day 2 (900 mg) of Cycle 1:
    • Prepare day 1 (100 mg) and day 2 (900 mg) infusion bags at the same time using one vial (1,000 mg/40 mL) on day 1.
    • Withdraw 40 mL of GAZYVA solution from the vial.
    • Dilute 4 mL (100 mg) of GAZYVA into a 100 mL 0.9% Sodium Chloride Injection, USP infusion bag for immediate administration.
    • Dilute the remaining 36 mL (900 mg) into a 250 mL 0.9% Sodium Chloride Injection, USP infusion bag at the same time for use on day 2 and store in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours. After allowing the diluted bag to come to room temperature, use immediately.
    • Clearly label each infusion bag.
  • Preparation of solution for infusion on day 8 and 15 of Cycle 1 and day 1 of Cycles 2–6:
    • Withdraw 40 mL of GAZYVA solution from the vial.
    • Dilute 40 mL (1,000 mg) into a 250 mL 0.9% Sodium Chloride Injection, USP infusion bag.
  Follicular Lymphoma, Active Lupus Nephritis and Childhood-Onset Idiopathic Nephrotic Syndrome patients weighing 45 kg or more
  • Preparation of solution for infusion:
    • Withdraw 40 mL of GAZYVA solution from the vial.
    • Dilute 40 mL (1,000 mg) into a 250 mL 0.9% Sodium Chloride Injection, USP infusion bag.
  Childhood-Onset Idiopathic Nephrotic Syndrome patients weighing less than 45 kg
  • Preparation of solution for infusion:
    • Calculate the dose (mg) based on the patient's body weight and the total volume of GAZYVA solution required.

    • Final GAZYVA solution to add to the infusion bag (mL)	=	Patient weight (kg) x 20 mg/kg	× 40 mL
      		1,000 mg

    • Withdraw a volume equal to the required GAZYVA solution from a 250 mL infusion bag of 0.9% Sodium Chloride Injection, USP and discard it.
    • Add the required volume of GAZYVA solution slowly into the 0.9% Sodium Chloride Injection, USP infusion bag. Discard any unused portion of GAZYVA solution remaining in the vial.
• Mix diluted solution by gentle inversion. Do not shake or freeze.
• For microbiological stability, immediately use diluted GAZYVA infusion solution. If not used immediately, store in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours prior to use.

The product can be administered at a final concentration of 0.4 mg/mL to 4 mg/mL.

Storage

Use the diluted solution immediately. If not used immediately, store for up to 24 hours at 2°C to 8°C. Discard after 24 hours.

Administration

• Administer as an intravenous infusion only.
• Do not administer as an intravenous push or bolus.
• Do not mix GAZYVA with other drugs.
• No incompatibilities between GAZYVA and polyvinylchloride (PVC) or non-PVC polyolefin bags and administration sets have been observed.

Lupus Nephritis

In the pooled double-blind periods of REGENCY (Week 76) and NOBILITY (Week 52), the incidence of Grade 3-5 infections was 11% (22/200) in patients treated with GAZYVA and standard therapy compared to 9% (18/193) in patients receiving placebo and standard therapy, corresponding to an exposure-adjusted incidence rate (EAIR) of 8.9 and 7.9 per 100 patient years, respectively. The incidence of fatal infections was 1% (2/200) in patients treated with GAZYVA and 0.5% (1/193) in patients receiving placebo, corresponding to an EAIR of 0.8 and 0.4 per 100 patient years, respectively.

In 40 patients who crossed-over from placebo to GAZYVA and standard therapy at Week 76 in the REGENCY study and patients who continued treatment with GAZYVA and standard therapy, including additional treatment after Week 76, the EAIR of Grade 3-5 infections for the GAZYVA arm was 9.0 per 100 patient-years while the EAIR of fatal infections for the GAZYVA arm was 1.8 per 100 patient-years.

Idiopathic Nephrotic Syndrome

In the INSHORE study, the incidence of Grade 3 (severe or medically significant) infections was 11% (5/44) in patients randomized to GAZYVA compared to 5% (2/41) in the mycophenolate mofetil (MMF) arm. The most frequently reported Grade 3 infection related to study treatment in the GAZYVA arm was pneumonia (2/44 patients, 5%) [see Adverse Reactions (6.1)]. No Grade 4 or Grade 5 (life-threatening or fatal) infections were reported in either arm.

CLL and FL

In GALLIUM, more Grade 3 to 5 infections were reported in the recipients of GAZYVA and bendamustine (117/410 patients, 29%) as compared to GAZYVA plus CHOP or CVP (43/281 patients, 15%). More fatal infections were reported in patients treated with GAZYVA and bendamustine (3%), as compared to GAZYVA plus CHOP or CVP (< 1%), including during the monotherapy phase and after completion of treatment.

Do not administer GAZYVA to patients with an active infection. Patients with a history of recurring or chronic infections may be at increased risk of infection. In patients who develop a serious infection while receiving GAZYVA, immediately discontinue GAZYVA and institute appropriate treatment. Consider the risk and benefit of resuming treatment with GAZYVA following resolution of serious infections.

Chronic Lymphocytic Leukemia

The data below are based on a safety population of 773 previously untreated patients with CLL in the CLL11 study. Patients were treated with chlorambucil alone, GAZYVA in combination with chlorambucil, or rituximab product in combination with chlorambucil. The Stage 1 analysis compared GAZYVA in combination with chlorambucil vs. chlorambucil alone and Stage 2 compared GAZYVA in combination with chlorambucil vs. rituximab product in combination with chlorambucil. Adverse reactions rates and laboratory abnormalities from the Stage 2 phase are presented below and are consistent with the rates in Stage 1. In addition to the adverse reactions observed in Stage 2, in Stage 1, back pain (5% vs. 2%), anemia (12% vs. 10%) and cough (10% vs. 7%) were observed at a higher incidence in the GAZYVA treated patients. The incidence of Grade 3 to 4 back pain (< 1% vs. 0%), cough (0% vs. < 1%) and anemia (5% vs. 4%) was similar in both treatment arms. With regard to laboratory abnormalities, in Stage 1 hyperkalemia (33% vs. 18%), creatinine increased (30% vs. 20%) and alkaline phosphatase increased (18% vs. 11%) were observed at a higher incidence in patients treated with GAZYVA with similar incidences of Grade 3 to 4 abnormalities between the two arms.

Patients received three 1,000 mg doses of GAZYVA on the first cycle and a single dose of 1,000 mg once every 28 days for 5 additional cycles in combination with chlorambucil (6 cycles of 28 days each in total). In the last 140 patients enrolled, the first dose of GAZYVA was split between day 1 (100 mg) and day 2 (900 mg) [see Dosage and Administration (2.2)]. In total, 81% of patients received all 6 cycles (of 28 days each) of GAZYVA-based therapy.

Adverse reactions in ≥ 10% of patients in the GAZYVA containing arm were infusion-related reactions, neutropenia, thrombocytopenia, and diarrhea. The most common Grade 3 to 4 adverse reactions (incidence ≥ 10%) in the GAZYVA containing arm were neutropenia, infusion-related reactions, and thrombocytopenia.

Non-Hodgkin Lymphoma

Lupus Nephritis

The data below reflects exposure to GAZYVA administered intravenously in patients with ISN/RPS 2003 Class III or IV with or without concomitant Class V lupus nephritis in the REGENCY and NOBILITY studies, up to week 76.

REGENCY (NCT04221477) is a Phase III study which included 136 patients treated with GAZYVA plus standard therapy consisting of mycophenolate mofetil (MMF) and corticosteroids [see Clinical Studies (14.3) ].

NOBILITY (NCT02550652) is a Phase II study which included 64 patients treated with GAZYVA plus standard therapy consisting of MMF/mycophenolic acid (MPA) and corticosteroids.

The most common adverse reactions (incidence ≥ 5% in the GAZYVA arm) were upper respiratory tract infection, COVID-19, urinary tract infection, bronchitis, pneumonia, infusion related reactions and neutropenia.

The most common serious adverse reactions in the GAZYVA arm were: COVID-19 (11 patients [5.5%]), pneumonia (9 patients [4.5%]), neutropenia (7 patients [3.5%]), urinary tract infections (5 patients [2.5%]) and infusion-related reactions (1 patient [0.5%]). No serious adverse reactions were reported for bronchitis, herpes simplex and upper respiratory tract infections. Two fatal adverse reactions of COVID-19 were reported in the GAZYVA arm.

Adverse reaction rates are presented in Table 14.

Childhood-Onset Idiopathic Nephrotic Syndrome

The data described in Table 15 reflect exposure to GAZYVA administered intravenously in patients with childhood-onset INS in the INSHORE study (NCT05627557). In INSHORE, 44 patients received GAZYVA, of which 41 patients were 4 to 18 years of age [see Clinical Studies (14.4)]. Adverse event severity was graded as Grades 1 to 5 defined as mild (1), moderate (2), severe (3), life-threatening (4), and fatal (5).

The most common adverse reactions (incidence ≥ 10% in the GAZYVA arm) are shown in Table 15. There were no Grade 5 adverse reactions in INSHORE.

Specific Adverse Reactions

Risk Summary

Based on findings from animal studies and its mechanism of action, GAZYVA can cause fetal B-cell depletion [see Clinical Pharmacology (12.1)]. There are no data with GAZYVA use in pregnant women to inform a drug-associated risk. Monoclonal antibodies are transferred across the placenta. In animal reproduction studies, weekly intravenous administration of obinutuzumab to pregnant cynomolgus monkeys from day 20 of pregnancy until parturition which includes the period of organogenesis at doses with exposures up to 2.4 times the exposure at the clinical dose of 1,000 mg monthly produced opportunistic infections and immune complex mediated hypersensitivity reactions. No embryo-toxic or teratogenic effects were observed in the monkeys (see Data). Advise pregnant women of the potential risk to the fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the estimated background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Clinical Considerations

Data

Risk Summary

There is no information regarding the presence of GAZYVA in human milk, the effects on the breastfed child, or the effects on milk production. However, low levels of obinutuzumab were present in the milk of lactating cynomolgus monkeys [see Data]. Human IgG is known to be present in human milk. Because of the potential of serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with GAZYVA and for 6 months after the last dose.

Data

Obinutuzumab was measured in the milk of lactating cynomolgus monkeys on day 28 postpartum after weekly intravenous administration from day 20 of pregnancy until parturition. Concentrations in milk were approximately 0.04% and 0.13% of concentrations in maternal serum in the 25 and 50 mg/kg groups, respectively.

GAZYVA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Contraception

Chronic Lymphocytic Leukemia

Of 336 patients with previously untreated CLL who received GAZYVA in combination with chlorambucil, 81% were 65 years and older, while 46% were 75 and older. Of the patients 75 years and older, 46% experienced serious adverse reactions and 7% experienced adverse reactions leading to death. Of the patients younger than 75, 33% experienced a serious adverse reaction and 2% an adverse reaction leading to death. No significant differences in efficacy were observed between younger and older patients [see Clinical Studies (14.1)].

Non-Hodgkin Lymphoma

Of 204 patients in GADOLIN with relapsed or refractory NHL treated with GAZYVA plus bendamustine, 44% were 65 and over, while 14% were 75 and over. In patients 65 and over, 55% of patients experienced serious adverse reactions and 28% experienced adverse reactions leading to treatment withdrawal while in patients under 65, 37% and 14% experienced serious adverse reactions and adverse reactions leading to treatment withdrawal, respectively. No clinically meaningful differences in efficacy were observed between these patients and younger patients in GADOLIN.

Of the 691 patients in GALLIUM treated with GAZYVA plus chemotherapy as first-line therapy, 33% were 65 and over, while 7% were 75 and over. Of patients 65 and over, 63% experienced serious adverse reactions and 26% experienced adverse reactions leading to treatment withdrawal, while in patients under 65, 43% experienced serious adverse reactions and 13% had an adverse reaction leading to treatment withdrawal. No clinically meaningful differences in efficacy were observed between these patients and younger patients in GALLIUM.

Lupus Nephritis and Childhood-Onset Idiopathic Nephrotic Syndrome

Clinical studies of GAZYVA in patients with active LN or childhood-onset INS did not include sufficient numbers of patients aged 65 years and older (1 patient and 0 patients, respectively) to determine whether they respond differently from younger adult patients.

Chronic Lymphocytic Leukemia

In patients with CLL, GAZYVA caused CD19 B-cell depletion (defined as CD19 B cell counts < 0.07 × 10⁹/L). Initial CD19 B cell recovery was observed in some patients approximately 9 months after the last GAZYVA dose. At 18 months of follow-up, some patients remain B cell depleted.

Although the depletion of B cells in the peripheral blood is a measurable pharmacodynamic effect, it is not directly correlated with the depletion of B-cells in solid organs or in malignant deposits. B cell depletion has not been shown to be directly correlated to clinical response.

Lupus Nephritis

In patients with LN (REGENCY study), total peripheral CD19+ B cell levels below the defined threshold of 10 cells/µl were achieved in 99% of patients treated with GAZYVA by Week 4 after treatment initiation and remained below this threshold in 95% of patients at Week 76.

Reductions in circulating naive B, memory B, and plasmablasts/plasma cells were observed by Week 4 and remained low through Week 76 after treatment initiation.

Treatment with GAZYVA led to improvements in complement (C3 and C4) and anti-double-stranded DNA antibodies (anti-dsDNA) by Week 4 and Week 12, respectively. These changes were sustained through Week 76.

In patients with low C3 at baseline, normalization of C3 levels occurred in 49% (by Week 12) and in 62% (by Week 76) of patients receiving GAZYVA compared to 33% and 29%, respectively, in the placebo group. In patients with low C4 at baseline, normalization of C4 levels occurred in 75% (by Week 12) and in 88% (by Week 76) of patients receiving GAZYVA compared to 55% and 55%, respectively, in the placebo group. Among patients with positive anti-dsDNA at baseline, 32% and 56% of patients treated with GAZYVA seroconverted by Week 4 and Week 76, respectively, compared with 16% and 16% of patients receiving placebo. The clinical relevance of the above mentioned pharmacodynamic biomarkers has not been established.

Childhood-Onset Idiopathic Nephrotic Syndrome

In evaluable patients aged 4 years and older with childhood-onset INS who received GAZYVA in INSHORE, 100% (43 out of 43) were B-cell depleted (defined as CD19+ B cell counts < 10 cells/µL) at Week 4, and 95% (40 out of 42) remained depleted at Week 52. At Week 64, 73% (19 out of 26) remained B-cell depleted, and at Week 76, 36% (8 out of 22) remained depleted.

Mean counts of circulating B-cell subsets such as naïve B cells, memory B cells, and plasmablasts/plasma cells were 0 cells/µL by Week 2 after treatment initiation and remained low (near 0 cells/µL) through Week 52.

Cardiac Electrophysiology

The potential effects of GAZYVA on the QTc interval have not been studied.

Distribution and Elimination

Specific Populations

GADOLIN

The efficacy of GAZYVA was evaluated in GADOLIN (NCT01059630), an open-label, multicenter, randomized study that included 335 patients with follicular lymphoma (FL) who had no response to or have progressed during or within 6 months of rituximab product or a rituximab product-containing regimen. These patients were randomized to receive either bendamustine alone (n = 171) or GAZYVA in combination with bendamustine (n = 164) for 6 cycles, each of 28 days duration. Patients in the GAZYVA plus bendamustine arm who did not have disease progression [patients with a complete response (CR), partial response (PR) or stable disease (SD)] at the end of the 6 cycles continued receiving GAZYVA monotherapy for 2 years. Patients were stratified according to the type of refractoriness to rituximab product (refractory to rituximab product monotherapy versus rituximab product in combination with chemotherapy), the number of prior therapies (≤ 2 versus > 2), and geographic region.

GAZYVA was given by intravenous infusion as a flat dose of 1,000 mg on Days 1, 8 and 15 of Cycle 1, on Day 1 of Cycles 2–6, and then every 2 months until disease progression for up to 2 years. Bendamustine was given intravenously on Days 1 and 2 for all treatment cycles (1–6) at 90 mg/m²/day when given in combination with GAZYVA or 120 mg/m²/day when given alone.

The primary analysis included 321 FL patients, including 166 patients randomized to bendamustine alone and 155 patients randomized to GAZYVA in combination with bendamustine. In the primary analysis, patients had a median age of 63 years, 88% were White and 56% were male. Thirty-four percent had bulky disease (> 6 cm), 15% had at least one B-symptom at baseline and 95% had an ECOG performance status of 0–1 at baseline. The median time since initial diagnosis was 3 years and the median number of prior therapies was 2 (range 1 to 10). Forty-six percent of patients received 1 prior therapy and 33% of patients received 2 prior therapies. Twenty percent of patients were refractory to prior rituximab product monotherapy, 37% of patients were refractory to prior rituximab product plus chemotherapy induction treatment, and 41% of patients were refractory to rituximab product maintenance treatment received following rituximab product plus chemotherapy induction. Seventy-nine percent of patients were refractory to both rituximab product and an alkylating agent during any prior regimen (double refractory).

The major efficacy outcome measure was PFS as determined by an independent review committee (IRC). At the time of the primary analysis, median observation time was 21.1 months. The median PFS in the bendamustine arm was 13.8 months. Median PFS was not reached in the GAZYVA plus bendamustine arm (PFS HR = 0.48, 95% CI: 0.34-0.68; stratified log-rank test p-value < 0.0001). The investigator assessed PFS result was consistent with the IRC-assessed PFS. The median investigator-assessed PFS in the bendamustine arm was 13.7 months and the median in the GAZYVA containing arm was 29.2 months (PFS HR = 0.48, 95% CI: 0.35-0.67; stratified log-rank test p-value < 0.0001).

Efficacy results are summarized in Table 19. The Kaplan-Meier curve for IRC-PFS is shown in Figure 3.

Figure 3 Kaplan-Meier Curve of IRC-Assessed Progression-Free Survival in Patients with FL

Figure 3

The final analysis included a total of 335 patients with 171 randomized to bendamustine alone and 164 to GAZYVA in combination with bendamustine. With an overall median observation time of 52.2 months (range: 0-100.9 months), there were 66 deaths (40.2%) in the GAZYVA arm and 85 deaths (51.3%) in the bendamustine-alone arm (OS HR = 0.71, 95% CI: 0.51, 0.98). The Kaplan-Meier curve for OS is presented in Figure 4.

Figure 4 Kaplan-Meier Curve of Overall Survival in Patients with FL

Figure 4

GALLIUM

The efficacy of GAZYVA was evaluated in GALLIUM (NCT01332968), a multicenter, open-label, randomized study that included 1202 patients with previously untreated, stage II bulky, III or IV FL. Patients were randomized 1:1 to receive either GAZYVA (n = 601) or rituximab product (n = 601) in combination with chemotherapy (CHOP, CVP, or bendamustine) for 6–8 cycles. Patients were stratified by chemotherapy (selected by each site; all patients at that site received the chosen chemotherapy regimen), FLIPI (Follicular Lymphoma International Prognostic Index) risk group and geographic region. Patients with at least PR to combination therapy received monotherapy with GAZYVA (1,000 mg) or rituximab product every two months until disease progression or for a maximum of two years. The study excluded patients with follicular lymphoma grade 3b or transformed disease; patients having an ANC < 1500 / µL, platelets < 75,000 / µL, or CLcr < 40 mL/min; and patients with hepatic transaminases > 2.5 × upper limit of normal unless attributable to lymphoma.

GAZYVA was given by intravenous infusion as a flat dose of 1,000 mg on Days 1, 8 and 15 of Cycle 1 and Day 1 of subsequent treatment cycles.

GAZYVA and bendamustine were given in six 28-day cycles. Bendamustine was administered at 90 mg/m²/day on Days 1 and 2 of each cycle, with prednisone 100 mg orally or equivalent on Day 1 of Cycle 1.

GAZYVA and CHOP were given in six 21-day cycles. Subsequently, two additional cycles of GAZYVA were given for a total of 8 GAZYVA cycles. CHOP consisted of cyclophosphamide 750 mg/m² intravenously, doxorubicin 50 mg/m², and vincristine 1.4 mg/m² (maximum dose, 2 mg) on Day 1 and prednisone 100 mg orally on Days 1-5.

GAZYVA and CVP were given in eight 21-day cycles. CVP consisted of cyclophosphamide 750 mg/m² intravenously and vincristine 1.4 mg/m² (maximum dose, 2 mg) on Day 1 and prednisone 100 mg orally on Days 1-5.

Patients had a median age of 59 years, 81% were White and 53% were female; 7% had Stage II, 35% had Stage III, and 56% had Stage IV disease, with 44% having bulky disease (≥ 7 cm) overall; 79% had a FLIPI score of > 2; and 97% had an ECOG performance status of 0–1. The chemotherapy was bendamustine in 57%, CHOP in 33%, and CVP in 10% of patients.

Efficacy was based on PFS per IRC, with a median observation time of 38 months. Upon interim analysis, the risk of progression or death was significantly reduced in the GAZYVA containing arm compared to the rituximab product containing arm (Table 20). Kaplan-Meier curves for PFS are shown in Figure 5. Overall response and complete remission rates were similar.

Study Design and Population

The efficacy of GAZYVA was evaluated in REGENCY (NCT04221477), a Phase III, randomized, double-blind, placebo-controlled, parallel-group, multicenter study in 271 patients with ISN/RPS 2003 Class III or IV, with or without concomitant Class V lupus nephritis (LN), treated with standard therapy consisting of mycophenolate mofetil (MMF) and corticosteroids. Patients had active or active/chronic ISN/RPS 2003 Class III or IV, with or without concomitant Class V proliferative LN determined by kidney biopsy, current or past positive antinuclear antibody (ANA), urine protein-to-creatinine ratio (UPCR) ≥ 1 g/g, and had received at least one dose of pulse intravenous (IV) methylprednisolone (≥ 250 mg) or equivalent treatment for LN during the 6 months prior to screening or during screening.

Patients with estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 or in need of dialysis or transplantation, with sclerosis in > 50% of glomeruli on kidney biopsy, presence of rapidly progressive glomerulonephritis, evidence of active infection, receipt of anti-CD20 therapy < 9 months before or during screening, or receipt of cyclophosphamide, tacrolimus, ciclosporin, or voclosporin within 2 months of or during screening were excluded.

Patients were randomized 1:1 to receive GAZYVA 1,000 mg (N=135) or placebo (N=136) intravenously, in combination with MMF 2-2.5 g/day and a tapering course of corticosteroids and were evaluated over 76 weeks. Patients randomized to receive GAZYVA were further randomized in a 1:1 ratio to receive either GAZYVA 1,000 mg IV on Day 1, Weeks 2, 24, 26, 50, and 52 (Arm 1), or GAZYVA 1,000 mg IV on Day 1, Weeks 2, 24, 26, and 52 (Arm 2). The totality of the GAZYVA efficacy data combining both treatment arms is shown in Table 21.

All patients received oral prednisone 0.5 mg/kg/day (maximum 60 mg/day) and remained at this dose until Week 2. Beginning on Day 15, prednisone was tapered to achieve a target dose of 5 mg/day by Week 24. Prednisone was maintained at a low dose (5 mg/day) from Week 24 until Week 80.

The median age of patients was 31 years, 85% were female, 58% were Hispanic or Latino, 48% were White, 19% were American Indian or Alaska Native, 15% were Black or African American and 6% were Asian. The distribution by kidney biopsy class was 39% Class III, 61% Class IV and 31% had concomitant Class V. Mean (SD) eGFR at baseline 102.3 (±30.8) mL/min/1.73 m². Mean (SD) UPCR at baseline was 3.3 (±2.9) mg/mg with 42% of patients exhibiting UPCR ≥3 mg/mg at baseline.

Efficacy Results

The primary endpoint measure was proportion of patients who achieved complete renal response (CRR) at Week 76, defined as meeting all of the following criteria: UPCR < 0.5 g/g; eGFR ≥ 85% of baseline, as calculated using the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation; with no occurrence of the following intercurrent events: rescue therapy, treatment failure, death or early study withdrawal.

Key secondary endpoint measures included: proportion of patients who achieved CRR with successful prednisone taper at Week 76 (defined as achievement of CRR at Week 76 without receiving prednisone > 7.5 mg/day or equivalent from Week 64 through Week 76), proportion of patients who achieved a proteinuric response at Week 76 (defined as achievement of UPCR < 0.8g/g and no occurrence of the following intercurrent events: rescue therapy, treatment failure, death or early study withdrawal) and proportion of patients who experience "renal-related events or deaths" through Week 76 (defined as occurrence of death, treatment failure, ≥ 50% increase in UPCR to a value ≥ 3 g/g and/or ≥ 30% decrease in eGFR to < 60 ml/min/1.73 m²).

The proportion of patients achieving CRR at Week 76 was significantly greater in patients treated with GAZYVA in combination with standard therapy compared to patients who received placebo plus standard therapy. There were also a higher proportion of patients who achieved CRR with successful prednisone taper at Week 76 and proteinuric response at Week 76 in the GAZYVA plus standard therapy arm compared to the placebo plus standard therapy arm (see Table 21).

In the REGENCY study, patients who received GAZYVA were less likely to experience the outcome of "renal-related event or death" compared with placebo. Fewer patients in the GAZYVA arm experienced worsening kidney function or doubling of serum creatinine (see Table 22).

Subgroup Analyses

In pre-specified subgroup efficacy analyses, the primary endpoint in patients was examined based on 24-hour UPCR at baseline (< 3 g/g or ≥ 3 g/g), lupus nephritis class at baseline (Class III or IV), and concomitant Class V at baseline. The results are displayed in Figure 6 below.

Figure 6 Forest Plot of CRR at Week 76 on Baseline Disease Characteristics, Efficacy-Evaluable Patients

Figure 6

Study Design and Population

The efficacy and safety of GAZYVA were evaluated in INSHORE (NCT05627557), a Phase III, randomized, controlled, open-label, multicenter study in 85 patients 2 years of age and older with frequently relapsing or steroid dependent childhood-onset idiopathic nephrotic syndrome (INS).

Frequently relapsing nephrotic syndrome (FRNS) was defined as two or more relapses in the first 6 months after disease onset (or after remission of the initial episode) or three or more relapses per 12 months thereafter. Steroid dependent nephrotic syndrome (SDNS) was defined as two consecutive relapses while on prednisone or prednisolone or within 14-15 days of prednisone or prednisolone discontinuation.

Patients had to be diagnosed before the age of 18 years, have a normal estimated glomerular filtration rate (eGFR) for age, and be in complete remission at study entry, as defined by the absence of edema, a urine protein-to-creatinine ratio (UPCR) of 0.2 g/g or less at screening, and trace or negative urine dipstick on 3 consecutive days within a week prior to randomization. Patients had to have had at least one relapse in the 6 months before screening.

Patients were excluded if they had secondary, steroid resistant, or genetic causes of nephrotic syndrome, treatment failure while receiving mycophenolate mofetil (MMF) (2 or more relapses in a 6 month period), received immunosuppressive medications other than MMF or oral corticosteroids within 2 months prior to randomization, or received biologic B cell-depleting therapy within 9 months prior to baseline. Patients with an active infection, or history of severe allergic or anaphylactic reactions to monoclonal antibodies were also excluded.

A total of 85 patients were randomized 1:1 to intravenous GAZYVA 1,000 mg (or 20 mg/kg if weighing less than 45 kg) on Day 1, Day 15, Week 24, and Week 26, or oral MMF titrated to a target dose of 1200 mg/m²/day divided in two doses (maximum 2,000 mg/day) by Week 4. Patients receiving GAZYVA received premedication with methylprednisolone 80 mg IV (or 1.5 mg/kg if less than 45 kg), acetaminophen/paracetamol 15 mg/kg orally (PO) (maximum dose 1,000 mg) and diphenhydramine 0.5 to 1 mg/kg (maximum dose 50 mg) orally or intravenous equivalent.

Patients who were receiving oral prednisone (or prednisolone equivalent) at randomization were tapered off steroids by Weeks 4−6 (and no later than Week 8) and were to remain off steroids to Week 52.

At baseline, the median age of patients was 9 years (range 2 to 22 years), 64% were 2 years to less than 12 years of age, 65% were male, median disease duration was 46 months, 25% were Hispanic or Latino, 27 % were Asian, 14% were Black or African American, and 55% were White. The mean eGFR was 171 mL/min/1.73 m², mean UPCR was 0.05 g/g, 45% had FRNS, and 55% had SDNS.

A total of 75% had received prior immunosuppressive therapy other than steroids for INS and 85% were receiving glucocorticoids at baseline. Of the 85 patients, 1 (2%) in the GAZYVA arm and 9 (22%) in the MMF arm discontinued their randomized treatment during the 52-week treatment period.

The primary endpoint was the proportion of patients who did not relapse after Week 8 and were in complete remission at one year, defined as first morning void UPCR ≤ 0.2 g/g at Week 52. Relapse was defined as any of the following: (1) UPCR ≥ 2 g/g, or (2) 3 consecutive daily (home-monitoring) urine dipstick readings of 3+ proteinuria and UPCR > 0.2 g/g in the last of those three urines, or (3) urine dipstick reading of 3+ proteinuria on any single day accompanied by edema and most recent UPCR > 0.2 g/g. In addition, patients were non-responders if they had (1) used systemic corticosteroids for > 14 days in a 30 day period (after Week 8), (2) initiated rescue therapy other than systemic corticosteroids prior to 52 weeks, (3) died prior to 52 weeks, (4) missing UPCR assessments at Week 52.

Efficacy Results

The proportion of patients who did not relapse after Week 8 and were in complete remission at Week 52 was significantly greater (95%) in the GAZYVA as compared to the MMF arm (73%) (see Table 23). Key secondary outcome measures are shown in Table 23.