2.1 Recommended Vaccination and Prophylaxis for Meningococcal Infection

Vaccinate patients for meningococcal infection (serogroups A, C, W, Y and B) according to current ACIP recommendations at least 2 weeks prior to initiation of PIASKY [see Warnings and Precautions (5.1)].

If urgent PIASKY therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible.

Healthcare providers who prescribe PIASKY must enroll in the PIASKY REMS [see Warnings and Precautions (5.2)].

2.2 Recommended Dosage Regimen

The recommended dosage regimen consists of one loading dose administered by intravenous (IV) infusion (on Day 1), followed by four additional weekly loading doses administered by subcutaneous (SUBQ) injection (on Days 2, 8, 15, and 22). The maintenance dose starts on Day 29 and is then administered every 4 weeks by subcutaneous injection. Administer doses based on the patient's actual body weight, as shown in Table 1.

The dosing schedule is allowed to occasionally vary within 2 days of the scheduled administration day (except at Day 1 and Day 2). If this occurs, the subsequent dose should be administered according to the regular schedule.

Modification of the maintenance dose is required if the patient's body weight changes to become consistently greater than or lower than 100 kg during the course of therapy.

2.3 Recommended Timing for Switching to PIASKY from Another C5 Inhibitor

Healthcare providers should consider the benefits of the timing of switching C5 inhibitors vs. the risks of Type III hypersensitivity reactions [see Warnings and Precautions (5.3)]. For patients switching from another C5 inhibitor (e.g., eculizumab or ravulizumab), the first intravenous loading dose of PIASKY should be administered no sooner than the time of the next scheduled complement inhibitor administration. The administration of the additional subcutaneous loading doses and maintenance doses of PIASKY should follow as per the schedule shown in Table 1.

2.4 Delayed or Missed Dose

If an entire planned dose or part of a planned dose of PIASKY is missed, administer the missed dose or remainder of the missed dose as soon as possible before the day of the next scheduled dose. Then administer the next dose on the regularly scheduled dosing day. Do not administer two doses or more than the prescribed dose on the same day to make up for a missed dose.

2.5 Preparation and Administration

Each vial of PIASKY is for one-time use in only one patient.

PIASKY is administered as an intravenous infusion (first dose) and as a subcutaneous injection (subsequent doses). Only healthcare providers should administer PIASKY.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. PIASKY is clear to opalescent, and an almost colorless to brownish-yellow solution. PIASKY should be discarded if the medicine looks cloudy, discolored, or has particles in it.

5.1 Serious Meningococcal Infection

PIASKY, a complement inhibitor, increases a patient's susceptibility to serious, life-threatening, or fatal infections caused by meningococcal bacteria (meningococcemia and/or meningitis) in any serogroup, including non-groupable strains. Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The initiation of PIASKY is contraindicated in patients with a serious unresolved Neisseria meningitidis infection.

Complete or update meningococcal vaccination (for serogroups A, C, W, Y, and B) at least 2 weeks prior to administration of the first dose of PIASKY, according to the current Advisory Committee on Immunization Practices (ACIP) recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations considering the duration of PIASKY therapy.

Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information.

If urgent PIASKY therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer meningococcal vaccines as soon as possible. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including PIASKY. The benefits and risks of treatment with PIASKY, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by N. meningitidis.

Vaccination does not eliminate the risk of meningococcal infections, despite development of antibodies following vaccination.

Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of PIASKY in patients who are undergoing treatment for serious meningococcal infection.

PIASKY is available only through a restricted program under a REMS [see Warnings and Precautions (5.2)].

5.2 PIASKY REMS

PIASKY is available only through a restricted program under a REMS called PIASKY REMS, because of the risk of serious meningococcal infections [see Warnings and Precautions (5.1)].

Notable requirements of the PIASKY REMS include the following:

• Prescribers must enroll in the REMS.
• Prescribers must counsel patients about the risk of serious meningococcal infection.
• Prescribers must provide the patients with the REMS educational materials.
• Prescribers must assess patient vaccination status for meningococcal vaccines (against serogroups A, C, W, Y, and B) and vaccinate if needed according to current ACIP recommendations two weeks prior to the first dose of PIASKY.
• Prescribers must provide a prescription for antibacterial drug prophylaxis if treatment must be started urgently, and the patient is not up to date with both meningococcal vaccines according to current ACIP recommendations at least two weeks prior to the first dose of PIASKY.
• Healthcare settings and pharmacies that dispense PIASKY must be certified in the REMS and must verify prescribers are certified.
• Patients must receive counseling from the prescriber about the need to receive meningococcal vaccines per ACIP recommendations, the need to take antibiotics as directed by the prescriber, and the signs and symptoms of meningococcal infection.
• Patients must be instructed to carry the Patient Safety Card with them at all times during and for 11 months following treatment with PIASKY.

Further information is available at www.PIASKYREMS.com or 1-866-4My-Skyy (469-7599).

5.3 Type III Hypersensitivity Reactions Related to Drug-Target-Drug Complexes

Patients who are switching from another C5 inhibitor (e.g., eculizumab or ravulizumab) to PIASKY or from PIASKY to another C5 inhibitor are at risk of serious Type III hypersensitivity reactions related to the formation of drug-target-drug-complexes (DTDCs), because PIASKY and these other C5 inhibitors bind different epitopes of C5 [see Drug Interactions (7)].

In clinical trials, Type III hypersensitivity reactions were reported in 39 of 201 patients (19%) who switched from eculizumab or ravulizumab to PIASKY. Four of these patients (10%) had not fully recovered from symptoms of Type III hypersensitivity reactions at the time of their last follow up visit. In addition, Type III hypersensitivity reactions were reported in 2 of 8 patients (25%) who switched from PIASKY to eculizumab or ravulizumab, including one patient who developed Grade 3 axonal neuropathy [see Adverse Reactions (6)].

Symptoms of Type III hypersensitivity reactions that occurred in more than 2 patients were arthralgia, rash, pyrexia, myalgia, headache, fatigue, petechiae and abdominal pain. Among patients who experienced Type III hypersensitivity reactions, 8 (21%) had events that were considered serious due to hospitalization. Symptoms of serious Type III hypersensitivity reactions included pyrexia and arthralgia. Type III hypersensitivity reactions can also cause renal abnormalities.

Healthcare providers should consider the benefits of the timing of switching C5 inhibitors vs. the risks of Type III hypersensitivity reactions. Patients are expected to no longer be at risk of Type III hypersensitivity reactions if the prior C5 inhibitor has been cleared from the body prior to starting PIASKY or if PIASKY has been cleared from the body prior to starting another C5 inhibitor. Therefore, initiating PIASKY sooner than 5.5 half-lives from the last dose of a C5 inhibitor (e.g., eculizumab or ravulizumab) or initiating a C5 inhibitor (e.g., eculizumab or ravulizumab) sooner than 5.5 half-lives from the last dose of PIASKY increases the risk of Type III hypersensitivity reactions.

Based on time-to-onset of Type III hypersensitivity reactions observed in clinical trials, patients should be monitored for the first 30 days of the new therapy for the occurrence of symptoms of Type III hypersensitivity reactions. For mild or moderate Type III hypersensitivity reactions, administer symptomatic treatment, such as topical corticosteroids, antihistamines, antipyretics, and/or analgesics. For severe reactions, initiate and taper oral or systemic corticosteroid therapy as clinically indicated.

5.4 Other Infections

Due to its mechanism of action, PIASKY may increase susceptibility to infections, especially with encapsulated bacteria, such as infections with Neisseria spp. but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria gonorrhoeae. Children treated with PIASKY may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Vaccinate patients against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP recommendations.

If PIASKY is administered to patients with active systemic infections, monitor closely for signs and symptoms of worsening infection. If the patient's infection worsens, consider whether to discontinue PIASKY.

5.5 Infusion- and Injection-Related Reactions

Administration of PIASKY may cause infusion-related reactions or systemic injection-related reactions, depending on the route of administration [see Adverse Reactions (6)]. These may include hypersensitivity reactions (including anaphylaxis) but also a range of other symptoms such as injection site pain, erythema, headache or myalgia. One patient experienced a serious infusion-related reaction that resolved 4 days after interruption of infusion with PIASKY. Instruct patients/caregivers to seek immediate medical attention if the patient develops symptoms of a serious hypersensitivity reaction and to report this reaction to their healthcare provider.

If a serious hypersensitivity reaction (including anaphylaxis) occurs, discontinue PIASKY treatment immediately, institute appropriate treatment, per standard of care, and monitor until signs and symptoms are resolved. PIASKY is contraindicated in patients with a known serious hypersensitivity reaction to crovalimab or any of the excipients.

5.6 Monitoring PNH Manifestations after Discontinuation of PIASKY

In case of PIASKY discontinuation, patients who do not switch to another treatment for PNH, must be closely monitored for at least 20 weeks for signs and symptoms of serious hemolysis, identified by elevated lactate dehydrogenase (LDH) levels, along with a sudden decrease in hemoglobin, or re-appearance of symptoms such as fatigue, hemoglobinuria, abdominal pain, dyspnea, major adverse vascular events (including thrombosis), dysphagia, erectile dysfunction or renal impairment.

If signs and symptoms of hemolysis occur after discontinuation of PIASKY, consider restarting treatment with PIASKY, if appropriate, or initiating another treatment for PNH.

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of PIASKY for the treatment of PNH have been established in pediatric patients 13 years and older with a body weight ≥ 40 kg. Use of PIASKY for this indication in pediatric patients is supported by evidence from adequate and well-controlled studies in adults along with additional pharmacokinetic, pharmacodynamic, efficacy and safety data in pediatric patients aged 13 to 17 years [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)].

The safety and effectiveness of PIASKY have not been established in pediatric patients less than 13 years of age and in those with body weight < 40 kg.

8.5 Geriatric Use

Clinical studies of PIASKY did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other therapy.

Of the 393 PIASKY-treated patients in COMMODORE 1, 2 and 3, 43 (10.9%) were 65 years of age and older. In patients who were complement inhibitor naïve, serious adverse reactions were reported in 1 patient (8%) who was 65 years or older compared to 6 (4%) patients who were 18 to 64 years of age. In patients who previously received a different C5 inhibitor and switched to PIASKY, serious adverse reactions were reported in 3 (7%) patients who were 65 years or older compared to 12 (4%) patients who were 18 to 64 years of age.

12.1 Mechanism of Action

Crovalimab-akkz is a monoclonal antibody that specifically binds with high affinity to the complement protein C5, inhibiting its cleavage into C5a and C5b, preventing the formation of the membrane attack complex (MAC). Crovalimab-akkz inhibits terminal complement-mediated intravascular hemolysis in patients with PNH.

12.2 Pharmacodynamics

Concentration-dependent inhibition of terminal complement activity following treatment with PIASKY was observed in patients with PNH naïve to complement inhibitor therapy and patients switching from another complement C5 inhibitor therapy. Terminal complement activity (CH50 as measured by Liposome Immunoassay [LIA]) inhibition was achieved by the end of the initial PIASKY infusion and was sustained through the duration of PIASKY treatment. Similarly, mean free C5 concentrations declined to low levels (<0.0001 g/L) in comparison to baseline and remained low throughout the treatment period.

12.3 Pharmacokinetics

Crovalimab-akkz exhibits dose proportional pharmacokinetics over the dose range from 75 to 1500 mg when given as a single intravenous infusion and from 100 to 1020 mg when given as a subcutaneous injection. Following the first intravenous loading dose, crovalimab-akkz concentrations exceeded the target threshold for complete terminal complement inhibition (100 µg/mL). After approximately 12 weeks, with the administration of subsequent subcutaneous doses, crovalimab-akkz attained a steady-state plateau of exposure. Pharmacokinetic exposures in patients with PNH are summarized for the recommended dosage of crovalimab-akkz in Table 6.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including other crovalimab-akkz products.

In the active-controlled COMMODORE 2 study, 30% (42/140) of treatment-naïve patients who received PIASKY and 34% (23/67) of patients who switched from treatment with another C5 inhibitor to PIASKY (switch patients) tested positive for anti-crovalimab-akkz-antibodies. The positive antidrug antibodies (ADAs) were detected after a median treatment duration of 48 weeks (range: 0.1 to 108 weeks) in treatment-naïve patients and 24 weeks (range: 0.3 to 76 weeks), in switch patients.

Across COMMODORE 1, COMMODORE 2, and COMMODORE 3, the incidence of treatment-emergent ADAs was 31% (60/191) following a median treatment duration of 52 weeks (range 0.1 to 108 weeks) in treatment-naïve patients and 23% (43/184) following a median treatment duration of 32 weeks (0.3 to 108 weeks) in switch patients.

Among the patients who were randomized to PIASKY, those who developed anti-crovalimab-akkz antibodies had reduced crovalimab-akkz concentrations, geometric mean decrease in the range of 39% to 56%, compared to those who did not develop anti-crovalimab-akkz antibodies through the course of the treatment period in COMMODORE 2. Despite this effect, crovalimab-akkz concentrations remained above 100 µg/mL (the threshold for complete terminal complement inhibition) in more than 80% of ADA-positive patients. Approximately 3% (11/375) of ADA-positive patients had a loss of pharmacological activity (based on CH50 or free C5) coinciding with a loss of exposure and with loss of efficacy, manifesting as a sustained loss of hemolysis control in 1.6% (6/375) of patients with PNH. There was no evidence for a clinical impact of ADA status on the safety profile of PIASKY.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies and genotoxicity studies have not been conducted with crovalimab-akkz. No effects on female or male reproductive organs were observed in cynomolgus monkeys following repeated administration of crovalimab-akkz for up to 6 months with subcutaneous doses up to 100 mg/kg/week which corresponds to 18- and 16- times for males and females, respectively, the MRHD based on AUC.

14.1 Paroxysmal Nocturnal Hemoglobinuria

The efficacy of PIASKY in patients with PNH was evaluated in COMMODORE 2 (NCT04434092), an active-controlled, open-label, non-inferiority study that randomized 204 patients (body weight ≥ 40 kg) with PNH not previously treated with a complement inhibitor in a 2:1 ratio to receive either PIASKY (n=135) or eculizumab (n=69). The study additionally enrolled 6 pediatric patients (aged >12 years and body weight ≥ 40 kg) to receive PIASKY in a separate non-randomized cohort.

Patients were required to be vaccinated against Neisseria meningitidis, either within 3 years prior to the start of treatment or within 7 days after starting treatment with PIASKY. Patients vaccinated within 2 weeks prior to initiating PIASKY or after the start of study treatment received prophylactic antibiotics until at least 2 weeks after the vaccination.

A single intravenous loading dose of PIASKY was given on Day 1 (1,000 mg for patients weighing ≥40 kg to <100 kg, or 1,500 mg for patients weighing >100 kg), followed by four additional weekly subcutaneous loading doses of 340 mg on Days 2, 8, 15 and 22. Starting at Day 29, maintenance subcutaneous doses were given every 4 weeks (680 mg for patients weighing ≥40 kg to <100 kg, or 1,020 mg for patients weighing ≥100 kg).

The study consisted of a primary treatment period of 24 weeks, after which patients had the option to continue or switch to PIASKY in an extension period.

Eligible patients had LDH level ≥ 2 × upper limit of normal (ULN) and at least one or more PNH-related signs or symptoms in the past 3 months. Randomization was stratified by the most recent LDH value (≥ 2 to ≤ 4 × ULN, or > 4× ULN) and by the transfusion history (0, > 0 to ≤ 6, or > 6 packed red blood cell (pRBC) units administered within 6 months prior to randomization). In the PIASKY and eculizumab arms, the median PNH clone size was 90.9% and 95.1% for monocytes, 91.4% and 93.6% for granulocytes and 25.3% and 44.6% for erythrocytes, respectively.

Demographics and baseline characteristics of the randomized study population were generally balanced between the treatment arms and are presented in Table 7.

Efficacy was based on hemolysis control, as measured by the mean proportion of patients with LDH ≤ 1.5× ULN from Week 5 to Week 25; and the proportion of patients who achieved transfusion avoidance, defined as patients who were pRBC transfusion-free, from baseline through Week 25. Other efficacy endpoints included the proportion of patients with breakthrough hemolysis and the proportion of patients with stabilized hemoglobin. Breakthrough hemolysis was defined as at least one new or worsening symptom or sign of intravascular hemolysis in the presence of elevated LDH ≥ 2 × ULN after prior reduction of LDH to ≤ 1.5 × ULN on treatment. Hemoglobin stabilization was defined as avoidance of a ≥ 2 g/dL decrease in hemoglobin level from baseline, in the absence of transfusion.

Efficacy results for these endpoints are shown in Table 8.

16.1 How Supplied

PIASKY (crovalimab-akkz) injection is a sterile, preservative-free, clear to opalescent, and almost colorless to brownish-yellow solution. Each PIASKY carton contains one 340 mg/2 mL (170 mg/mL) single-dose vial (NDC 50242-115-01).

16.2 Storage and Handling

• Store refrigerated at 2°C to 8°C (36°F to 46°F) in the outer carton to protect from light. Do not freeze. Do not shake.
• Once removed from the refrigerator, the unopened vial can be kept at room temperature up to 30°C (86°F) in its outer carton for no longer than 7 days.
• Prior to administration, unopened vials of PIASKY may be stored out of the refrigerator at room temperature if needed and then returned to refrigeration. The total combined time out of refrigeration should not exceed 7 days and the temperature should not exceed 30°C (86°F). Discard if stored out of the refrigerator at room temperature for longer than 7 days.

Serious Meningococcal Infection

Advise patients of the risk of serious meningococcal infection. Inform patients of the need to complete or update their meningococcal vaccinations at least 2 weeks prior to receiving the first dose of PIASKY or receive antibacterial drug prophylaxis if PIASKY treatment must be initiated immediately and they have not previously been vaccinated. Inform patients of the requirement to be revaccinated according to current ACIP recommendations for meningococcal infection while on PIASKY therapy.

Inform patients that vaccination may not prevent serious meningococcal infection and to seek immediate medical attention if the following signs or symptoms occur [see Warnings and Precautions (5.1)].

• fever
• fever and a rash
• headache with nausea or vomiting
• fever with a high heart rate
• headache and a fever
• headache with a stiff neck or stiff back
• confusion
• muscle aches, with flu-like symptoms
• eye sensitive to light

Inform patients that they will be given a Patient Safety Card for PIASKY that they should carry with them at all times during and for 11 months following treatment with PIASKY. This card describes symptoms which, if experienced, should prompt the patient to immediately seek medical evaluation.

PIASKY REMS

PIASKY is available only through a restricted program called PIASKY REMS [see Warnings and Precautions (5.2)].

Inform the patient of the following requirements:

• Patients must receive counseling about the risk of serious meningococcal infections.
• Patients must receive written educational materials about this risk.
• Patients must be instructed to carry the Patient Safety Card with them at all times during and for 11 months following treatment with PIASKY.
• Patients must be instructed to complete or update meningococcal vaccines for serogroups A, C, W, Y and B per ACIP recommendations as directed by the prescriber prior to treatment with PIASKY.
• Patients must receive antibiotics as directed by the prescriber if they are not up to date with meningococcal vaccines and have to start PIASKY right away.

Type III Hypersensitivity Reactions

Inform patients of the risk of experiencing a Type III hypersensitivity reaction in the first 30 days after switching from another C5 inhibitor to PIASKY (or if they are planning to switch from PIASKY to another C5 inhibitor) [see Warnings and Precautions (5.3)]. Inform patients about the signs and symptoms of a Type III hypersensitivity reaction, and advise patients to seek immediate medical attention if the following signs or symptoms occur:

• rash
• itching
• joint pain
• numbness and tingling or a feeling of pins and needles, especially of the hands and feet

Other Infections

Counsel patients of the increased risk of infections, particularly those due to encapsulated bacteria, especially Neisseria species [see Warnings and Precautions (5.4)]. Advise patients of the need for vaccination against Streptococcus pneumoniae infections according to current ACIP recommendations. Inform parents or caregivers of children receiving PIASKY that their child should be vaccinated against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) according to current medical guidelines.

Advise patients to report any new signs and symptoms of infection.

Infusion- and Injection-Related Reactions

Advise patients that administration of PIASKY may result in infusion-related reactions or systemic injection-related reactions depending on the route of administration [see Warnings and Precautions (5.5)]. Advise patients to seek immediate medical attention if symptoms of serious allergic reactions occur.

Discontinuation of PIASKY

Inform patients that they may develop hemolysis due to PNH when PIASKY is discontinued and that they will be closely monitored by their healthcare professional for at least 20 weeks following PIASKY discontinuation [see Warnings and Precautions (5.6)]. Inform patients who discontinue PIASKY to keep the Patient Safety Card with them for 11 months after the last PIASKY dose, because the increased risk of meningococcal infection persists for several months following discontinuation of PIASKY [see Warnings and Precautions (5.1 and 5.2)].

Lactation

Advise patients it is not recommended to breastfeed during treatment with PIASKY and for 9 months after the final dose [see Use in Specific Populations (8.2)].