Crovalimab

Crovalimab has not been studied in patients with moderate to severe hepatic impairment and no recommendation on posology can be provided.

Crovalimab and other C5 inhibitors bind different epitopes on C5 such that immune complexes comprised of the antibodies bridged by C5 may form when both are present in the circulation. These immune complexes, also referred to as drug-target-drug complexes (DTDCs), can comprise one or more units of C5 bound to both crovalimab and to another C5 inhibitor and are expected to be cleared within approximately 8 weeks (in the case of eculizumab). The immune complexes may be cleared after a longer duration in the case of switch from C5 inhibitors with an extended half-life such as ravulizumab. In some patients, the formation of these complexes results in Type III immune complex reactions. In patients switching from another C5 inhibitor therapy, a transient increase in clearance is observed due to the formation of the immune complexes, leading to a faster elimination of crovalimab. However, this transient increase in clearance is not clinically relevant and does not require dose adjustment in patients switching from another C5 inhibitor.

Due to its mechanism of action, crovalimab must be administered with caution to patients with active systemic infections. Patients may have increased susceptibility to infections, especially with Neisseria spp. and other encapsulated bacteria. Vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections should be administered according to local guidelines.

If local guidelines mandate vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections, this should be performed at least 2 weeks prior receiving the first dose of crovalimab. If immediate treatment with crovalimab is indicated in an unvaccinated patient, the required vaccine should be administered as soon as possible and patients should receive prophylactic antibiotics from the time they start crovalimab until 2 weeks after vaccination or according to local standard of care, whichever is longer.

If crovalimab is administered to patients with active systemic infections, patients should be monitored closely for signs and symptoms of worsening infection. Patients were excluded from clinical studies with crovalimab if they had any active systemic bacterial, viral, or fungal infection within 14 days prior to starting treatment.

Patients should be provided with information from the package leaflet to increase their awareness of the signs and symptoms of potential serious infections.

There is no data from the use of crovalimab in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Human IgG is known to cross the placenta after first trimester of pregnancy. Based on its mechanism of action, crovalimab may potentially cause terminal complement inhibition in the foetal circulation.

Therefore, the use of crovalimab may be considered in pregnant women if the clinical condition of the woman requires treatment with crovalimab.

It is not known whether crovalimab is excreted into human breast milk. Human IgG1 is known to be excreted in human milk. A risk to the breastfed infant cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue from crovalimab therapy taking into account the benefit of breast-feeding for the infant and the benefit of therapy for the mother.

Fertility

No clinical data are available on the effect of crovalimab on human fertility. Animal data from repeated-dose toxicity studies showed no effect on male or female reproductive organs.

Crovalimab has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most common adverse reactions observed were Type III immune complex mediated reaction (18.9% in patients who switched from treatment with another C5 inhibitor to crovalimab), upper respiratory tract infection (18.6%), pyrexia (13.5%), headache (10.9%) and infusion-related reaction (10.2%). The most common serious adverse reactions observed were Type III immune complex mediated reaction (4.0% in patients who switched from treatment with another C5 inhibitor to crovalimab) and pneumonia (1.5%).

The safety results from the 44 patients in the COMPOSER study where the median treatment duration was 4.69 years (range: 0.4-6.3 years) did not reveal any additional safety concerns associated with long term use of crovalimab.

Tabulated list of adverse reactions

The safety of crovalimab in patients with PNH was evaluated in three Phase III studies, COMMODORE 2 (BO42162), COMMODORE 3 (YO42311), and COMMODORE 1 (BO42161), and one Phase I/II study (COMPOSER, BP39144).

The table below lists the adverse reactions that have been reported in association with the use of crovalimab in a pooled analysis of 393 patients enrolled in the Phase III studies, unless otherwise stated. The median treatment duration for crovalimab based on the pooled analysis of 393 patients was 64 weeks (range: 0.1-136.4 weeks).

Adverse reactions are listed by MedDRA system organ class. The corresponding frequency category for each adverse reaction is based on the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000). Within each frequency category, adverse reactions are presented in the order of decreasing seriousness.

Summary of adverse reactions occurring in patients treated with Piasky:

^* Type III immune complex mediated reaction (also referred to as Type III immune complex reaction) is limited to patients who switch from another C5 inhibitor to crovalimab or from crovalimab to another C5 inhibitor. The frequency of Type III immune complex reactions is reported for a subset of N=201 patients who switched from treatment with another C5 inhibitor to crovalimab, with incidence rates being calculated using these N=201 patients as the denominator. See below.

Description of selected adverse reactions

Type III immune complex reactions

Across Phase III studies, 19.4% (39 out of 201) of patients who switched from treatment with eculizumab or ravulizumab to crovalimab experienced a Type III immune complex reaction (reported as Type III immune complex mediated reaction). Of these 39 patients, 2 patients experienced a second Type III immune complex reaction after discontinuing crovalimab and switching to ravulizumab. The most common signs and symptoms that were reported were arthralgia and rash, and other symptoms reported include pyrexia, headache, myalgia, abdominal pain, asthenia/fatigue and axonal neuropathy. The median time to onset of a Type III immune complex reaction in patients who switched from treatment with eculizumab or ravulizumab to crovalimab was 1.6 weeks (range: 0.7-4.4 weeks), with 5.1% of patients (2 of 39) experiencing a Type III immune complex reaction with a time to onset that exceeded 4 weeks. Most cases of Type III immune complex reaction were transient with a median duration of 1.7 weeks (range 0.4-34.1 weeks). The majority of patients experienced a Grade 1 or 2 event (23 of 39 patients), with Grade 3 events affecting 8% (16 of 39) of crovalimab-treated patients who switched from eculizumab or ravulizumab. Most events resolved with no change in study treatment with crovalimab.

In the COMPOSER study, among 26 patients who switched from eculizumab to crovalimab, 2 patients each reported 1 adverse event of Type III immune complex reaction. These events were mild/moderate and non-serious. One additional patient developed a mild Type III immune complex reaction after discontinuing crovalimab and switching to a different C5 inhibitor.

Immunogenicity

Across two randomised Phase III studies (COMMODORE 1 and COMMODORE 2) and one single-arm Phase III study (COMMODORE 3), ADA status was evaluable in 392 patients. Out of these 392 patients, 118 (30.1%) were ADA-positive. No differences in the rates of adverse reactions typically associated with immunogenicity (such as infusion-related reactions, injection site reactions, or hypersensitivity) were observed between ADA-positive and ADA-negative patients.

Immunogenicity leading to loss of exposure and efficacy

Patients may develop ADAs that can interfere with crovalimab exposure. Out of 392 patients evaluated for ADA status, partial or complete loss of exposure associated with ADA onset was observed in 23 patients (5.9%); among them, 17 (4.3%) had a loss of pharmacological activity coinciding with a loss of exposure and with loss of efficacy, manifesting as a sustained loss of haemolysis control in 7 patients (1.8%).

In case of clinical signs of loss of efficacy, prompt evaluation by a healthcare professional should be sought.

Infusion and Injection-Related Reactions

Across Phase III studies, 10.2% of patients who were treated with crovalimab experienced an infusion related reaction. The most common signs and symptoms that were reported were headache (7.1%), rash (0.8%), dizziness (0.8%), abdominal pain (0.5%), erythema (0.5%), nausea (0.5%), pyrexia (0.5%), and paraesthesia (0.3%). All events reported were Grade 1-2.

Across Phase III studies, 8.4% of patients who were treated with crovalimab experienced an injection-related reaction. The most common signs and symptoms that were reported were headache (2.5%), injection site erythema (1.0%), injection site pain (1.0%), and injection site rash (1.0%). The majority of events were Grade 1-2.

Infections with encapsulated bacteria

Based on its mechanism of action, the use of crovalimab may potentially increase the risk of infections, particularly infections caused by encapsulated bacteria including Streptococcus pneumoniae, Neisseria meningitidis types A, C, W, Y, and B, and Haemophilus influenzae.

Across Phase III studies, infections with encapsulated bacteria that were reported were Klebsiella pneumoniae, Klebsiella (not otherwise specified), Haemophilus influenzae and Neisseria subflava, the latter of which caused an adverse event of bacteriaemia in a patient.

Paediatric population

In 12 paediatric PNH patients with body weight ≥40 kg (aged 13-17 years old) included in COMMODORE 1, COMMODORE 2 and COMMODORE 3 studies, the safety profile appeared similar to that observed in adult PNH patients. The adverse reactions associated with crovalimab that were reported in paediatric PNH patients are upper respiratory tract infection (16.7%), urinary tract infection (16.7%), fatigue (16.7%), pyrexia (16.7%), headache (8.3%), infusion-related reaction (8.3%) and injection-related reaction (8.3%).