Regkirona - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Regkirona 60 mg/mL concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 960 mg of regdanvimab*.

Each mL of concentrate contains 60 mg of regdanvimab.

• * Regdanvimab is a recombinant human IgG1 monoclonal antibody produced through recombinant DNA technology in a mammalian cell line (Chinese Hamster Ovary).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion (sterile concentrate)

Clear to opalescent, colourless to pale yellow solution with pH of 5.7– 6.3 and osmolality of 250 –300 mOsmol/kg

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Regdanvimab is indicated for the treatment of adults with coronavirus disease 2019 (COVID-19) who do not require supplemental oxygen and who are at increased risk of progressing to severe COVID-19 (see section 5.1).

4.2 Posology and method of administration

Regdanvimab should only be administered in settings in which health care providers have immediate access to appropriate resuscitation equipment and medicinal products to treat a severe infusion reaction, including anaphylaxis, and where patients can be clinically monitored during administration and be observed for at least 1 hour after infusion is complete (see section 4.4).

Posology

The recommended dosage of regdanvimab in adults is a single IV infusion of 40 mg/kg. Regdanvimab should be administered within 7 days of onset of symptoms of COVID-19 (see section 5.1).

The volume of Regkirona is calculated as follows.

Calculation to determine the total volume of Regkirona to be administered:

Patient’s body weight (kg) x Regkirona dose (40 mg/kg) = Volume of Rekirona (mL) = o ume o eg rona (m )

Vial concentration (60 mg/mL)

Calculation to determine the total number of Regkirona vials needed:

Total Regkirona volume (mL) to be administered

Total volume per vial (16 mL/vial)

Table 1:         Sample calculations for patients receiving the recommended dose of 40 mg/kg

of Regkirona for weights ranging from 40 kg to 120 kg

Body weight (kg)	Total dose (mg)	Volume (mL)	Vials (n)
40	1,600	27	2
60	2,400	40	3
80	3,200	53	4
100	4,000	67	5
120	4,800	80	5

Note: If a patient’s weight is more than 200 kg, the dose calculation should use 200 kg. The maximal recommended dose is 8,000 mg.

Special populations

Elderly

No dose adjustment of regdanvimab is required in elderly patients (see section 5.2).

Renal impairment

No dose adjustments are recommended.

Hepatic impairment

No dose adjustments are recommended.

Paediatric population

The safety and efficacy of regdanvimab in paediatric patients have not yet been established. No data are available.

Method of administration

For intravenous use only.

Regdanvimab should be diluted and administered intravenously over 60 minutes.

The rate of infusion may be slowed or interrupted if the patient develops any signs of infusion-related reactions or other adverse reactions and appropriate treatment should be initiated as necessary (see section 4.4).

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Hypersensitivity including infusion-related reactions and anaphylactic reactions

Hypersensitivity reactions, including infusion-related and anaphylactic reactions, have been observed during and following administration of regdanvimab (see section 4.8).

Patients should be clinically monitored during administration and be observed for at least 1 hour after infusion is complete.

Signs and symptoms of infusion-related reactions may include fever, difficulty breathing, reduced oxygen saturation, chills, fatigue, arrhythmia (e.g., atrial fibrillation, tachycardia, bradycardia, palpitation), chest pain or discomfort, weakness, altered mental status, nausea, headache, bronchospasm, hypotension, hypertension, angioedema, throat irritation, rash including urticaria, pruritus, myalgia, vaso-vagal reactions (e.g., presyncope, syncope), dizziness and diaphoresis.

If an infusion-related reaction occurs, slowing or stopping the infusion should be considered and appropriate medicinal products and/or supportive care should be administered.

Antiviral resistance

The clinical trials with regdanvimab were conducted in subjects who were predominantly infected with the wild-type virus and the Alpha (UK origin/B.1.1.7 li­neage) variant. Clinical efficacy data for regdanvimab against some circulating SARS-CoV-2 variants with decreased in vitro susceptibility is currently limited (see section 5.1).

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacokinetic interactions

No interaction studies have been performed with regdanvimab.

Regdanvimab is a monoclonal antibody, which is not renally excreted or metabolised by cytochrome P450 enzymes; therefore, interactions with concomitant medicinal products that are renally excreted or that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are considered unlikely.

Pharmacodynamic interactions

No interaction studies have been performed.

4.6 Fertility, pregnancy and lactation

Pregnancy

Reproductive and developmental studies have not been performed with regdanvimab.

Nonclinical reproductive toxicity studies have not been conducted with regdanvimab (see section 5.3). In tissue cross-reactivity (TCR) studies with regdanvimab using human foetal and neonatal tissues, no binding of clinical concern was detected in the foetal tissues. Human immunoglobulin G1 (IgG1) antibodies are known to cross the placental barrier; therefore, regdanvimab has the potential to be transferred from the mother to the developing foetus. It is unknown whether the potential transfer of regdanvimab provides any treatment benefit or risk to the developing foetus.

Regdanvimab should be used during pregnancy only if the expected benefit to the mother justifies the potential risk to the foetus.

Breast-feeding

It is not known whether regdanvimab is excreted in human milk or absorbed systemically after ingestion. Administration of regdanvimab while breast-feeding can be considered when clinically indicated.

Fertility

No fertility studies have been performed.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

Overall, 906 subjects have been exposed to regdanvimab in clinical trials in both healthy subjects and non-hospitalised patients. The safety of regdanvimab is based on exposure of ambulatory (nonhospitalised) patients with COVID-19.

Tabulated list of adverse reactions

Adverse reactions reported with regdanvimab based on experience from clinical trials in healthy subjects and mild to moderate COVID-19 patients as well as adverse reactions reported from post-marketing experience are listed in Table 2 by system organ class and frequency. Frequencies are defined as follows: 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). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 2:         Tabulated list of adverse reactions

System organ class Frequency	Adverse reaction
Injury, poisoning and procedural complications
Uncommon	Infusion-related reactions1

• 1 Infusion-related reaction (IRR) includes hypersensitivity and anaphylaxis, and symptoms reported as IRRs are described below in ‘Infusion-related reactions’. Anaphylaxis was identified from postmarketing experience.

Description of selected adverse reactions

Infusion-related reactions

Immediate infusion-related reactions were noted for 0.6% of regdanvimab-treated patients and 1.2% of placebo-treated patients. Reported events of fever, pruritus, hypertension and dyspnoea were mild with two cases of fever being moderate and one case of hypertension being severe and palpitation, presyncope and urticaria were moderate in the regdanvimab-treated patients. All patients in the regdanvimab treatment group recovered from the events.

In post-marketing experience, one case of anaphylaxis was reported during infusion of regdanvimab with symptoms of dyspnoea, chest discomfort and cough.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Single doses up to 8,000 mg have been administered in clinical trials without dose-limiting toxicity. Treatment of overdose should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with regdanvimab.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, ATC code: not yet assigned

Mechanism of action

Regdanvimab is a recombinant human IgG1 monoclonal antibody that binds to the receptor binding domain (RBD) of the spike(s) protein of SARS-CoV-2 consequently blocking cellular entry and SARS-CoV-2 infection.

Antiviral activity

The in vitro neutralisation activity of regdanvimab against SARS-CoV-2 (BetaCoV/Kore­a/KCDC03/ 2020) was assessed by plaque reduction neutralisation test (PRNT) using VeroE6 cells. Regdanvimab neutralised this SARS-CoV-2 strain with an IC50 value of 9.70 ng/mL and an IC90 value of 25.09 ng/mL.

The plaque reduction neutralisation test (PRNT) using authentic SARS-CoV-2 variant virus indicate that regdanvimab retained activity against the Alpha (UK origin/B.1.1.7 li­neage), Zeta (Brazilian origin/P.2), Iota (New York origin/B.1.526) and Eta (Nigerian origin/B.1.525) variants. Reduced neutralising activity against Gamma (Brazilian origin/P.1), Beta (South African origin/B.1.351), Epsilon (Californian origin/B.1.427 and B.1.429), Kappa (Indian origin/B.1.617.1) and Delta (Indian origin/B.1.617.2) variants were observed (Table 3). Microneutralisation data using authentic SARS-CoV-2 variant virus indicate that regdanivimab retains activity against the Alpha variant and has reduced activity against the Beta and Gamma variants (Table 3).

Table 3: _______ Authentic SARS-CoV-2 and Pseudovirus Neutralisation Data for Regdanvimab

Lineage with Spike Protein Substitution	Key Substitutions Testeda	Fold Reduction in Susceptibility (Authentic Virus)	Fold Reduction in Susceptibility (Pseudovirus)f
B.1.1.7 (Alpha, UK)	N501Y/P681H	No changeb, d, e	No changeb
P.1 (Gamma, Brazil)	K417T/E484K/N501Y	137.88e/167.90d	61.42
P.2 (Zeta, Brazil)	E484K	No changeb, d	8.66
B.1.351 (Beta, South Africa)	K417N/E484K/N501Y	19.75e/310.06d	184.29
B.1.427 (Epsilon, California)	L452R	73.89d	34.97
B.1.429 (Epsilon, California)	L452R	54.08d	34.97
B.1.526 (Iota, New York)c	E484K/A701V	No changeb, d	6.84
B.1.525 (Eta, Nigeria)	E484K/Q677H	No changeb, d	7.22
B.1.617.1 (Kappa, India)	L452R/E484Q/P681R	23.89d	44.14
B.1.617.2 (Delta, India)	L452R/T478K/P681R	182.99d	27.70
AY.1 (Delta plus, India)	K417N/L452R/T478K	Not determined	63.65
C.37 (Lambda, Peru)	L452Q/F490S	Not determined	15.50

Lineage with Spike Protein Substitution	Key Substitutions Testeda	Fold Reduction in Susceptibility (Authentic Virus)	Fold Reduction in Susceptibility (Pseudovirus)f
B.1.621 (Mu, Columbia)	R346K/E484K/N501Y/ P681H	Not determined	38.65

a For variants with more than one substitution of concern, only the one(s) with the greatest impact on activity is(are) listed

b No change: <5-fold reduction in susceptibility

c Not all isolates of the New York lineage harbours E484K substitution (as of February 2021) d The study was conducted using plaque reduction neutralisation test

e The study was conducted using microneutrali­sation assay

f Key substitutions for global variants have been tested in a pseudovirus assay

Antiviral resistance

In vitro virus passaging with authentic SARS-CoV-2 viruses in VeroE6 cells in the presence/absence of regdanvimab identified a S494P amino acid substitution located in the RBD of the spike protein. Pseudovirus assay results with Q493K, Q493R, S494L and S494P showed IC50 above 500 ng/mL.

Clinical efficacy

A Phase 3 of Study CT-P59 3.2 was a randomised, double-blind, placebo-controlled clinical trial studying regdanvimab for the treatment of unvaccinated adult patients with mild to moderate COVID-19 and was conducted in multiple countries including the European Union (79.5%), the United States (7.6%) and Asia (0.9%). This study enrolled adult patients who were not hospitalised, had at least one or more symptoms of COVID-19 for <7 days, oxygen saturation >94% on room air and not requiring supplemental oxygen therapy and they were enrolled from January 18, 2021 and clinical efficacy endpoints were analysed based on data up to the cut-off date of May 21, 2021. Treatment was initiated after obtaining a positive SARS-CoV-2 viral infection determination.

A total of 1315 patients were randomised in a 1:1 manner to receive a single infusion of regdanvimab at doses of 40 mg/kg (N=656) or placebo (N=659) over 60 minutes.

The primary efficacy endpoint was the proportion of patients with clinical symptoms requiring hospitalisation, oxygen therapy, or experiencing mortality due to SARS-CoV-2 infection up to Day 28. This was analysed in all patients randomly assigned to the study drug, who are at increased risk of progressing to severe COVID-19 and/or hospitalisation (defined as having at least one of the following risk factors for severe COVID-19: age >50 years; BMI >30 kg/m2; cardiovascular disease, including hypertension; chronic lung disease, including asthma; type 1 or type 2 diabetes mellitus; chronic kidney disease, including those on dialysis; chronic liver disease; and immunosuppressed, based on investigator’s as­sessment).

Among all randomised patients, 66.9% of patients were at increased risk of progressing to severe COVID-19 and/or hospitalisation. Among patients at increased risk of progressing to severe COVID-19 and/or hospitalisation, the baseline median age was 54 years (range: 18 to 87); 19.4% of patients aged 65 or older and 4.0% of patients aged 75 or older; 53.6% of patients were male; 88.6% were White, 19.9% were Hispanic or Latino, 0.8% were Asian and 0.8% were Black or African American. The median time from the initial symptom onset was 4 days; mean viral load at baseline was 5.8 log10 copies/mL in the regdanvimab treatment group and 5.9 log10 copies/mL in placebo group. Forty-seven percent and 52.4% of patients had mild and moderate COVID-19, respectively. The most common risk factors were advanced age (age >50 years) (66.1%), cardiovascular disease, including hypertension, (50.3%) and obesity (BMI >30 kg/m2) (47.2%).

Proportion of patients with clinical symptom requiring hospitalisation, oxygen therapy, or experiencing mortality due to SARS-CoV-2 infection up to Day 28

Table 4: _______ Result of Primary Endpoint in Study CT-P59 3.2 (Phase 3)

		Regdanvimab (40 mg/kg IV infusion)	Placebo
Proportion of Patients with Clinical Symptoms Requiring Hospitalisation, Oxygen Therapy, or Experiencing Mortality due to SARS-CoV-2 Infection up to Day 28	Proportion (n, %)	14/446 (3.1%)	48/434 (11.1%)
	Difference (95% CI)a	–8.0 (-11.7, –4.5)
	P-valueb	<0.0001

Note: Clinical symptom which requires hospitalisation, oxygen therapy, or experiencing mortality due to SARS-CoV-2 infection up to Day 28 is included. Criterion of hospitalisation is >24 hours of acute care. Criteria of oxygen therapy are at least 24 hours of supplemental oxygen care and SpO2 measure in room air before applying supplemental oxygen showing <94%.

a The difference of proportions between two treatment groups estimated using CMH (Cochran-Mantel-Haenszel) weights, and the 95% stratified Newcombe confidence interval (CI) with CMH weights are presented. Analysis was stratified by Age (>60 years vs. <60 years), baseline comorbidities (Yes vs. No) and region (United States vs. European Union vs. other).

b The p-value from stratified CMH test is presented. The CMH test is stratified by age (>60 years vs. <60 years), baseline comorbidities (Yes vs. No) and region (United States vs. European Union vs. other).

In addition, a total of 3 patients died (1 regdanvimab-treated patient and 2 placebo-treated patients) due to worsening of COVID-19.

Time to Clinical Recovery up to Day 14

Time to clinical recovery was defined as time from study drug administration to the time when symptoms, which were scored as ‘moderate’ or ‘severe’ at baseline reduced to ‘mild’ or ‘absent’, and symptoms scored as ‘mild’ or ‘absent’ at baseline were scored as ‘absent’. Symptoms ‘absent’ in intensity at baseline should maintain as ‘absent’ for at least 48 hours. Symptoms that were absent at baseline but became ‘severe’, ‘moderate’, or ‘mild’ in intensity during the study were considered clinically recovered if it changed back to ‘absent’ for at least 48 hours. Missing symptoms at baseline were considered to be clinically recovered if they were ‘absent’ for at least 48 hours. Symptoms assessed were limited to feeling feverish, cough, shortness of breath or difficulty breathing, sore throat, body pain or muscle pain, fatigue, and headache.

The median time to clinical recovery (at least 48 hours) in all randomised patients who are at increased risk of progressing to severe COVID-19 and/or hospitalisation (as defined above) was significantly shorter for regdanvimab-treated patients as compared to placebo-treated patients (median, 9.27 days vs. not calculated). As less than 50% of the patients in the placebo group achieved clinical recovery up to Day 14, it was not possible to calculate the median time to clinical recovery up to Day 14. However, it can be considered that the patients in the regdanvimab treatment group demonstrated a shortened time to clinical recovery of at least 4.73 days compared to the placebo group assuming the median time to clinical recovery in the placebo-treated patients as a minimum of 14 days. The difference in time to clinical recovery between the treatment groups was statistically significant (p<0.0001 [stratified log-rank test]; clinical recovery ratio [95% CI] = 1.58 [1.31, 1.90]).

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Regkirona in the treatment of Coronavirus disease 2019 (COVID-19) in one or more subsets of the paediatric population (see section 4.2 and section 5.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption and distribution

Following the administration of the recommended dose regimen (a single dose of 40 mg/kg) in COVID-19 patients, the mean (CV%) Cmax level was 1017 pg/mL (27%).

The mean (CV%) apparent volume of distribution at steady-state (Vss) after intravenous administration of regdanvimab 40 mg/kg was 83 mL/kg (26%) in COVID-19 patients.

Elimination

Regdanvimab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. No major age- or weight-related differences in clearance or volume of distribution were observed in COVID-19 patients.

In studies with COVID-19 patients, the mean (CV%) clearance of regdanvimab 40 mg/kg was 0.20 mL/hr/kg (­24%).

In patients with COVID-19, the mean (CV%) terminal half-life for 40 mg/kg of regdanvimab was 17 days (37%).

Linearity

Based on the PK analysis in healthy subjects, regdanvimab was approximately dose proportional in terms of maximal and systemic exposure (Cmax, AUC0-last, and AUC0-inf) over the dose range of 10 mg/kg to 80 mg/kg.

Other special populations

Elderly

Based on pharmacokinetic subgroup analyses, there is no difference in pharmacokinetics of regdanvimab in elderly patients compared to younger patients.

Paediatric patients

The pharmacokinetics of regdanvimab in paediatric patients has not been evaluated.

Hepatic and renal impairment

The pharmacokinetics of regdanvimab has not been evaluated in patients with renal and/or hepatic impairment. Regdanvimab is not eliminated intact in the urine, thus renal impairment is not expected to affect the exposure of regdanvimab.

5.3 Preclinical safety data

Non-clinical data revealed no special hazard for humans based on conventional studies of tissue crossreactivity and repeated dose toxicity.

In a 3-week repeat-dose toxicity study in cynomolgus monkeys, transient moderate to marked decreases in neutrophils and haematology parameter changes were observed in 20% of animals at a dose of about 9 times the human clinical exposure.

In the TCR studies with regdanvimab using human adult, neonatal, and cynomolgus tissues, specific positive stainings in meningeal arachnoid cap cells in the brain and/or spinal cord tissues were observed. These findings were not associated with neurological symptoms and histopathological findings in the toxicity study, indicating that this TCR finding is less likely to have clinical relevance.

Carcinogenicity, genotoxicity and reproductive toxicology studies have not been conducted with regdanvimab.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

L-histidine

L-histidine monohydrochloride monohydrate

Polysorbate 80

L-arginine monohydrochloride

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Unopened vials

15 months

Diluted solution for infusion

Chemically and physical in-use stability has been demonstrated for 72 hours at 2°C – 8°C or 4 hours at <30°C after dilution in sodium chloride 9 mg/mL (0.9%) solution for infusion.

From a microbiological point of view, the prepared infusion solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C – 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C).

Do not freeze. Keep the medicinal product in its outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Type I glass vial with a chlorobutyl rubber stopper.

Pack size of 1 vial.

6.6 Special precautions for disposal and other handling

Preparation

Regkirona solution for infusion should be prepared by a qualified healthcare professional using aseptic technique:

• • Remove Regkirona vial(s) from refrigerated storage and allow to equilibrate to room

temperature (not exceeding 30°C) for approximately 20 minutes before preparation. Do not expose to direct heat. Do not shake the vial(s).

• • Regkirona is a clear to opalescent, colourless to pale yellow solution for infusion. Inspect

Regkirona vial(s) visually for particulate matter and discolouration prior to dilution. Should either be observed, the vial(s) must be discarded, and new vial(s) should be used for preparation.

• • Calculate total volume of Regkirona to be administered (see section 4.2).
• • Dilute Regkirona in a bag containing sodium chloride 9 mg/mL (0.9%) solution for infusion.

The total volume of the medicinal product and sodium chloride should be 250 mL.

o In a 250 mL bag of sodium chloride, withdraw and discard the required volume (which is identical to the calculated volume of Regkirona) of sodium chloride 9 mg/mL (0.9%) from the infusion bag.

o Withdraw the calculated volume of Regkirona from the vial(s) using a sterile syringe.

o Transfer Regkirona to the infusion bag.

• • Gently invert IV bag by hand approximately 10 times to mix. Do not shake.

Administration

Regkirona solution for infusion should be administered by a qualified healthcare professional.

• • Gather the recommended materials for infusion: Infusion set with in-line filter (PES

(Polyethersulfone) filter with a pore size of 1.2 gm or less would be recommended).

• • Attach the infusion set to the IV bag.
• • Prime the infusion set.
• • Administer as an IV infusion via pump over 60 minutes.
• • The prepared solution for infusion should not be administered simultaneously with any other

7. MARKETING AUTHORISATION HOLDER

Celltrion Healthcare Hungary Kft.

1062 Budapest

Vaci ut 1–3. WestEnd Office Building B torony

Hungary

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/21/1597/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 12 November 2021