Dawnzera 80 mg solution for injection in pre-filled pen

Dawnzera is indicated for routine prevention of recurrent attacks of hereditary angioedema (HAE) in adults and adolescents aged 12 years and older.

Treatment is to be initiated under the supervision of a physician experienced in the diagnosis and management of patients with HAE.

Posology

The recommended starting dose in adult and adolescent patients aged 12 years and older is 80 mg donidalorsen by subcutaneous injection once monthly.

A dosing interval of 80 mg once every 2 months may be considered if the patient is well controlled (e.g., attack free) for at least 3 months while receiving Dawnzera.

Based on the clinical data, a gradual reduction in attack rate is seen as early as Week 1 after the initial dose of donidalorsen with an expected maximum effect after 1 month.

Consideration should be given to discontinuing treatment in patients with normal C1-INH HAE (nC1- INH) who have shown insufficient reduction in attacks after 4 months of treatment (see section 4.4 and 5.1).

Dawnzera is not intended for the treatment of acute HAE attacks (see section 4.4).

Missed dose

If a dose is missed, the patient or caregiver should be instructed to administer the dose as soon as possible. Thereafter, dosing should be resumed at the prescribed dosing frequency (once monthly or once every 2 months) from the date of the most recently administered dose.

Special populations

Elderly

No dose adjustment is required for patients above 65 years of age (see section 5.2).

Hepatic impairment

No dose adjustment of donidalorsen is required for patients with mild hepatic impairment (see section 5.2).

Dawnzera has not been studied in patients with moderate or severe impairment. Donidalorsen should only be used in these patients if the anticipated clinical benefit outweighs the risk.

Renal impairment

No dose adjustment of donidalorsen is required for patients with mild renal impairment.

Dawnzera has not been studied in patients with moderate or severe impairment or end stage renal disease. Donidalorsen should only be used in these patients if the anticipated clinical benefit outweighs the risk.

Paediatric population

The safety and efficacy of donidalorsen in children aged < 12 years have not yet been established. No data are available.

See sections 4.8 and 5.1.

Changing from other HAE prophylactic medicinal products

The following treatment schedules (Table 1) are recommended for patients that are changing their HAE prophylactic therapy from berotralstat, a C1 esterase inhibitor, or lanadelumab to Dawnzera (see section 5.1).

Table 1: Treatment schedule for patients changing from other prophylactic therapy to Dawnzera.

Method of administration

Dawnzera is intended for subcutaneous use only.

Dawnzera is to be administered as a subcutaneous injection in the abdomen, upper thigh region, or for caregivers only, the back of the upper arm. Rotation of the injection site is recommended.

Dawnzera must not be injected into areas where the skin is tender, bruised, red, hard, infected or discoloured.

After proper training on correct subcutaneous injection technique, a patient or caregiver may inject Dawnzera if their physician determines it is appropriate. Comprehensive instructions for administration using the pre-filled pen are provided in the package leaflet and the instructions for use.

For further instructions on preparation and special precautions for handling, see section 6.6.

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

Hypersensitivity including anaphylaxis

Hypersensitivity reactions including anaphylaxis have been observed (see section 4.8). In case of a severe hypersensitivity reaction, administration of donidalorsen must be stopped immediately and appropriate treatment must be initiated.

Patients must be advised on the signs and symptoms of hypersensitivity reactions and instructed to promptly seek medical attention and to discontinue use of donidalorsen if serious hypersensitivity reactions occur.

General

Dawnzera is not intended for treatment of acute HAE attacks. In case of a breakthrough HAE attack, individualised treatment should be initiated with an approved rescue medicinal product.

There are limited data available on the use of donidalorsen in HAE patients with HAE-nC1INH (see section 5.1). Patients with HAE nC1-INH having mutations that are not associated with the kallikrein-kinin system (KKS) pathway are not expected to respond to Dawnzera.

It is recommended to perform genetic testing, if available, according to current HAE guidelines and to discontinue the treatment if clinical response is not observed (see sections 4.2 and 5.1).

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

No clinical drug-drug interaction studies have been performed with donidalorsen. In vitro studies show that donidalorsen is not a substrate or inhibitor of transporters, does not interact with highly plasma protein bound active substances, and is not a substrate or inhibitor/inducer of cytochrome P450 (CYP) enzymes. Donidalorsen is not expected to cause or be affected by drug-drug interactions mediated through drug transporters, plasma protein binding, or CYP enzymes.

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of donidalorsen in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of donidalorsen during pregnancy.

Breast-feeding

Available pharmacodynamic/toxicological data in animals have shown excretion of donidalorsen/metabolites in milk (see section 5.3).

A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from donidalorsen therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No clinical data on the effect of this medicinal product on human fertility are available. Donidalorsen had no effect on fertility and early embryonic development toxicity in murine models (see section 5.3).

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

Summary of the safety profile

The most frequently observed adverse drug reactions (ADRs) in patients treated with 80 mg donidalorsen every 4 weeks were injection site reactions (24.4 %).

Tabulated list of adverse reactions

Adverse reactions associated with donidalorsen obtained from clinical trials are tabulated below.

All ADRs are listed by system organ class and frequency; 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) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2: Adverse drug reactions to donidalorsen

^a Injection site reactions include also: erythema, discolouration, pain, pruritus, induration, haematoma, bruising, exfoliation, hypersensitivity and swelling.

^b mainly mild, and mostly in alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

Description of selected adverse reactions

Hypersensitivity including anaphylaxis

In clinical trials, a serious hypersensitivity reaction of anaphylaxis was reported in one patient. Symptoms included generalised rash, dyspnoea, chest pain and peri-oral swelling (see sections 4.3 and 4.4).

Injection site reactions

During double-blinded, placebo-controlled trials, injection site reactions were observed. All injection site reactions were non serious, mild to moderate in severity, and generally resolved over time. In some patients, the injection site reactions such as injection site erythema, injection site pruritus, and injection site discolouration persisted for 2 or more days. In one patient who received higher than labelled doses in accordance with the protocol, injection site discoloration led to permanent discontinuation of treatment.

Paediatric population

The safety of donidalorsen was evaluated in a double-blind placebo-controlled clinical trial in a subset of 7 adolescent patients aged 12 to 17 years. The safety profile in these adolescent patients was similar to the profile observed in adult patients.

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 Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

There is no available information to identify potential signs and symptoms of overdose. If symptoms should occur, symptomatic treatment is recommended. There is no antidote available.

Pharmacotherapeutic group: Other haematological agents, drugs used in hereditary angioedema, ATC code: B06AC09.

Mechanism of action

Donidalorsen is a 2'-O-methoxyethyl–modified antisense oligonucleotide (ASO) conjugated to a triantennary N-acetylgalactosamine (GalNAc₃) moiety that causes ribonuclease H1 (RNase H1) mediated degradation of prekallikrein (PKK) mRNA through selective binding to PKK mRNA, which results in reduced production of PKK protein. PKK is a pro-enzyme for plasma kallikrein, which results in the release of bradykinin, a potent vasodilator causing inflammation and swelling in HAE.

Pharmacodynamic effects

In Trial 1, a 24-week multicenter, randomised, double blind, placebo-controlled trial in adult and paediatric patients (≥ 12 years) with HAE 1 or HAE 2 (see clinical efficacy and safety below), a decrease in plasma PKK concentrations was observed. The mean percentage change from baseline to Week 24 in trough plasma PKK concentrations indicated reductions of 73 % and 47 % following treatment with donidalorsen 80 mg every 4 weeks and every 8 weeks, respectively, compared with 2 % in the placebo group.

Clinical efficacy and safety

The efficacy of Dawnzera for the prevention of angioedema attacks in patients was studied in Trial 1.

Trial 1- “OASIS-HAE”

Trial 1 included 90 (48 female and 42 male) adult and paediatric patients (≥ 12 years) with at least 2 investigator-confirmed attacks during the 8-week run in period, who received at least 1 dose of investigational medicinal product (IMP). Paediatric patients were 7 adolescents aged 12 years and older; furthermore, the trial included 2 elderly patients (≥ 65 years). 3 patients had a body weight of < 50 kg at baseline, of which 2 were adolescents (see also section 5.2). Patients were randomised in a 2:1 ratio to 1 of 2 groups to receive study treatment either once every 4 weeks (q4wks group) or once every 8 weeks (q8wks group). Within each group, patients were randomised in a 3:1 ratio to receive Dawnzera 80 mg or a matching volume of placebo. The 2 placebo-treated groups were combined for analysis. Patients were required to discontinue other prophylactic HAE medicinal products prior to entering the trial; however, all patients were allowed to use rescue medicinal products for treatment of any breakthrough HAE attacks.

Overall, 93 % of patients had HAE 1 and 7 % had HAE 2. A history of laryngeal angioedema attacks was reported in 52 % of patients, and 18 % of patients were on prophylactic therapy prior to enrolment. The mean HAE attack rate during the prospective run-in period (baseline attack rate) was 3.33 (SD 2.086) attacks/4 weeks and an attack rate of > 2 attacks/4 weeks was observed in 69 % of patients overall.

Donidalorsen administered every 4 or 8 weeks produced statistically significant reductions in the HAE attack rate (number of investigator-confirmed HAE attacks per 4 weeks) compared to placebo. A sustained response to donidalorsen with mean decreases from baseline in the HAE attack rate was observed throughout the treatment period in the Dawnzera treatment groups.

Table 3: Results of primary and secondary efficacy endpoints (full analysis set)

CI = confidence interval; HAE = hereditary angioedema; LS = least square; N = number of patients in the specific treatment group; NS = not statistically significant; q4wks = every 4 weeks; q8wks = every 8 weeks.

* Primary efficacy endpoint = comparison of the time normalised number of investigator-confirmed HAE attacks per 4 weeks from baseline to Week 24 between the Dawnzera 80 mg q4wks group and the placebo group.

† Moderate: mild to moderate limitation in activity, some assistance needed; severe: marked limitation in activity, assistance required.

‡ Statistically significant.

For 4 adolescent patients (aged 12 to 17 years) in the q4wks group, a 97.1 % decrease (95 % CI: -106.26 %, -88.01 %) from baseline (run-in period) in the time-normalized HAE attack rate (per 4 weeks) from Week 0 to Week 24 was observed.

Additional pre-defined trial secondary endpoints included the proportion of responders to IMP and percentage of patients who had well controlled angioedema activity. The proportion of patients with a ≥50 %, ≥70 %, ≥90 %, and 100 % (attack free) reduction from baseline in HAE attack rate from Week 4 to Week 24 in the Dawnzera treatment group was 93 %, 82 %, 62 %, and 53 %, respectively, in the 80 mg q4wks group, and 83 %, 65 %, 48 %, and 35 %, respectively, in the 80 mg q8wks group, compared to 27 %, 18 %, 9 %, and 9 %, respectively, in the placebo group.

The number of patients who had well controlled disease at Week 24 in the Dawnzera treatment group based on the Angioedema Control Test (AECT) score ≥10 at

Week 24 was 41 (91 %) in the 80 mg q4wks group and 17 (74 %) in the 80 mg q8wks group, compared to 9 (41 %) in the placebo group.

Health-related quality of life

An improvement was observed for Dawnzera treatment groups compared to placebo in the Angioedema Quality of Life Questionnaire (AE-QoL) total score. A reduction of 6 points is considered a clinically meaningful improvement. For the total AE-QoL score at Week 24, the least square mean change from baseline in the Dawnzera treatment group was −24.8 and −19.9 for the 80 mg q4wks group (p <0.001) and 80 mg q8wks group, respectively, compared to −6.2 in the placebo group.

Trial 2 – “OASISplus”

A total of 147 adult and paediatric patients (≥12 years) with HAE 1 or HAE 2 received at least 1 dose of Dawnzera in an open-label extension trial (Trial 2) of up to 3 years. Of these, 83 patients were previously treated with Dawnzera or placebo in Trial 1 and were included in the rollover group. Non-rollover patients (n=64) were to continue to take their prior HAE prophylactic treatment (berotralstat, C1 esterase inhibitors, or lanadelumab) during the run-in period as per the respective recommended treatment schedules based on the half-life of the individual medicinal products (see section 4.2).

Open label extension rollover group (Trial 1 rollover patients, n = 83)

After 52 weeks of Dawnzera treatment, patients showed a sustained 93 % mean reduction in HAE attack rate compared to the baseline (0.22 vs. 3.42 attacks/4 weeks), with well-controlled disease by AECT increasing from 20.3 % to 91.3 % in the Q4W group and from 41.7 % to 100.0 % in the Q8W group, alongside improvements in AE-QoL scores at Week 24.

Non-rollover group (patients previously treated with other HAE long-term prophylactic medicinal products, n = 64)

During the switch from lanadelumab, berotralstat, or C1-esterase inhibitor to Dawnzera, no increase in HAE attack rate was observed, with mean rates reduced by 66.1 % (95 % CI -79.69, -52.55) at Week 52, with overall disease control by AECT improving from 66.7 % to 93.0 % by Week 16, and AE-QoL scores showing meaningful reductions across all groups.

Trial 3 – Phase 2 trial including patients with HAE-nC1INH

The phase 2 Trial 3 had an open-label arm for patients with HAE-nC1INH. It included 3 adult patients who received donidalorsen 80 mg every 4 weeks for up to 16 weeks. None of these patients had an established mutation in factor XII, plasminogen or angiopoietin-1 gene and only one had a positive family history.

For the 3 HAE-nC1-INH patients, there was an overall 76 % reduction in HAE attack rate during the treatment period. The reduction in mean HAE attack rate was from 4.23 attacks/4 weeks during the run-in period to 1.52 attacks/4 weeks from baseline to Week 16. One patient was attack free from Week 1 to end of treatment. Quality of life improved concurrently.

A reduction in investigator-confirmed monthly angioedema attack rate was observed in all three enrolled patients with HAE with normal functional and antigenic C1-inhibitor levels following monthly administration of 80 mg donidalorsen.

Immunogenicity

Anti-drug antibodies (ADA) were commonly detected. ADA did not affect maximum plasma concentrations, but increased trough plasma concentrations. No evidence of ADA impact on pharmacodynamics, efficacy or safety was observed, however, the available data are limited to make definitive conclusions.

Paediatric population

The Licensing Authority has deferred the obligation to submit the results of trials with Dawnzera in one or more subsets of the paediatric population in the treatment of hereditary angioedema for the routine prevention of recurrent attacks of hereditary angioedema. See section 4.2.

The pharmacokinetic properties of donidalorsen were evaluated following subcutaneous administration of multiple doses every 4 weeks in healthy subjects and every 4 weeks or every 8 weeks in patients with HAE.

Donidalorsen exposure (area under the plasma concentration time curve [AUC]) increased in a dose dependent manner following subcutaneous doses ranging from 20 to 80 mg in healthy volunteers but was greater than dose proportional over the entire dose range.

Population estimates (geometric mean) of steady state maximum plasma concentration (C_max,ss), trough plasma concentration (C_trough,ss), and area under the plasma concentration time curve over the dosing interval (AUC_,ss) are presented in

Table 4. No accumulation of donidalorsen C_max and AUC was observed in plasma after repeated dosing every 4 weeks.

Table 4: Summary of simulated pharmacokinetic parameters from population pharmacokinetic analysis following dosing of donidalorsen 80 mg q4wks or 80 mg q8wks in patients with HAE at steady state

AUC_,ss = area under the plasma concentration time curve over the dosing interval at steady state; C_max,ss = maximum plasma concentration at steady state; C_trough,ss = trough plasma concentration at steady state; q4wks = every 4 weeks; q8wks = every 8 weeks.

Absorption

Following subcutaneous administration, donidalorsen is absorbed with the time to maximum plasma concentration of approximately 2.5 hours post dose, based on population estimates.

Distribution

Donidalorsen is expected to distribute primarily to the liver and kidney cortex after subcutaneous dosing. The population estimate of apparent volume of distribution for the central (Vc/F) and peripheral (Vp/F) compartment were 69.8 L and 1 840 L, respectively. Donidalorsen is highly bound to human plasma proteins (>98 % bound) in vitro.

Biotransformation

Donidalorsen is metabolised by endo- and exonucleases to short oligonucleotide fragments of varying sizes within the liver.

Elimination

The population estimate of the terminal elimination half-life of donidalorsen in a typical patient with HAE is approximately 1 month.

The mean fraction of unchanged ASO eliminated in urine was less than 1 % of the administered dose in healthy subjects within 24 hours. Linker related metabolites are minimally released to circulation and subsequently rapidly excreted to urine or faeces.

Special populations

Population pharmacokinetics and pharmacodynamics analyses showed no clinically meaningful differences in the pharmacokinetics or pharmacodynamics of donidalorsen based on age (12 to 74 years), sex, mild renal impairment (eGFR ≥ 60 to < 90 mL/min/1.73 m²), or mild hepatic impairment (total bilirubin ≤ 1 × ULN and

AST > 1 × ULN, or total bilirubin >1 to 1.5 × ULN and any AST). Regarding body weight, donidalorsen AUC predicted values for the 30-40 kg body weight range were

> 17 500 ng·h/mL, > 10 000 ng·h/mL for 40-50 kg and around 10 000 ng·h/mL for 50-60 kg. The corresponding values for patients with body weights > 60 kg were

< 7 500 ng·h/mL. Donidalorsen has not been studied in patients with moderate or severe renal impairment, end stage renal disease, or moderate or severe hepatic impairment.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and development.

Carcinogenicity

In a 6 month carcinogenicity study in transgenic (Tg.rasH2) mice, subcutaneous administration of donidalorsen (5, 10, 20, or 60 mg/kg) or a rodent specific surrogate (10 mg/kg) once every 2 weeks did not result in an increase in malignant tumors, indicating a lack of human carcinogenic risk.

Genotoxicity

Donidalorsen was negative for genotoxicity in in vitro (bacterial reverse mutation, chromosomal aberration in Chinese hamster lung cells) and in vivo (mouse bone marrow micronucleus) assays.

Pregnancy, lactation and fertility

Subcutaneous administration of donidalorsen (0, 5, 10, or 20 mg/kg/week) or a rodent active inhibitor of PKK (5 mg/kg/week) to mice every other day throughout pregnancy and weekly throughout lactation produced no adverse effects on pre- and postnatal development.

In the mouse pre- and postnatal development study, the concentrations of donidalorsen in breast milk from lactating mice increased in a dose dependent manner at doses ≥ 10 mg/kg/week, but these concentrations of donidalorsen in breast milk were > 3 000 fold lower than the observed tissue concentrations. Even though donidalorsen was detected in the maternal mouse milk, systemic exposure in pups was not expected due to the lack of oral absorption of donidalorsen.

In animal studies, administration of donidalorsen or a pharmacologically active rodent specific surrogate in a combined fertility and embryofetal development toxicity study in mice did not result in effects on male and female fertility or embryofetal development.

Subcutaneous administration of donidalorsen (0, 1, 4, or 10 mg/kg/week) or a rodent active inhibitor of prekallikrein (PKK) (4 mg/kg/week) to male and female mice weekly, prior to and during mating, and continuing every other day in females throughout the period of organogenesis, resulted in no adverse effects on fertility, pregnancy, or embryofetal development.

Sodium dihydrogen phosphate (E 339)

Disodium hydrogen phosphate (E 339)

Sodium chloride

Water for injections

Hydrochloric acid (E 507) (for pH adjustment)

Sodium hydroxide (E 524) (for pH adjustment)

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

3 years.

Dawnzera may be stored in the original carton at room temperature (up to 30 °C) for a single period of up to 6 weeks, but not beyond the expiry date.

Store in a refrigerator (2 °C – 8 °C).

Keep the pre-filled pen in the outer carton in order to protect from light.

0.8 mL sterile solution in a single-use Type I glass syringe with a stainless steel staked needle, rigid needle shield, and siliconised chlorobutyl elastomer plunger stopper. The filled primary container and a pen are assembled to a pre-filled pen, which is labelled and packaged in an opaque carton with a partition to secure the pre-filled pen and protect from light.

Pack size of one pre-filled pen.

Pack size of three pre-filled pens.

Not all pack sizes may be marketed.

Prior to initiation, patients and/or caregivers must be trained on proper preparation and administration of Dawnzera (see Instructions for Use).

• The single-dose pre-filled pen should be removed from the refrigerator 30 minutes prior to the injection to reach room temperature. Other warming methods must not be used.

• The pre-filled pen must be inspected visually before use. The solution should appear clear and colourless to yellow. The solution must not be injected if it appears frozen. The pre-filled pen must not be used if cloudiness, particulate matter, or discolouration is observed prior to administration.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.