Leaflet DAWNZERA 80mg solution for injection in pre-filled pen

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

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

In Trial 1, a 24-week multicenter, randomised, double blind, placebo-controlled trial in adult andpaediatric patients (≥ 12 years) with HAE 1 or HAE 2 (see clinical efficacy and safety below), adecrease 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 % followingtreatment with donidalorsen 80 mg every 4 weeks and every 8 weeks, respectively, compared with2 % in the placebo group.

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 least2 investigator-confirmed attacks during the 8-week run in period, who received at least 1 dose ofinvestigational medicinal product (IMP). Paediatric patients were 7 adolescents aged 12 years andolder; 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 a2:1 ratio to 1 of 2 groups to receive study treatment either once every 4 weeks (q4wks group) or onceevery 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 foranalysis. Patients were required to discontinue other prophylactic HAE medicinal products prior toentering the trial; however, all patients were allowed to use rescue medicinal products for treatment ofany breakthrough HAE attacks.

Overall, 93 % of patients had HAE 1 and 7 % had HAE 2. A history of laryngeal angioedema attackswas reported in 52 % of patients, and 18 % of patients were on prophylactic therapy prior toenrolment. The mean HAE attack rate during the prospective run-in period (baseline attack rate) was3.33 (SD 2.086) attacks/4 weeks and an attack rate of > 2 attacks/4 weeks was observed in 69 % ofpatients overall.

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

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

Endpoint statistics Placebo Dawnzera 80 mg Dawnzera 80 mg(N=22) q4wks q8wks(N=45) (N=23)

HAE attack rate per 4 weeks from baseline to Week 24*

LS mean (95 % CI) attack 2.26 0.44 1.02rate (1.66, 3.09) (0.27, 0.73) (0.65, 1.59)% Reduction (95 % CI) −81 −55relative to placebo (−89, −65) (−74, −22)

Wald chi-square p-value < 0.001‡ 0.004‡

HAE attack rate per 4 weeks from Week 4 to Week 24

LS mean (95 % CI) attackrate starting from second dose 2.25 0.30 0.90(Week 4) (1.59, 3.18) (0.15, 0.58) (0.53, 1.52)% Reduction (95 % CI)relative to placebo starting −87 −60from second dose (Week 4) (−94, −72) (−79, −25)

Wald chi-square p-value <0.001‡ 0.004‡

Moderate or severe† HAE attack rate per 4 weeks from Week 4 to Week 24

LS mean (95 % CI) moderate 1.15 0.12 0.68or severe attack rate starting (0.72, 1.83) (0.04, 0.35) (0.37, 1.23)

Endpoint statistics Placebo Dawnzera 80 mg Dawnzera 80 mg(N=22) q4wks q8wks(N=45) (N=23)from second dose (Week 4)% Reduction (95 % CI)relative to placebo starting −89 −41from second dose (Week 4) (−97, −66) (−72, 26)

Wald chi-square p-value <0.001‡ NS

HAE attacks per 4 weeks requiring acute therapy from Week 4 to Week 24

LS mean (95 % CI) HAE 1.80 0.15 0.59attacks requiring acute (1.23, 2.62) (0.06, 0.39) (0.31, 1.15)therapy starting from seconddose (Week 4)% Reduction (95 % CI) −92 −67relative to placebo starting (−97, −77) (−85, −29)from second dose (Week 4)

Wald chi-square p-value <0.001‡ 0.004‡

CI = confidence interval; HAE = hereditary angioedema; LS = least square; N = number of patients in thespecific 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 HAEattacks 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 inactivity, 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 (per4 weeks) from Week 0 to Week 24 was observed.

Additional pre-defined trial secondary endpoints included the proportion of responders to IMP andpercentage 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 groupbased on the Angioedema Control Test (AECT) score ≥10 at Week 24 was 41 (91 %) in the 80 mgq4wks group and 17 (74 %) in the 80 mg q8wks group, compared to 9 (41 %) in the placebo group.

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 isconsidered a clinically meaningful improvement. For the total AE-QoL score at Week 24, the leastsquare mean change from baseline in the Dawnzera treatment group was −24.8 and −19.9 for the80 mg q4wks group (p <0.001) and 80 mg q8wks group, respectively, compared to −6.2 in the placebogroup.

Trial 2 - “OASISplus”

A total of 147 adult and paediatric patients (≥12 years) with HAE 1 or HAE 2 received at least 1 doseof Dawnzera in an open-label extension trial (Trial 2) of up to 3 years. Of these, 83 patients werepreviously 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 recommendedtreatment 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 HAEattack 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 Q8Wgroup, alongside improvements in AE-QoL scores at Week 24.

Non-rollover group (patients previously treated with other HAE long-term prophylactic medicinalproducts, 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 patientswho received donidalorsen 80 mg every 4 weeks for up to 16 weeks. None of these patients had anestablished mutation in factor XII, plasminogen or angiopoietin-1 gene and only one had a positivefamily history.

For the 3 HAE-nC1-INH patients, there was an overall 76 % reduction in HAE attack rate during thetreatment period. The reduction in mean HAE attack rate was from 4.23 attacks/4 weeks during therun-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 threeenrolled patients with HAE with normal functional and antigenic C1-inhibitor levels followingmonthly administration of 80 mg donidalorsen.

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

The European Medicines Agency 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 hereditaryangioedema for the routine prevention of recurrent attacks of hereditary angioedema. See section 4.2.