An Open-label Study to Evaluate the Long-term Safety and Efficacy of CSL312 (Garadacimab) in the Prophylactic Treatment of Hereditary Angioedema

In spite of the growing attention to HAE patients by the medical community and
stakeholders, the burden of this disease is very high and
quality of life is still negatively impacted. Hereditary angioedema negatively
impacts a patient*s daily-life, psycho-social health, and
productivity both during times of attack and during times of remission
[Aygoren-Pursun et al. 2014].

The availability of prophylactic therapies that reduce the frequency and / or
severity of attacks has improved, however there are
limitations to the treatment armament such as an unfavorable side effect
profile (ie, attenuated androgens), a lack of effect (ie, antifibrinolytics),
or the frequency of administration (intravenous [IV] or subcutaneous [SC]
C1-INH). Furthermore, there are currently no
therapies specifically developed for treatment or prevention of HAE attacks due
to nC1-INH HAE. There remains a medical need for effective and safe therapies
that prevent and reduce the disease burden, improve the quality of life, and
offer a convenient dosing regimen for patients with HAE
[Valerieva 2018].

CSL312 may have the potential to address current unmet needs as a mAb with a
novel mechanism of action targeting FXIIa, which is
elevated in the serum during acute HAE attacks compared to normal levels
observed during times of remission [Cugno et al. 1996].
CSL312 targets FXIIa to inhibit the kallikrein-kinin pathway, thereby
inhibiting excessive production of BK, the mediator of swelling in
HAE attacks. In addition, the SC route of administration and CSL312 may offer
improved patient convenience compared to other products registered for
prevention of HAE attacks.

The efficacy and safety of CSL312 in patients with HAE has been demonstrated in
a phase 2 study. This phase 3b is to evaluate long-term safety and efficacy of
CSL312 200 mg when administered once a month for at least 12 months.

This study has been transitioned to CTIS with ID 2024-510777-18-00 check the CTIS register for the current data.

The primary objective of the study is to evaluate the long-term safety of SC
administration of CSL312 in the prophylactic treatment of subjects with C1-INH
HAE.

The secondary objectives of this study are to evaluate the long-term efficacy,
safety and patient reported assessment of response to therapy.

This phase 3b study will evaluate long-term safety and efficacy of CSL312 (also
known as garadacimab) when administered subcutaneously (SC) once monthly for at
least 12 months. Subjects entering CSL312_3002 will be from 3 sources:
• Subjects who participated in Study CSL312_2001
• Subjects who participated in Study CSL312_3001
• CSL312-naïve HAE subjects who have not participated in either of the above
studies

The study will consist of screening, run-in (for CSL312-naïve subjects), open
label treatment, and follow-up periods. For subjects naïve to CSL312, there
will be up to 1 month Screening Period followed by a Run-In Period, which may
last at least 1 month and up to 2 months.

CSL312-naïve subjects who meet all eligibility criteria during the Run-In
Period will then enter the at least 12-month Treatment Period. Subjects rolling
over from Studies CSL312_2001 or CSL312_3001 will enter directly into the
Treatment Period.

Subjects who reach the end of treatment or terminate the study early will have
a follow-up phone call 2 months after the End of Treatment Visit.

A Pharmacokinetic (PK) subgroup analysis will be conducted in adult
CSL312-naïve subjects to further characterize the PK of CSL312 following the SC
loading dose. A target number of 12 CSL312-naïve adult subjects will be
included in the subgroup analysis.

Per Amendment 1, administration of the study drug, CSL312, will be done with
the use of an autoinjector.

Subjects will be treated with CSL312 a minimum of 1 years.

CSL312 will be administered as 1 dose (200 mg) SC once monthly for a total
minimum of 12 doses (ie, 12 months of treatment). For CSL312-naïve subjects, a
loading dose of 400 mg (two 200 mg doses) will be administered SC on the first
month, then 200 mg once monthly for at least 11 months.

Per Amendment 1, administration of the study drug, CSL312, will be done with
the use of an autoinjector, The dose, 200 mg, and the injection frequency, once
a month, will continue to be the same.

The subjects participation in this study will last a minimum of 12 month. In
total the subject will visit the hospital approximately 9-13 times. Ech visit
will take between 30 minutes and 2 hours to complete.

The study will consist of screening, run-in (for CSL312-naïve subjects), open
label treatment, and follow-up periods. For subjects naïve to CSL312, there
will be up to 1 month Screening Period followed by a Run-In Period, which may
last at least 1 month and up to 2 months.

Please refer to page 16-25 of the protocol (schedule of events) for more
information.

The following tests and procedures will take place during the hospital visits
- questions are asked about the medical history, demographics and eligibility
questions
- Measurement of vital signs / physical examination (e.g. blood pressure, heart
rate, temperature and respiratory rate), height,weight
- Blood and urine samples are taken
- Pregnancy test for woman of childbearing potential

In addition patients are asked to complete the eDiary and questionnaires.

Possible side effects that are already known are described in the
Investigator's Brochure and in paragraph 6 of the subject informed consent
form.