An Open-Label Extension Study of ISIS 721744 in Patients with Hereditary Angioedema

Hereditary angioedema is a rare genetic disorder that is characterized by
disabling recurrent episodes of local skin swellings, painful abdominal
attacks, and, occasionally, laryngeal attacks that can be life-threatening. The
disorder is classified in 3 subtypes. Hereditary angioedema type 1 and HAE-2
are caused by an autosomal dominant mutation in the SERPING1 gene, resulting in
either decreased levels of C1-INH (HAE-1) or loss of-function of this protein
(HAE 2) (Bissler et al. 1997). The third form of HAE is associated with normal
levels and function of C1-INH (HAE-nC1-INH). This form is currently categorized
as 4 subtypes, with either specific genetic mutations in the factor XII gene,
the plasminogen gene, or the angiopoietin-1 gene, or due to an unknown cause
(Maurer et al. 2018). Extensive evidence from in vitro and in vivo studies
supports the key role of bradykinin (BK) in HAE attacks, although the data
linking HAE-nC1-INH with BK are less strong (Zuraw and Christiansen 2016).
Diagnosing HAE
nC1 INH can be challenging given the large heterogeneity of this patient
population, the lack of diagnostic tests, and the fact that specific genetic
mutations account only partially for the occurrence of this type of HAE.
Recently, a threshold-stimulated kallikrein activity assay was shown to
discriminate BK-mediated angioedema from histamine-mediated angioedema
(Lara*Marquez et al. 2018). This technique may, therefore, enhance the
identification of HAE nC1 INH patients that are likely to benefit from
inhibition of the contact activation pathway.
This study involves the use of the investigational medicinal product known as
ISIS 744721. When prekallikrein, a protein that is
produced by the liver, is released into the blood stream, it can lead to HAE
attacks. The study drug is designed to lower the amount
of prekallikrein produced by the liver. The study is to assess if reducing the
amount of prekallikrein can reduce HAE attacks.

This study has been transitioned to CTIS with ID 2024-517249-15-00 check the CTIS register for the current data.

Primary Objective:
To evaluate the safety of extended dosing, and alternative dosing and/or dose
frequency with ISIS 721744 in patients with HAE
Secondary Objective:
To evaluate the efficacy of extended dosing, and alternative dosing and/or dose
frequency with ISIS 721744 in patients with HAE
Additional/Exploratory Objectives:
To evaluate the effects of ISIS 721744 on plasma prekallikrein (PKK) levels,
plasma proenzyme activation and cleaved high molecular weight kininogen (cHK)
levels.
To evaluate the effects of ISIS 721744 on the clinical and angioedema quality
of life (AE-QoL) endpoints.
To evaluate PK exposure over time.

Sub-Study:
To evaluate the effect of chronic administration of ISIS 721744 on platelet
function.

Multi-center open-label extension study with ISIS 721744.
Dose Treatment Period 1 (Fixed Dosing Period): All patients will receive a
subcutaneous (SC) injection of ISIS 721744 (80 mg) every 4 weeks for at
least 12 weeks.
Dose Treatment Period 2 (Flexible Dosing Period): During the Treatment Period
2, if the patient is attack-free for >= 12 weeks after entering this OLE
study, the Investigator can initiate a switch to 80 mg ISIS 721744 every 8
weeks. The switch may begin at any Study Center visit starting at Week 17. If
patients are not adequately controlled on 80 mg every 8 weeks, then dosing can
return to 80 mg every 4 weeks. For patients who are not attack free for >= 12
weeks the Investigator can initiate a switch to 100 mg ISIS 721744 every 4
weeks. The switch may begin at any Study Center visit starting at Week 17 . If
patients develop any tolerability or safety issue the dose can be reduced back
to 80 mg every 4 weeks.
After completion of the 52-week Treatment Period, there is an option to
participate in an Extended Treatment Period (up to an additional 156 weeks;
Year 2, Year 3 and Year 4). There is a 12-week Follow-up Period after Year 1,
Year 2, Year 3 or Year 4.
During the course of the study, the use of acute medication (plasma-derived or
recombinant C1-INH concentrate, BK2-receptor antagonist or kallikrein
inhibitor) to treat angioedema attacks is allowed as medically indicated.
Patients can be treated with on-demand therapy as determined by their treating
physician.

The total duration of the trial is 64 weeks with 52 weeks for the treatment
phase and 12 weeks of follow-up. There is an option to participate in an
Extended Treatment Period (up to an additional 156 weeks). The 12-week
Follow-up Period will be conducted after the patient completes treatment

All patients will begin treatment with ISIS 721744 (80 mg) every 4 weeks for at
least 12 weeks. Following completion of treatment period 1 and continuing
through the extended treatment period, the patient and the Investigator (in
consultation with the Sponsor Medical Monitor) can decide which option to
choose:
Option 1: Patients continue 80 mg ISIS 721744 every 4 weeks
Option 2: For patients who are attack free for >= 12 weeks, after entering this
OLE study, the Investigator can initiate a switch to 80 mg every 8 weeks. This
switch may begin at any Study Center visit starting at Week 17. If patients are
not adequately controlled on 80 mg every 8 weeks, then dosing can return to 80
mg every 4 weeks.
Option 3: For patients who are not attack free for >= 12 weeks, after entering
this OLE study, the Investigator can initiate a switch to 100 mg ISIS 721744
every 4 weeks. This switch may begin at any Study Center visit starting at Week
17. If patients develop any tolerability or safety issue the dose can be
reduced back to 80 mg every 4 weeks.

Burden: During the study patients will be asked to come to the study centre for
16 visits. Patients will be treated with ISIS 721744 every 4 weeks for at least
12 weeks. ISIS 721744 will be administered as a SC injection in the abdomen,
thigh, or outer area of the upper arm. At the end of this time, there are three
treatment options:
Option 1: Patients continue 80 mg ISIS 721744 every 4 weeks
Option 2: Switch to 80 mg every 8 weeks. This switch may begin at any Study
Center visit starting at Week 17. If patients are not adequately controlled on
80 mg every 8 weeks, then dosing can return to 80 mg every 4 weeks.
Option 3: Switch to 100 mg ISIS 721744 every 4 weeks. This switch may begin at
any Study Center visit starting at Week 17. If patients develop any
tolerability or safety issue the dose can be reduced back to 80 mg every 4
weeks.

During the main study (year 1) and extension period (year 2, year 3 and year 4)
there will be asked questions about your health and medications you are taking.
A Quality of life questionnaire will be conducted. The HAE attack history of
the patients will be recorded and their HAE attacks will be tracked daily by
completing a questionnaire. Furthermore, patients need to inform their doctor
of any adverse events they experienced. A physical examination and heart
tracing (ECG) will be done and weight and vital signs will be measured. Also
urine and blood tests will be done to see if patients are able to participate
in the study and to check general health, pregnancy, pharmacodynamics,
pharmocokinetics, inflammatory markers and antibodies in the body.

Risk: Possible side effects of the study drug and study procedures.