A Randomized, Double Blind, Placebo Controlled, Phase 2a Study to Assess the Clinical Efficacy of ISIS 721744, a Second Generation Ligand Conjugated Antisense Inhibitor of Prekallikrein, 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.

The primary objective of the study is to evaluate the clinical efficacy of
antisense inhibitor of prekallikrein (ISIS 721744) in patients with hereditary
angioedema (HAE) type 1 (HAE 1), HAE type 2 (HAE 2), or HAE with normal
C1-inhibitor (C1-INH).
The secondary objectives of the study are to evaluate safety and tolerability
of ISIS 721744 in patients with HAE 1/HAE 2 or HAE with normal C1 INH
(HAE-nC1-INH) and to evaluate the effect of ISIS 721744 on plasma prekallikrein
(PKK) and other relevant biomarkers.
The exploratory objectives of the study are to evaluate pharmacokinetics (PK)
of ISIS 721744 (as a total full-length antisense oligonucleotide [ASO],
including fully conjugated, partially conjugated, and unconjugated ISIS 721744)
over time and to assess potential PK/pharmacodynamic (PD) correlations on
relevant biomarkers and clinical outcomes, as appropriate.

This is a global, Phase 2a randomized, double-blind, placebo-controlled study
designed to assess the clinical efficacy of ISIS 721744, a second-generation
ligand-conjugated antisense inhibitor of prekallikrein, in patients with
Hereditary Angioedema. The study will be conducted concurrently in 2 parts
(Part A and Part B); patients will be allocated into Part A or Part B according
to type of HAE (i.e., either HAE 1/HAE 2 in Part A or HAE nC1 INH in Part B).
Part A is randomized, double blind, and placebo controlled; and Part B is open
label. The study visit schedule and procedures are nearly identical in Part A
and Part B.
In Part A, patients with HAE-1/HAE-2 will be randomized to subcutaneous (SC)
injections of ISIS 721744 80 mg or placebo in a 2:1 ratio (ISIS
721744:placebo). In Part B patients with HAE-nC1-INH will be administered
open-label SC injections of ISIS 721744 80 mg. Due to the rarity of HAE
nC1-INH, enrollment in Part B may be ended early if Study Centers are unable to
enroll sufficient patients; this will not impact the completion of Part A.
The length of each patient*s participation in the study is approximately 8
months, which includes an up to 8-week Screening Period, a 12-week Treatment
Period, and a 13-week Post Treatment Period. During Treatment Period patients
will receive fixed SC doses of Study Drug (ISIS 721744 or Placebo) every 4
weeks.

This study includes an option for some study visits to occur at home with a
home care nurse and may be considered for assessments and procedures at Weeks
3, 5, 9, 13, 17, 21, and 26 (at Screening and Week 1, patients must come to the
study center for the assessments and procedures).

Eligible patients may elect to enroll in the open label extension (OLE) study
(ISIS 721744-CS3).

During the Treatment Period, study drug (ISIS 721744 or Placebo) will be
administered as a single-SC injection every 4 weeks. For Part A, approximately
18 eligible patients (HAE 1 or HAE 2) will be randomized to SC injections of
ISIS 721744 (80 mg/mL) or placebo in a 2:1 ratio. In Part B about 6 patients
with HAE-nC1-INH will be administered open-label SC injections of ISIS 721744
(80 mg/mL).

Burden: During the study patients will be asked to come to the study centre for
9 visit. Also, they will be contacted every week by phone by the study staff to
discuss their HAE attacks. Patients will be treated with ISIS 721744 or placebo
every 4 weeks during the treatment period, meaning they will receive a
subcutaneous injection in their abdomen, thigh or upper arm 4 times in total.
A demographic questionnaire, health and medication questionnaire and 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, height 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, post-menopausal status, pharmacodynamics,
pharmocokinetics, inflammatory markers, antibodies and the activity of
kallikrein protein and HAE related proteins in the body. If patients do not
have HAE genetic diagnostic testing results prior to screening for
participation in Part B, they will give a blood sample for genetic testing.
Patients will also be tested for HIV and hepatitis B and C.
Risk: Possible side effects of the study drug and study procedures.