An Open-Label, Single Arm Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of Leniolisib in Pediatric Patients (Aged 4 to 11 Years) With APDS (Activated Phosphoinositide 3-Kinase Delta Syndrome) Followed By an Open-Label Long-Term Extension

Activated PI3Kδ syndrome is an ultra-rare, genetic, life-threatening disorder
of the immune system classified within a group of
disorders called primary immune deficiencies (PIDs). Activated PI3Kδ syndrome 1
(APDS1) was also known as p110δ-activating
mutations causing senescent T cells, lymphadenopathy, and immunodeficiency
(PASLI) following its characterization (Lucas 2014).
Activated PI3Kδ syndrome is caused by mutations in the gene PIK3CD (type 1
APDS, APDS1, or PASLI-CD) or PIK3R1 (type 2
APDS, APDS2, or PASLI R1) that activate PI3Kδ (Michalovich 2018). The role of
genetic variation of phosphoinositide 3-kinase
(PI3K) coding genes in children with defects in B*cell immunodeficiency was
first described in 2006 (Jou 2006) with the full PI3Kδ
syndrome being first described in 2013 (Angulo 2013).
As with other PIDs, the majority of patients with APDS show symptoms and
manifestations before the age of 18 years, although,
there are some manifestations that are recognized when patients are adults.
Although the age of clinical onset can vary widely, most
patients present with symptoms early in childhood. Due to the wide phenotypic
variation and lack of consistent clinical diagnostic
criteria in APDS, genetic testing showing the characteristic mutations are the
current standard for accurate diagnosis.
In a systematic review involving the largest group of patients described so far
(n=243), half of the patients were younger than 12
years of age when described in literature (n=213), with a median age at
diagnosis of 10.0 years (range: 5.0 to 19.0) and a median
age of symptom onset being 1.66 years (range: 0.58 to 3.0) (Jamee 2019). These
data show that patients had a significant delay in
diagnosis of 7.0 years (range: 3.4 to 14.0). In this analysis, 74% of the
patients were APDS1 and 26% were APDS2; a positive
family history was reported in 38.6%. Diagnostic testing for APDS is often only
initiated when specialized medical treatment is
required; unfortunately, this is often preceded by many years of severe
clinical manifestations without specific diagnosis. This period
of delay may shorten in the future as awareness among specialized physicians
grows.
A mean age at onset of 1.66 (range: 0.6 to 3.0) years (n=111) has been
reported, with recurrent respiratory infections starting at a
median age of 1.2 (range: 0.6 to 2.0) years (n=36). Of the 103 patients for
whom survival data was available, 14 (12%) had died
from malignancy, bowel perforation, sepsis, multiple organ failure, or
pulmonary hemorrhage. Infections occurred early in life (before
1 year of age) while enteropathy, lymphoproliferation, autoimmunity, and
malignancy occurred somewhat later at median ages of 5
(range: 1 to 18), 3 (range: 1 to 6), 10.5 (range: 6.0 to 15.0), and 18 (range:
13 to 24) years, respectively (Jamee 2019). The
phenotypic expression of APDS by APDS1 and APDS2 shows some variability.
Activated PI3Kδ syndrome 1 shows increased
presence of hepatomegaly, bronchiectasis, and sinusitis. Activated PI3Kδ
syndrome 2 shows increased presence of
lymphadenopathy, pneumonia, failure to thrive, neurodevelopment delay, and
malignancy (Jamee 2019). In a cohort study, it was
calculated that APDS2 patients have a 78% risk of developing a lymphoid
malignancy by the age of 40 years (Elkaim 2016).
Common clinical hallmarks of the disease include recurrent sinopulmonary
infections, severe or persistent viral infections,
autoimmunity (eg, cytopenia, arthritis, enteropathy) and chronic benign
lymphoproliferation with increased risk of developing
lymphomas. Clinical and immunological features can range from asymptomatic or
rarely symptomatic patients to more severe and
life-threatening forms. Growth retardation and neurodevelopmental delay are
frequently noticed in children with APDS (Elkaim 2016,
Jamee 2019, Condliffe 2018). A total of 28% of patients with an established
primary diagnosis were initially diagnosed with hyper
immunoglobulin (Ig) M syndrome with a history of chronic infections beginning
in the first year of life (n=11) (Jamee 2019). Nearly
half of all APDS patients who develop bronchiectasis in their disease course
have no reported history of pneumonias. Malignancy
can appear later in the disease course and most commonly presents as diffuse
large B cell lymphoma (Jamee 2019). The
manifestations of APDS are variable, even within families carrying the same
mutation, ranging from a few isolated cases of
seemingly symptomless adult patients to children with primary antibody
deficiency and/or early onset recurrent respiratory infections
with bronchiectasis to others suffering from lymphoproliferation, autoimmunity,
or malignancy. A pattern is emerging of onset in early
childhood in most cases, first with excess infections and respiratory disease,
then lymphoproliferation and autoimmunity, and finally
malignancy.
Currently, there are no approved therapies for APDS and no available targeted
therapies that normalize the hyperactive PI3Kδ
pathway in APDS. Current medical practice constitutes mainly of preventive,
supportive, or symptomatic treatment tailored to the
individual patient. Currently available therapies are not specific to the
underlying biology of APDS. The available symptomatic and
preventive treatments only address part of the manifestation of APDS.
Hematopoietic stem cell transplantation (HSCT) is only an
option for a small subset of APDS patients (12.8%), but carries significant
risks, including mortality in 10% to 20% of patients
(Jamee 2019, Nademi 2017, Okano 2019). The estimated graft failure-free
survival rate in a series of 27 APDS patients receiving
HSCT at a median age of 12 years (range 2 to 66) is 68% at 2 years (Dimitrova
2020).
There is an unmet need for therapies targeting the PI3K pathway that have the
potential to mitigate progression and disease burden
by inhibiting the root cause of the disease manifestations versus the current
standard of care. Therapies targeting the underlying
biology of APDS are anticipated to improve the clinical outcomes and quality of
life for patients with APDS.
DocuSign Envelope ID: 9E6641D1-C0B0-49A0-A9A8-AF6664A928AF
Leniolisib (previously known as CDZ173 and now referred to as PH-E6) is an
orally available, small molecule inhibitor of p110δ that
inhibits the production of PIP3. Leniolisib has been investigated for safety
and tolerability in a first-in-human study (CCDZ173X2101)
and 2 drug drug interaction studies (CCDZ173X2102 and CCDZ173X2104). Healthy
volunteers were exposed to single ascending
doses up to 400 mg and multiple doses up to 140 mg BID for 15 days. Leniolisib
has also been investigated in a study
(CCDZ173X2203) in patients with primary Sjögren*s syndrome (pSS). In addition,
leniolisib is being evaluated in Phase 3 studies
(CCDZ173X2201 and CCDZ173X2201E1) in adolescent (>=12 years of age) and adult
patients with APDS. The completed study
CCDZ173X2201 consists of 2 parts. Part I was an open-label, within-patient,
up-titration dose escalation study designed to establish
the safety and PK of leniolisib in the target population, as well as to select
the optimal dose to be tested in Part II. Part II was
designed to assess efficacy and safety of leniolisib in this population. The
ongoing study CCDZ173X2201E1 is an open-label, non-randomized, safety,
tolerability, efficacy, and PK study to extend active oral treatment with
leniolisib 70 mg BID to those adolescent
and adult patients with APDS who participated in study CCDZ173X2201 or who were
previously treated with PI3Kδ inhibitors other
than leniolisib; treatment with leniolisib will last up to 6 years for an
individual patient.
Given the specificity of leniolisib to selectively inhibit the PI3K class IA
p110δ subunit, which harbors the gain-of-function mutation
driving APDS, leniolisib specifically targets the causative factor resulting in
the pathogenesis of APDS, and thereby may provide
effective treatment for this newly described disease with a significant unmet
medical need. This will be the first study to evaluate
leniolisib in children (aged 4 to 11 years) with mutations of either the PIK3CD
(APDS1) or PIK3R1 (APDS2) gene confirming APDS.
Further information regarding the nonclinical and clinical data for leniolisib
is provided in the Investigator*s Brochure.

Objective Endpoint
• To assess the clinical safety and tolerability of leniolisib in pediatric
patients (aged 4 to 11 years) with APDS
• Incidence of treatment-emergent AEs (TEAEs), SAEs, and AEs leading to
discontinuation of study drug
• Change from baseline in clinical laboratory test results (hematology, blood
chemistry, urinalysis)
• Change from baseline in vital signs
• Change from baseline in physical examination findings
• Change from baseline in electrocardiograms (ECGs)
• Change from baseline in growth and physical development
• To assess the efficacy of leniolisib in pediatric patients (aged 4 to 11
years) with APDS
• Reduction in lymphadenopathy as measured by MRI or low-dose CT at end of 12
weeks of treatment
• Immunophenotype assessed by changes from baseline in the percentage of naïve
B cells to total B cells to end of 12 weeks of
treatment

This study is a 2-part, prospective, open-label, single arm, multicenter study
to evaluate the safety, tolerability, PK, PDx, and efficacy of leniolisib in at
least 15 pediatric patients (aged 4 to 11 years) with mutations of either the
PIK3CD (APDS1) or PIK3R1 (APDS2) genes confirming APDS. At least 4 patients <6
years of age will be enrolled. Part I will consist of a 12-week period to
assess the safety and efficacy of treatment with leniolisib. Part II will
consist of a 1-year, long term, safety follow-up extension, with a possible
interim analysis. The leniolisib doses to be used in study were selected based
on safety, tolerability, PK, and PDx data from the adult Phase 2/3 study, as
well as PK modeling data (see Section 3.4 for more details.) In both parts of
the study, leniolisib will be administered orally based on body weight. Doses
will range from 20 to 70 mg BID (resulting in total daily doses ranging from 40
to 140 mg per day). In Part I of the study, patients will stay on the same dose
based on their weight at baseline throughout the 12-week treatment period. In
Part II, doses will be adjusted as needed for changes in weight at each
scheduled study visit. Safety and tolerability will be assessed. Safety will be
assessed from start of treatment through 28±5 days following completion of
treatment. Safety assessments will include physical examinations, vital signs
(body temperature, blood pressure, and pulse rate), standard clinical
laboratory evaluations (hematology, blood chemistry, and urinalysis), AE and
SAE monitoring, and cardiac safety, which will be monitored by means of 12-lead
ECGs. Further assessments will include the PedsQL Child Self Report Health
Related Quality of Life Questionnaire for patients age 5 to 11 years, the
PedsQL Parent Proxy Report Health Related Quality of Life Questionnaire for
patients age 4 years, and PGA. Tablet tolerability will be assessed. Population
PK will be assessed, using a sparse sampling technique to minimize burden.
During each part of the study, patients will be randomized to 1 of 3 PK
sampling groups. In each group, up to 4 blood samples will be collected on any
1 day during Part I and 1-year (Part II) treatment periods. Efficacy will
assess reduction of lymphadenopathy and immunophenotype. Reduction of
lymphadenopathy will be measured by the SPD in the index lesions selected as
per the Cheson methodology from imaging. For imaging, sites may choose either
of the 2 imaging modalities (MRI or CT) as per clinical practice and local
regulations (see imaging review charter). Baseline and end of treatment
assessments must be done using the same imaging modality. The immunophenotype
efficacy will be assessed by change from baseline in the percentage of nai*ve B
cells to total B cells. For ongoing or as needed safety review, a Data
Monitoring Committee will be established. See Section 10.3, Appendix 3 for
further details. If an epidemic or pandemic (eg, COVID-19 pandemic) limits or
prevents on-site study visits, alternative methods of providing continuing care
may be implemented. Phone calls or virtual contacts (eg, teleconsult) to the
patient, depending on local regulations and capabilities, can replace on-site
study visits, for the duration of the pandemic until it is safe for the patient
to visit the site again.

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