Peanut allergy oral immunotherapy study of AR101 for desensitization in children and adults (Palisade) follow-on study.

Peanut allergy is a common and serious condition that often affects children,
and is commonly associated with severe reactions, including life-threatening
anaphylaxis. Despite efforts at strict peanut avoidance, accidental exposure
continues to be a major concern in peanut allergy because allergic responses
can be triggered after ingestion of just milligram quantities of peanut
protein. Accidental exposures may result from commercial food products
mislabeling as well as inattention to, or mistrust of, food warning labels.
Oral immunotherapy for peanut allergy has been widely studied in recent years
and has demonstrated encouraging safety and efficacy results in early clinical
trials. In practical terms, this state of desensitization should be sufficient
to protect a patient with peanut allergy in case of an accidental exposure to
peanut while the patient is attempting to maintain a peanut avoidant diet.

The primary objective of this study is to determine the safety, tolerability
and efficacy of AR101 characterized oral desensitization immunotherapy
(CODITTM) using alternative maintenance dosing intervals.

The secondary objectives are:
* To confirm the safety profile of AR101 as measured by the incidence of
adverse events (AEs), including serious adverse events (SAEs)
* To confirm the efficacy of AR101 through reduction in clinical reactivity,
measured in a double-blind, placebo-controlled food challenge (DBPCFC) to a
cumulative dose of 4043 mg
* To evaluate subjects* quality of life (QoL) and treatment satisfaction during
AR101 treatment on daily and non-daily treatment regimens
* To evaluate the long-term immunologic effects of AR101 treatment

This is an international, multicenter, open-label, 2-arm follow-on study that
will explore alternate dosing interval regimens during extended maintenance
with AR101.

Group 1 (Placebo Crossovers):
Subjects who complete the placebo arm of ARC003 are eligible to enroll in
ARC004. Subjects will enter Group 1 and will undergo initial escalation,
up-dosing, and maintenance with AR101 as in the active arm of ARC003. The
Initial Escalation Period consists of a step-wise dose-escalation from 0.5 to 3
or 6 mg (as tolerated) on Day 1 and confirmation of the ability to tolerate a
single dose of 3 mg on Day 2. The Up-dosing Period is 22 to 40 weeks in
duration and consists of dose escalations every 2 weeks up to a maximum of 300
mg/d (as tolerated). The Maintenance Period consists of daily dosing at 300
mg/d for approximately 24 weeks, at which point Group 1 subjects will undergo a
DBPCFC to a maximum cumulative dose of 4043 mg peanut protein to test the
efficacy of AR101 in ARC003 placebo crossovers after 6 months of daily
maintenance. All Group 1 subjects tolerating * 443 mg of cumulative peanut
protein will be eligible to continue in ARC004, and enter the Extended
Maintenance (EM) Period, initially consisting of ongoing daily maintenance
therapy at 300 mg/d. Dependent upon the EM results from ARC004 Group 2 (below),
subjects in Group 1 EM will test the gradual lengthening of their dosing
interval from daily (QD) to every other day (QOD), twice weekly (BIW), once
weekly (QW), and finally every other week (QOW), as tolerated. Lengthening to
each level will occur sequentially (QD then QOD then BIW then QW and finally
QOW), and only if sufficient evidence exists, based on the analyses of the
Group 2 EM subjects and the ongoing safety of Group 1 subjects, to support
progression to each level.

Group 2 (Active Rollovers):
Subjects who complete the active arm of ARC003 and tolerate a challenge dose of
* 443 mg cumulative of peanut protein at the ARC003 exit food challenge are
eligible to enroll in ARC004. Group 2 subjects will have undergone the Initial
Escalation, Up dosing, and Initial Maintenance Periods in ARC003 and will
therefore enter the ARC004 EM period directly, where they will be evaluated in
1 of 3 cohorts as outlined below.

Extended Maintenance:
The EM periods will differ between and within the 2 groups in duration and
dosing regimen. All EM subjects who complete their dosing regimen, regardless
of group or cohort assignment, will have an Exit DBPCFC up to a single highest
dose of 2000 mg of peanut protein (4043 mg cumulative). ARC004 will conclude
after the last visit for the last subject is completed.

Group 1 Extended Maintenance:
Group 1 subjects who tolerate * 443 mg cumulative peanut protein in the
Post-Maintenance DBPCFC will enter the EM period. Subjects who do not tolerate
* 443mg cumulative peanut protein are not eligible to continue for safety
reasons. The EM period for Group 1 subjects will initially consist of QD
dosing. Conditional upon the safety and DBPCFC outcomes assessed in the Group 2
participants, Group 1 subjects may have their dosing interval serially
lengthened from QD to QOD, QOD to BIW, BIW to QW, and QW to QOW, as tolerated.
The duration of each of these interval extension periods will be adjusted,
based on Group 2*s experience, from between 8 to 24 weeks, as tolerated.
Following the completion of their longest tested dosing interval, Group 1
subjects will undergo an Exit DBPCFC.

Group 2 Extended Maintenance:
Upon entry into the EM phase of the study (Figure 1), Group 2 subjects will be
consecutively enrolled into cohorts that will conditionally explore alternate
dosing interval regimens over 28-week study periods, as follows:
1. EM Cohort 1: The first 120 Group 2 subjects to enter ARC004 will make up
Cohort 1, and will continue on 300 mg of AR101 daily for 28 weeks before
undergoing an Exit DBPCFC.
2. EM Cohort 2: The next 50 Group 2 subjects (subjects 121 to 170) enrolling in
ARC004 will make up Cohort 2 and will take 300 mg of AR101 QOD for 4 weeks and
then BIW (eg, Monday/Thursday) for 24 weeks as tolerated before undergoing an
Exit DBPCFC.
3. EM Cohort 3: All remaining Group 2 subjects recruited into ARC004 (subjects
171 to the end) will make up Cohort 3. This cohort will be randomized 1:1:1 to
1 of 3 initial strategies:
a. 300 mg QD for 56 weeks followed by an Exit DBPCFC (Cohort 3A)
b. 300 mg QD for 28 weeks, then 300 mg QOD for 4 weeks, then BIW for 24 weeks
followed by an Exit DBPCFC (Cohort 3B)
c. 300 mg QD for 28 weeks, then 300 mg QOD for 4 weeks, then BIW for 24 weeks,
then 300 mg QW for 28 weeks followed by an Exit DBPCFC (Cohort 3C)
Group 2 cohorts will produce evidence during the trial concerning the
feasibility and safety of adjusting EM dosing from daily to a less frequent
schedule. The information that becomes available as each cohort proceeds
through the study will be evaluated before determining whether the next cohort
is to advance to a longer interval between doses. Lengthening the dosing
intervals in subsequent cohorts depends on the safety experience of previous
cohorts, which will be reviewed by a Safety Monitoring Committee. Individual
and cohort stopping rules are discussed further in Section 7.8.3.

End of Participation in ARC004 and Entry into ARC008:
After the end of participation in ARC004, subjects may enroll in the long-term,
open-label extension study ARC008 to continue treatment with AR101 at their
current dosing regimen (QD, BIW, QW, or QOW) or switch to AR101 daily dosing,
until AR101 becomes commercially available or ARC008 is terminated, as follows:
* Subjects on any dosing regimen able to tolerate at least the 600 mg single
dose of peanut protein (* 1043 mg cumulative) at their ARC004 Exit DBPCFC will
continue their current dosing regimen in Treatment Pathway 1 of ARC008 when
that study is available. If ARC008 is not available at the study site, these
subjects may continue their current dosing regimen and have visits in ARC004
until they can enroll in ARC008.
* Subjects who tolerate their nondaily dosing regimen and tolerate at least the
300 mg single dose of peanut protein (* 443 mg cumulative) but are unable to
tolerate the 600 mg single dose of peanut protein (1043 mg cumulative) at the
ARC004 Exit DBPCFC will switch to daily dosing with 300 mg AR101 in Treatment
Pathway 1 of ARC008, per investigator discretion. If ARC008 is not available at
the study site, these subjects may start AR101 daily dosing and
have visits in ARC004 until ARC008 is available, then continue dosing in ARC008.
* Subjects on a nondaily dosing regimen who tolerate less than the 300 mg
single dose of peanut protein (443 mg cumulative) at the Exit DBPCFC may be
eligible for treatment in ARC008 per investigator judgment and after discussion
with the medical monitor. If continued treatment with AR101 is determined to be
safe, these subjects will have the option to receive AR101 daily in Treatment
Pathway 2 of ARC008, which consists of Repeat Up-dosing (dose escalation from
80, 120, or 160 mg to 300 mg daily), Initial Maintenance, and Extended
Maintenance. If ARC008 is not yet available or able to accept these subjects at
the study site, these subjects may start AR101 daily dosing and have visits in
ARC004 until they can enroll in ARC008.
* Subjects who do not tolerate their nondaily dosing regimen (described in
study procedures for Extended Maintenance) will have the option to receive
AR101 daily in Treatment Pathway 2 of ARC008, which consists of Repeat
Up-dosing (dose escalation from 80, 120, or 160 mg to 300 mg daily), Initial
Maintenance, and Extended Maintenance. If ARC008 is not available at the study
site, these subjects may start AR101 daily dosing and have visits in ARC004
until
ARC008 is available, then continue dosing in ARC008.
* Subjects on a nondaily dosing regimen who miss or withhold their dose for > 3
days, including subjects receiving QOD, BIW, or QW dosing who miss or withhold
their dose for > 14 days, will have the option to receive AR101 daily in
Treatment Pathway 2 of ARC008, which consists of Repeat Up-dosing (dose
escalation from 80, 120, or 160 mg to 300 mg daily), Initial Maintenance, and
Extended Maintenance. If ARC008 is not available at the study site, these
subjects may start AR101 daily dosing and have visits in ARC004 until they
can enroll in ARC008.
Subjects are not eligible to enroll in ARC008 when continued treatment with
AR101 is determined to be unsafe as follows:
* Subjects on a daily dosing regimen who are unable to tolerate at least the
300 mg single dose of peanut protein (443 mg cumulative) at the Exit DBPCFC.
* Subjects not tolerating their nondaily dosing regimen who begin Repeat
Up-dosing in ARC004, but are unable to dose escalate to AR101 300 mg daily and
tolerate that dose level for 2 weeks within 26 weeks.

The investigational product is AR101.
Doses are expressed as mg of peanut protein. For the Initial Escalation and
Up-dosing periods, AR101 will be provided in pull-apart capsules at doses of
0.5, 1.0, 10, 20, and 100 mg. For the Maintenance and EM periods, AR101 will be
provided in foil-lined sachets at a dose of 300 mg. AR101 will be shipped
directly to investigational sites and will be dispensed according to subject
identification number, using an interactive response system. Trained
investigational site personnel will administer AR101 directly or dispense AR101
to the subject/ guardian in a manner consistent with the assigned dose level.
AR101 is administered by QD dosing during Initial Escalation, Up-dosing, and
Maintenance, and by either QD, QOD, BIW, QW, or QOW dosing during EM.

Please Note: The number of visits per group / cohort varies. Please review
Protocol Appendix 1 page 89 -104.
Please Note: Screening/Baseline is conducted at the same time as the End of
Study Visit of the preceding ARC003 study. Procedures / Tests performed then
are not counted as this has been done already in the ARC003 study.


Burden::
- Blood draw: 2 -5 times appr. 9 ml each time.
- number of visits: 3-29. lasting 1-3 hours. In case of updosing (group 1) and
DBPCFC test the visit may last up till 7 hours.
- Physical Exam: full exam 3 times + at the investigator's discretion limited
or symptom directed physical exams may be completed.
- Peak expiratory flow rate (PEFR) in subjects 6 years and older: each visit
- Spirometry (FEV1) in subjects 6 years and older when PEFR shows a clinically
relevant reduction or the subject shows clinical deterioration (e.g., active
wheeze on physical examination): each visit.
- questionnaires: once at end of study
- skin prick test: 2 to 5 times
- DBPCFC: once or twice
- Asthma test: 3 to 8 times
- Diary: entire duration of the study.

Side Effects Associated with the study drug (AR101)
Side effects are mostly allergic reactions and most subjects receiving AR101
experienced at least one side effect of allergic reaction during the course of
treatment. These reactions were all of mild to moderate intensity and none was
severe.
Symptoms included vomiting, abdominal pain, nausea, cough, mouth and throat
discomfort or pain, throat irritation, hives, itching of the lips, lip
swelling, lip blister, itchy tongue, runny nose, sneezing, nasal congestion,
wheezing, skin itching, eye itching, ear itching, facial swelling, and fatigue.

Other common side effects experienced by 1% to 10% of subjects included
gastrointestinal symptoms (nausea, vomiting, diarrhea), respiratory symptoms
(nasal congestion, pain in the mouth and throat, cough, wheezing), skin
disorders (itching, rash, redness), sleepiness, anaphylaxis, and eosinophilic
esophagitis (EoE). Most of the side effects were mild to moderate and became
less frequent over time. Although the episodes of anaphylaxis were infrequent
and successfully managed, severe or life-threatening anaphylaxis is a potential
risk of AR101. Also, whenever reoccurring gastrointestinal symptoms occur with
AR101, there is a suspicion that EoE might be present.

It is expected that the chance of having an allergic reaction is reduced when
the study drug is started at very small doses, and when the dosing is increased
slowly while being observed by the Study Doctor.

There may be a risk that during study participation subjects may decrease their
vigilance against accidental peanut ingestion because they believe they are
protected from it. This phenomenon has been reported in previous trials.
Subjects (and partents/guardians) will be warned that they should continue to
practice their usual vigilance against accidental ingestion of peanuts or
peanut containing food.


Side Effects Associated with Oral Food Challenges
Oral food challenges are expected to induce an allergic response in
food-allergic individuals. Allergic reactions can be severe, including
life-threatening allergic reactions; however, the risk of an allergic reaction
is reduced by beginning the challenge with a very small amount of the food,
gradually increasing the dose, and stopping the challenge at the first sign of
a significant reaction. In case of an allergic reaction during the challenges,
medication will be administered (if needed) and the subject will be provided
with the standard care.


Side Effects Associated with Collecting Blood Samples
- pain or bruising at the site where the blood will be drawn, fainting,
swelling of the vein, infection or bleeding at the puncture site. *

Possible benifits:
-The study drug does not cure an allergy. However, it may lessen the body*s
sensitivity or allergic response to the allergen, resulting in fewer symptoms.
-. Information from this study may help researchers to better understand peanut
allergy or to develop future tests or treatments to help patients with this
condition.