A Phase 1b/2a, Open Label Trial Evaluating the Safety, Pharmacokinetics, and Efficacy of EP-104IAR in Adults with Eosinophilic Esophagitis (RESOLVE)

Eosinophilic esophagitis (EoE) is a rare, chronic, immune-mediated disease that
is characterized by inflammation and the accumulation of large numbers of
eosinophils within the epithelial lining of the esophagus.

The investigational medicinal product (IMP), EP-104IAR (long-acting fluticasone
propionate [FP] injectable suspension), is being developed to treat pain and
inflammation in patients diagnosed with EoE. EP-104IAR is intended to release
drug steadily at the injection site, maintaining local site concentrations
while minimizing systemic exposure to FP.

The active ingredient in EP-104IAR, FP, is a synthetic trifluorinated
corticosteroid with potent anti-inflammatory activity. It has high selectivity
for the glucocorticoid receptor and has little activity at other steroid
receptors. FP is more lipophilic than budesonide and triamcinolone acetonide
(TCA) and has one of the highest affinities for the glucocorticoid receptor and
lowest rate of dissociation. In vitro tests for anti-inflammatory activity have
demonstrated that FP is more potent than other corticosteroids, e.g.,
beclomethasone dipropionate, budesonide, TCA, and mometasone furoate. Animal
studies of systemic responses to various corticosteroids have shown FP to be
less potent, or equipotent, compared to beclomethasone dipropionate,
fluocinolone acetonide, and betamethasone alcohol in its ability to elicit
thymus involution, hypothalamicpituitary-adrenal axis suppression, and/or
adrenal atrophy. FP has known pharmacologic activity, absorption, distribution,
metabolism, excretion, and side effects when given as an inhaled product.

Fluticasone propionate is currently approved by the US FDA, EMA, Health Canada,
and other regulatory agencies to treat inflammatory effects associated with
asthma, COPD, rhinitis, and dermatological disorders.

EP-104IAR is also currently in development to treat pain in patients diagnosed
with osteoarthritis (OA). A Phase 2 clinical study is underway to evaluate the
safety and efficacy of a single dose of 25 mg EP-104IAR in patients with OA of
the knee.

This study has been transitioned to CTIS with ID 2024-516689-13-00 check the CTIS register for the current data.

The primary objectives of this study are:
• To determine the safety, tolerability, and RP2D(s) and regimen(s) of EP 104IAR
• To determine the pharmacokinetic (PK) profile of EP-104IAR

A secondary/exploratory objective is:
• To evaluate the efficacy of EP-104IAR on eosinophilic esophagitis (EoE)
disease activity as measured by
symptoms, endoscopy, and histology

EP-104IAR-102 is a Phase 1b/2a, open-label, multicenter, dose escalation study
designed to explore multiple types of outcomes, including clinical safety, PK,
endoscopic, and histologic. Both endoscopic and histologic assessments will be
scored centrally. Approximately 27 to 33 adult participants with a history of
histologically confirmed EoE with active symptoms (patient-reported) are
planned to be enrolled in the dose escalation of this study. An additional
10-24 participants will be enrolled in 1 or 2 dose confirmation cohorts at
tolerable dose(s) to identify the recommended RP2D(s).

At the Baseline (Visit 2), Week 4 (Visit 5), and Week 12 visits (Visit 7), or
at early discontinuation (ED), all participants will undergo an
esophagogastroduodenoscopy (EGD) with esophageal biopsies for endoscopic and
histologic assessment. Additionally, participants who receive >40 mg total dose
will undergo EGD with esophageal biopsies at Week 36. For regimens of 4-16
injections, a total of 16 biopsy specimens will be obtained from 8 different
heights along the esophagus in a quadrant-like manner. The number of biopsies
will be increased to 20 (at 10 heights in the esophagus) for regimens of 20
injections. Participants will complete paper questionnaires at clinic visits to
assess symptoms of dysphagia and odynophagia. Safety will be assessed
throughout the study, and blood samples will be collected for safety and PK
assessments of EP-104IAR.

Dose escalation (and de-escalation):
Participants will be dosed in cohorts of 3 participants each. The initial
cohort of 3 participants will receive submucosal injections of 1 mg EP-104IAR
at 4 different sites providing a total administered dose of 4 mg EP 104IAR.

Dose escalation (or de-escalation) in subsequent cohorts will be determined by
the Safety Monitoring Committee (SMC) using a modification of the traditional
3+3 oncology design. Dose escalation (or de-escalation) is permitted such that
in each step, one of the following 2 axes may be increased: the number of
injection sites; and the dose injected per site. Both axes may be changed in
one escalation, providing only one axis is increased e.g. an increased dose per
site at a lower number of injection sites. The SMC will determine whether each
of the dose escalation regimens are allowable following review of safety data
provided. The SMC may alternatively recommend dose escalation (or
de-escalation) to an intermediate dose not shown in Table A. For an
intermediate dose escalation, e.g. to 5 mg/site, the total dose will not exceed
that which would be achieved by a permissible dose escalation step shown in
Table A. The Sponsor will select the dose regimen for the next cohort based on
the SMCs determination. Details of the possible dosing regimens are presented
in Table A.

Table A: Possible dose regimens and total administered dose.

1
mg/site 2,5 mg/site 4
mg/site 6 mg/site
Number of injections of EP-104IAR Total Dose Total Volume Total Dose Total
Volume Total Dose Total Volume Total Dose Total Volume
4 injection sites 4 mg 4 ml
10 mg 4 ml 16 mg 4 ml 24
mg 4 ml
8 injection sites 8 mg 8 ml
20 mg 8 ml 32 mg 8 ml 48
mg 8 ml
12 injection sites 12 mg 12 ml 30
mg 12 ml 48 mg 12 ml 72
mg 12 ml
16 injection sites 16 mg 16 ml 40
mg 16 ml 64 mg 16 ml 96
mg 16 ml
20 injection sites 20 mg 20 ml 50
mg 20 ml 80 mg 20 ml 120
mg 20 ml

Across all dose levels, the volume administered per injection site is 1 mL; the
EP-104IAR Powder is constituted to concentrations of 1 mg/mL, 2.5 mg/mL, 4
mg/mL, or 6 mg/mL to meet dose requirements.

The maximum dose of EP-104IAR that could be administered per injection site is
2.5 mg. The maximum total dose of EP-104IAR that could be administered is 120
mg.


The dose-limiting toxicity (DLT) evaluation period is 4-weeks post injection.
Upon review of the 4-week data for each cohort of 3 participants, the following
rules will be followed:
• If zero participants exhibit a DLT (see definitions below), then dose
escalation is permitted in the next cohort.
• If 1 of the 3 participants exhibits a systemic DLT or 1 of the 3 participants
exhibits a local DLT, then a second cohort of 3 participants will be dosed with
the same dose regimen. Of the 6 total participants at this dose:
o If there was a total of 1 (of 6) systemic DLT:
* Escalation is permitted, absent any restrictions from local DLTs.
o If there were 2 (of 6) or more systemic DLTs:
* Escalation of the total dose is complete.
* Further cohorts may study any other dosing strategies from Table A or
intermediate dose level(s) recommended by the SMC e.g. 5 mg/site not shown in
Table A, that have a total dose lower than the current cohort.
* Absent any local DLTs, there is no cap on the dose per-site (except as
described in Table A).
o If there was a total of 1 (of 6) local DLT:
* Escalation is permitted, absent any restrictions from systemic DLTs.
o If there were 2 (of 6) or more local DLTs:
* Escalation of the per-site dose is complete.
* Further cohorts may study any other dosing strategies from Table A or
intermediate dose level(s) recommended by the SMC e.g. 5 mg/site not shown in
Table A, that have a per site dose lower than the current cohort.
* Absent any systemic DLTs, there is no cap on number of sites (except as
described in Table A).
• If 2 or more (of 3) participants exhibit a systemic DLT:
o Escalation of the total dose is complete.
o Further cohorts may study any other dosing strategies from Table A, or
intermediate dose level(s) recommended by the SMC e.g. 5 mg/site not shown in
Table A, that have a total dose lower than the current cohort.
o Absent any local DLTs, there is no cap on the dose per-site (except as
described in Table A).
• If 2 or more (of 3) participants exhibit a local DLT:
o Escalation of the per-site dose is complete.
o Further cohorts may study any other dosing strategies from Table A, or
intermediate dose level(s) recommended by the SMC e.g. 5 mg/site not shown in
Table A, that have a per-site dose lower than the current cohort.
o Absent any systemic DLTs, there is no cap on the number of sites (except as
described in Table A).

When dose escalation is permitted:
• The decision (absent any restrictions from the above algorithm) to increase
either the number of sites or dose per-site may be made on the basis of
histological, PK, and safety data.
• At no point may a dose escalation step increase from a previously studied
cohort by more than 1 row or column of the 2 axes shown in Table A (number of
injection sites; and the dose injected per site) at a time, and only one axis
may be increased per dose escalation step. Both axes may be changed in one
escalation, providing only one axis is increased e.g. an increased dose per
site at a lower number of injection sites.
• After each cohort, systemic PK will be predicted for future doses under
consideration in the next cohort. A future dose with a predicted area under the
curve from time zero to 4 weeks (AUC0-4weeks) > 3 ng•day/mL is not permitted.

Based on their review of safety data, the SMC may recommend dose de-escalation
to an intermediate dose or regimen below the current dose, but not explored
previously during dose es

At Baseline, participants will undergo an upper EGD in combination with
treatment administration where participants will receive submucosal injections
of EP-104IAR.Administration of the IMP will be given in the clinic. All
participants will be observed for at least 2 hours following treatment
administration.

Table A: Possible dose regimens and total administered dose.

1
mg/site 2,5 mg/site 4
mg/site 6 mg/site
Number of injections of EP-104IAR Total Dose Total Volume Total Dose Total
Volume Total Dose Total Volume Total Dose Total Volume
4 injection sites 4 mg 4 ml
10 mg 4 ml 16 mg 4 ml 24
mg 4 ml
8 injection sites 8 mg 8 ml
20 mg 8 ml 32 mg 8 ml 48
mg 8 ml
12 injection sites 12 mg 12 ml 30
mg 12 ml 48 mg 12 ml 72
mg 12 ml
16 injection sites 16 mg 16 ml 40
mg 16 ml 64 mg 16 ml 96
mg 16 ml
20 injection sites 20 mg 20 ml 50
mg 20 ml 80 mg 20 ml 120
mg 20 ml

Across all dose levels, the volume administered per injection site is 1 mL; the
EP-104IAR Powder is constituted to concentrations of 1 mg/mL, 2.5 mg/mL, 4
mg/mL, or 6 mg/mL to meet dose requirements.

The maximum dose of EP-104IAR that could be administered per injection site is
2.5 mg. The maximum total dose of EP-104IAR that could be administered is 120
mg.

Risks associated with EP-104IAR:
The main ingredient in study medication is fluticasone propionate. Fluticasone
propionate is a type of drug called a corticosteroid. Participants allergic to
any corticosteroids, or any of the ingredients in study medication, cannot take
part in this study.

The ingredients of study medication (fluticasone propionate and polyvinyl
alcohol) have been used in people individually for a long time. But they have
only been used together as EP-104IAR and injected in approximately 183 people
with knee osteoarthritis. The most frequently reported side effects in the
previous study were common cold, influenza, stomach flu, headache, and
arthralgia (pain in a joint). No serious risks related to EP-104IAR were
identified. EP-104IAR is also being tested in another ongoing study in 300
participants with knee osteoarthritis. If any new information from this study
becomes available while you are taking part in this study, the study doctor
will tell you about it.

When fluticasone propionate is taken through the nose or by inhaling, side
effects such as a hoarse voice, fungus in the mouth (oral candidiasis), asthma,
lung and sinus infections, sore throat, cough, bronchitis, and headache have
been reported. If you have low thyroid hormone levels (hypothyroidism) or liver
disease (cirrhosis), you could have more side effects from fluticasone
propionate.

As EP-104IAR contains a corticosteroid, it may have similar risks to other
corticosteroid drugs. Not all patients will develop side effects from
corticosteroids. How often any side effect occurs varies from person to person
and depends on the dose, type of corticosteroid, how it is taken and the length
of treatment. Some side effects are more serious than others. As EP-104IAR has
only been used in a small number of people, it is not known how likely or
unlikely it is that you might have one or more of these side effects.

Using corticosteroids together with other medications may result in drug-drug
interactions (DDIs). DDIs occur when taking 2 (or more) drugs together results
in possible changes to the effects (both good and bad) of 1 or both drugs and
can potentially cause certain side effects.
When taking corticosteroids, you may have interactions with other medications.
• The use of medications that are strong CYP3A4 inhibitors (e.g., ritonavir,
atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir,
saquinavir, ketoconazole, telithromycin) is not recommended because increased
systemic corticosteroid side effects may occur (meaning side effects affecting
the entire body).
• Vaccines are products that trains a person*s immune system to fight a certain
disease it has not come into contact with before by mimicking the infectious
bacteria or viruses that cause the disease. Vaccines are designed to prevent
disease, rather than treat a disease once you have
caught it. Corticosteroids may prevent your body's immune system from
responding correctly to the vaccine. Corticosteroids may lower your body's
resistance and the vaccine may not work as well or you might get the illness
the vaccine was supposed to prevent.

Possible side effects of corticosteroids in the body outside of the esophagus:
There may be a temporary elevation of blood sugar which can trigger or worsen
diabetes. For people with high blood pressure, there may be temporary elevated
blood pressure. Injection of a corticosteroid is sometimes associated with a
flushing reaction of the face and upper body, glaucoma (elevated pressure in
the eyes), cataract formation (clouding in the lens on one or both eyes), fluid
retention causing swelling the legs, mood changes, and insomnia.

Rarely, corticosteroid injections have been associated with a temporary feeling
of numbness and weakness in the limbs. Also rarely, corticosteroid injections
have been associated with conditions limiting the body*s ability to fight
infections or deal with stressful situations (e.g., during surgery or illness),
causing low blood pressure, changes in weight and fat deposits, or an allergic
reaction. These rare events could possibly be life threatening.

Possible side effects of injected corticosteroids specific to the esophagus are
currently unknown.

Risks associated with study procedures/tests:

Blood sample collection
• Pain, bruising and/or bleeding where the needle enters your vein.
• Some people feel light-headed or faint.
• In rare cases, blood taking can lead to swelling and/or infection of the vein.

Pregnancy test
Pregnancy tests may find a pregnancy you did not know about.

HIV test
HIV testing may find HIV infections you did not know about.

Urinalysis
Urine testing may find an infection or evidence of an underlying health
condition you did not know about.

ACTH stimulation test
Side effects usually occur within 30 minutes after the ACTH injection and
include:
• Pain, bruising and/or bleeding where the needle enters your muscle or vein.
• Nausea, vomiting, anxiety, sweating, dizziness, fast or irregular heartbeat,
and facial flushing.
• Itchy skin, redness and swelling and/or infection at injection site.
• Feel light-headed or fainting, headache, severe dizziness, blurred vision,
rash, severe swelling of face, lips, tongue, or other parts of the body,
trouble breathing, and irregular heartbeat (rare)
• Allergic reactions (rare)

Esophagogastroduodenoscopy (EGD)
• Sore throat (common).
• Persistent bleeding after biopsy (if taken) (less common).
• Side effects such as drowsiness following sedative or pain medication (less
common) or aspiration pneumonia, which is infection of the lungs (very
rare).
• Perforation (a hole) of the esophageal muscle (rare). Surgery may be needed
if a perforation occurs (rare).

EP-104IAR injection
There may be minor bleeding, infection, and perforation (a hole) of the
esophageal muscle associated with the injections.

Esophageal biopsy
• Persistent bleeding after biopsy or polyp removal (if taken) can occur.
• Up to 16 samples will be taken at each of 3 visits.
• Biopsy results can identify a cancer of the esophagus you did not know about.

Video capture during the EGD procedure
• No discomfort/risk is expected from the video capture.
• Video images are identified by study identification number. There is the
chance that the video images may accidentally identify you; however, that
is not planned or expected.