2. 1
EXECUTIVE SUMMARY
Scientific
Rationale
PDE4 is an important enzyme responsible for hydrolyzing cAMP within immune cells, resulting in increases of
AMP. Research has shown that increases in cAMP levels directly correlate to a weakened immune response.
Therefore, developing PDE4 inhibitors designed to decrease the hydrolyzation of cAMP to AMP may provide
potential therapeutic benefits to a variety of immune disorders where an increased immune response is
unwarranted.
Discovery The screening process identified a small molecule that selectively inhibited the clinically relevant PDE4
isoenzymes.
Pre-clinical
Studies
The small molecule was found to reduce the production of key pro-inflammatory markers in vitro. UV light
induced TNF-α release was reduced by 58% when treated with 1 μM of the molecule. VEGF induced AKT
phosphorylation was inhibited by 40-70% when treated with 100 μM of the molecule. Similarly, oral
administration of the drug in TNCB induced Ds-Nh mice showed dose dependent reduction of atopic dermatitis
scores and inflammatory cytokines. Similarly, oral treatment of dust mite antigen-induced mice demonstrated
inhibition of dermatitis scores and decreases ofmRNA expression corresponding to atopic dermatitis
biomarkers.
Toxicology Pilot toxicology studies showthat monkeys responded well to single dose studies of 300 mg/kg/day. A 7-day
repeated dose study in rats yielded no signs of toxicity at 50 mg/kg/day and no signs of severe toxicity at 200
mg/kg/day. A separate 4-day repeated dose study in rats showed signs of weight loss and inflammation in
females at 300 and 1000 mg/kg/day. The MTD for females was deemed to be 100 mg/kg/day and the MTD for
males = 1000 mg/kg/day. A 28-day GLP multi-dose study in rats showed a NOAEL of 30 mg/kg/day.
Ultimately 4, 28 and 90-day studies on monkeys found no mortality or adverse effects therefore NOAEL
considered to be 1000 mg/kg/day.
Phase I SAD and MAD studies were performed. Slightly more adverse events were observed in the MAD studies at all
drug concentrations (50 mg – 200 mg bid to placebo). The findings indicate that the higher dosage and
frequency can cause more adverse events.Ultimately, no severe adverse events were documented at the
conclusion of Phase 1.
Phase II The proposed phase II schematic consists ofa randomized, double blind, three-arm, dose-ranging study.By
design,30 adult patients would be receiving 200 mg BID of drug, 30 would be receiving 250 mg BID of drug
staggered 2 weeks after arm 1 begins and 15 patients would be on the placebo. The decision point would be
determined after 8 weeks and based on the IGA. Safety and efficacy data obtained from this study will open the
doors
Phase III If the phase II safety and efficacy data meets internal and external regulatory satisfaction (i.e. no severe adverse
events,no critical organ failures, no immune systemdefects and decrease of atopic dermatitis symptoms), phase
III studies will be initiated.
NDA Filing Once phase I, II and III internal and external regulatory satisfaction/criteria are met, an investment will be made
to file a NDA.
Lifecycle Plan Due to the safety and efficacy data obtained from our trials, RTG-07103 has the potential to treat a variety of
disorders. At the minimum, RTG-07103 will immediately become the best orally available treatment option for
patients with atopic dermatitis. With slight modifications and adjustments to increase bioavailability, RTG-
07103 may be beneficial to a variety of otherdiseases.
4. 3
1.1 Epidemiology
Atopic dermatitis (AD) is not necessarily a disease that most people would claim they are
familiar with. This is because the disease is more commonly referred to by its common names
such as eczema or just simply dermatitis. However, when trying to understand the disease, an
easy way to start is to breakdown the actual scientific term. The word “atopic” is most often
associated with allergies while “dermatitis” is termed for inflammation of the skin. So, one could
assume that atopic dermatitis would be inflammation of the skin caused by some sort of an
allergic reaction. While this is a good summary, a better definition would be that it is a chronic
inflammatory disease characterized by eczematous lesions and intense itching. These breakouts
are not always associated with a specific allergen and can often be quite random from a patient’s
point of view due to the wide array of causative agents These can be anything from pollen,
cigarette smoke, foods, stress, and/or common environmental irritants.
Atopic dermatitis is often broken down into two different types: intrinsic or extrinsic
atopic dermatitis. While both forms are indistinguishable from each other from a layman's
perspective, there are some differences between the two. Extrinsic atopic dermatitis is defined as
atopic dermatitis that is stemmed from some sort of allergen or external factor while intrinsic is
defined by an absence of allergens and often does not result certain inflammatory responses.
Extrinsic atopic dermatitis is the much more common of the two which makes up about 70-85%
of all known cases1. It is associated with high levels of IGE, high cytokine levels of IL-4 and IL-
13, and will have a positive reaction to skin prick test. Intrinsic atopic dermatitis is much less
common only making up about 15-30% of cases and is attributed with normal levels of IGE, low
IL4- IL-13 levels, and a negative skin prick test to allergens. The age of onset for atopic
dermatitis occurs more commonly in childhood than adults. Usually when a child is diagnosed it
is because of extrinsic factors while later onset in adults are more likely due to intrinsic factors.
When diagnosing atopic dermatitis doctors and patients are often looking for rashes with
dry skin. These affected areas are often dry and associated with an intense itch. If the rashes go
untreated the skin can go on to begin to become darker or lighter, develop bumpy skin, or
become infected. This is normally due to the patient’s common reaction of intense scratching in
the areas which often leads to further irritation and/or bleeding. Common occurrences of the
disease are shown to be the neck, wrist, ankles, and/or the creases of the buttocks, legs, elbows,
or knees. Although it is more uncommon for adults to be diagnosed, rashes may cover much
larger parts of the body including the face, and possibly to the extent of the entire body. These
symptoms are considered to be very distracting for many patients and often have an effect on
their quality of life.
1.2 Pathogenesis
Current research supports that one of the main biological causes of atopic dermatitis is an
increase in the hydrolyzation of cyclic adenosine monophosphate (cAMP) into AMP. This
1
Petersen, Jennifer D., Chan, Lawrence S. “A Comprehensive Management Guide for Atopic Dermatitis.”
Dermatology Nursing. (2006) 18(6):531-542.
5. 4
hydrolyzation of cAMP is mediated by an enzyme known as phosphodiesterase 4 (PDE4). Once
cAMP is broken down by PDE4, AMP plays a critical signaling role that ultimately leads to the
synthesis of inflammatory cells. Changes to the regulation of this pathway may result in an
increase of these inflammatory cells. Therefore, autoimmune disorders, including atopic
dermatitis often stem from these molecular pathway errors. In these cases, when a PDE4
inhibitor is introduced, it has then been shown to decrease the breakdown of cAMP. Given with
this decrease in cAMP hydrolyzation results in a decreased pool of AMP and inflammatory
signaling. A current example is a drug known as Roflumilast which inhibits PDE4 in patients
needing treatment of inflammatory conditions of the lungs such as chronic obstructive
pulmonary disease more commonly known as COPD.
1.3 Current Therapy
With respect to current therapies and treatment options, atopic dermatitis currently has no
cure. The therapies that exist serve to mask disease severity through the suppression of its
symptoms. Patients are advised to follow good skin scare practices, such as moisturizing and
avoiding potential irritants to help to combat dry skin and unwarranted injury. These practices
are occasionally attributed with a decrease in breakouts, however, in many cases symptoms still
develop despite these practices being followed. The most common advice given to patients with
extrinsic atopic dermatitis is to try and identify what exactly may be triggering their breakouts.
As previously discussed, potential atopic dermatitis triggers may arise from a variety of factors
such as cigarette smoke, food allergies, environmental contaminants or stress. If a common
trigger is identified, patients are advised to avoid those triggers if possible. Often times, and with
regards to the more common atopic dermatitis inducing factors such as environmental
contaminants and stress, the factors are unavoidable and the symptoms still develop.
In the majority of cases where the breakouts cannot be confidently identified, such as
patients with intrinsic atopic dermatitis, or in cases where breakouts continue to persist, there are
medications that are commonly prescribed. Most commonly doctors will recommend over the
counter medications as a first line of defense such as topical steroids like hydrocortisone. These
steroids come in many different forms from creams, ointments, gels, foams, and solutions. More
commonly ointments are considered to be a little more potent due to their capabilities of keeping
the top layer of the skin hydrated. Prescription strength topical therapies are also an option,
however, many of these are expensive and not always covered by insurance. While many of
these may work at a better rate than an over the counter, the cost-to-benefit ratio may not be
enough in some patients’ eyes. Often times, patients avoid applying their creams according to the
appropriate treatment regimen due to discomforts and inconveniences associated with the
application process.
Although topical therapies are more commonly prescribed, doctors are increasingly
finding the need to turn to systemic therapies as a primary or second line of defense for some
patients. Many different oral treatments have been studied but most commonly given are oral
antihistamines or oral steroids. While antihistamines are not seen to work as well as steroids it
may relieve some symptoms and induce drowsiness to allow patients to sleep better and avoid
6. 5
itching while asleep. Prednisone is a common oral steroid given, however, due to side effects,
doctors normally only prescribe this to patients who meet a milder or severe case of atopic
dermatitis.
At this time there are currently no PDE4 inhibitors on the market targeted specifically for
atopic dermatitis leaving it as an unmet need in this form of therapy. As previously stated
Roflumilast is a PDE4 inhibitor currently on the market that is being prescribed for patients with
COPD, a similar inflammatory disease to atopic dermatitis however the inflammation occurs at
the site of the lungs.
8. 7
TargetRationale:RTG-07103 forAtopic Dermatitis
In order to provide an orally administered therapeutic treatment for Atopic Dermatitis,
the proposed small molecule is RTG-07103. RTG-07103 is a PDE4 small molecule inhibitor.
PDE4 is an important enzyme responsible for catalyzing the hydrolysis of intracellular cAMP,
which is a secondary messenger responsible for maintaining cellular homeostasis. Once cAMP is
hydrolyzed, AMP is able to promote the synthesis of inflammatory cells if improperly regulated.
Below is a schematic figure that depicts the molecular mechanisms of PDE4 and PDE4
inhibitors: :
Figure 1: RTG-07103 on left (normal state) and right (diseasedstate)
The use of PDE4 inhibitors is designed to decrease the hydrolyzation of cAMP as shown
in Figure 1 (Left). This decrease in levels of cAMP results in decreases of AMP, which help
restore cells to a “normal” immune response and therefore providing potential benefits for
various immune disorders such as atopic dermatitis. As shown in Figure 1 (Right), 5’AMP leads
to an increased immune response through the upregulation of certain pro-inflammatory markets,
which will ultimately serve to promote the recruitment of inflammatory cells. These pro-
inflammatory cytokines are the basis of atopic dermatitis as well as other autoimmune disorders.
Thus, using RTG-07103 for its anti-inflammatory function may prove to be beneficial
therapeutic treatment for atopic dermatitis.
There have been some studies conducted to examine RTG-07103 and its relevance with
atopic dermatitis. In one in vitro study, PDE4 genes were transfected into COS cells and
measured for their PDE activity with a radioimmunoassay kit. From this cell-based PDE4 assay,
the results indicate that the transfected cell line with PDE4 maintained a stable level of cAMP
production. The cAMP production provided the initial measurement of PDE activity with any
9. 8
addition of a TSH receptor. According to Titus et al.2, without the PDE inhibitor, the balanced
cAMP levels in PDE4 cell line were hydrolyzed by other PDEs, such as the PDE4 from the
HEK293 cells. Titus et. al.’s study showed that with the presence of a PDE4 inhibitor, levels of
cAMP could rise and trigger the opening of ion channels, which include the Na+ and Ca2+
channels.
The in vivo studies primarily use the mouse model. In Jin et al.’s3 experiment, three
mouse models was used for analyzing atopic dermatitis. There were three categories; the first
type were the models that were induced by an application of sensitizing, the second one were the
transgenic mice that overexpressed or had an absence of the particular molecules, and finally the
third category were the mice that spontaneously developed skin lesions similar to atopic
dermatitis. This study aimed to provide better knowledge of how atopic dermatitis works (its
pathogenesis) and how skin injury is affected by inflammation. This experiment concluded that
mouse models could have a similar genetic defect and present similar symptoms as the human
disease for atopic dermatitis.
Another in vivo study also used the mouse model to analyze atopic dermatitis. Tanaka
et.al’s4 experiment used the Nc/NgaTnd mouse model for atopic dermatitis. These mice
spontaneously developed itchy dermatitis in an unregulated air environment from 6-8 weeks of
age. According to the study, the affected NC/NgaTnd mice showed an increase of mast cells and
recruitment of inflammatory cells. The results from this study showed similar clinical symptoms
between the NC/NgaTnd mice and human atopic dermatitis.
Based on the in vivo and in-vitro experiments, atopic dermatitis is a chronic
inflammatory disorder characterized by intense itching and skin lesions. The in vivo studies
aimed to analyze atopic dermatitis and its level of inflammation in mouse models while the in
vitro study showed the effect of using a PDE4 inhibitor. Patients with atopic dermatitis show
high levels of PDE4 activity and thus, introducing a PDE4 inhibitor would significantly reduce
the symptoms and inflammation.
2
Titus SA, Li X, Southall N, et al. A Cell-based PDE4 Assay in 1536-well Plate format for High Throughput
Screening. Journal of biomolecularscreening.2008;13(7):609-618. doi:10.1177/1087057108319977
3
Jin H, He R, Oyoshi M, Geha R. Animal models of atopic dermatitis. The Journal of investigative dermatology.
2009;129(1):31-40. doi:10.1038/jid.2008.106.
4
Tanaka AMatsuda H. Evaluation of Itch by Using NC/NgaTnd Mice: A Model of Human Atopic Dermatitis.
Journal of Biomedicine and Biotechnology.2011;2011:1-5. doi:10.1155/2011/790436.
11. 10
3.1 Physicochemical Properties and Clinical Formulation
3.1.1 Description and composition of the drug product
RTG-07103 is a PDE4 inhibitor designed for atopic dermatitis. The composition of RTG-
07103 is similar to Roflumilast white to off-white and does not have an affinity for moisture with
a melting point of about 160°C. It is insoluble in hexane and water, sparingly soluble in ethanol,
and completely soluble in acetone.5
3.2 Non-clinical Studies
3.2.1 Non-clinical Pharmacology
Summary
The pharmacological properties of RTG-07103 have been investigated both in vitro and in vivo.
RTG-07103 passively enters cells and specifically inhibits PDE4 isoforms.
In vitro activity
In cell based assays, the five PDE4 isoforms are inhibited on average by over 85%, with some
isoforms (PDE4B1) showing an inhibition of 100% when treated with RTG-07103
concentrations of 10 μM. IC50 values were demonstrated to be about 100 nM. Similarly, RTG-
07103 showed significant reduction in PBMC TNF-a, fMLF-induced Neutrophil LTB4, CD18,
CD11b and VEGF-induced HUVEC proliferation at IC50 values of 51, 10, 23, 30 and 54 nM,
respectively. All aforementioned markers are clinically relevant in the development of atopic
dermatitis-like symptoms. Studies also reveal that in LPS-induced PBMC assays, the IC50 of
TNF-a and IL-12 production were reported at concentrations of 100 and 57 nM, respectively.
Whereas a similar study utilizing Anti-CD3 mAb-stimulated primary human T cells required
much higher concentrations of drug to see an inhibitory response.
In vivo/animal efficacy
In vivo, a dose dependent inhibition of dermatitis severity was observed when NC/Nga
mice were administered the drug orally beginning at week 5 and continuing for 4 weeks.
Similarly, mRNA expression of atopic dermatitis related chemokines was also reduced in a dose-
dependent fashion. These chemokines included, TARC, MDC and normal T-cell expressed and
secreted (RANTES). The ED50 in this model was 3 mg/kg/day.
When assessing RTG-07103 in a COPD mouse model, there was a significant decrease in
the total white blood cell count in the bronchoalveolar lavage (BAL). Lymphocytes and
monocytes are the two cell types that were affected the most. However, RTG-07103 cannot
inhibit all the inflammatory mechanisms associated with lung diseases such as the fibrotic
components of the lung.
5
RxList, 12/07/2015, http://www.rxlist.com/daliresp-drug.htm.
12. 11
3.2.2 Pharmacokinetics and Product Metabolism in Animals
Clearance, bioavailability, volume of distribution, route of elimination, variability, half-life
Based on our data from a research study determining the mean plasma pharmacokinetic
parameters of our drug in rats, the clearance when administered intravenously (1mg/kg
administered) was 419 ml/h/kg and 237 ml/h/kg for male and female, respectively. When
administered orally (10mg/kg), the clearances for male and female species were 4745 and 1517
respectively.
When applied orally, in rats, males and females had a bioavailability of 9.48 and 17.24%,
respectively. This differed from the bioavailability found in monkeys in which there was less of a
disparity between male and female with 17.8% for the male and 17.2% for the female species.
The volume of distribution is determined by the physiological conditions of the body as
well as the pharmacokinetic properties of the administered drug. The volume of distribution in
was 933 mL/kg and 1037 ml/kg for male and female rats, respectively while for monkeys it was
1840 mL/kg and 1750 mL/kg for male and female monkeys.
This drug will be excreted as a metabolite with other waste products of the body after
being modified via a number of systemic processes. Studies showed that it has a half-life of 1.49
hours in male rats and 2.51 hours in female mice when administered intravenously. When
applied orally, the drug had a higher half-life of 2.21 hours in males and 3.47 hours in female
rats. Data showed that the time it took to reach maximum concentration when administered
orally higher in female rats than in males. Due to the size difference and a number of other
variables, the half-life was higher in monkeys, as expected, with an intravenous half-life of 3.17
hours for male and 2.30 hours for female monkeys. This number is higher when applied orally
with a half-life of 6.68 hours for males and 6.21 hours for female. The time difference is most
likely due to the time it takes for the drug to get to the bloodstream and to reach maximum
concentration.
The drug did not show much variability within rats and monkeys. While figures varied
between male and female species, the standard deviation was relatively low and showed little
variability. The NOEL for this drug is 1000 mg/kg.
Potential for DDI
Cytochrome P450 inhibition was tested in mixed gender human liver microsomes at
concentrations of 0.01, 0.1, 1.0, 10 and 50 μM. RTG-07103 was concluded to have no inhibitory
effects on CYP1A2, CYP2D6, CYP2E1 and clinically insignificant effects on CYP2B6-,
CYP2C9-, CYP2C19-, and CYP3A4-dependent activities with IC50 >50 μM in all cases. In
vitro, RTG-07103 inhibitory activity on recombinant human phosphodiesterase enzymes at 10
μM showed minimal PDE1, PDE2, PDE3, PDE5, PDE7, PDE8, PDE9, PDE10 isoform
inhibition while selectively inhibiting PDE4 isoforms.
Induction of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4/5 isoforms was also
tested in primary cultures of human hepatocytes. RTG-07013 did not increase catalytic activities
of CYP to a clinically significant extent and can be concluded to not be inducers of CYP
enzymes.
13. 12
3.2.3 Toxicology
Pilot Toxicology Studies
The single dose in vivo study with RTG-07103 for the cynomolgus monkey (oral gavage/
100 and 300 mg/kg) showed increased amount of acute phase proteins and liver enzymes at 300
mg/kg in one mammal. The MTD (maximum tolerated dose) was estimated to be higher than the
300-mg/kg dose.
The repeated dose in vivo study with RTG-07103 for Sprague-Dawley rat orally
administered in 7-day duration showed different findings from three separate routes and doses.
One course for the study consisted of the oral gavage of 0, 50 mg/kg per day with RTG-07103
showed no signs of toxicity and that all animals were administered with the drug at the seven day
dosage period. The Sprague-Dawley rats were treated with RTG-07103 (200 mg/kg/day) and
completed their seven-day dosage protocol. The findings did not show any signs of severe
toxicity. However, there was some weight loss present. The rats that lost weight showed
symptoms of diarrhea and had the appearance of porphyrin. Based on this finding, blood
chemistry, and hematology exams were conducted and the RTG-07103 treated animals with the
vehicle. From these testings, it was noted that there was a decrease in albumin, an increase in
globulin, and an increase of monocytes associated with the RTG-07103 treated animals.
The in vivo repeated dose also conducted a study in which the Sprague-Dawley rats were
orally administered 0 (0.5% methylcellulose) 30, 100, 300, and 1000 mg/kg per day during the
four-day dosage period. The findings showed signs of weight loss and decreased consumption of
food in females that were orally gavaged 300 and 1000 mg/kg per day. Other findings stated that
there was inflammation present in the thymus, heart, or intestines that were observed in the
groups treated with RTG-07103. When more doses were given, the lesions and inflammations
increased and became more severe in females. Since there was minor injuries or inflammation
present for males treated with the same drug, the maximum tolerated dose was considered to be
1000 mg/kg per day. In females that were treated with the same drug, the MTD was said to be at
100 mg/kg per day.
Based on these in vivo rat studies data, it can be concluded that RTG-07103 is tolerated
with lower dosages such as given in 100 or 50 mg/kg per day. Although severe toxicity was not
present in higher dosages of 200 mg/kg per day, there were minor side effects such as weight
loss and decreased albumin. Results from rodents that were treated with higher dosages of 300
and 1000 mg/kg per day experienced more severe adverse effects, which may lead toxicity.
GLP Toxicology Studies
During the 28-day multidose in vivo study with RTG-07103 for the Sprague-Dawley rat
(oral gavage/ 0, 3, 10, 30, 300 (males)/100 (females) mg/kg/day) there was no mortality and only
minor acute inflammatory responses in the high dosed subjects. The NOAEL was observed to be
30 mg/ kg/day.
14. 13
The 90-day multidose in vivo study for the Sprague-Dawley rat (oral gavage/0, 15, 45,
150(100), and 750(150) mg/kg/day) had toxic and lethal observations for the dosages at both 150
and 750 mg/kg/day. Due to these comments, the dosages were reduced respectively to 100 and
150. These doses continued to show toxic and lethal effects. Therefore, the NOEL for this study
was observed to be 45 mg/kg/day.
Both the 4-day, 28-day, and 90-day multidose in vivo studies for the cynomolgus monkey
found no mortality in all doses up to 1000 mg/kg/day. Therefore, the NOAEL for all studies on
the cynomolgus monkey were found to be 1000 mg/kg/day. At 15 and 45 mg/kg/day there were
no adverse effects found and was well tolerated. After a 14 day dosage of 150 and 750
mg/kg/day it was reduced to 100 and 150 mg/kg/day due to severe toxicity and lethality.
However, systemic toxicity was still observed at 100 and 150 mg/kg/day (53-day recovery
period). The NOAEL was observed to be 45 mg/kg/day.
16. 15
Protocol Number 00374929
Title A Randomized, Double Blind, Three-arm Dose-Ranging, Placebo-controlled Study to
Assess the Safety, Tolerability, and Efficacy of Oral RTG-07103 in Patients With
Moderate-Severe Atopic Dermatitis
Brief Title Study of Safety and Efficacy of RTG-07103 in Patients with Mild-Severe Atopic
Dermatitis
Sponsorand
Clinical Phase
M2M Pharmaceuticals
Phase 2
Investigation Type Drug
Study Type Interventional
Purpose and
Rationale
This study is designed to assess the safety ofRTG-07103 while identifying the optimal
therapeutic dose for patients suffering from moderate-severe Atopic Dermatitis. The
study is designed as a three-arm, staggered schematic to properly determine the ideal
dose while minimizing possible side effects from an increased dosage.RTG-07103 will
be compared with an oral placebo, as there is currently no oral atopic dermatitis
therapeutics in the market. The primary endpoint will be a score of 0-1 on the
Investigator’s Global Assessment,which is defined as “treatment success”.
Primary
Objectives
• To determine an optimal therapeutic dose for oral administration
• Provide safety,efficacy and tolerability in patients with moderate-severe atopic
dermatitis using RTG-07103
Secondary
Objectives
• To optimize bioavailability on solid dosage prior to developing a liquid
formulation appropriate for pediatric studies.
• To prove improved efficacy compared to topical agents currently in the market.
Study Design A randomized, double blind, staggered three-arm, placebo-controlled, dose-ranging
study.Patients in Arm 1 treated with 200 mg BID, patients in Arm 2 treated with 250
mg BID and patients in Arm 3 given an oral placebo. Patients in Arm 2 will begin
dosing 2 weeks after Arm 1 begins. Study will conclude in 8 weeks and patients will
have a study visit at 4 weeks.
Population • Arm 1 – 30 adult patients
• Arm 2 – 30 adult patients
• Arm 3 – 15 adult patients
Inclusion Criteria • Patient must sign informed consent prior to enrollment.
• Patient is a 18 – 65 year old adult with moderate-severe atopic dermatitis.
17. 16
• Patient has a medical history of atopic dermatitis for at least 3 years.
• Patient with atopic dermatitis affecting at least two regions of the body >10cm2
per target area.
• Patient’s Eczema Area and Severity Index (EASI) ≥10 at
the screening and baseline visit.
• Patient has an IGA Score ≥ 3 at screening and baseline
visit.
Exclusion Criteria • Patients who are using any concomitant medication(s) that, in the investigator's'
opinion, could affect the subject's Atopic Dermatitis. Patients using such medications
may be included, at the investigator's discretion, if they have been stable on treatment
for at least 1 month prior to the start of study treatment and no changes to these
medications are planned during the study period.
• Patient has serological evidence of hepatitis B virus or hepatitis C viral
infections.
• Patient has known history of human immunodeficiency virus infection.
• Patient has concurrent diseases/conditions and history of other
diseases/conditions in the selected treatment areas(s)that may have an impact on the
study assessments.
• Patient has evidence of tuberculosis (TB) infection as defined by a positive
purified protein derivative (PPD) and/orpositive interferon-gamma release assay.
• Patient is pregnant or has been pregnant in the last 6 months.
Investigational and
Reference Therapy
Investigational Therapy: 200 mg BID, 250 mg BID
Reference Therapy: Hydrocortisone cream and ointment 2.5%
Efficacy
Assessments
"Treatment Success," a static endpoint defined as a score of 0 to 1 at Week 8 by the
Investigator's Global Assessment (IGA) scoring systemfor atopic dermatitis status.
Eczema Area Severity Index (EASI) score changes ofindividual atopic dermatitis signs
at each visit from Day 1 pre-treatment. Time Frame: 8 weeks
Pruritus Self-Assessment score changes of atopic dermatitis related itching/scratching
at each visit from Day 1 pre-treatment. Time Frame: 8 weeks
Safety
Assessments
Physical examination to assess vital signs (BP, pulse, temperature).
Clinical laboratory tests (CBC and CMP) to measure biomarkers and avoid
toxicity/drug-drug interactions.
Adverse experience as reported by patient, including pain and dermatologic/skin
toxicity (incidence, severity, frequency, duration and causality).
Other Assessments Food effect studies
Measurement of PDE4 at baseline and 8 weeks
18. 17
Data Analysis 75 patients will be screened and enrolled at baseline to participate in a double blind
dose ranging study.In the first arm of the study,30 patients will be randomly selected
to receive 200 mg BID of RTG-07103 for 8 weeks in concurrence with 15 patients
receiving a placebo. Within 2 weeks of the study,if there are no adverse events
reported/observed,Arm 2 of the study will commence and 30 remaining patients will
be treated with 250 mg BID.
At 4 weeks, patients will report for a study visit in which safety will be assessed by
adverse events,physical and dermatological examinations, vital signs,laboratory
assessments and electrocardiograms. Patient’s Investigator’s Global Assessment (IGA)
and Eczema Area Severity Index (EASI) will be measured.
At 8 weeks, patients will report for their final study visit; safety assessments,IGA and
EASI will be recorded. In addition, patients will complete a Pruritus Self-Assessment
Score to report improvement, stagnation,or worsening of their atopic dermatitis.
Data will be analyzed by evaluating and comparing IGA from baseline, 4 weeks and 8
weeks. In this study,IGA is the key determinant of efficacy for RTG-07103.
Key Words Atopic Dermatitis, PDE4 Inhibitor, RTG-07103, Randomized Double Blind Three Arm
Dose Ranging, Oral Therapy, Investigator’s Global Assessment
20. 19
5.1 Introduction
Two clinical studies were conducted in Phase 1 of this drug’s development process.
These were; a Single Ascending Dose (SAD) study and a Multiple Ascending Dose (MAD)
study. The SAD study was a randomized, double blind study and was conducted in order to
assess safety and tolerability of a single dose of RTG-07103. In addition, it was imperative that a
number of other factors were assessed secondarily such as the single dose of RTG-07103, effect
of this drug on pharmacodynamic markers in the blood and the effect of RTG-07103 on QTc
interval following single oral doses. The MAD study was a randomized, double blind, single-
centered study and was conducted to assess similar effects, however, a few primary and
secondary objectives differ from that of the SAD study. Objectives such as, our desire to identify
dose(s) of RTG-07103 for Phase II evaluation in patients with moderate-severe Atopic
Dermatitis and evaluation of the pharmacokinetics of RTG-07103 as well as to describe
preliminary evidence of efficacy.
Our SAD study was conducted with 60-70 healthy volunteers (~20 placebo) with ages
ranging from 18-67 so as to get a look at these effects in all age groups of adults. The starting
dose was 10mg once a day and with seven dose escalations, we ended with a maximum dose of
150mg twice a day. We had a number of endpoints to ensure safety of the volunteer and to show
us certain effects of the drug on the body. Endpoints included physical exams, laboratory
evaluations, the half-life of the drug, and strength of immune response. Our MAD study, while
having similar endpoints, used different logistics. This study comprised of 40-50 healthy
volunteers (~10 placebo) with a starting dose of of 50mg once a day and after 4 dose escalations,
we administered the maximum dose of 200mg twice a day. Following the MAD, we decided to
run an expansion cohort in ten patients with moderate to severe Atopic Dermatitis. This cohort
would prove preliminary efficacy over the span of a 90 day trial that showed improvement in the
EASI (index indicating severity of disease) over the trial in all of the patients.
5.2 Pharmacokinetics and Metabolism in Humans
Both the SAD and MAD studies had similar pharmacokinetic indications. This data
showed that at higher dosage levels, the concentration levels increased within the first few hours
when RTG-07103 was administered. Pharmacokinetic variability had an increase during the first
hour after drug administered but began to decrease over time. This implied that variability
occurred during the absorption phase. We concluded that our dosage level required for efficacy
is 200mg administered twice a day as we needed a dose level that would be able to achieve
50ng/mL in a safe manner. Our bioavailability was about 25% which is significantly lower than
anticipated and also saw that when co-administered with a lipid rich diet, our bioavailability
almost doubled, indicating that the food increased the lipid solubility of our drug. Interestingly,
our studies also showed that as dosage increased, bioavailability decreased, Upon observation of
this finding, we decided to reformulate RTG-07103 in order to increase bioavailability.
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5.3 Safety and Tolerability
Our Phase I data showed overall safety with minimal adverse events in volunteers. RTG-
07103 was tolerated in both studies with slightly more adverse events in the MAD study than the
SAD study. Some of these were mild such as nausea & abdominal pain and there were fewer
more moderate adverse events such as diarrhea and headaches. There were 12 adverse events in
the SAD study with 25% of these coming from the placebo group. In the MAD study however,
there were 44 adverse events with 14 of these events occurring at the highest dose level of
200mg twice a day and 10 of these events occurring in the placebo group. These numbers of
adverse events indicated the evident occurrence of the placebo effect within both of our studies
in healthy volunteers. The fact that 13 of the 56 adverse events that occurred were by the placebo
group showed us that only roughly three-quarters of these adverse events were really a
consequence of the drug and one quarter were negligible. When comparing both SAD and MAD
studies, the findings indicated that high dosage in high frequency can cause more adverse events.
This data concluded that RTG-07103 was safe for Phase I since there were no severe adverse
events and thus, can proceed to phase 2 with no major specific conditions to monitor.
5.4 Pharmacodynamic Effects
Our phase I studies concluded that RTG-07103 decreased the inflammatory response of
the body. The levels of cytokine release in both our SAD and MAD studies showed were
decreased indicating that RTG-07103 is performing its function. We observed release levels for
cytokines such as IRF7, MXA, LY6E, CXCL9 and many others. The decreased release of these
cytokines was to be expected because upon the drug reaching the target, the exerted effects
should inhibit inflammation and thereby reduce and inhibit, release of numerous cytokines and
other immune response cells.
5.5 Efficacy
While concerned about bioavailability, we were optimistic and not surprised to see that
our efficacy data showed our drug to be very effective. Our SAD and MAD studies both showed
that RTG-07103 caused a substantial decrease in pruritus. In addition, we saw that within the
expansion cohort, almost 80% of the patients had a 50% improvement in the severity of the
disease. EASI-50 assessment showed that most patients with moderate to severe Atopic
Dermatitis saw improvement to EASI-50 scores of less than 50. Because the EASI is scored from
0-72, this is indicative of less than severe conditions and closer to mild conditions of the disease.
All patients saw a reduction in the severity of their which showed us that despite the inevitable
variability of any drug, RTG-07103 appears to be efficacious for all adults.
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5.6 Guidance to Investigators
On the basis of the preclinical data and phase I clinical data, there are no major concerns
with the safety of the drug in the treatment of Atopic Dermatitis. While RTG-07103 has shown
fairly low bioavailability, there is a plan to reformulate in order to increase this by adding
components that will make the drug more lipid soluble. This will allow the drug to reach the
target in a higher dose and thereby reduce the dosage or increase its exerted effects so as to
decrease the time taken to positively affect severity of atopic dermatitis in adults. The probability
of overdose is low because our data shows that even when the drug is taken in proportions of ten
times more than the prescribed or recommended dose, adverse effects were still moderate and
minimal. This is true for undesirable effects as well. We have seen that a minimal number of
volunteers saw any problems while taking the drug. Furthermore, the repeated occurrence of
these events were also minimal. While we do not have data on drug abuse/dependency or effects
of drug use during lactation, there are future plans to research these effects and observe clinical
outcomes. We have concluded that there is little to no potential for drug-drug interactions based
on DDI studies conducted during phase II. RTG-07103 has an oral method of administration.
This is the first drug for atopic dermatitis that will be administered orally and we believe that this
administration will more effectively target the disease and lead to life changing benefits for those
with moderate to severe atopic dermatitis which also treating and completely absolving patients
with mild forms of the disease.
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