A PHASE II, RANDOMISED, ADAPTIVE, OPEN-LABEL
PLATFORM TRIAL TO EVALUATE EFFICACY AND
SAFETY OF MULTIPLE COMBINATION THERAPIES IN
PARTICIPANTS WITH CHRONIC HEPATITIS B

Chronic HBV infection (defined as persistent detection of serum HBsAg, the
hallmarks of which are high levels of circulating HBV DNA and HBsAg) is a
consequence of the presence of a viral reservoir, i.e., episomal covalently
closed circular deoxyribonucleic acid (cccDNA) in the nucleus of an infected
hepatocyte. Despite advancements in the understanding of HBV disease biology,
complete cure, i.e., eradication of cccDNA is not
currently possible by available treatments. Nevertheless, the sustained
clearance of HBsAg has been shown to protect against disease progression and
development of HBV complications including cirrhosis, liver failure, and HCC.
Accordingly, functional cure is defined as sustained, undetectable HBsAg in
serum and HBV DNA in circulation, with or without seroconversion to anti-HBs,
after completion of a finite course of treatment
(Lok et al 2017). Partial cure will demonstrate sustained plasma HBV DNA
suppression after completion of treatment, but with persistently detectable
circulating HBsAg.
Other clinically meaningful endpoints include HBV DNA suppression and alanine
aminotransferase (ALT) normalization, which indicate virologic and biochemical
responses to therapies, respectively. For hepatitis B e antigen
(HBeAg)-positive patients,HBeAg seroconversion is indicative of a better
prognosis, including lower rates of cirrhosis and slower disease progression.
Sustained suppression of HBV replication,
regardless of HBeAg status, is associated with biochemical remission,
histological improvement, and reduced risk of disease progression.

Primary
* To estimate the effect of NME combination therapies on inducing a functional
cure over the control arm.

Secondary
* To characterize the efficacy profile of NME combination therapies.
* To characterize the PD profile of NME combination therapies.
* To characterize the plasma PK profiles of NMEs.
* To assess the safety and tolerability of NME combination therapies.
* To identify presence of PK/PD relationship.
* To explore potential effects of ADA on NMEs and/or IMP, as applicable.

This is a Phase II, randomized, adaptive, open-label, multi-arm, multi-center,
international, platform study designed to evaluate safety, tolerability, and
efficacy of new combination therapies including one or more NMEs in CHB
participants with preserved liver function and without significant
fibrosis/cirrhosis. The platform design allows comparison of multiple new
combination therapies against a common control, and introduction of additional
treatment arms at later study time points.

This study is designed to be adaptive to open additional shorter duration
treatment arms or to expand existing treatment arms for NME combination
therapies that show promising efficacy outcomes. The platform design also has
the flexibility to open new treatment arms to explore different combination
regimens or different patient populations pending new submission and HA/EC
approval. Treatment arms may be staggered relative to other treatment arms in
order to increase study efficiency with regards to timely interim data readouts
or to reduce the complexity of study conduct.
For the first combination, participants will be randomized on Day 1 to an NME
combination arm (N=30) or the control arm (N=30) using an adaptive stratified
sampling method, stratified at screening HBsAg level (* 1,000 IU/mL, * 1000
IU/mL), with a minimum of 12 participants per arm with a screening HBsAg level
of * 1000 IU/mL. For NME combination arms that will be introduced later into
the platform study, the allocation ratio of participants to the control arm,
will depend on the number of actively enrolling arms with the stipulation that
no more than 17% of participants will be randomly allocated to a control arm.
Additionally, for subsequent arms the proportion of patients with HBsAg level
* 1000 IU/mL, * 1000 IU/mL within each treatment arm, will be maintained as
closely as possible to the first combination treatment arm.

The treatment period duration will be a maximum of 48 weeks, after which
participants will enter a 48-week follow-up period. A shorter treatment
duration (12 or 24 weeks) for NME combination arms, and a 48-week
response-guided therapy (RGT) arm may be added following planned interim
analyses; four interim analyses are planned for each treatment arm. Treatment
arms that achieve 30% difference, compared to NUC control arm, for HBsAg loss
at EOT or follow-up Weeks 12 and 24 (primary endpoint) may be expanded to
accrue additional efficacy and safety data and to contribute to Phase 3 design
planning as guided by the emerging data, for example, enrichment for HBeAg
positive or HBeAg negative participant populations.

Screening
* Physical examination
* Vital Signs
* Electrocardiogram (ECG)
* Abdominal ultrasound scan
* Liver elastography
* Blood collection
* Urine samples
* Breath test: A breath test to test for alcohol consumption.
These tests may be repeated or extra samples may be collected if the laboratory
results fall outside of the required ranges.

NUC Control arm
* Physical examination:
* Vital Signs:
* Electrocardiogram (ECG)
* Abdominal ultrasound scan:
* Blood collection
* Urine samples
* Breath test:
These tests may be repeated or extra samples may be collected if the laboratory
results fall outside of the required ranges, or if the patient has a reaction
to the study medications.

siRNA + NUC arm
* Physical examination:
* Vital Signs
* Electrocardiogram (ECG)
* Ultrasound
* Blood collection
* Urine samples
* Breath test
These tests may be repeated or extra samples may be collected if the laboratory
results fall outside of the required ranges, or if the patient has a reaction
to the study medications.

siRNA + PEG-IFN + NUC arm
* Physical examination:
* Vital Signs
* Electrocardiogram (ECG)
* Abdominal ultrasound scan
* Blood collection
* Urine samples
* Breath test
These tests may be repeated or extra samples may be collected if the laboratory
results fall outside of the required ranges, or if the patient has a reaction
to the study medications.

siRNA + TRL7 + NUC arm
* Physical examination:
* Vital Signs
* Electrocardiogram (ECG)
* Abdominal ultrasound scan
* Blood collection
* Urine samples
* Breath test
These tests may be repeated or extra samples may be collected if the laboratory
results fall outside of the required ranges, or if the patient has a reaction
to the study medications.

There is no guarantee that the patient will receive any benefits from this
study, and taking part in this study may or may not cause patient's health to
improve. Information from this study may help doctors learn more about the
investigation combination treatments and the treatment of chronic HBV
infection. This information may benefit other patients with chronic HBV
infection or a similar condition in the future.

Disadvantages of participation in the study may be:
- possible side effects of the study drug
- possible discomforts from the measurements during the study
- (additional) testing
- appointments that need to be attended
- possibly confrontational questionnaires

Patients may have side effects from the medications or procedures used in this
study. Side effects can vary from mild to serious and may vary from person to
person. Some side effects go away soon after patients stop the medication that
is causing them. In some cases, side effects can be serious (in very rare cases
may be fatal) and may be long lasting or may never go away. Patients should
talk to the study doctor about any side effects that they have while taking
part in the study. Everyone taking part in the study will be monitored
carefully for any side effects, and cared for as appropriate. Study doctors may
give patients medications to help lessen any side effects.

Allergic reactions can occur with any medication and this can be in the form of
itching, difficulty breathing, and a skin rash and/or drop in blood pressure.
In very rare cases, patients could suffer a life-threatening allergic reaction.

Side Effects Potentially Associated with NUCs and PEG-IFN
NUCs and PEG-IFN have been used for many years to treat chronic HBV infection.
* For entecavir: https://packageinserts.bms.com/ppi/ppi_baraclude.pdf
The most common side effects of entecavir are headache, feeling tired,
dizziness, nausea, and elevated liver enzyme (ALT). Patients with HBV may
experience worsening of their liver disease if entecavir treatment is stopped
prematurely.
* For tenofovir alafenamide (TAF): https://www.vemlidy.com/isi
In patients with HBV treated with TAF, the most common side effects (greater
than 10% of subjects) was headache. Patients with HBV may experience worsening
of their liver disease if TAF treatment is stopped prematurely. TAF may also
impair kidney function.
* For tenofovir disoproxil fumarate (TDF):

http://www.gilead.com/~/media/Files/pdfs/medicines/hiv/viread/viread_patient_pi.
pdf
In patients with HBV treated with TDF, the most frequently reported side
effects were nausea (9%), abdominal pain (>5%), diarrhea (>5%), headache (>5%),
dizziness (>5%), fatigue (>5%), nasopharyngitis (common cold) (>5%), back pain
(>5%), and skin rash (>5%). Patients with HBV may experience worsening of their
liver disease if TDF treatment is stopped prematurely. TDF may also impair
kidney function.
* For pegylated interferon alfa-2a (PEG-IFN):
https://www.medicines.org.uk/emc/files/pil.1697.pdf
In HBV patients treated with PEG-IFN, the most common side effects were pyrexia
(54%), headache (27%), fatigue (24%), myalgia (26%), alopecia (18%), and
anorexia (16%). Overall 5% of HBV subjects discontinued PEG-IFN therapy and 40%
of subjects required modification of PEG-IFN dose. The most common reason for
dose modification in subjects receiving PEG-IFN therapy was for laboratory
abnormalities including neutropenia (20%), thrombocytopenia (13%), and liver
enzyme (ALT) elevation (11%).

Side Effects Potentially Associated with RO7445482
Therapies such as RO7445482, which are called oligonucleotides, may be
associated with certain side effects (called class effect) in animals or
humans. Known oligonucleotide class effects may affect the kidneys (the organ
where the drug is eliminated), the liver (the organ where the drug is
metabolized/broken down), the skin (at the sites where the drug is
administered), or trigger immune reactions (such as flu-like symptoms, or
antibodies against the drug). RO7445482 is an experimental drug with limited
clinical experience in humans. For this reason, the side effects are not known
at this time. There is one clinical study with RO7445482, (DCR-HBVs-101) that
is currently ongoing. By the 25th of June 2020, 30 healthy volunteers, 9
patients with HBV who had not previously been treated with standard therapy and
18 patients with chronic HBV who were being treated with NUCs had received
RO7445482 or placebo (a substance that looks like RO7445482, but has no
medication). RO70445482 was generally well tolerated, the majority of the side
effects were mild in nature, and most had resolved. The healthy volunteers
received single doses of RO7445482 or placebo and the most frequently reported
side effects were reactions at the injection site, headaches, abdominal pain,
dizziness, and vomiting. The patients with HBV received single or multiple dose
of RO7445482 or placebo and the most frequent side effects reported were
injection site reactions (ISRs), increases in liver enzymes (ALT, AST and GGT),
headache, and fatigue.

Injection Site Reactions and Risks Associated with Drug Administration
For SC administration, the study drug will be given through a syringe into the
skin layer in the abdomen or thigh. Patient may experience mild discomfort
during the procedure, and there is a small chance of infection or bruising by
placing the needle in the abdomen/thigh (subcutaneously).
ISRs could occur at the time of RO7445482 administration, within 24 hours after
administration, or even later. Most of the ISRs were considered mild in
intensity. Most common symptoms generally reported in the ongoing clinical
study were redness, rash, local swelling, discoloration, and pain or tenderness
at the injection site. Study doctor will be carefully assessing the injection
site and every medical precaution will be taken to avoid an infection or
complication.

Liver Effects
In animal studies (in mice), some changes in liver enzyme laboratory tests were
observed, however, no liver safety signals were observed in monkeys (monkey is
considered the most relevant animal for assessing the risk to humans). Study
doctor will carry out safety laboratory tests to monitor patien's liver and
avoid any complications. Transient elevations in liver enzymes were observed in
patients with HBV who had not previously been treated with standard therapy in
the ongoing clinical trial between 2 to 4 weeks after receiving RO7445482,
which resolved during the follow-up period without the need of treatment.

Other Potential Oligonucleotide Class Effects
To date, studies in animals (mice and monkeys) showed that RO7445482 was not
associated with any changes in kidney functions. In the ongoing studies, no
drug-related kidney side effects, changes in kidney laboratory parameters, or
abnormalities in urine microscopy were reported. Study doctor will carry out
safety laboratory tests to monitor your kidney to avoid any complications.
Based on information from animal studies and other similar drugs, RO7445482 is
considered of low risk to trigger immune reactions (meaning, reactions of the
system in the body that fights infections). Study doctor will monitor the
patient for any immediate reactions after the administration of the study drug.
All participants will be closely monitored.

Unknown Risks:
RO7445482 might have other side effects, including serious side effects, that
could occur with long-term treatment or when used in combination, which are not
known at this time. Such side effects cannot always be predicted. If new
information is discovered that might change patient's decision to stay in the
study, the patient will be told about it in due time, so the patient can decide
whether he/she want to continue.

Side Effects Potentially Associated with RO7020531
RO7020531 is an experimental medication that, as of 01 May 2020, had been
administered to 88 healthy volunteers, 24 HBV patients, and to 56 Chinese
healthy volunteers in two clinical studies, one of which is currently ongoing.
Patient will be informed about any additional side effects that may occur in
this ongoing study. The study medication was considered safe and with
acceptable tolerability in the majority of patients. Nineteen (out of 72)
subjects who received multiple doses of RO7020531 at 140 mg or higher
experienced flu-like symptoms (such as fever, body ache, headache, chills,
dizziness, and nausea). In some subjects, flu-like symptoms may re-appear with
the subsequent dosing. However, these symptoms are commonly resolved with
treatment to reduce fever (e.g. paracetamol). Some subjects with flu-like
symptoms may also experience a temporary decline in their blood cells count,
but these cells return to normal within 24-48 hours after dosing. Since
RO7020531 causes the activation of patient's immune system, the body will
produce some molecules (called cytokines) that include interferon-*. A modified
version of interferon-* is currently used as treatment for HBV. Even though
RO7020531 induces lower levels of interferon-* and will be given for shorter
duration, there is the potential to cause a similar spectrum of side effects,
which patient may find here:
https://www.medicines.org.uk/emc/files/pil.8244.pdf
In rare cases, there is a potential for medications with a similar mechanism of
action of RO7020531 to cause an excessive activation of patient's immune system
(an extreme form of flu-like symptoms including fever). This may cause a
potentially life-threatening condition that can lead to blood pressure drop and
toxicity to patient's organs which requires hospitalization. RO7020531 has been
given to 168 healthy volunteers/HBV patients, 96 of which received doses equal
to or higher than 140 mg, similar to the dose to be used for this study (150
mg) and no participant experienced this condition.

Risks Associated with Study Procedures
- Blood Sampling
During this study, small amounts of blood will be drawn from a vein and used
for tests that allow study doctors to see how the patients are doing. Drawing
blood may cause pain where the needle is inserted, and there is a small risk of
bruising or infection at the place where the needle is inserted. Very rarely, a
blockage of the vein or a small nerve injury can occur, resulting in numbness
and pain. However, this will resolve with time. Some people experience
dizziness, upset stomach, or fainting when their blood is drawn. On days when
several blood samples will be taken, the study nurse may use a cannula (small
plastic tube) inserted in patient's arm using a small needle. This cannula may
remain in place for the day and will be taken out before patients go to bed at
night. There is a small chance of infection by placing the cannula in the arm,
but every medical precaution will be taken to avoid an infection.
- Electrocardiogram (ECG)
Patients will have small, soft pads, placed stuck temporarily on different
parts of their body. There is no pain or discomfort during an ECG; however, the
area of skin in which the ECG pads will be stuck may need to be shaved, and the
pads may cause a skin reaction such as redness or itching. Taking the pads off
may cause localized irritation to the skin and/or hair loss, similar to having
a plaster taken off.
- Liver biopsy
In case patients experience any marked and persistent liver enzyme (ALT)
elevations, study doctor may suggest to perform a liver biopsy, if this
procedure is considered a relevant assessment for patient's clinical condition.
If a liver biopsy is to be done, then patients may need to stay in the hospital
for several hours. The procedure includes numbing the skin over the liver with
a local anesthetic, followed by passing a needle through the skin into the
liver and removing a small core of liver tissue. A specialist will examine the
tissue carefully under a microscope. There is some discomfort associated with
the procedure. The discomfort should generally not last more than several
hours. The risks include bleeding from the biopsy site, significant bleeding
requiring a blood transfusion or surgery to control the bleeding (rare),
perforation of internal organs (rare), and death (very rare).