A PHASE 2 RANDOMIZED, DOUBLE-BLIND PLACEBO-CONTROLLED TRIAL OF MHAA4549A,
A MONOCLONAL ANTIBODY, IN COMBINATION WITH OSELTAMIVIR VERSUS OSELTAMIVIR FOR
TREATMENT OF SEVERE INFLUENZA A INFECTION

1. BACKGROUND
1.1 BACKGROUND ON INFLUENZA
Influenza A is a membrane-enveloped RNA virus that causes significant morbidity
and mortality. Currently, there is a great need in hospitalized influenza
patients for a parenteral therapeutic option that is well tolerated, can
rapidly resolve influenza-related signs and symptoms, decrease mortality,
reduce hospital and intensive care unit (ICU) stays, as well as have a
prolonged window for initiation of treatment beyond the current standard of
care (SOC) (i.e., within 48 hours of the onset of flu symptoms).
Approximately 200,000 to 278,000 patients are hospitalized with severe
influenza infections annually in the United States (U.S.) (Thompson et al.
2004; Zhou et al. 2012), and assuming the same rate reported in the U.S., an
estimated 319,000 to 445,000 patients are hospitalized in the European Union
(E.U.). Hospitalization due to severe influenza is associated with high
mortality (4%*8%), ICU admission (5%*17%; Lee and Ison 2012), mechanical
ventilation support in an ICU setting (7%*11%; Doshi et al. 2011), and
prolonged hospital stays (5*9 days; Lee and Ison 2012). During a pandemic
season, the outcomes may be more serious, with up to 34% of patients requiring
ICU care and a mortality rate as high as 15% (Lee and Ison 2012).
Influenza infection is an upper and lower respiratory disease with a broad
spectrum of presentations that can result in fever, shortness-of-breath,
pneumonia, respiratory failure, secondary respiratory infections, and even
death. The SOC therapy for patients hospitalized with influenza consists of
supportive measures and administration of available antiviral agents, primarily
neuraminidase inhibitors (NAI) that include but are not limited to oseltamivir,
zanamivir, and peramivir. However, a significant unmet medical need still
exists in the severely ill patient population, as evidenced by the considerable
degree of morbidity and mortality in this setting. To address this need,
Genentech Inc. /F.Hoffmann-La Roche Ltd. (Genentech) is developing a
highly-specific, anti-influenza A (MHAA4549A) antibody therapy for treatment of
hospitalized patients with severe influenza.
1.2 BACKGROUND ON MHAA4549A
MHAA4549A is a human monoclonal IgG1 antibody (mAb) that binds to the influenza
A virus and is cloned from a single-human plasmablast cell isolated from an
influenza vaccinated donor (Nakamura et al. 2013). This antibody binds to a
highly conserved epitope on the influenza A hemagglutinin stalk region, which
allows broad neutralization of the influenza A virus by blocking the
hemagglutinin-mediated, membrane-fusion event in the late endosome.
In vitro, MHAA4549A is capable of neutralizing all current clinically relevant
influenza A strains. In vivo, efficacy of MHAA4549A has been demonstrated in
mouse models of influenza A infection, both as a single agent and in
combination with oseltamivir. MHAA4549A specifically targets an epitope on the
human influenza A hemagglutinin
glycoprotein, which does not appear to be endogenously expressed on human or
rat tissues and, therefore, is unlikely to be present in the absence of viral
infection. Weekly administration of MHAA4549A (total of 5 doses) in
Sprague-Dawley rats was well tolerated up to the maximum feasible dose of 150
mg/kg. The results of the ex vivo tissue cross-reactivity study indicates no
specific binding of MHAA4549A to any of the human or rat tissues examined.
Clinical experience with MHAA4549A has consisted of two studies in 122 healthy
volunteers, and has been shown to be safe and well tolerated to date. The first
study was a Phase 1 study (GV28916) in 21 healthy volunteers where single doses
of 1.5 mg/kg, 5 mg/kg, 15 mg/kg, and 45 mg/kg were tested with an extended
follow-up period of 120 days. MHAA4549A was safe and well tolerated with no
serious adverse events (SAEs). All adverse events (AEs) were mild or
mild-to-moderate and resolved fully. In addition, the observed pharmacokinetics
were generally dose proportional, appeared to have a pharmacokinetic (PK)
profile consistent with that of a IgG1 human antibody that lack known
endogenous host targets, and no anti-therapeutic antibodies (ATAs) were
detected with available samples.
The second study was a Phase 2a (GV28985) challenge study in 101 healthy
volunteers infected with a H3N2 strain of influenza virus. Fixed dosing was
selected for this study. Three doses were tested: 400 mg, 1200 mg, and 3600 mg.
All subjects have completed dosing, and interim PK and efficacy data are
available for the 1200-mg and 3600-mg dose groups. During the Phase 2a
(GV28985) study, the related AEs that were observed included elevated liver
function tests (LFTs) and amylase levels. No dose relationship was observed for
LFTs (i.e., placebo 30.8%, 1200 mg 40%, 3600 mg 35%), and no SAEs were observed
that were related to MHAA4549A. Based on this data, MHAA4549A is considered
generally safe and well tolerated to date at all doses tested including the
3600 mg dose. Analysis of efficacy from the 3600-mg dose level demonstrated a
statistically significant decrease in viral shedding from upper respiratory
tract as measured by area under the curve (97% reduction by quantitative
polymerase chain reaction [qPCR]) and peak viral load (77% reduction by qPCR) .
In this study, oseltamivir was started on Day 7 for a 5-day course, and there
were no observed AEs or imbalances in safety events that were considered
attributable to interactions between oseltamivir and MHAA4549A. The PK profile
of MHAA4549A and oseltamivir are being analyzed in GV28985 to exclude potential
drug-drug interactions and will be available before the start of this study.
Testing for ATAs in the Phase 2a has not been concluded.

2. OBJECTIVES
2.1 SAFETY OBJECTIVES
The safety objectives for this study are as follows:
* To evaluate the safety of MHAA4549A in combination with oseltamivir compared
with placebo and oseltamivir in patients with severe influenza A, focusing on
the nature, frequency, and severity of serious and non-serious adverse events
as well as effects on laboratory values, vital signs, electrocardiogram (ECG)
parameters, ATAs, or other safety biomarkers
2.2 PRIMARY EFFICACY OBJECTIVES
The primary efficacy objective for this study is as follows:
* To determine the time to normalization of respiratory function of patients
dosed with MHAA4549A in combination with oseltamivir compared to patients dosed
with placebo and oseltamivir.
2.3 SECONDARY EFFICACY OBJECTIVES
The secondary efficacy objectives for this study are as follows:
* To measure clinical failure, after 24 hours post-infusion of study drug
* To determine the time to clinical resolution of vital signs
* To measure mortality in patients
* To determine changes in the extent and duration of viral shedding in upper
respiratory samples
* To measure the duration of hospital and/or ICU stay
* To identify any potential viral resistance to MHAA4549A in influenza A
isolates from upper respiratory samples
* To measure antibiotic usage for respiratory infections
* To measure the frequency and severity of the following secondary
complications of influenza:
o Pneumonia (hospital acquired pneumonia [HAP]/ ventilator acquired pneumonia
[VAP])
o Exacerbations of chronic lung disease
o Myocarditis
o Acute respiratory distress syndrome (ARDS)
o Otitis media
o Other related complications
o Readmission rates at 30 days after study treatment
* To measure duration of PPV
* To measure readmission rates
2.4 PHARMACOKINETIC OBJECTIVES
The major PK objective for this study is as follows:
* To characterize the PK profile of MHAA4549A in serum
The exploratory PK objectives for this study are as follows:
* To characterize the PK profile of MHAA4549A in upper and/or lower respiratory
samples
* To assess the PK profile of oseltamivir and its metabolite, oseltamivir
carboxylate, in plasma
2.5 EXPLORATORY OBJECTIVES
The exploratory objectives of this study are as follows:
* To identify any potential resistance to MHAA4549A in influenza A isolates
from tracheal aspirate samples
* To investigate the pre-existing and acquired host-immune response to
influenza A and other biomarkers related to influenza infection in patients
treated with MHAA4549A
* To determine changes in the extent and duration of viral infection from lower
respiratory samples
* To measure the effect of prior NAI therapy on clinical and virological
parameters
* To assess patients* return to pre-influenza baseline activity, type of
residence, and type of care assistance
* To determine the time to *ready for discharge* status in patients with
influenza A treated with MHAA4549A
* To measure the frequency of secondary bacterial and/or viral infections in
patients with influenza A treated with MHAA4549A

This is a Phase 2b (GV29216) randomized, double-blind, placebo-controlled study
designed to assess the safety and clinical activity of a single IV dose of
3600mg MHAA4549A or a single IV dose of 8400mg MHAA4549A in hospitalized
patients with severe influenza A in combination with oseltamivir versus a
comparator arm of placebo with oseltamivir. This study is planned to take place
in approximately 170 study centers globally.
In this version of the protocol patients will be randomized 1:1:1 into three
treatment groups: a single IV dose of 3600 mg of MHAA4549A with oseltamivir, a
single IV dose of 8400 mg of MHAA4549A with oseltamivir, or a single IV dose of
placebo with oseltamivir. All patients will receive oseltamivir, a NAI, as
standard therapy for a minimum of 5 days after study drug administration.
Oseltamivir at doses of 75 BID or 150 mg BID is permitted in order to be
consistent with local SOC practice. Treatment for longer than 5 days is
permitted based on local investigator discretion. The patient must start
oseltamivir no later than 8 hours of study drug administration. The study has a
planned enrollment of approximately 334 patients globally.
Hospitalized patients with an O2 or PPV requirement will be evaluated for
influenza A infection. Enrollment in this study requires ongoing treatment
within 24 hours of hospital admission with one of the following:
* any PPV or
* any supplemental O2 to maintain oxygen saturation (SpO2) >92%
Patients on PPV should not exceed 45% of the total patients enrolled.
A Sponsor-supplied rapid influenza test and/or a local polymerase chain
reaction (PCR) test must be used as an aid in the diagnosis of influenza A
infection.
Patients who are intubated and mechanically ventilated should also have lower
respiratory tract sampling performed, if it is determined to be safe by the
patient*s medical care team. While patients are on supplementary low flow O2 (2
* 6 L/min), they should have a daily trial off O2 support, to check if they are
able to maintain their SpO2 at 95% or above on room air.
At the time of randomization, patients who are eligible for enrollment as
described above, will be randomized to receive MHAA4549A at a dose of 3600 mg
or placebo. Patients will be stratified by country, PPV versus supplemental O2
on the day of admission, and suspected or confirmed bacterial pneumonia versus
no bacterial pneumonia based on the status on the day of admission.
Eligible patients who are enrolled into the study will receive either a single
IV infusion of MHAA4549A or a single IV infusion of placebo on Day 1. All
patients must have the study drug infused within 48 hours of hospital admission
or sooner if possible. All patients will receive oseltamivir for a minimum of 5
days (10 doses), starting on Day 1, beginning no later than 8 hours after study
drug administration.
All patients will be followed and evaluated at minimum on a daily basis for the
duration of their hospital stay consistent with the planned schedule of
assessments. Any suspicion of bacterial superinfection should be thoroughly
evaluated including microbiological confirmation, if possible. A follow-up
study visit should occur on Day 14 ± 1 (if discharged before Day 14) and Day 30
± 4 days, if discharged before Day 30.

The randomization of patients will be managed by a central Interactive Voice
and Web Response System (IxRS). All patients will be randomly assigned to
receive either MHAA4549A 3600 mg, 8400 mg or placebo at a 1:1:1 ratio
stratified by country, whether patient is on PPV vs supplemental O2 on the day
of admission, and whether the patient has suspected or confirmed bacterial
pneumonia vs no bacterial pneumonia on the day of admission. All patients will
receive oseltamivir (75 mg or 150 mg BID) for a minimum of 5 days. Treatment
for longer than 5 days is permitted based on local investigator discretion.
The treatment assignments will be unblinded to an external IDCC to facilitate
the iDMC assessment of safety.

The Study Drug MHAA4549A:

Common
* Elevated liver tests
Less common
Less common, non serious side effects associated with putting this type of drug
into your vein (also known as an *infusion*) might include flushing, back pain,
fainting, chills, feeling sick, headache, excessive sweating, light-headedness,
and muscular aches and pains.
* Headache
Rare but serious (There have been no serious side effects seen in 121 study
subjects who received this study drug.)
* Rare but serious risks associated with an infusion of this type of drug
include severe allergic or hypersensitivity reactions.
* There is a rare chance that you could have a serious and potentially
life-threatening allergic reaction to the study drug called *anaphylaxis* that
can lead to difficulty breathing and shock. Symptoms include rash; flushing;
itching, sneezing, or runny nose; abdominal pain; diarrhea; swelling of the
face, tongue, or throat; dizziness, light-headedness, or fainting; trouble
breathing; irregular or racing heart rate; and seizures (fits).
* As with other drugs of this type, giving a person the study drug may cause
them to develop antibodies to the drug, which could affect whether the drug
works or the safety of this study drug or other drugs of the same type. If
this occurs, it is not expected to result in any significant effects to your
health, but it is difficult to know what symptoms might develop or the effect
they might have on this drug or other similar drugs in the future.

Neuraminidase Inhibitor: Oseltamivir (Tamiflu):

Oseltamivir is a prescription medicine normally given to people who have had
influenza symptoms for no more than 2 days. Oseltamivir was also shown to
reduce the symptoms of influenza by 1 day in a study of adults with influenza
who were not hospitalized. It is considered one of the accepted treatments to
give patients hospitalized with influenza, although it has not been officially
approved for this indication.
Everyone in this study is required to be given oseltamivir for a minimum of 5
days. Treatment of longer than 5 days is permitted based on local investigator
discretion.
Common (occurred in 7% * 10% of patients treated during the clinical studies of
oseltamivir):
* Nausea
* Vomiting
* Diarrhea

Less common (occurred in 2% of patients treated during the clinical studies of
oseltamivir):
* Bronchitis,
* Abdominal pain
* Dizziness
* Headache

Rare but serious
* Cases of anaphylaxis and serious skin reactions including toxic epidermal
necrolysis (blistering of the skin), Stevens-Johnson Syndrome (blistering of
skin, mouth, eyes, genitals), and erythema multiforme (skin reaction) have been
reported in postmarketing experience with oseltamivir.
* Influenza can be associated with hallucinations, delirium, and abnormal
behavior, in some cases resulting in fatal outcomes. The contribution of
oseltamivir to these events has not been established.