Study in Healthy Volunteers to Evaluate the Efficacy and Safety of CR6261 in an H1N1 Influenza Healthy Human Challenge Model

The high morbidity and mortality associated with both pandemic and seasonal influenza and the
threat of new potentially pandemic strains emerging makes influenza an important infectious
disease and public health problem. Mean annual estimates of influenza deaths due to seasonal
influenza alone attributes up to 49,000 deaths in the US and 250,000 to 500,000 deaths in
industrialized countries to influenza. Pandemics can have an even more devastating effect.
Public health agencies must continue to be prepared by making attempts to reduce the public
health impact of this important virus.

In the realm of influenza therapeutics, antiviral drugs are currently used to treat influenza
infection in those who fail to be protected by current vaccines or those who do not receive a
vaccine. Currently, only two classes of antivirals are FDA approved for the treatment of
influenza A: neuraminidase inhibitors and matrix M2 channel blockers. Although these drugs
have been shown to be effective in reducing influenza illness by 24-48 hours and reducing
shedding in relatively healthy adults, as with vaccination, they have had limited
effectiveness in high risk groups and those who have severe or complicated influenza
infections. In addition, antiviral resistance has become very common in human influenza A
viruses, as currently circulating H1N1 and H3N2 strains are resistant to the adamantane M2
channel blockers and many cases of neuraminidase inhibitor resistance have also been reported
with strains of both subtypes. This resistance can develop quickly and in most cases only
requires a single amino acid change. Given these significant issues with currently available
treatments, novel therapies for influenza are clearly needed.

Live virus challenge studies have played a pivotal role in developing influenza therapeutics
in the past, and they will be instrumental in the future. No novel therapeutic or
prophylactic agent has been FDA-approved since the last influenza challenge studies ceased
over a decade ago. In collaboration with the Crucell Vaccine Institute (part of Crucell which
is in the Janssen family of Pharmaceutical Companies of Johnson & Johnson) this protocol will
evaluate mAb CR6261 for possible therapeutic value. Unlike the current antivirals that are
compounds which interfere with some portion of the viral replicative cycle, this agent is a
mAb that targets the stem of HA, neutralizing the virus by stabilizing the pre-fusion state
and preventing the pH-dependent fusion of viral and cellular membranes. Pre-clinical data
suggest that this mAb has good cross-protective efficacy with a variety of HA subtypes unlike
current vaccines, making it potentially effective in the event of an emerging influenza virus
outbreak with a novel HA subtype. In addition, the conserved nature of the HA stem region
suggests that amino acid changes conferring resistance are much less likely. We will effort
to demonstrate that CR6261 leads to improved outcomes compared with placebo with respect to
the AUC of virus shedding as determined by qPCR in NP swabs in all treated subjects.

-INCLUSION CRITERIA:

1. Greater than or equal to 18 and less than or equal to 45 years of age.

2. Non-smoker.

3. Willingness to remain in isolation for the duration of viral shedding (at a minimum 10
days) and to comply with all study requirements.

4. A male subject is eligible for the study if he agrees to practicing abstinence or
using a condom with spermicide plus an acceptable form of contraception (see inclusion
criteria 5) being used by any female partner from 4 weeks before to 12 weeks after
intranasal challenge with influenza.

5. A female participant is eligible for this study if she is not pregnant or breast
feeding and 1 of the following:

- Of nonchildbearing potential (i.e., women who have had a hysterectomy or tubal
ligation or are postmenopausal, as defined by no menses in greater than or equal
to 1 year).

- Of childbearing potential but agrees to practice effective contraception or
abstinence for 4 weeks prior to and 8 weeks after administration of the influenza
challenge virus. Acceptable methods of contraception include a male partner who
is sterile and is the sole sexual partner of the female participant or a male
partner who uses a condom with spermicide plus 1 or more of the following: 1)
implants of levonorgestrel; 2) injectable progestogen; 3) an intrauterine device
with a documented failure rate of <1%; 4) oral contraceptives; and 5) double
barrier method including diaphragm.

6. Willing to have samples stored for future research.

7. Prechallenge serum HAI titer against the challenge virus less than or equal to 1:10
within 60 days of admission for the study.

8. HIV uninfected confirmed by testing within 60 days of admission for the study.

9. Agrees to abstain from alcohol intake 24 hours before admission on Day -1, during the
inpatient period of the study, and 24 hours prior to all other outpatient clinic
visits.

10. Agrees to not use over-the-counter medications (including aspirin, decongestants,
antihistamines, and other NSAIDs), and herbal medication (including, but not limited
to, herbal tea, St. John s Wort), within 14 days prior to study drug administration
through the final follow-up visit, unless approved by the investigator.

EXCLUSION CRITERIA:

1. Presence of self-reported or medically documented significant medical condition
including but not limited to:

1. Chronic pulmonary disease (e.g., asthma, emphysema).

2. Chronic cardiovascular disease (e.g., cardiomyopathy, congestive heart failure,
cardiac surgery, ischemic heart disease, known anatomic defects).

3. Chronic medical conditions requiring close medical follow-up or hospitalization
during the past 5 years (e.g., insulin dependent diabetes mellitus, renal
dysfunction, hemoglobinopathies).

4. Immunosuppression or ongoing malignancy.

5. Neurological and neurodevelopmental conditions (e.g., cerebral palsy, epilepsy,
stroke, seizures).

6. Postinfectious or postvaccine neurological sequelae.

7. Hyperlipidemia requiring medical therapy per current American College of
Cardiology (ACC) and American Heart Association (AHA) guidelines published in
2013.

2. Have close or household (i.e., share the same apartment or house) high-risk contacts
including but not limited to:

1. Persons greater than or equal to 65 years of age.

2. Children less than or equal to 5 years of age.

3. Residents of nursing homes.

4. Persons of any age with significant chronic medical conditions such as:

- Chronic pulmonary disease (e.g., severe asthma, COPD).

- Chronic cardiovascular disease (e.g., cardiomyopathy, congestive heart
failure, cardiac surgery, ischemic heart disease, known anatomic defects).

- Contacts who required medical follow-up or hospitalization during the past 5
years because of chronic metabolic disease (e.g., insulin dependent diabetes
mellitus, renal dysfunction, hemoglobinopathies).

- Immunosuppression or cancer.

- Neurological and neurodevelopmental conditions (e.g., cerebral palsy,
epilepsy, stroke, seizures).

- Individuals who are receiving long-term aspirin therapy.

- Women who are pregnant or who are trying to become pregnant.

3. Positive serology for hepatitis C virus antibody or hepatitis B surface antigen.

4. Individual with body mass index (BMI) greater than or equal to 18 and greater than or
equal to 35 or weight > 114kg.

5. Acute illness within 7 days of admission and inoculation with the challenge virus (Day
-1).

6. Complete blood count (CBC) with differential outside of the NIH Department of
Laboratory Medicine (DLM) normal reference range and deemed clinically significant by
the PI.

7. Chemistries in the acute care, mineral, and/or hepatic panels, and/or any of the
following: lactate dehydrogenase, uric acid, creatine kinase, and total protein
outside of the NIH DLM normal reference range and deemed clinically significant by the
PI.

8. Amylase or Lipase outside of the NIH DLM normal reference range and deemed clinically
significant by the PI.

9. Urinalysis outside of the NIH DLM normal reference range and deemed clinically
significant by the PI.

10. Clinically significant abnormality as deemed by the PI on electrocardiogram.

11. Clinically significant abnormality as deemed by the PI on echocardiographic (ECHO)
testing.

12. Clinically significant abnormality as deemed by the PI on the Pulmonary Function Test
(PFT).

13. Known allergy to treatments for influenza (including but not limited to oseltamivir,
nonsteroidals).

14. Known allergy to 2 or more classes of antibiotics (e.g., penicillins, cephalosporins,
fluoroquinolones, or glycopeptides).

15. Receipt of blood or blood products (including immunoglobulins) within 3 months prior
to enrollment.

16. Receipt of any unlicensed drug within 3 months or 5.5 half-lives (whichever is
greater) prior to enrollment.

17. Receipt of any non-influenza-related unlicensed vaccine within 6 months prior to
enrollment.

18. Self-reported or known history of current alcoholism or drug abuse, or positive
urine/serum test for drugs of abuse and/or ethanol (i.e., amphetamines, cocaine,
benzodiazepines, opiates, or metabolites, but not tetrahydrocannabinol (THC) or
metabolites).

19. Self-reported or known history of psychiatric or psychological issues deemed by the PI
to be a contraindication to protocol participation.

19. Known close contact with anyone known to have influenza in the past 7 days.

21. Known or suspected hypersensitivity to CR6261 or its excipients (sucrose, Lhistidine,
L-histidine monohydrochloride, polysorbate 20).

22. History of a previous severe allergic reaction with generalized urticaria, angioedema,
or anaphylaxis.

23. Drinks more than 1200 mL (or 5 cups of 240 mL per cup) of tea/coffee/cocoa/cola or
other caffeinated beverage per day more than 1 day per week in the 2 weeks before
screening.

24. Any condition or event that, in the judgment of the PI, is a contraindication to
protocol participation or impairs the volunteer s ability to give informed consent.