Efficacy and Safety of Ofatumumab in Treatment of Pemphigus Vulgaris

Inclusion criteria

- Adults (18 through 70 years of age) with clinically-documented diagnosis of PV for >2
months and <10 years.

- History of biopsy consistent with PV (Hematoxylin and Eosin staining and direct
immunofluorescence). If no history, a biopsy may be performed during the Screening
Period.

- At least 1 previous episode of a failed steroid taper (ie, disease flare/relapse) at a
prednisone/prednisolone dose >10 mg/day. The following criteria must have been met as
evidence of disease severity at the time of the failed steroid taper: a) A Pemphigus
Severity of Clinical Disease score of moderate (2) or severe (3) (may be
historical/retrospective assessment). b) Required a treatment change at the time of
the failed steroid taper of at least one of the following: i) A steroid increase to
>=20 mg/day OR ii) The addition of immunosuppressive/immunomodulatory agent/treatment
OR iii) A dose increase of immunosuppressive/immunomodulatory agent/treatment

- Screening anti-Dsg antibodies consistent with a diagnosis of PV (ie, elevated antiDsg3
antibodies).

- Has initiated and received a stable dose of prednisone/prednisolone from a minimum of
20 mg/day (example: 0.25 mg/kg/day for an 80 kg person) up to a maximum of 120 mg/day
or 1.5 mg/kg/day (whichever is higher) for >=2 weeks prior to randomization.

- Has exhibited PV disease control, defined as no new lesions for >=2 weeks.

- A female subject is eligible to enter the study if she: Is of non-child bearing
potential, who is either surgically sterile (bilateral tubal ligation, bilateral
oophorectomy, or post-hysterectomy) or is postmenopausal without menses for >2 years.
Women who are <2 years postmenopausal are required to have menopausal status confirmed
by follicle-stimulating hormone (FSH) and estradiol levels at the screening
evaluation. If FSH and estradiol levels do not provide confirmation of menopause,
subject will be considered to be of childbearing potential; Is of childbearing
potential, defined as a woman who has functional ovaries, ducts, and a uterus with no
documented impairment that would cause sterility. This includes women with
oligomenorrhea (even severe), women who are perimenopausal, and women who have just
begun to menstruate. Subject must have a negative serum pregnancy test at screening
and must agree to the consistent and correct use of acceptable methods of
contraception during heterosexual intercourse, beginning when the subject provides
informed consent and lasting until 12 months after last dose of investigational
product.

Acceptable methods of contraception are limited to the oral contraceptives (either combined
or progesterone only), injectable progesterone, levonorgestrel implants, estrogenic vaginal
ring, percutaneous contraceptive patches, intrauterine device or intrauterine system with a
documented failure rate of <1% per year, male partner sterilization (vasectomy with
documentation of azoospermia) prior to the female subject's entry into the study; this male
must be the subject's sole partner, double barrier method (condom and an occlusive cap
[diaphragm or cervical/vault caps] with a vaginal spermicidal agent
[foam/gel/film/cream/suppository]) and complete abstinence from heterosexual intercourse,
For Japan subjects, in the list of acceptable methods of contraception, the following
methods are not applicable in Japan: oral contraceptives with progestogen alone, injectable
progesterone, levonorgestrel implants, estrogenic vaginal ring, percutaneous contraceptive
patches, vaginal spermicidal foam, gel, film, and cream French subjects: In France, a
subject will be eligible for inclusion in this study only if either affiliated to or a
beneficiary of a social security category.

Exclusion Criteria:

- Diagnosis of pemphigus foliaceus, paraneoplastic pemphigus, or other autoimmune
blistering disease (other than pemphigus vulgaris).

- Past or current history of hypersensitivity to components of the investigational
product or medically significant adverse effects (including allergic reactions) from
cetirizine (or antihistamine equivalent) or paracetamol/acetaminophen.

- Prior treatment with rituximab without achieving disease control within 6 months of
initiating rituximab dosing.

- Prior treatment with with any of the following within the specified periods: any time:
ofatumumab, total body irradiation, bone marrow transplantation, anti-CD4 ; within 2
weeks: systemic steroids (except for prednisone/prednisolone) ; within 6 weeks: live
vaccine ; within 8 weeks: azathioprine, cyclosporine, dapsone, mycophenolate,
methotrexate and tacrolimus; within 6 months:cladribine, cyclophosphamide,
plasmapheresis, immunoabsorption or immunoglobulin therapy, alemtuzumab, mitoxantrone;
and within 18 months: Rituximab or other drugs affecting the number and function of
B-cells- Confirmed progressive multifocal leukoencephalopathy (PML), or neurological
findings potentially consistent with PML

- Evidence or history of clinically significant infection including: Chronic or ongoing
active infectious disease requiring long term systemic treatment, including, but not
limited to, chronic renal infection, chronic chest infection with bronchiectasis, or
active hepatitis C; Positive test for hepatitis B surface antigen (HBsAg). For HBsAg
negative, but hepatitis B core antibody (anti-HBc/HBcAb positive (regardless of
hepatitis B surface antibody [HbsAb] status), an HBV deoxyribonucleic acid (DNA) test
will be performed and the subject will be excluded if results are positive; Consult
with a physician experienced in the care and management of subjects with hepatitis B
to manage/treat subjects who are anti-HBc positive; History of positive serology for
human immunodeficiency virus; Previous serious opportunistic or atypical infections;
Prior history, or suspicion, of tuberculosis (TB);

For Japan: Evidence or history of clinically significant infection or medical condition
including: Pneumocystis pneumonia or interstitial pneumonia (based on results of screening
posterior-anterior chest X-ray, KL-6, and beta-D glucan). Order these tests from a local
laboratory during screening and as part of a work-up for a subject with signs or symptoms
of potential concern during the study; Based on the Japanese Guideline for Hepatitis B, for
subjects who are HBsAg negative, anti-HBc (HBcAb) negative, but HBsAb positive, an HBV DNA
test will be performed and the subject will be excluded from the study if results are
positive; If any of the following criteria for TB screening are met:Past medical history
for latent or active TB before screening; Sign(s) or symptom(s) suggestive of active TB in
medical history on examination; Recent close contact with a patient with active TB;
Positive interferon-gamma release assay or tuberculin skin test within 1 month before the
first dose of study treatment; Chest x-ray, taken within 3 months before first dose of
study treatment, shows evidence indicating currently active or previous TB.

For South Korea: Evidence or history of clinically significant infection including: For
subjects who are HBsAg negative, anti-HBc (HBcAb) negative, but HBsAb positive, an HBV DNA
test will be performed and the subject will be excluded from the study if results are
positive; If any of the following criteria for TB screening are met: Past medical history
for latent or active TB before screening, Sign(s) or symptom(s) suggestive of active TB in
medical history on examination; Recent close contact with a patient with active TB;
Positive interferon-gamma release assay or tuberculin skin test within 1 month before the
first dose of study treatment; Chest x-ray, taken within 3 months before first dose of
study treatment, shows evidence indicating currently active or previous TB.

- Past or current malignancy, except for cervical carcinoma Stage 1B or less,
noninvasive basal cell and squamous cell skin carcinoma and cancer diagnoses with a
duration of complete response (remission) >5 years

- Significant concurrent, uncontrolled medical condition that could affect the subject's
safety, impair the subject's reliable participation in the study, impair the
evaluation of endpoints, or necessitate the use of medication not allowed by the
protocol. This includes subjects who require any systemic steroid treatment for a
concurrent medical condition (other than pemphigus vulgaris).

- White blood cells (WBC) <3.8 GI/L (<3800/mm^3), neutrophils <2 GI/L (<2000/mm^3),
platelets <130 GI/L (130,000/mm^3), circulating IgG, IgA, or IgM levels <10% of the
LLN and requiring treatment in the opinion of the investigator, alanine
aminotransferase (ALT) >2.0 times the upper limit of normal (ULN), aspartate
aminotransferase (AST) >2.0 X ULN, alkaline phosphatase (ALP) >1.5 X ULN, bilirubin
>1.5 X ULN (except in cases of isolated predominantly indirect hyperbilirubinemia due
to Gilbert's syndrome).

- Use of an investigational drug or other experimental therapy within 4 weeks, 5
pharmacokinetic half-lives, or the duration of biological effect (whichever is longer)
prior to Screening.

- Electrocardiogram (ECG) showing a clinically significant abnormality or showing a QTc
interval ≥450 msec (≥480 msec for subjects with a bundle branch block) (ECG to be
obtained during Screening/prior to receiving the first dose of study drug).

- Woman who is breastfeeding.