A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of BG00011 in Patients With Idiopathic Pulmonary Fibrosis

IPF is a serious, chronic, progressively fatal lung disease involving
replacement of normal lung tissue with fibrotic scar tissue. IPF is a rare
disease that predominantly affects the middle aged and elderly (after age 60
years; median age at diagnosis: 66 years). Patients with IPF typically live for
only 3 to 5 years after diagnosis, with a median survival time of approximately
3.5 years from diagnosis. IPF significantly impairs health related quality of
life, and the majority of patients also have serious comorbid conditions.
Clinical features of IPF include progressive cough, dyspnea, restrictive
ventilatory defect, and progressive fibrosis and destruction of the lung
parenchyma. The diagnosis is made in patients with the appropriate clinical
features and the histologic pattern of usual interstitial pneumonia (UIP)
[based on lung biopsy or high-resolution computed tomography (HRCT)].
Challenging factors for clinical management include older age, comorbid
conditions, and acute unpredictable exacerbations. Acute exacerbations of IPF
are defined as sudden (typically less than 30 days onset) unexplained worsening
of underlying disease, including new radiological infiltrates (based on HRCT)
or UIP pattern. The progressive deterioration of lung function results in
respiratory failure. The prognosis following acute exacerbation and
deterioration of lung function is poor, with 1-year and 5-year survival rates
of 56.2% and 18.4% following acute exacerbation, which is considerably shorter
than in IPF patients without acute exacerbation.
The underlying pathophysiology of IPF is unknown. Whatever the inciting event
is, it triggers a TGF-* mediated fibrogenic response. As a part of this
response, alveolar epithelial cells via the production of signaling mediators,
including TGF-*, tumor necrosis factor, endothelin 1, and cytokines, induce
proliferation and activation of fibroblasts and myofibroblasts. This leads to
secretion of connective tissue matrix molecules, such as collagen, to replace
the damaged tissue but also displaces healthy tissue leading to scarring and
ultimately organ failure .
To date, no therapies have demonstrated efficacy in halting IPF disease
progression. Historically, disease-modifying agents for IPF have included
nonspecific anti-inflammatory or immunosuppressive agents (i.e.,
corticosteroids, azathioprine, and cyclophosphamide), which were used in the
United States despite the absence of clinical studies to demonstrate their
efficacy, with some ultimately demonstrating harm.
Two recently approved therapies, pirfenidone (Esbriet®) and nintedanib (Ofev®),
have demonstrated a similar ability to slow deterioration in lung function by
nearly 50%; however, patients are still faced with death or lung
transplantation as the ultimate outcome.

Therapies that can halt or reverse disease progression, increase life
expectancy, and improve quality of life while demonstrating minimal side
effects remain a treatment goal for patients diagnosed with IPF.

BG00011 (humanized, immunoglobulin G subtype 1 [IgG1] anti-alpha v beta 6
[*v*6] monoclonal antibody [mAb]), formerly known as STX-100, is being
developed by Biogen as a novel therapeutic treatment for patients with
idiopathic pulmonary fibrosis (IPF). BG00011 binds to the *v*6 integrin, which
inhibits the integrin from binding to and activating the latent form of
transforming growth factor-beta (TGF *). TGF-* plays a critical role in the
initiation and maintenance of fibrosis, and targeted inhibition of the *v*6/
TGF-* pathway may prevent the development of fibrosis, organ scarring, and
organ failure. The clinical development plan for BG00011 is designed to
demonstrate that blocking *v*6 and inhibiting the activation of TGF-* in
patients with IPF can prevent or reduce the progression of fibrosis, resulting
in preservation of pulmonary function.

The primary objective of the study is To evaluate the efficacy of BG00011
compared with placebo in subjects with IPF.
The secondary objectives of the study are:
* To evaluate the efficacy of BG00011 compared with placebo in subjects with
IPF as determined by change in percent predicted FVC.
* To assess progression-free survival in subjects who receive BG00011 compared
with placebo.
* To assess the occurrence of IPF exacerbation (using modified diagnostic
criteria for acute IPF exacerbation derived from [Collard 2007]) in subjects
who receive BG00011 compared with placebo.
* To assess the incidence of absolute decline in FVC *10% in subjects who
receive BG00011 compared with placebo.
* To assess the time to death or lung transplantation in subjects who receive
BG00011 compared with placebo, and the transplant-free survival rate at Week 26
and Week 52.
* To assess the time to nonelective hospitalizations in subjects who receive
BG00011 compared with placebo.
* To assess additional pulmonary function test (PFT) findings in subjects who
receive BG00011 compared with placebo.
* To assess performance on the 6 Minute Walk Test (6MWT) in subjects who
receive BG00011 compared with placebo.
* To evaluate the safety and tolerability of BG00011.
* To evaluate the serum concentration of BG00011

Phase 2b randomized, double-blind, placebo-controlled study to evaluate the
efficacy, safety, PK, and tolerability of BG00011 in subjects with IPF.
Subjects will be stratified by background therapy status (subjects receiving
background therapy and subjects not receiving background therapy) and
randomized in a 1:1 ratio of BG00011 to placebo. Enrollment will also be
monitored to ensure that subjects receiving background therapy represent
approximately 50% of each treatment group.
Subjects will receive weekly injections of BG00011 or placebo, as a solution
for SC injection in a prefilled syringe, for 52 consecutive weeks (a total of
52 doses). The first dose will be administered at the Baseline (Day 0) Visit.
The rest of the doses may be administered independently (e.g., not at the study
site) by the subject or the subject*s caregiver.
Background therapy for IPF with pirfenidone or nintedanib will be allowed
during the study.
An independent data safety monitoring board (DSMB) will review the unblinded
safety and available PK data throughout the study (at least quarterly) to
assess the overall safety profile.

Study duration for an individual subject is approximately 65 weeks, including a
Screening Visit up to 5 weeks prior to the first dose of study treatment, a
Placebo-Controlled Treatment Period of 52 weeks, and a Safety Follow-Up Visit 8
weeks after the end of the Treatment Period.

Patients should visit the clinics and be willing to receive their study drug or
placebo according to the dosing schema.

Furthermore their data of Medical history and demographic data will be
collected. They must undergo physicial and vital signs examinations. An
electrocardiogram, spirometry plethysmography 6-minute walk test and carbon
monoxide diffusion capacity test will be made. Blood and urine will be
collected. Several Questionnaires need to be filled in at different timepoints.
They will be tested for HIV, HCV and pregnancy if applicable.

As a first-in-class treatment for patients with IPF, the reduction in pSMAD2
levels and gene expression required for clinical efficacy is unknown. Across
multiple mouse models of lung fibrosis, *v*6-blocking antibody treatment with
dosing between 0.3 and 1.0 mg/kg leads to significant reductions in pSMAD2 and
reduced collagen expression (a marker of fibrosis) without inducing lung
inflammation. The steep dose response in pSMAD2 is consistently observed in
subjects with IPF (Study 203PF201), in nonhuman primate biomarker studies, and
in the rodent models of epithelial injury and fibrotic diseases.

As of 28 February 2017, a total of 61 subjects (31 subjects with IPF and 30
healthy volunteers) have received BG00011 in 2 completed clinical studies,
Phase 1 Study STX-001 and Phase 2a Study 203PF201.
STX-001, BG00011 was well tolerated, with no deaths, serious adverse events
(SAEs), or premature discontinuations related to an AE. No clinically
significant changes were noted for any safety measures including AEs, physical
examination, vital signs, or clinical laboratory parameters, including
pulmonary function tests (PFTs). AEs occurred in 21 of 30 subjects (70%) who
received BG00011 and 8 of 10 subjects (80%) who received placebo. The most
common AEs were headache, diarrhea, vomiting, arthropod stings,
nasopharyngitis, and nasal congestion.
Study 203PF201 multiple SC doses of BG00011 up to 1.0 mg/kg were generally well
tolerated in the population of subjects with IPF, with the incidence and
severity of AEs, and changes in physical examination, vital signs, or clinical
laboratory parameters comparable to those expected in the IPF population.
Based on a detailed review of the safety, PK, and PD data for Study 203PF201,
Biogen considers that the potential benefit/risk of BG00011 is acceptable for
dosing in subjects with IPF at doses not exceeding 1.0 mg/kg.