Comparing and Combining Bortezomib and Mycophenolate in SSc Pulmonary Fibrosis

Systemic sclerosis (SSc) is a chronic multisystem autoimmune connective tissue disease for
which the etiology remains unknown. The prevalence for SSc is between 19-75 cases per 100,000
and it is more frequent in women, with a peak occurrence in the 4th or 5th decade of life.
Morbidity and Mortality in SSc are substantial and pulmonary complications are now the
leading cause of death among patients with SSc.

Bortezomib is an FDA approved therapy for the treatment of multiple myeloma and other
malignancies. The investigators have data that bortezomib inhibits TGF- signaling in vitro
and promotes normal repair and prevents against lung fibrosis in the TGF-mediated
intratracheal bleomycin mouse model as well as in a mouse model for skin fibrosis. This is
consistent with other data in the literature that proteasomal inhibition can prevent the
development of fibrosis. Further there are multiple reports on the efficacy of bortezomib in
ameliorating cGVHD in patients after allogeneic HSCT for multiple myeloma. Bortezomib was
also well tolerated in the large clinical trials of multiple myeloma patients with neuropathy
and thrombocytopenia the primary adverse events. No pulmonary toxicities were reported in
these studies.

Mycophenolate mofetil (CellCept or Myfortic) belongs to a class of medications known as
immunosuppressives. This medication was used originally in the management of patients with
organ transplants, but is now recommended in the treatment of some autoimmune diseases such
as SSc.

Mycophenolate mofetil targets an enzyme in the body called inosine monophosphate
dehydrogenase that is important for the formation of deoxyribonucleic acid (DNA) in cells. By
interfering with DNA, the medication impairs function of immune system cells that become
overactive in autoimmune diseases. Mycophenolate mofetil is currently approved in the
treatment of patients with SSc.

This study is being conducted to establish the safety and tolerability of bortezomib in SSc
patients at high risk for pulmonary disease progression. In addition, the study will examine
the effect of bortezomib on the rate of FVC decline (a physiologic parameter closely
associated with disease outcome) and other clinical parameters. In addition the investigators
will also measure the effect of bortezomib on biomarkers associated with fibroblast
activation. If successful, the study will provide the rationale for a multi-center placebo
controlled trial to test the efficacy of bortezomib in SSc patients at high risk for
progressive pulmonary disease.

Inclusion Criteria:

- Meet established criteria for diffuse or limited SSc and evidence of pulmonary at high
risk of progression with or without progressive skin disease.

- Definition includes subjects who meet the ACR criteria for scleroderma

- High Risk of disease progression (see rationale) will be defined as follows

- If first non-Raynaud's manifestation of SSc < 36 months, then if any of the following
are true: FVC <70% predicted or HRCT Fibmax >3 or FVC < 85% and MRSS increase > 5 over
6 months Regardless of disease duration

- Fall in FVC > 10% over the preceding 12 months or less in the absence of prior therapy
or another identified causative process as assessed by the primary scleroderma
physician

- Fall in FVC > 10% over 6 months on at least 12 months of prior therapy

- Age > 18 years

- Ability to give informed consent.

- Willingness to discontinue present therapy for the duration of the study

- Female subject is either post-menopausal or surgically sterilized or willing to use an
acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine
device, diaphragm with spermicide, condom with spermicide, or abstinence) for the
duration of the study.

- Male subject agrees to use an acceptable method for contraception for the duration of
the study.

- No evidence of acute infection

- ANC >1000

- Platelets >75,000

- Stable MMF dose for 16 weeks

Exclusion Criteria:

- Inability to give informed consent or comply with protocol procedures

- FVC < 40% or DLCO <30% predicted

- Patient has a platelet count of less than 50,000 within 14 days before enrollment.

- Patient has an absolute neutrophil count of less 1000 within 14 days before
enrollment.

- Patient has a calculated or measured creatinine clearance of < 20 ml/minute within 14
days before enrollment.

- Patient has Grade 2 peripheral neuropathy by history within 14 days before enrollment.

- Myocardial infarction within 6 months prior to enrollment or has New York Heart
Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities. Prior to study entry, any ECG
abnormality at Screening has to be documented by the investigator as not medically
relevant.

- Patient has hypersensitivity to bortezomib, boron or mannitol.

- Female subject is pregnant or breast-feeding. Confirmation that the subject is not
pregnant must be established by a negative serum -human chorionic gonadotropin (- hCG)
pregnancy test result obtained during screening. Pregnancy testing is not required for
post-menopausal or surgically sterilized women.

- Patient has received other investigational drugs within 4 weeks before enrollment

- Serious medical co-morbidity which in the opinion of the investigator makes
participation in the study too high risk

- Psychiatric illness likely to interfere with participation in this clinical study.