Baminercept, a Lymphotoxin-Beta Receptor Fusion Protein, for Treatment of Sjögren's Syndrome

A Randomized, Double-blind, Placebo-controlled Phase II Clinical Trial of Baminercept, a Lymphotoxin-beta Receptor Fusion Protein, for the Treatment of Primary Sjögren's Syndrome (ASJ02)

The purpose of the study is to find out if the experimental study agent, baminercept, is effective in treating patients with Sjögren's syndrome. The study will also determine if the study agent can be safely given to patients with Sjögren's syndrome; examine how it affects symptoms of the disease; and attempt to understand how baminercept affects the underlying mechanisms of Sjögren's syndrome and the immune system.

Sjögren's syndrome is an autoimmune disorder in which a person's own immune cells attack the body's tear and salivary glands. This disease is the second most common autoimmune disorder, affects close to four million people in the U.S., and has no known cause. About one-third of patients with Sjögren's syndrome have enlarged parotid glands (the largest salivary glands, the glands that make saliva); inflammation of organs such as the lungs and joints may also occur. There is no known effective treatment other than measures that can relieve symptoms. One of the most bothersome symptoms is dryness of the eyes and mouth. Eye drops and saliva stimulants (which help make more saliva) are common treatments. When other organs are affected, symptoms are treated with corticosteroids (prednisone), non-steroidal anti-inflammatory drugs (NSAIDs, such as ibuprofen and naproxen), hydroxychloroquine (Plaquenil®) or other medications that suppress the immune system. These drugs may curb or kill cells of the immune system, but they are not always helpful, do not cure Sjögren's syndrome, and can have many side effects.

Inclusion Criteria:

• Has provided written informed consent;

• Between the ages of 18-75 years (inclusive);

• Body weight ≥ 40 kg;

• Meets the revised European criteria proposed by the American-European Consensus Group for primary Sjögren's Syndrome at screening. These criteria include 3 of the following 4 items:

  • ocular symptoms;
  • oral symptoms;
  • Schirmer's I test showing less than 6 mm of wetting per five minutes in at least one eye, or filamentary keratitis on slit lamp examination, or positive lissamine green staining; or
  • diminished salivary production (unstimulated whole salivary flow rate ≤ 1.5 mL/15 min); PLUS, either:
  • a positive test for serum SS-A and/or SS-B antibodies, or
  • focal lymphocytic sialadenitis, with a focus score ≥ 1.0 per 4 millimeters ^2(mm^2) on minor salivary biopsy.

• Stimulated salivary flow of ≥ 0.1 mL/minute (min) (at screening);

• Has one or more of the following systemic manifestations of Sjögren's Syndrome that are not life-threatening:

  • fatigue (as measured by > 50 mm on a 100 mm VAS);
  • joint pain (as measured by > 50 mm on a 100 mm VAS);
  • peripheral neuropathy (documented by nerve conduction velocity study);
  • interstitial lung disease (documented by radiography and/or altered pulmonary function tests;
  • leukocytoclastic vasculitis;
  • renal tubular acidosis;
  • interstitial nephritis;
  • severe parotid swelling;
  • other extraglandular manifestations causing organ system dysfunction.

• If taking prednisone (or equivalent corticosteroid), the dose must be ≤ 10 mg/day and stable for at least 4 weeks prior to Screening;

• If taking hydroxychloroquine, the dose must be stable for at least 12 weeks prior to Screening;

• If taking a cholinergic stimulant (e.g. pilocarpine, cevimeline), the dose must be stable for at least 4 weeks prior to Screening;

• Subjects must agree not to become pregnant or to impregnate a female. Because of the risk involved, participants and their partners (if of reproductive potential) must use two methods of birth control. They must continue to use both methods until 6 months after stopping study drug. Two of the birth control methods listed below may be chosen:

  • Hormonal contraception;
  • Male or female condoms with or without spermicide;
  • Diaphragm or cervical cap with a spermicide;
  • Intrauterine device (IUD).

Exclusion Criteria:

• Has an active infection excluding superficial cutaneous fungal or viral infections;

• Has a chronic or persistent infection that might be worsened by immunosuppressive treatment (e.g., human immunodeficiency virus [HIV], hepatitis B, hepatitis C, or tuberculosis);

• History of TB or positive intradermal skin test for purified protein derivative (PPD); positive Mantoux test defined as 10 mm of induration (size of raised bump, not redness), or equivalent positive TB test result, as per country clinical standards, during the screening period. Subjects whose PPD induration is ≥ 5 mm but < 10 mm are eligible for the study if they had a negative chest x-ray during the screening period. There must be no other clinical evidence of TB on physical examination of the subject. Note: Subjects who have had prior adequate prophylaxis treatment for latent TB with an appropriate course of isoniazid or equivalent, per country standards, are not excluded from study participation. PPD should not be administered within 6 weeks of a live-virus vaccine;

• History of recurrent significant infections or occurrence of a serious local infection (e.g., cellulitis, abscess) or systemic infection (e.g., pneumonia, septicemia) within twelve weeks prior to Day 0;

• Receipt of live vaccine within six weeks prior to Day 0;

• History or presence of primary or secondary immunodeficiency;

• History of any life-threatening allergic reactions;

• Is a pregnant or nursing female;

• Ongoing anticoagulant therapy, which is a contraindication for labial salivary biopsy or tonsil biopsy;

• Concurrent use of anticholinergic agents, such as tricyclic antidepressants, antihistamines, phenothiazines, antiparkinsonian drugs, anti-asthmatic medications, or gastrointestinal (GI) medications that cause xerostomia in more than 10% of patients;

• Treatment with any of the following within the defined period prior to Screening:

  • 2 years for rituximab;
  • 24 weeks for cyclophosphamide;
  • 8 weeks for azathioprine, cyclosporine, methotrexate, or mycophenolate mofetil;
  • 4 weeks for intravenous immunoglobulin;
  • 4 weeks for etanercept;
  • 8 weeks for adalimumab;
  • 12 weeks for infliximab.

• Prednisone (or equivalent corticosteroid) > 10 mg/day;

• A definite diagnosis of RA, SLE, systemic sclerosis, or dermatomyositis;

• A history of alcohol or substance abuse within 12 months of the screening visit;

• A history of head and neck radiation therapy, sarcoidosis, or graft-versus-host disease;

• A history of malignancy, except for a resected basal or major squamous cell carcinoma, cervical dysplasia, or in situ cervical cancer Grade I, within the last five years;

• Severe pulmonary disease as manifested by one of the following at Screening:

  • Resting oxygen saturation < 92%;
  • Force vital capacity (FVC) < 50% predicted;
  • Diffusion lung capacity for carbon monoxide (DLCO) < 50%;

• Abnormal laboratory results for the following parameters at the screening visit:

  • Absolute neutrophil count (ANC): < 1,500/mm^3;
  • Platelets: < 100,000/mm^3;
  • Hemoglobin: < 9 grams (g)/deciliter (dL);
  • Serum creatinine: ≥ 2.0 mg/dL;
  • AST: > 1.5x upper limit of normal, or
  • ALT: > 1.5x upper limit of normal.

• A psychiatric disorder rendering the subject incapable of providing informed consent;

• Plans for foreign travel to countries other than Canada or Western Europe within the treatment period;

• Inability or unwillingness to follow the protocol;

• Any condition or treatment that, in the opinion of the investigator, places the subject at an unacceptable risk as a participant in the trial;

• Rochester substudy subjects who meet the following criteria are disqualified from enrolling in the tonsil biopsy substudy if they:

  • Have any side effects to local anesthetics (e.g., lidocaine);
  • Have any side effects to silver nitrate;
  • Do not have tonsils;
  • Are not able to go 48 hours without any NSAIDS;
  • Are not able to go 2 weeks without acetylsalicylic acid (aspirin).