Safety and Efficacy of Subcutaneous Sarilumab in Improving the Quality of Life in People With Indolent Systemic Mastocytosis

Systemic mastocytosis is a disorder caused by clonal mast cell proliferation and release of
mast cell mediators including tryptase. As a result, mast cell numbers may increase and
affect target organs including the dermis (maculopapular cutaneous mastocytosis/urticaria
pigmentosa, flushing), gastrointestinal tract (abdominal pain, diarrhea), skeletal system
(osteoporosis), hematological system (anemia, thrombocytopenia), and spleen and liver
(organomegaly). Patients with indolent (non-aggressive) systemic mastocytosis (ISM) are not
candidates for cytoreductive therapy and are generally treated with symptomatic therapy that
only partly decreases symptoms. There is, however, a documented association between severity
of mastocytosis and elevated serum levels of interleukin (IL)-6. Furthermore, mast cells have
been shown to double their rate of division and exhibit increased reactivity and release of
mediators when cultured in the presence of IL-6. In addition, in an animal model of
mastocytosis, anti-IL-6 has been shown to slow disease progression. In this study, adults
with ISM will thus be randomized and treated with sarilumab, a recombinant monoclonal
antibody directed against the IL-6 receptor, or receive placebo. Sarilumab is marketed in the
United States as Kevzara (Regeneron [Tarrytown, NY, USA]) and is approved by the Food and
Drug Administration for the treatment of rheumatoid arthritis. Binding of sarilumab to the
IL-6 receptor inhibits IL-6-associated human mast cell signaling and proliferation with a
resultant decrease in proliferation and reactivity (decreased mediator release), and
therefore is a rational choice for the treatment of ISM.

In this study, participants will be randomized with approximately half of the participants
receiving study drug, which will be administered at 200 mg via subcutaneous (SC) injection
once every 2 weeks (Q2W) for a total of 16 weeks. The other participants will receive a
placebo administered via SC injection Q2W for 16 weeks. Participants will return for a
follow-up visit 2 weeks after the final dose (treatment peak), and then again 12 weeks later.
Evaluations at study visits will include quality of life and symptom assessments and
measurement of serum tryptase levels. Bone marrow examination will be performed at the onset
and conclusion of the study. After the week 28 visit, all participants will have the option
to continue sarilumab for 52 more weeks, at 200 mg administered via SC injections.
Participants will continue to be monitored on a regular basis for safety concerns, as
instructed in the study drug s package insert.

- INCLUSION CRITERIA:

Participants must meet all of the following criteria to be enrolled in this study:

1. Male or female participant greater than or equal to 18 and < 75 years of age at
screening.

2. Enrolled on NIAID protocol 02-I-0277.

3. Documented pathologic diagnosis of ISM.

4. MC-QoL score of at least 25% (which suggests participant is at least somewhat affected
by all McQoL questions).

5. Willing and able to undergo a bone marrow biopsy and aspirate.

6. Absolute neutrophil count (ANC) greater than or equal to 2000/mL.

7. Hemoglobin greater than or equal to 12.0 g/dL (males), greater than or equal to 11
g/dL (females).

8. Platelet count greater than or equal to 150,000/microliters.

9. Alanine transaminase (ALT) and aspartate transaminase (AST) < 1.5 times the upper
limit of normal (ULN).

10. Willing to allow storage of blood and bone marrow for future use in medical research.

11. Willing to allow genetic testing on biospecimens.

12. Able to provide informed consent.

13. Participants who can become pregnant must agree to use adequate contraception when
engaging in sexual activities that can result in pregnancy. Adequate contraception
must be used consistently, beginning at least 1 month before the beginning of dosing
and lasting until 3 months after the final dose of study drug. Acceptable methods of
contraception include the following:

- Hormonal contraception (non-oral only).

- Male or female condom with spermicide.

- Diaphragm or cervical cap with a spermicide.

- Intrauterine device.

EXCLUSION CRITERIA:

Individuals meeting any of the following criteria will be excluded from study
participation:

1. Any abnormality that would be scored as a Grade 4 toxicity on the Common Terminology
Criteria for Adverse Events (CTCAE) version 5.0.

2. Infected with HIV or has other known immunodeficiency.

3. Has an active infection, including localized infection.

4. Active diverticulitis.

5. Active or chronic viral hepatitis.

6. Active or latent tuberculosis.

7. Use of any other anti-IL-6 or anti-IL-6R agent within 1 year prior to the date
informed consent was obtained.

8. Use of cytoreductive therapy for mastocytosis within 1 year prior to the date informed
consent was obtained.

9. Known lymphoma or advanced and metastatic solid tumors on active therapy (including
chemotherapy) within 1 year prior to the date informed consent was obtained

10. Use of chemotherapy or monoclonal antibodies (experimental or licensed) within 1 year
prior to the date informed consent was obtained.

11. Receipt of any marketed (eg, omalizumab) or investigational biologic within 4 months
or 5 half-lives prior to date informed consent was obtained, whichever is longer.

12. Receipt of intravenous (IV) immunoglobulin within 30 days prior to the date informed
consent was obtained.

13. Receipt of live attenuated vaccines within 30 days prior to the date informed consent
was obtained.

14. History of alcohol or drug/abuse within 12 months prior to date informed consent was
obtained.

15. Is allergic to any component of the sarilumab formulation.

16. Pregnant or breastfeeding.

17. Any condition that, in the opinion of the investigator, contraindicates participation
in this study.