Study of the Selective GlyT1 Inhibitor Bitopertin for Steroid-Refractory Diamond-Blackfan Anemia

• INCLUSION CRITERIA:

To be eligible to participate in this study, an individual must meet all of the following criteria:

1. Diamond-Blackfan anemia defined as chronic anemia presenting on or before the thirdyear of life, associated with reticulocytopenia and greatly reduced or absent bonemarrow erythroid precursors, supported by, but not requiring either:

2. familial history

3. gene mutation testing demonstrating a known disease-causing mutation or amutation of disease-associated gene in combination with clinicalcharacteristics of DBA Patients with late-onset DBA (diagnosed after the third year of life) may also beincluded if (but only if) gene mutation testing confirms a disease-causing mutation,as above.

4. Clinically-significant anemia as defined as either:

5. hemoglobin less than 9.0 g/dL

6. red cell transfusion of at least 2 units PRBC for adults in the eight weeksprior to study enrollment

7. Relapsed and/or steroid-refractory disease or patient intolerance of systemiccorticosteroids

8. Age >= 18 years at the time of consent

Although all patients without a molecular diagnosis (i.e., genetic testing positive for a disease- causing lesion) will undergo targeted gene panel testing for mutations in all known genes associated with DBA , the diagnosis of DBA is a clinical one, and as such, consent and enrollment does not require results from these genetic tests in the absence of any features that would suggest an alternative diagnosis (e.g., Fanconi Anemia, Dyskeratosis Congenita, etc.).

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Treatment with androgens (danazol or oxymetholone) or corticosteroids less than 4weeks prior to initiating bitopertin.

-Stable physiologic dose steroid replacement for adrenal insufficiency or othersimilar conditions is not an exclusion criterium.

2. Hypersensitivity to bitopertin or its components

3. Patient Health Questionnaire-8 (PHQ-8) score greater than or equal to 10 or imminentsuicidal risk identified by the Columbia-Suicide Severity Rating Scale (C-SSRS) asdefined as suicidal ideation with intent (grade 4 or 5) within the last year or anysuicidal behavior within the last five years

4. Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary,infectious, or metabolic disease of such severity that it would preclude the patients ability to tolerate protocol therapy

5. Life expectancy of less than 3 months from any cause

6. History or current diagnosis of cardiac disease indicating significant risk ofsafety for patients participating in the study such as uncontrolled or significantcardiac disease, including any of the following:

• Recent myocardial infarction (within last 6 months),

• Uncontrolled congestive heart failure,

• Unstable angina (within last 6 months),

• Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustainedventricular tachycardia, and clinically significant second or third-degree AVblock without a pacemaker.)

• Long QT syndrome, family history of idiopathic sudden death, congenital long QTsyndrome or additional risk factors for cardiac repolarization abnormality, asdetermined by the investigator

• Impaired cardiac function such as corrected QTc>450msec using Fridericiacorrection on the screening ECG, other clinically significant cardio-vasculardisease (e.g., uncontrolled hypertension, history of labile hypertension),history of known structural abnormalities (e.g. cardiomyopathy).

7. Known active or uncontrolled infections not adequately responding to appropriatetherapy.

• Note, HIV infection is not exclusive of trial participation if the infection iseffectively controlled with medications not known to interfere with bitopertinmetabolism or be metabolized by pathways known to be altered by bitopertin. HIVRNA viral load must be undetectable at the time of enrollment, and CD4 cellcount must be >= 200/microL. Patients must remain on antiretroviral therapythroughout study participation and must be periodically monitored forsuppression of viral load and CD4 cell count.

• If drug-drug interactions between antiretroviral (e.g. HIV), antiviral (e.g.,hepatitis), or antifungal medications and bitopertin are suspected (such aslopinavir, ritonavir or other strong CYP3A4 inhibitors), these must beaddressed by a qualified clinical pharmacist or pharmacologist, and any changesto antiretroviral therapy need to be approved in consultation with anInfectious Disease and/or HIV specialist prior to enrollment.

8. Evidence for MDS or AML as defined by WHO criteria, or any active malignancy orlikelihood of recurrence of malignancies within 12 months

9. Patients who have received chemotherapeutic treatment or other specificantineoplastic drugs or radiation therapy within 6 months of study entry

10. Female subjects who are nursing or pregnant (positive serum or urine beta-humanchorionic gonadotrophin (beta-hCG) pregnancy test) at screening/baseline visit

11. Women of child-bearing potential, defined as all women physiologically capable ofbecoming pregnant, not using highly effective methods of contraception during dosingand for 30 days after the last dose of bitopertin. Highly effective contraceptionmethods include:

• Total abstinence (when this is in line with the preferred and usual lifestyleof the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal,post- ovulation methods) and withdrawal are not acceptable methods ofcontraception

• Female sterilization (have had surgical bilateral oophorectomy with or withouthysterectomy), total hysterectomy or tubal ligation at least six weeks beforetaking study treatment. In case of oophorectomy alone, only when thereproductive status of the woman has been confirmed by follow up hormone levelassessment

• Male sterilization (at least 6 months prior to screening). For female patientson the study the vasectomized male partner should be the sole partner for thatpatient.

• Use of oral, injected or implanted hormonal methods of contraception orplacement of an intrauterine device (IUD) or intrauterine system (IUS), orother forms of hormonal contraception that have comparable efficacy (failurerate

<1%), for example hormone vaginal ring or transdermal hormone contraception.

• In case of use of oral contraception women should have been stable on the samepill for a minimum of 3 months before taking study treatment. -Women are considered post-menopausal and not of childbearing potential if theyhave had over 12 months of natural (spontaneous) amenorrhea with an appropriateclinical profile age appropriate (e.g., generally 40-59 years), history ofvasomotor symptoms (e.g., hot flushes) in the absence of other medicaljustification or have had surgical bilateral oophorectomy (with or withouthysterectomy), total hysterectomy or tubal ligation at least six weeks ago. Inthe case of oophorectomy alone, only when the reproductive status of the womanhas been confirmed by follow up hormone level assessment should she beconsidered not of childbearing potential.

• Sexually active males unless they use a condom during intercourse while takingthe study treatment and for 30 days after stopping study treatment and shouldnot father a child in this period. A condom is required to be used also byvasectomized men as well as during intercourse with a male partner in order toprevent delivery of the drug via seminal fluid.

12. Active alcohol/drug abuse.

13. Unable to understand the investigational nature of the study or give informedconsent and does not have a legally authorized representative or surrogate that canprovide informed consent.

14. Unable to take the oral study drug.

15. Concurrent participation in an investigational study within 30 days prior toenrollment or within 5-half-lives of the study drug, whichever is longer. Note:parallel enrollment in a disease registry is permitted.