Therapies for Down Syndrome Regression Disorder

Inclusion Criteria:

• Individuals with DS between the ages of 8 and 30 years, inclusive. DS is broadlydefined to include complete trisomy 21, Robertsonian translocation trisomy 21,partial trisomy 21 (segmental duplication), and mosaic trisomy 21.

• Diagnosis of possible or probable DSRD per 2022 consensus guidelines.

• Must agree to random treatment assignment.

• Must agree to complete a washout of any medications intended to treat symptoms ofDSRD or that may interfere with study interventions.

• Must be able to present with a study partner or legal guardian at all study visits.

Exclusion Criteria:

General

• Weight less than 40 kg.

• Pregnant or breast feeding.

• Past or current tobacco smoking.

• Poor venous access not allowing repeated blood tests or non-compliance withvenipuncture requirements.

• Known allergies, hypersensitivity, or intolerance to lorazepam, IVIG, ortofacitinib.

• Participants may be excluded for other unforeseen reasons or confounding reasons forDSRD symptoms at the study doctor's discretion.

Co-occurring Conditions

• Any co-occurring genetic disorder.

• Active symptomatic cardiac disease.

• Clinically significant chronic or active viral infection, including but not limitedto HIV, hepatitis, CMV, EBV, HSV or untreated tuberculosis.

• Untreated chronic or active bacterial infection.

• Untreated hypothyroidism or hyperthyroidism.

• History of disseminated herpes zoster, disseminated herpes simplex, or recurrentlocalized dermatomal herpes zoster.

• History of malignancy (solid tumor or leukemia).

• Moyamoya syndrome or stroke (active or prior).

• Baseline abnormal renal function indicative of moderate or severe renal disease byeGFR <=45.

• History of acute narrow-angle glaucoma.

• History of venous or arterial thrombosis.

• IgA deficiency with antibodies against IgA.

• Pathogenic neuronal autoantibody positivity against established causes of autoimmuneencephalopathy in CSF.

• Any subject with a history of anaphylaxis or a severe systemic response to blood orplasma-derived products.

Medications or Interventions

• Any vaccination planned during the study or within the last 6 weeks.

• Use of electroconvulsive therapy, lorazepam, or a JAK inhibitor within the last 4weeks.

• Use of IVIG within the last 8 weeks.

• Use of immunosuppressant drugs (e.g., prednisone, mycophenolate mofetil,azathioprine) within the last 8 weeks.

• Use of rituximab within the past 6 months, unless B cell levels have recovered andare above 50 cells/uL.

• Use of other immunosuppressant biologics (e.g., adalimumab, etanercept) within thepast 6 months.

• Use of strong CP3A4 inhibitors or inducers (e.g., ketoconazole, rifampin) within thelast 4 weeks.

• Use of moderate CP3A4 inhibitors with a strong CYP2C19 inhibitor (e.g., fluconazole)within the last 4 weeks.

• Use of moderate CYP2C9 inhibitors (e.g., valproic acid) within the last 4 weeks.

• Use of strong CYP1A2 inducers (e.g., phenobarbital) or moderate CYP1A2 inhibitors (e.g., fluvoxamine) within the last 4 weeks.

• Use of certain mood stabilizers or anticonvulsants (e.g., clonazepam, lithium,oxcarbazepine) within the last 4 weeks.

• Any prior use of methotrexate, cyclophosphamide, or other chemotherapeutics.

• Any prior solid organ transplant.

• Any prior neurosurgical intervention.

• Any subject who has received blood or plasma products ≤ 30 days prior to firstBaseline visit.