1.1. Confirmed diagnosis of aHUS at initial presentation, defined by presence of TMA:

1.1.1. ADAMTS-13 activity ≥ 10% on blood samples taken before PE/PI; and

1.1.2. STEC test negative in patients with a history of bloody diarrhea in the preceding 2 weeks.

1.1.3. TMA must be unexplained (not a secondary TMA).

1.2. Evidence of ongoing active TMA and progressing, defined by laboratory test abnormalities despite plasmapheresis, if appropriate. Patients must demonstrate:

1.2.1. Unexplained (not a secondary TMA) thrombocytopenia (platelet count < 150 × 10⁹ /L); and hemolysis as indicated by the documentation of 2 of the following: schistocytes on the blood film; low or absent haptoglobin; or LDH above normal. OR

1.2.2. Tissue biopsy confirms TMA in patients who do not have evidence of platelet consumption and hemolysis.

1.3. Evidence of at least 1 of the following documented clinical features of active organ damage or impairment:

1.3.1. Kidney impairment, as demonstrated by one of the following:

1.3.1.1. A decline in eGFR of > 20% in a patient with pre-existing renal impairment; and/or

1.3.1.2. SCr > ULN for age or GFR < 60mL/min and renal function deteriorating despite prior PE/PI in patients who have no history of preexisting renal impairment (i.e., who have no baseline eGFR measurement); OR

1.3.1.3. SCr > the age-appropriate ULN in pediatric patients (as determined by or in consultation with a pediatric nephrologist) OR

1.3.2. The onset of neurological impairment related to TMA.

1.3.3. Other TMA-related manifestations, such as cardiac ischemia, bowel ischemia, pancreatitis, and retinal vein occlusion.

Based on clinical expert opinion, in pediatrics, where TTP is less common, clinicians would likely not first initiate plasmapheresis (i.e., not early initiation of plasmapheresis until the diagnosis is confirmed) since use of plasmapheresis is not recommended in this setting; however, they agree this would be prudent to do in older patients.

2.1. Develop TMA immediately (within hours to 1 month) following a kidney transplant; or

2.2. Previously lost a native or transplanted kidney due to the development of TMA; or

2.3. Have a history of proven aHUS and require prophylaxis with ravulizumab at the time of a kidney transplant

TMAs most commonly appear within 1 month of post-transplant, as such immediately could be considered within hours to 1 month.

If a patient previously lost their native kidney to TMA/aHUS, and aHUS is now occurring in their transplanted kidney, they should be eligible to receive treatment with ravulizumab, as their current graft is similarly at risk with each subsequent transplant.

3.1. Treatment failure is defined as:

3.1.1. Dialysis-dependent at 6 months, and failed to demonstrate resolution or stabilization of neurological or extrarenal complications if these were originally present; OR

3.1.2. On dialysis for ≥ 4 of the previous 6 months while receiving ravulizumab and failed to demonstrate resolution or stabilization of neurological or extrarenal complications if these were originally present; OR

3.1.3. Worsening of kidney function with a reduction in eGFR or increase in SCr ≥ 25% from baseline.

• Identified drug exposure-related HUS.
• Prior use of eculizumab or other complement inhibitors.

4.1. Treatment response is defined as, but not limited to, hematological normalization (e.g., platelet count, LDH), stabilization of end-organ damage (such as acute kidney injury and brain ischemia), transplant graft survival in susceptible individuals, and dialysis avoidance in patients who are pre-ESKD.

4.2. Treatment with ravulizumab can be renewed as long as the patient exhibits a response to treatment or as per physician discretion (e.g., long-term funding based on factors like limited organ reserve or high-risk genetic mutation such as Factor H deficiency).

4.3. At the 6-month assessment, treatment response and no treatment failure (defined in 3.1 above) is required.

4.4. At the 12-month and annual assessments, treatment response, no treatment failure (defined in 3.1 above), and the patient has limited organ reserve or high-risk genetic mutation are required.

4.4.1. Limited organ reserve is defined as significant cardiomyopathy, neurological, gastrointestinal, or pulmonary impairment related to TMA; or Grade 4 or 5 chronic kidney disease (eGFR < 30mL/min) is required.

According to clinical experts, the required duration of treatment with C5 inhibition is unknown. It is possible to discontinue treatment with ravulizumab in patients with aHUS without a genetic mutation in complement 3 to 6 months after remission is achieved. Lifelong treatment may be considered for patients with high-risk complement genetic variations (such as, but not limited to, Factor H deficiency,) or limited organ reserve. Patients with DGKE mutations may discontinue if no response to treatment is observed.

5.1. Significant hemolysis as evidenced by presence of schistocytes on the blood film, or low or absent haptoglobin, or LDH above normal; AND

5.2. EITHER

5.2.1. Platelet consumption as measured by either ≥ 25% decline from patient baseline or thrombocytopenia (platelet count < 150,000 × 109/L); OR

5.2.2. TMA-related organ impairment (e.g., unexplained rise in serum creatinine with onset of urine dipstick positive for hemoglobin) including on recent biopsy.

As such, there is insufficient evidence to justify a cost premium for ravulizumab over the least expensive complement inhibitor reimbursed for aHUS.