What is the best approach to manage a patient with Hemolytic Uremic Syndrome (HUS) and Impaired Renal Function, currently on dialysis, corticosteroids, and Plasma Exchange, requiring Ravulizumab (Eculizumab) to prevent further kidney damage?

From the Guidelines

I strongly recommend immediate administration of Ravulizumab for this 32-year-old man with Hemolytic Uremic Syndrome (HUS) who is experiencing kidney failure, as it offers the best chance to prevent permanent kidney failure and potentially eliminate the need for lifelong dialysis. Ravulizumab should be given as an intravenous infusion with a weight-based loading dose (typically 2,400-3,000 mg for adults), followed by maintenance doses every 8 weeks 1. The medication should be administered in a controlled setting where the patient can be monitored for infusion reactions. Treatment should continue until clinical improvement is observed, particularly regarding kidney function parameters. While the patient continues dialysis, Ravulizumab therapy should be coordinated with his existing treatments including steroids and plasma exchange.

Key Considerations

• Ravulizumab works by inhibiting complement activation, which is a key pathological mechanism in HUS, by blocking the terminal complement pathway, specifically C5, the medication prevents further formation of the membrane attack complex that damages blood vessels in the kidneys 1.
• Given that some kidney tissue remains viable in this patient, prompt intervention with Ravulizumab is crucial to stop ongoing microvascular thrombosis and hemolysis, potentially allowing kidney tissue to recover.
• The use of immunosuppressive agents, such as high-dose steroids and IVIg, may also be considered in the treatment of HUS, but Ravulizumab is the most effective treatment for preventing further kidney damage and improving chances for recovery 1.

Treatment Coordination

• The patient's treatment plan should be coordinated with his existing treatments, including steroids and plasma exchange, to ensure the best possible outcome.
• Serial monitoring of the patient's kidney function parameters, as well as his overall clinical condition, is essential to assess the effectiveness of the treatment and make any necessary adjustments.

Potential Benefits and Risks

• The potential benefits of Ravulizumab treatment in this patient include preventing permanent kidney failure, reducing the need for lifelong dialysis, and improving overall quality of life.
• The potential risks associated with Ravulizumab treatment, such as infusion reactions and increased risk of meningococcal infection, should be carefully monitored and managed to minimize their impact on the patient's outcome.

From the FDA Drug Label

14.2 Atypical Hemolytic Uremic Syndrome (aHUS) The safety and efficacy of ULTOMIRIS in adult patients with aHUS was assessed in a single-arm, open-label, Phase 3 study [ALXN1210-aHUS-312; NCT02495940] conducted in 41 adult patients with aHUS.

Patients received intravenous ULTOMIRIS according to the weight-based dosing described in Section 2.3 (4 infusions of ULTOMIRIS over 26 weeks) above.

The primary endpoint was complete TMA response, defined as

• Platelet count ≥ 150 × 10^9/L
• LDH ≤ 1.8 × ULN
• Improvement of at least one scale score in the eGFR or a 15% or greater increase from baseline in eGFR
• No new dialysis requirement or eGFR increase of at least 15 mL/min/1.73 m^2 from baseline in patients with baseline eGFR < 35 mL/min/1.73 m^2

At 26 weeks, 54% (22/41) of patients achieved a complete TMA response.

Key findings:

• The study demonstrated the efficacy of ULTOMIRIS in adult patients with aHUS.
• The primary endpoint of complete TMA response was achieved by 54% of patients at 26 weeks.

Clinical decision: Based on the study results, Ravulizumab (ULTOMIRIS) may be effective in treating adult patients with aHUS, including improving kidney function and reducing the need for dialysis.

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From the Research

Treatment of Hemolytic Uremic Syndrome (HUS) with Ravulizumab

• Ravulizumab is a humanized monoclonal antibody that inhibits complement protein C5, indicated for the treatment of atypical haemolytic uraemic syndrome (aHUS) 3.
• The medication has been shown to resolve thrombotic microangiopathy in 54% and 78% of treatment-naïve adult and pediatric patients with aHUS, respectively, within 26 weeks 3.
• Ravulizumab has a more convenient maintenance dosage regimen of once every 4-8 weeks compared to eculizumab, another C5 inhibitor 3.

Efficacy and Safety of Ravulizumab

• Studies have demonstrated the efficacy and safety of ravulizumab in adult patients with aHUS naïve to complement inhibitor treatment, with complete thrombotic microangiopathy response achieved in 53.6% of patients 4.
• Long-term treatment with ravulizumab has been associated with improved hematologic and renal parameters, as well as quality of life, in adults and pediatric patients with aHUS 5.
• The most common treatment-related adverse events with ravulizumab include headache, diarrhea, and vomiting 3.

Comparison with Other Treatments

• An indirect comparison of ravulizumab and eculizumab using clinical trial data found no differences in outcomes between the two treatments, although confidence intervals were wide 6.
• Ravulizumab has been engineered from eculizumab to have an increased half-life, allowing for reduced dosing frequency 6, 4.

Pathogenesis and Diagnosis of HUS

• HUS is related to a renal thrombotic microangiopathy, inducing hypertension and acute renal failure (ARF), with an activation/lesion of microvascular endothelial cells 7.
• The pathogenesis of HUS involves an overactivation of the complement alternate pathway, which can be caused by genetic or acquired factors 7.