Paroxysmal Nocturnal Haemoglobinuria

From 1 March 2022, eculizumab and ravulizumab are available on the Pharmaceutical Benefits Scheme (PBS) for the treatment of paroxysmal nocturnal haemoglobinuria (PNH). This is an extension of indications for eculizumab which was listed on the PBS in 2014 for the treatment of atypical haemolytic uraemic syndrome. For ravulizumab, this is the first time it is available on the PBS. Both agents are supplied under the Section 100 Highly Specialised Drugs (HSD) program.

This new PBS listing changes the way that patients with PNH can access subsidised eculizumab. Eculizumab has previously been fully subsidised for patients with PNH via the Life Saving Drugs Program (LSDP). Access to eculizumab under the LSDP has now ceased for new patients. Existing patients may continue to receive their medication under the LSDP until they can transition to PBS supply or up to 31 May 2022 (whichever is sooner).

A fact sheet outlining these arrangements is available on the PBS website.

What is paroxysmal nocturnal haemoglobinuria?

Paroxysmal nocturnal haemoglobinuria is a rare and life-threatening disease of the blood. An acquired gene mutation leads to the production of defective haematopoietic stem cells, which go on to produce defective blood cells. These red blood cells are deficient in terminal complement inhibitors, making them highly susceptible to complement activation and intravascular haemolysis.

Haemolysis occurs throughout the day, not just at night as the name suggests. However, episodes of haemoglobinuria are typically more noticeable in the morning after the urine has concentrated overnight. This classic symptom of visible haemoglobin in the urine does not occur in all patients. Other signs and symptoms are variable but may include:

• Anaemia;
• Fatigue;
• Dark urine;
• Kidney disease;
• Bruising or bleeding easily;
• Shortness of breath;
• Recurring infections;
• Severe headache;
• Oesophageal spasms;
• Erectile dysfunction; and
• Thrombosis.

The complement inhibitor, eculizumab, is the mainstay of treatment. Supportive measures include iron and folic acid supplementation; transfusions may be required. Bone marrow transplantation can be curative. However, due to the significant complications associated with stem cell transplants, this approach is typically not a first-line option.

Eculizumab

Eculizumab is a terminal complement inhibitor. It specifically binds to the complement protein C5, preventing its cleavage to C5a and C5b. This blocks the subsequent formation of membrane attack complex (MAC) and intravascular haemolysis.

The double-blind TRIUMPH study investigated the safety and efficacy of eculizumab in patients with PNH. There was an immediate decline in lactate dehydrogenase levels (a marker of tissue damage) in the eculizumab group, while levels remained elevated in the placebo group. The primary efficacy endpoints were stabilisation of haemoglobin levels and the number of units of packed red cells transfused.

At the end of the 26-week treatment period, stabilisation of haemoglobin levels in the absence of transfusions occurred in 49% of eculizumab patients and 0% of placebo. The median number of units of packed cells transfused per patient was 0 in the eculizumab group and 10 in the placebo group. In comparison, the median number of units transfused per patient in the six-month period before the study was 9.0 in the eculizumab group and 8.5 in the placebo group. A long-term extension study demonstrated that this reduction in haemolysis was sustained and accompanied by a significant reduction in thromboembolic events.

Eculizumab is administered as an intravenous infusion. It is dosed on a weekly basis for the first five weeks, followed by maintenance dosing every two weeks. Patients should be monitored for signs and symptoms of infusion-related reactions for one hour after the completion of each infusion.

Adverse events reported in clinical trials include headache, fatigue, nausea, abdominal pain, oral herpes, upper respiratory tract infections, and dry skin.

Eculizumab is an effective therapy for PNH but does have some limitations. The frequent dosing schedule may be burdensome. In addition, some patients may experience breakthrough haemolysis due to insufficient complement inhibition in the 24-48 hours prior to their next dose. It is thought that up to 35% of patients treated with eculizumab will continue to require red cell transfusions.

Ravulizumab

Ravulizumab is a newer agent that has been engineered from eculizumab to address some of its limitations. The terminal half-life of ravulizumab is around four times longer than eculizumab, enabling an extended dosing interval. Two weeks after the initial loading dose, ravulizumab is dosed once every eight weeks. Patients switching to ravulizumab from eculizumab should receive the ravulizumab loading dose two weeks after their last eculizumab dose.

The 301 study assessed the non-inferiority of ravulizumab compared to eculizumab in complement inhibitor-naïve adults with PNH. Upon completion of the 26-week treatment period, ravulizumab achieved non-inferiority for all efficacy endpoints and a similar safety profile. The proportion of patients experiencing breakthrough haemolysis was 4.0% in the ravulizumab group and 10.7% in the eculizumab group. The study authors suggest that this positive result may be due to the sustained C5 inhibition achieved by ravulizumab.

In Australia, ravulizumab is currently only indicated for use in adult patients due to limited data in paediatric populations. However, interim results from a Phase III trial indicates that the efficacy and safety profile of ravulizumab in children is consistent with the profile observed in adults.

Precautions

While inhibition of MAC formation is desirable in PNH to prevent haemolysis, MAC also has an important role in the removal of pathogens. MAC is most effective against gram-negative bacteria and enveloped viruses, and is thought to be particularly important for the elimination of Neisseria species. Therefore, patients treated with complement inhibitors may be at higher risk of meningococcal and gonococcal infections.

Both eculizumab and ravulizumab are known to increase the risk of meningococcal infection/sepsis. All patients should be vaccinated against Neisseria meningitidis at least two weeks prior to their first dose unless the risk of delaying treatment outweighs the risk of meningococcal infection. If the monoclonal antibody is initiated less than two weeks after vaccination, prophylactic antibiotics are recommended until two weeks after administration of the vaccine. As infection can occur with any serogroup, vaccination against serogroup B as well as serogroups A, C, W135, and Y is advised. The Australian Immunisation Handbook provides guidelines for meningococcal vaccination.

Although vaccination reduces the risk of meningococcal infection, it does not eliminate the risk. Patients should be educated on the signs and symptoms of meningococcal infection and advised to seek immediate medical attention if infection is suspected.

Conclusions

Eculizumab and ravulizumab are effective therapies for the management of PNH and are now available on the PBS. Ravulizumab may offer an advantage for patients as it requires less frequent dosing. However, as it is a newer agent, there is less long-term safety data available.