Comparison of the efficacy of rVA576 versus standard of care for patients with uncontrolled haemolysis due to paroxysmal nocturnal haemoglobinuria (PNH). Standard of care is defined as packed red blood cells (PRBC)

Study sites • Colombo North Teaching Hospital, Ragama • Colombo South Teaching Hospital, Kalubowila • Jaffna Teaching Hospital, Jaffna • National Hospital of Sri Lanka

CAPSTONE is a three-part, two-arm randomised, controlled (standard of care), parallel group study. The trial will run in 3 parts as below:

Screening Period: Up to 21 days where patients will be assessed in order to confirm they meet all Inclusion criteria and do not to meet any of the Exclusion criteria.

Part 1– Observation Period: A 3-month observation period in which patients will be treated with Standard of Care (SoC). During Part 1, the following 2 events may occur: • Patients receive a qualifying transfusion that permits entry into Part 2 of the trial • Patients who do not require a qualifying transfusion by the end of the observation period will leave the trial (withdrawn patients) and will not be permitted to be rescreened. Patients who receive a qualifying transfusion will have the haemoglobin (Hb) value which triggered the requirement for a transfusion used as their set point which mandates the Hb level at which further transfusions will take place in Part 2 (see below). Patients should receive their qualifying transfusion based on the algorithm within a maximum of 48 hours of the Hb value which triggered the clinical decision to transfuse.

Part 2: A 6-month treatment period where patients will be randomised 1:1 to either rVA576 plus SoC (Arm 1) or SoC (Arm 2). Following receipt of the qualifying transfusion in Part 1, patients should move into Part 2 within 1- 3 days to begin treatment under Part 2. The ablating dose cannot be given the same day as the qualifying transfusion, since patients should receive the ablating dose at a suitable time in the morning. Patients in Part 2 who fall below their Hb set point will receive an appropriate number of units of packed red blood cells (PRBCs) according to a pre-determined algorithm based on prior transfusion history. The Hb value which triggered the requirement for the qualifying transfusion in Part 1 will be used as their set point.

Part 3: A 3-month maintenance period at the end of Part 2 after 6 months of treatment, all patients will move to Part 3 for 3 months: the patients in Arm 1 (rVA576 plus SoC) will continue receiving treatment for a further 3 months. The patients in Arm 2 (SoC) will switch from SoC only to rVA576 plus SoC for 3 months. At the end of Part 3 all patients will be offered the chance of continuing to receive rVA576 under the long-term Safety study AK581 (CONSERVE) if the Investigator believes the patient is benefitting from treatment. This study will randomise 1:1 a minimum of 30 patients into Part 2 of the study (approximately 15 to receive rVA576 plus SoC, and approximately 15 to continue with their SoC). Randomisation will be stratified based on the number of transfusions of whole blood or packed red blood cells (PRBC) received within the 12 months prior to entering the observation period (low stratum: 4-14 units, high stratum: ? 15 units). For each arm starting treatment with rVA576, the patient will receive an ablation dose (AD) of 60 mg followed by one dose of 30 mg 12 hours later (this will be considered Day 1 for rVA576 treatment). The patient will then continue with a dose of 22.5 mg every 12 hours administered for Days 2 – 28 (± 3days), during which the patient is stabilised on treatment with rVA576. At Day 29, the patient will move to a dose of 45mg once daily up to Day 270 in Arm 1 and up to Day 90 in Arm 2. rVA576 will be administered subcutaneously.

1. Willing to give informed consent to treatment with rVA576
2. Diagnosed with paroxysmal nocturnal haemoglobinuria (PNH) confirmed by flow cytometry
3. Have not received any complement inhibitor within the 4 months prior to screening
4. ?18 years of age at the time of screening
5. Weight ?50kg
6. Complete transfusion medical history for 12 months prior to entering the observation period and definitely prior to receiving the qualifying transfusion must be available to the patient's investigator and be verifiable by the Sponsor or its representative.
7. Transfusion dependent and has received at least 4 episodes of transfusion of whole blood or PRBC during the 12 months prior to entering the observation period (Part 1), with a minimum of 4 units in total, and a minimum of 1unit at each transfusion episode.
8. LDH ?1.5 x the ULN per the local lab.
9. Willing to receive appropriate prophylaxis against Neisseria meningitidis infection by both immunisation and continuous or intermittent antibiotics.
10. Willing to avoid prohibited medications such as other complement inhibitors and chemotherapeutic agents
11. Patients must agree to avoid pregnancy and fathering children from the time of signing the Informed Consent Form until 90 days after the last dose of rVA576. Permitted contraceptive methods that are ?99% effective in preventing pregnancy should be communicated to trial patients and their understanding confirmed. Two approved methods of highly effective contraception must be used by the patient and their partner.
12. Patients who are on erythropoietin and/or immunosuppressant treatment should be on stable doses for at least 6 months prior to entering the observation period (Part 1). The dose of these drugs should not be changed during Part 1 or 2.
13. Patients who are taking systemic corticosteroids should be on a stable dose for at least 4 weeks prior entering the observation period (Part 1). If corticosteroids, either topical or systemic, are being taken for reasons unconnected with the target condition (e.g. for allergic rhino-conjunctivitis) they may be adjusted as clinically appropriate but otherwise should remain at constant dosage.
14. Patients on anticoagulant therapy should be well-controlled prior to entry into the observation period (Part 1) and control should be maintained as long as anticoagulation is considered to be an appropriate therapy. A change of up to 20% to a previously stable anticoagulant therapy is permitted
15. Patients taking iron and/or folic acid supplements should be on a stable dose for at least 4 weeks prior to entering the observation period (Part 1). The dose of iron and/or folic acid supplements should not be adjusted during the trial.

Part 2 inclusion criteria 1. Complete transfusion medical history for 12 months prior to receiving qualifying transfusion must be available to the patient's investigator and be verifiable by the Sponsor or its representative. 2. A qualifying transfusion is mandatory during Part 1 with Hb?70g/L (7g/dL) with or without symptoms or >70g/L (7g/dL) to ?90g/L (9g/dL) with symptoms. 3. The qualifying transfusion during the observation period (Part 1) requiring a minimum of 1 unit of PRBC. The quantity of PRBC to be transfused will be according to the algorithm in the protocol. 4. Patient must be within 15g/L (1.5g/dL) of the mean haemoglobin from the previous 12 months 5. Will have a minimum of 1 sign or 1 symptom of PNH from the following list: frank haemoglobinuria, dysphagia, dyspnoea, abdominal pain, erectile dysfunction, evidence of recent thrombotic event, or excessive fatigue, which leads to the qualifying transfusion. 6. A negative nasal and throat swab result for N. meningitidis in the last assessment. 7. Patient must be available to enter Part 2 within 3 days of receiving a qualifying transfusion in Part 1. 8. Continues to meet all the inclusion criteria and none of the exclusion criteria

1. Patients whose mean haemoglobin level over the previous 12 months prior to screening was greater than 105 g/L (10.5g/dL).
2. Severe bone marrow failure as manifested by (a) a peripheral blood reticulocyte count <20 x 109/L OR (b) neutrophils < 0.5 x 109/L
3. Patients with a platelet count of ? 70 x 109/L.
4. Patients with known or suspected acquired somatic mutations affecting the bone marrow (e.g. acute myeloid leukaemia) which may be associated with PNH.
5. Chemotherapy within 3 months of screening visit.
6. History of recurrent bacterial infections or suspicion of active bacterial infections requiring antibiotic therapy.
7. Planned or actual pregnancy or breast feeding (females).
8. Known allergy to ticks or severe reaction to arthropod venom (e.g. bee or wasp venom).
9. Unresolved N. meningitidis infection. Patients who have positive nasal or throat swabs must be excluded until eradication of the organism by antibiotic treatment has been confirmed by repeat swabbing and growth testing.
10. Patients who are not willing to receive adequate immunisation against N. meningitidis unless, in the opinion of the investigator, the risks of delaying therapy outweigh the risks of developing a meningococcal infection.
11. Impaired hepatic function (bilirubin > 1.5 x ULN and AST/ALT >2.5 x ULN) unless, in the opinion of the investigator, the risks of delaying therapy outweigh the risks of treatment in the presence of impaired hepatic function.
12. Patients with a glomerular filtration rate (GFR) of <30mL/min/1.73m2 unless, in the opinion of the investigator, the risks of delaying therapy outweigh the risks of treatment in the presence of impaired renal function.
13. Participation in other clinical trials within 4 weeks of signing the consent form.
14. History of active systemic autoimmune diseases other than the target condition. Dermatologic diseases such as psoriasis will not be a reason for exclusion unless there are associated systemic symptoms such as psoriatic arthritis.
15. Any other systemic disorders that could interfere with the evaluation of the study treatment.
16. Failure to comply with protocol requirements
17. Known Hepatitis B or Hepatitis C, as per medical history. Part 2 exclusion criteria Presence or suspicion of active bacterial infection requiring antibiotic therapy in the opinion of the Investigator.