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Paroxysmal Nocturnal Hemoglobinuria (PNH)
1. At least 18 years of age
2. With a primary diagnosis of PNH confirmed by high-sensitivity flow cytometry
3. On treatment with a stable dose of eculizumab for at least 3 months prior to the screening visit
4. With a hemoglobin <10.5 g/dL, an absolute reticulocyte count > 1.5× ULN, a platelet count of >50,000/mm3, and an absolute neutrophil count >500/mm3 at the screening visit
Designed for Patients
New Phase III Clinical TrialEnrolling Now
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic, potentially life-threatening blood disorder. PNH can present at any age, in people of any race or gender. However, it is diagnosed most often in people in their early 30s, and it usually continues throughout the life of the patient.1 In PNH, stem cells acquire a gene mutation that results in the production of abnormal blood cells. Defective red blood cells become open to attack by complement, which is part of the immune system.1 This destruction of red blood cells is called hemolysis.2 As a result, the person will suffer from anemia, which is a shortage of healthy red blood cells.2
In addition to suffering from anemia, a patient with PNH may experience a multitude of problems, including renal failure, pulmonary hypertension (high blood pressure in the lungs), thrombosis (blood clots within blood vessels), abdominal pain, dyspnea (shortness of breath), dysphagia (discomfort when swallowing), fatigue, impaired quality of life, and erectile dysfunction in men.3 Thrombosis has a significant impact on survival and is the leading cause of death in patients with PNH.4
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Role of Complement in PNHIn PNH, stem cells acquire a gene mutation which causes the production of abnormal blood cells that lack two important surface proteins (CD55 and CD59). These proteins protect normal blood cells from attack by the complement system (Figure 1): • CD55 prevents activation of C3, which can lead to opsonization of the red blood cell, marking it for destruction in the spleen and liver. This process is called extravascular hemolysis.3 C3 activation can also lead to activation of C5.1 • CD59 protects red blood cells and platelets from the membrane attack complexes (MACs) produced by activation of C5.3 MACs cause intravascular hemolysis.
Figure 1: The complement system is an important part of the immune system. The complement system can be activated through three separate pathways (classical, lectin, and alternative). All 3 eventually lead to the cleavage of C3 (into C3a and C3b) by C3 convertases. C3b plays a key role in opsonization, which marks a particle or cell for destruction by white blood cells, especially in the liver or spleen. C3b also leads to the cleavage of C5 (into C5a and C5b) by C5 convertases. C5b is a subunit of the membrane attack complex (MAC), which creates a pore that can lead to the death of the cell. Normally, blood cells carry 2 surface proteins that protect them against the complement system. CD55 blocks activation of C3. Thus, CD55 helps to prevent extravascular hemolysis. CD59 protects the cell against MACs, thus preventing intravascular hemolysis. In people with PNH, many of the red blood cells and platelets lack the substance that would normally anchor CD55 and CD59 onto the cell’s surface. The defective red blood cells have an abnormally short life span. The defective platelets can lead to abnormal clotting.3
The Role of Complement in the Development of PNHNormal blood cells carry 2 surface proteins (CD55 and CD59) that protect them against the complement system. CD55 prevents activation of C3, and CD59 protects against the membrane attack complexes (MACs) produced by activation of C5.
In PNH, many blood cells lack the anchors that would hold CD55 and CD59 onto their surface. As a result, they can be damaged by activation of any pathway of the complement system.
MAC-mediated intravascular hemolysisMAC is a pore inserted into the RBC membrane, which causes its destruction and release of its contents into blood
C3b-mediated extravascular hemolysisC3b coats RBCs and facilitates their destruction in the liver and spleen
CD59CD
55
CD59CD
55
C3a
C3b C3b C5b C3
C3 Convertase C5 Convertase
Thrombosis
C5a
C5 C3b C5b MAC
C3b
To establish the efficacy and safety of the investigational drug APL-2, as compared to eculizumab, in patients with PNH who continue to have hemoglobin levels <10.5 g/dL despite treatment with eculizumab.5
This study will enroll approximately 70 subjects to compare APL-2 to eculizumab treatment. Through a process known as randomization, roughly ½ of subjects will be assigned to group 1 (APL-2) or group 2 (eculizumab, with a transition to APL-2 at week 17).
Purpose of PNH Clinical Trial
1. Age ≥18 years
2. Primary diagnosis of PNH confirmed by high-sensitivity flow cytometry
3. On treatment with eculizumab. Dose of eculizumab must have been stable for ≥3 months
4. Hemoglobin <10.5 g/dL at the screening visit
5. Absolute reticulocyte count > 1.5x ULN at the screening visit
Key Inclusion Criteria
Key Exclusion Criteria
1. Active bacterial infection within 4 weeks prior to day-28 (run-in period)
2. Receiving iron, folic acid, vitamin B12, and erythropoietin, unless the dose is stable
3. Hereditary complement deficiency
4. History of bone marrow transplantation
APL-2 is a PEGylated cyclic peptide inhibitor of complement C3.6 PEGylation helps keep APL-2 in the body longer, reducing dosing frequency.6 The peptide portion of APL-2 binds to C3, blocking the complement cascade and helping to restore normal complement activity.6
What Is APL-2?
• Starting on day-28 (visit 2), subjects will receive self-administered twice-weekly subcutaneous (SC) doses of 1080 mg of APL-2 in addition to their current dose of eculizumab until day 1.
• Subjects will then be randomized to either group 1 (monotherapy APL-2) or group 2 (monotherapy eculizumab).
• Subjects in group 1 will receive APL-2 (1080 mg twice a week) each treatment week until the end of week 48.
• Subjects in group 2 must continue to receive their pre-screening stable dose of eculizumab until the end of week 20. At week 17, subjects will also receive APL-2 (1080 mg twice a week) until the end of week 48. At week 20, subjects will discontinue their eculizumab treatment and remain solely on APL-2 for the remainder of the treatment period of the study.
Dosing of APL-2
Pegasus Key Endpoints
Primary Efficacy Endpoint
• Week 16 change from baseline in hemoglobin level
Secondary Endpoints
• Week 16 change from baseline in: 0 Reticulocyte count 0 Lactate dehydrogenase (LDH) level 0 FACIT-fatigue scale score • Number of packed red blood cell units transfused from week 4 to week 16 (day 28 to day 112) • Hemoglobin response (1-g/dL increase from baseline at week 16) in the absence of transfusions (yes/no) • Reticulocyte normalization (count being below the upper limit of the normal range) in the absence of transfusions at week 16 (yes/no)
Safety Endpoints
• Incidence and severity of treatment-emergent adverse events (TEAE) • Incidence of thromboembolic events • Changes from baseline in laboratory parameters • Changes from baseline in electrocardiography (ECG) parameters
Current PNH treatment blocks the activation of C5, which is the latter part of the complement system.7 However, roughly 70% of patients remain anemic, and 35% to 50% of the patients are still dependent on transfusions due to the early part of the complement system remaining active.6 The activation of C3, which is upstream of C5 in the complement cascade, can also lead to the destruction of the abnormal red blood cells in people with PNH.8
By targeting C3, which is the central protein in the complement cascade and the point where all 3 complement activation pathways meet, APL-2 has the potential to block activation from any pathway and to prevent both intravascular and extravascular hemolysis.7,9
APL-2 Provides Broad Hematologic Improvement in Patients with PNH
In a Phase I trial evaluating APL-2 in PNH patients who have never taken eculizumab, clinical markers of hemolysis have shown improvement, such as LDH levels below the upper limit of normal, as well as significant hemoglobin correction within 12 weeks.
Mean lactate dehydrogenase (LDH) was reduced from 11.6x ULN to 0.9x ULN by day 28 in 8 eculizumab-naïve patients with PNH that were treated with 270 mg/day of APL-2.
The same patients had an average increase in hemoglobin of 4.3 g/dL, from a baseline average of 7.9 g/dL to an average last measurement of 12.2 g/dL (range, 11.9-12.9 g/dL), within the �rst 12 weeks.
NumberMultiple of ULN
12.0x
11.0x
10.0x
9.0x
8.0x
7.0x
6.0x
5.0x
4.0x
3.0x
2.0x
1.0x
0.0x
x U
LN
14
13
12
11
10
9
8
7
6
5
4
0
0 1 2 3 4 5 6 7 8
* Normal ≥12 g/dL Weeks2 4 6 8 10 12
g/dL
Week
n=811.6x
n=84.8x
n=82.2x
n=81.1x
n=80.9x
n=40.6x
n=40.7x
n=30.6x
Not Taken
LDH levels below upper limit of normal (ULN) in 88% of patients6
Significant hemoglobin correction within 12 weeks6
Pt. 1 Pt. 2 Pt. 3 Pt. 4 Pt. 5 Pt. 6 Pt. 7 Pt. 8
References
©2018 Apellis Pharmaceuticals, Inc. All rights reserved.
To Recommend a Patient for This Trial, Email
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https://pnhstudy.com
1. De Castro C, Rosse W. Paroxysmal nocturnal hemoglobinuria (PNH). National Organization for Rare Disorders Web site. https://rarediseases.org/physician-guide/ paroxysmal-nocturnal-hemoglobinuria-pnh/. Accessed May 15, 2018.
2. Parker CJ. Paroxysmal nocturnal hemoglobinuria. National Organization for Rare Disorders. https://rarediseases.org/rare-diseases/paroxysmal-nocturnal- hemoglobinuria.
3. Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood. 2014;124(18):2804-2811.
4. Hill A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood. 2013;121(25):4985-4996; quiz 5105.
5. Apellis Pharmaceuticals. Study to evaluate the efficacy and safety of APL-2 in patients with PNH. Clinicaltrials.gov Web site. https://www.clinicaltrials.gov/ct2/show/ NCT03500549. Accessed May 24, 2018.
6. Data on file, Apellis Pharmaceuticals.
7. Murphy K, Weaver C. Innate immunity: the first lines of defense. In: Janeway's Immunobiology. 9th ed. London, UK: Garland Science; 2016.
8. Risitano AM, Notaro R, Marando L, et al. Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab. Blood. 2009;113(17):4094-4100.9. Mastellos DC, Ricklin D, Yancopoulou D, et al. Complement in paroxysmal nocturnal hemoglobinuria: exploiting our current knowledge to improve the treatment landscape. Expert Rev Hematol. 2014;7(5):583-598.
