Data demonstrated clinically meaningful increases in haemoglobin levels and control of intravascular haemolysis sustained through 72 weeks
Results build on findings from 12-week primary analysis and 24-week and long-term extension period, supporting sustained efficacy and safety profiles
New, positive, long-term results from the pivotal ALPHA Phase III trial were published in Blood, further demonstrating that Voydeya (danicopan) as add-on to standard of care Ultomiris (ravulizumab) or Soliris (eculizumab) offers sustained disease control for patients with paroxysmal nocturnal haemoglobinuria (PNH) who experience clinically significant extravascular haemolysis (EVH) while maintaining terminal complement control.1
Data from this larger cohort (n=86) showed that improvements in haemoglobin (Hgb) levels, absolute reticulocyte count (ARC) levels, transfusion avoidance and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores were maintained through 72 weeks. Lactate dehydrogenase (LDH) levels remained well-controlled throughout the trial, demonstrating effective control of terminal complement activity and intravascular haemolysis (IVH) with Ultomiris or Soliris.1
PNH is a rare and severe blood disorder characterised by uncontrolled terminal complement activation, resulting in the destruction of red blood cells within blood vessels, known as IVH, and white blood cell and platelet activation that can cause thrombosis (blood clots), resulting in organ damage and potentially premature death.2,3 Immediate, complete and sustained terminal complement inhibition by blocking the C5 protein helps reduce symptoms and complications, resulting in improved survival for patients with PNH.4-7 Approximately 10-20% of people living with PNH who are treated with a C5 inhibitor experience clinically significant EVH, which can result in symptomatic anaemia and may require blood transfusions.8-13
Austin Kulasekararaj, MD, Consultant Haematologist at King's College Hospital, London, and investigator in the ALPHA trial, said: “These long-term results demonstrate the sustained efficacy and safety of Voydeya as an add-on to Ultomiris or Soliris to control clinically significant EVH and enhance PNH disease management in the small subset of patients impacted. This follow-on evidence underscores that Voydeya can provide meaningful and sustained benefits for those patients who experience the manifestations of EVH, while standard-of-care therapy maintains critical control of terminal complement activity and IVH.”
Christophe Hotermans, Senior Vice President, Global Medical Affairs, Alexion, AstraZeneca Rare Disease, said: “These results featured in Blood mark the first long-term data publication for this first-in-class, oral, Factor D inhibitor. These data through 72 weeks reinforce the importance of dual complement pathway inhibition at Factor D and C5 to address the needs of people with PNH who experience clinically significant EVH while, importantly, maintaining effective control of terminal complement activity, which is essential for patients with this rare disease.”
The pivotal, randomised, double-blind, placebo-controlled ALPHA Phase III trial was designed as a superiority study to evaluate the efficacy and safety of Voydeya as an add-on to C5 inhibitor therapy Ultomiris or Soliris in patients with PNH who experience clinically significant EVH. The trial included a 12-week double-blind treatment period (TP1), followed by a 12-week open-label treatment period (TP2) and an optional, two-year, long-term extension (LTE) period in which all patients received Voydeya add-on therapy. During the open-label period, participants receiving placebo plus Ultomiris or Soliris switched to Voydeya plus Ultomiris or Soliris, and participants receiving add-on therapy with Voydeya continued treatment with Voydeya add-on therapy.1
A total of 86 patients were randomised in the study. At the time of study completion, 82 patients completed TP1, 80 patients completed TP2, and 71 and 70 patients completed one year and two years of the LTE, respectively.1
Data from this larger cohort, comprised of all randomised participants at week 12 (TP1 completion), week 24 (TP2 completion) and week 72 (one year of LTE), confirm previously reported results from the prespecified primary efficacy analysis (63 participants) and show that these improvements are maintained long-term. Clinically meaningful improvements in haemoglobin levels observed at 12 weeks [LSM (SEM)i change 2.8 (0.2) g/dL] continued through 24 weeks [LSM (SEM) change 2.9 (0.3) g/dL] and were sustained through 72 weeks among patients treated with Voydeya plus Ultomiris or Soliris. Minimal changes in haemoglobin levels were observed from baseline to week 12 in the placebo arm but improved by week 24 after switching to Voydeya add-on therapy [week 12: LSM (SEM) change 0.5 (0.3) g/dL; week 24: LSM (SEM) change 2.3 (0.3) g/dL].1
Key secondary endpoints included percentage of patients with haemoglobin increase of ≥2 g/dL in the absence of transfusion, percentage of patients achieving transfusion avoidance, change from baseline in FACIT-Fatigue scores and change from baseline in ARC levels.1
At week 12, 54.4% of participants receiving Voydeya plus Ultomiris or Soliris exhibited clinically meaningful increases in haemoglobin (≥2 g/dL) in the absence of transfusion, which were maintained at week 72 (53.7%). Among patients in the placebo group switching to Voydeya plus Ultomiris or Soliris at week 12, clinically meaningful increases were observed at week 24 (29.6%) and week 72 (46.2%).1
In patients treated with Voydeya plus Ultomiris or Soliris, the proportion of patients achieving transfusion avoidance increased from baseline to week 12 (78.9%) and was maintained at week 24 (80.0%), week 48 (81.5%) and week 72 (80.0%). While there was no improvement observed among participants in the placebo arm at week 12 (27.6%), a greater proportion of patients achieved transfusion avoidance at weeks 24 (81.5%), 48 (73.1%) and 72 (79.2%), after transitioning to Voydeya plus Ultomiris or Soliris.1
Clinically meaningful improvements in FACIT-Fatigue scores were observed at week 12 and maintained at week 24 in patients receiving Voydeya plus Ultomiris or Soliris [week 12: LSM (SEM) change 8.1 (0.9); week 24: LSM (SEM) change 6.2 (1.0)]. There were minimal changes exhibited from baseline to 12 weeks among patients receiving placebo plus Ultomiris or Soliris [LSM (SEM) change 2.4 (1.3)], but clinically meaningful improvements were observed at week 24 after switching to Voydeya plus Ultomiris or Soliris [LSM (SEM) change 5.6 (1.9)].1
Improvements in ARC levels were observed from baseline to week 12 [LSM (SEM) change –92.5 (8.2) ×109/L] and maintained at week 24 [LSM (SEM) change –87.9 (7.8) ×109/L] among patients treated with Voydeya plus Ultomiris or Soliris. In the placebo arm, changes in ARC levels from baseline to week 12 were minimal [LSM (SEM) change –0.8 (11.8) ×109/L], but improvements were observed at week 24 after transitioning to Voydeya add-on therapy [LSM (SEM) change –53.6 (11.7) ×109/L].1
Importantly, mean LDH levels remained well controlled (<1.5 × upper limit of normal [ULN]) in both treatment arms from baseline to week 72.1
Results from the ALPHA Phase III trial and LTE showed Voydeya is generally well tolerated, and safety data were consistent with those previously reported for the primary evaluation period with no new safety signals identified. The safety analysis was performed using data from all participants who received at least one dose of Voydeya (84 participants). The most common treatment-emergent adverse events (TEAEs) (≥5%) were COVID-19 (31.0%), pyrexia (26.2%), headache (21.4%), nausea (15.5%) and diarrhoea (14.3%).1
Results from the ALPHA Phase III trial were presented at the European Hematology Association (EHA) 2023 Hybrid Congress and the American Society of Hematology (ASH) 2023 Annual Congress, as well as published in The Lancet Haematology.
Voydeya is approved in Japan, the United States (US), the European Union (EU) and other countries, with additional regulatory reviews ongoing.
i LSM, least square means; SEM, standard error of the mean
Notes
PNH
PNH is a rare, chronic, progressive and potentially life-threatening blood disorder. It is characterised by red blood cell destruction within blood vessels (also known as intravascular haemolysis) and white blood cell and platelet activation, which can result in thrombosis (blood clots).2,3
PNH is caused by an acquired genetic mutation that may happen any time after birth and results in the production of abnormal blood cells that are missing important protective blood cell surface proteins. These missing proteins enable the complement system, which is part of the immune system and is essential to the body’s defence against infection, to ‘attack’ and destroy or activate these abnormal blood cells.2,3 Living with PNH can be debilitating, and signs and symptoms may include blood clots, abdominal pain, difficulty swallowing, erectile dysfunction, shortness of breath, excessive fatigue, anaemia and dark-coloured urine.14
Clinically Significant EVH
EVH, the removal of red blood cells outside of the blood vessels, can sometimes occur in PNH patients who are treated with C5 inhibitors.15,16 Since C5 inhibition enables PNH red blood cells to survive and circulate, EVH may occur when these now surviving PNH red blood cells are marked by proteins in the complement system for removal by the spleen and liver.4,6,13 PNH patients with EVH may continue to experience anaemia, which can have various causes, and may require blood transfusions.15-18 A small subset of people living with PNH who are treated with a C5 inhibitor experience clinically significant EVH, which results in symptomatic anaemia and may require blood transfusions.10-13
ALPHA
ALPHA is a pivotal, global Phase III trial designed as a superiority study to evaluate the efficacy and safety of Voydeya as an add-on to C5 inhibitor therapy Soliris or Ultomiris in patients with PNH who experience clinically significant EVH. In the double-blind, placebo-controlled, multiple-dose trial, patients were enrolled and randomised to receive Voydeya or placebo (2:1) in addition to their ongoing Soliris or Ultomiris therapy for 12 weeks. A prespecified interim analysis was performed once 63 randomised patients had completed 12 weeks of the primary evaluation period or discontinued treatment as of 28 June 2022. At 12 weeks, patients on placebo plus Soliris or Ultomiris were switched to Voydeya plus Soliris or Ultomiris, and patients on Voydeya plus Soliris or Ultomiris remained on this treatment for an additional 12 weeks. Patients who completed both treatment periods (24 weeks) had the option to participate in a two-year long-term extension period and continue to receive Voydeya in addition to Soliris or Ultomiris.8,19
Voydeya
Voydeya (danicopan) is a first-in-class oral Factor D inhibitor. The medication works by selectively inhibiting Factor D, a complement system protein that plays a key role in the amplification of the complement system response. When activated in an uncontrolled manner, the complement cascade over-responds, leading the body to attack its own healthy cells. Voydeya has been granted Breakthrough Therapy designation by the US Food and Drug Administration and PRIority MEdicines (PRIME) status by the European Medicines Agency. Voydeya has also been granted Orphan Drug Designation in the US, EU and Japan for the treatment of PNH.
Voydeya is approved in the US, EU, Japan and other countries as add-on therapy to ravulizumab or eculizumab for the treatment of certain adults with PNH.
Ultomiris
Ultomiris (ravulizumab), the longest-acting C5 complement inhibitor, provides immediate, complete and sustained complement inhibition. The medication works by inhibiting the C5 protein in the terminal complement cascade, a part of the body’s immune system. When activated in an uncontrolled manner, the complement cascade over-responds, leading the body to attack its own healthy cells. Following a loading dose, Ultomiris is administered intravenously every eight weeks in adults, or every four or eight weeks in paediatric patients (based on body weight).
Ultomiris is approved in the US, EU, Japan and other countries for the treatment of certain adults with paroxysmal nocturnal haemoglobinuria (PNH) and for certain children with PNH in the US and EU.
Ultomiris is also approved in the US, EU, Japan and other countries for the treatment of certain adults and children with atypical haemolytic uraemic syndrome (aHUS).
Additionally, Ultomiris is approved in the US, EU, Japan and other countries for the treatment of certain adults with generalised myasthenia gravis (gMG).
Further, Ultomiris is approved in the US, EU, Japan and other countries for the treatment of certain adults with neuromyelitis optica spectrum disorder (NMOSD).
Ultomiris is being assessed as a treatment for additional indications as part of a broad development programme.
Soliris
Soliris (eculizumab) is a first-in-class C5 complement inhibitor. The medication works by inhibiting the C5 protein in the terminal complement cascade, a part of the body’s immune system. When activated in an uncontrolled manner, the terminal complement cascade over-responds, leading the body to attack its own healthy cells. Soliris is administered intravenously every two weeks, following an introductory dosing period.
Soliris is approved in the US, EU, Japan, China and other countries for the treatment of certain children and adults with paroxysmal nocturnal haemoglobinuria (PNH).
Soliris is also approved in the US, EU, Japan, China and other countries for the treatment of certain children and adults with atypical haemolytic uraemic syndrome (aHUS).
Additionally, Soliris is approved in the US, EU, Japan, China and other countries for the treatment of certain adults with generalised myasthenia gravis (gMG), and for certain paediatric patients with gMG in the EU, Japan and other countries.
Further, Soliris is approved in the US, EU, Japan, China and other countries for the treatment of certain adults with neuromyelitis optica spectrum disorder (NMOSD).
Soliris is not indicated for the treatment of patients with Shiga-toxin E. coli-related haemolytic uraemic syndrome.
Alexion
Alexion, AstraZeneca Rare Disease, is focused on serving patients and families affected by rare diseases and devastating conditions through the discovery, development and delivery of life-changing medicines. A pioneering leader in rare disease for more than three decades, Alexion was the first to translate the complex biology of the complement system into transformative medicines, and today it continues to build a diversified pipeline across disease areas with significant unmet need, using an array of innovative modalities. As part of AstraZeneca, Alexion is continually expanding its global geographic footprint to serve more rare disease patients around the world. It is headquartered in Boston, US.
AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca’s innovative medicines are sold in more than 125 countries and used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on social media @AstraZeneca.
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Veeva ID: GL/VOY-PNH/0009 V2 01/2025
Date of Preparation: January 2025