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Data demonstrated effective control of intravascular and extravascular haemolysis through 48 weeks. Results showed increase in mean haemoglobin levels were maintained through 48 weeks.

Positive results from the 24-week and long-term extension (LTE) period of the pivotal ALPHA Phase III trial showed danicopan as add-on to standard of care C5 inhibitor therapy Ultomiris (ravulizumab) or Soliris (eculizumab) continued to demonstrate clinical benefit for patients with paroxysmal nocturnal haemoglobinuria (PNH) who experience clinically significant extravascular haemolysis (EVH).¹

Results from the trial were presented today at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California. Danicopan is an investigational, first-in-class, oral, Factor D inhibitor.

Data showed that improvements in mean haemoglobin levels and absolute reticulocyte count (ARC) levels, which were demonstrated at 12 weeks, were maintained through 48 weeks.¹

PNH is a rare and severe blood disorder characterised by the destruction of red blood cells within blood vessels, known as intravascular haemolysis (IVH), and white blood cell and platelet activation that can cause thrombosis (blood clots) and result in organ damage and potentially premature death.^2-4 Immediate, complete and sustained terminal complement inhibition by blocking the C5 protein with Ultomiris or Soliris 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 continued symptoms of anaemia and require blood transfusions.^2,8-12

Austin Kulasekararaj, MD, Consultant Haematologist at King's College Hospital, London and investigator in the ALPHA trial, said: “These new data further demonstrate the potential of danicopan as add-on to Ultomiris or Soliris to address the needs of the small subset of patients with PNH who experience clinically significant EVH. Expanding on positive 12-week results, the findings demonstrate sustained improvements in haemoglobin levels for up to 48 weeks, while also maintaining disease control, as measured by lactate dehydrogenase levels.”

Gianluca Pirozzi, Senior Vice President, Head of Development, Regulatory and Safety, Alexion, said: “Unlike IVH, EVH is not life-threatening, but its manifestations can be burdensome for people living with this condition, which is why we continue to explore the potential of the complement system to advance patient care. The pivotal ALPHA results suggest that dual complement pathway inhibition at Factor D and C5 may be an optimal treatment approach for the 10-20% of patients with PNH who experience clinically significant EVH. Importantly, C5 inhibition maintains effective IVH control, which is critical for patients, and the addition of Factor D inhibition addresses signs and symptoms of EVH.”

The pivotal ALPHA Phase III trial is designed as a superiority study to evaluate the efficacy and safety of danicopan as an add-on to C5 inhibitor therapy Ultomiris or Soliris in patients with PNH who experience clinically significant EVH. A total of 86 patients were randomised. The prespecified interim analysis (primary analysis) occurred after 63 participants either completed or discontinued from the primary treatment period of 12 weeks. Following the 12-week randomised control period, patients were eligible to enrol in an open-label treatment period for an additional 12 weeks. During the open-label period, participants receiving placebo plus Ultomiris or Soliris switched to danicopan plus Ultomiris or Soliris (placebo-danicopan), and participants receiving add-on therapy with danicopan continued treatment with danicopan add-on therapy (danicopan-danicopan). The open-label treatment period was followed by the option to join a two-year LTE period during which all participants received danicopan add-on therapy. At the time of data cut-off on 20 September 2022, 60 of the 63 patients who were included in the primary analysis had reached 24 weeks and entered the LTE.¹

Data showed that the significant improvements in haemoglobin levels observed at 12 weeks [LSM (SEM) change 2.94 (0.21) g/dL] continued at 24 weeks [LSM (SEM) change 3.17 (0.30) g/dL] among patients treated with danicopan plus Ultomiris or Soliris and were sustained through 48 weeks.¹

Secondary endpoints measured at 24 weeks include change from baseline in haemoglobin, ARC, and lactate dehydrogenase (LDH) levels; the percentage of patients with haemoglobin increase of ≥2 g/dL in the absence of transfusion; and the percentage of patients with transfusion avoidance.¹

All key secondary endpoints met superiority in favour of danicopan plus Ultomiris or Soliris compared to placebo plus Ultomiris or Soliris at 12 weeks, and data showed benefits were maintained at 24 weeks in the danicopan-danicopan arm.¹

Further, all key secondary endpoints showed meaningful improvement at 24 weeks in patients who switched from placebo to add-on treatment with danicopan at 12 weeks, including ARC levels and percentage of patients with transfusion avoidance, two indicators of potential EVH.¹

Additionally, mean (SD) LDH levels were maintained from baseline through 48 weeks in both treatment arms, demonstrating effective control of terminal complement activity and IVH with Ultomiris or Soliris.¹

Summary of efficacy resultsⁱ
Haemoglobin and ARC levels improved with danicopan at 12 weeks and were maintained through 48 weeks




 

 i. LDH, lactate dehydrogenase; ARC, absolute reticulocyte count; LSM, least squares mean; SEM, standard error of the mean; ULN, upper limit of normal.

Results from the ALPHA Phase III trial and LTE showed danicopan is generally well tolerated, and no new safety concerns were identified. The safety analysis was performed using data from all participants who took at least one dose of danicopan (n=80). The most common treatment-emergent adverse events (TEAEs) (≥10%) were COVID-19 (21.3%), diarrhoea (15%), headache (15%), pyrexia (13.8%), nausea (12.5%) and fatigue (10%).¹

Additionally, an analysis of patient-reported outcomes from the ALPHA Phase III trial at 24 weeks was also presented at ASH, suggesting danicopan plus Ultomiris or Soliris has the potential to improve quality of life compared to C5 inhibitor therapy alone for the 10-20% of patients with PNH who experience clinically significant EVH.¹³ Findings showed clinically relevant patient-reported outcomes were observed in patients treated with danicopan as add-on to Ultomiris or Soliris during the first 12 weeks of treatment, compared to placebo plus C5 inhibition. Additionally, data showed improvements in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Scale (EORTC-QLQ-C30) scores were maintained during the open-label period to 24 weeks in the danicopan-danicopan arm and improved at 24 weeks in the placebo-danicopan arm.¹³

ALPHA Phase III trial results from the primary prespecified interim analysis at 12 weeks were presented at the European Hematology Association (EHA) 2023 Hybrid Congress and published in The Lancet Haematology.

Regulatory submissions for danicopan are currently under review with multiple global health authorities.

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).^2-4

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 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.^2,10,14

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.^2,4,6 Patients with PNH 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 can result in continued symptoms of anaemia and require blood transfusions.^2,10-12

ALPHA
ALPHA is a pivotal, global Phase III trial designed as a superiority study to evaluate the efficacy and safety of danicopan as an add-on to C5 inhibitor therapy eculizumab or ravulizumab 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 danicopan or placebo (2:1) in addition to their ongoing eculizumab or ravulizumab 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 a C5 inhibitor were switched to danicopan plus eculizumab or ravulizumab, and patients on danicopan plus eculizumab or ravulizumab remained on 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 danicopan in addition to eculizumab or ravulizumab. The open-label period of the study is still ongoing.^5,19

Danicopan
Danicopan is an investigational oral medicine in development as an add-on to C5 inhibitor therapy eculizumab or ravulizumab for patients with PNH who experience clinically significant EVH. It is designed to selectively inhibit Factor D, a complement system protein that plays a key role in the amplification of the complement system response. Danicopan has been granted Breakthrough Therapy designation by the US Food and Drug Administration and PRIority MEdicines (PRIME) status by the European Medicines Agency. Danicopan has also been granted Orphan Drug Designation in the US, EU and Japan for the treatment of PNH. Alexion is also evaluating danicopan as a potential monotherapy for geographic atrophy in a Phase II clinical trial.

Ultomiris
Ultomiris (ravulizumab), the first and only long-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. Ultomiris is administered intravenously every eight weeks in adult patients, following a loading dose.

Ultomiris is approved in the US, EU and Japan for the treatment of certain adults with generalised myasthenia gravis (gMG).

Ultomiris is also approved in the US, EU and Japan for the treatment of certain adults with PNH and for certain children with PNH in the US and EU.

Additionally, Ultomiris is approved in the US, EU and Japan for certain adults and children with atypical haemolytic uraemic syndrome to inhibit complement-mediated thrombotic microangiopathy (aHUS).

Further, Ultomiris is approved in the EU and Japan for the treatment of certain adults with neuromyelitis optica spectrum disorder (NMOSD).

As part of a broad development programme, Ultomiris is being assessed for the treatment of additional haematology and neurology indications.

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 and China for the treatment of patients with PNH and aHUS. 

Additionally, Soliris is approved in Japan and the EU for the treatment of certain adult and paediatric patients with gMG, and in the US and China for certain adults with gMG.  

Further, Soliris is approved in the US, EU, Japan and China for the treatment of certain adults with 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 the group within AstraZeneca focused on rare diseases, created following the 2021 acquisition of Alexion Pharmaceuticals, Inc. As a leader in rare diseases for more than 30 years, Alexion is focused on serving patients and families affected by rare diseases and devastating conditions through the discovery, development and commercialisation of life-changing medicines. Alexion focuses its research efforts on novel molecules and targets in the complement cascade and its development efforts on haematology, nephrology, neurology, metabolic disorders, cardiology and ophthalmology. Headquartered in Boston, Massachusetts, Alexion has offices around the globe and serves patients in more than 50 countries. For more information, please visit www.alexion.com.

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 operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on social media @AstraZeneca. 

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References 

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