Danicopan as add-on to Ultomiris or Soliris improved haemoglobin levels and maintained disease control in patients with PNH experiencing signs of clinically significant extravascular haemolysis

Results from ALPHA Phase III trial demonstrated statistically significant increase compared to placebo in mean haemoglobin from baseline to week 12. All key secondary endpoints met statistical superiority, showing danicopan reduced fatigue and anaemia as well as the need for transfusions.

Positive results from the pivotal Phase III ALPHA trial showed that investigational, first-in-class oral Factor D inhibitor danicopan as add-on to standard of care C5 inhibitor therapy Ultomiris (ravulizumab) or Soliris (eculizumab) demonstrated a statistically significant and clinically meaningful increase in haemoglobin levels and maintained disease control in patients with paroxysmal nocturnal haemoglobinuria (PNH) who experience clinically significant extravascular haemolysis (EVH), compared to placebo plus established C5 inhibitor therapy.1

The data were presented today at the European Hematology Association (EHA) Annual Meeting in Frankfurt, Germany.

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 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.1,5,6

Professor Jong Wook Lee, MD, PhD, Department of Haematology at Seoul St. Mary’s Hospital of The Catholic University of Korea, and investigator in the ALPHA trial, said: “While EVH is not life-threatening, its manifestations can be burdensome for patients. The ALPHA trial demonstrated that adding danicopan to standard of care with eculizumab or ravulizumab significantly improved fatigue and anaemia and reduced transfusion dependence, while still allowing for sustained control of IVH with terminal complement inhibition addressing the thrombotic risks associated with PNH. These results suggest danicopan has the potential to be an important option for the small subset of patients with PNH who experience clinically significant EVH while being treated with eculizumab or ravulizumab.”

Gianluca Pirozzi, Senior Vice President, Head of Development, Regulatory and Safety, Alexion, said: “As a leader in PNH for decades, Alexion has transformed the treatment landscape by developing the first approved medicine for this rare disease and establishing C5 complement inhibition as standard of care. These promising results presented at the EHA Annual Meeting underscore the potential for targeted Factor D inhibition with danicopan as an add-on to Ultomiris or Soliris to address clinically significant EVH while allowing patients to maintain disease control with established C5 complement inhibitors.”

At the prespecified interim analysis for the ALPHA trial – occurring after 63 study participants either completed or discontinued from the primary treatment period of 12 weeks – danicopan met the primary efficacy endpoint. In patients managing PNH with Ultomiris or Soliris, add-on treatment with danicopan was superior to placebo plus Ultomiris or Soliris based on change in haemoglobin from baseline to week 12, reported as least squares mean change from baseline and standard error of the mean (2.94 [0.211] g/dL vs 0.50 [0.313] g/dL; p<0.0001). Further, significant improvements in haemoglobin were observed with danicopan by week 2 and maintained through week 12.1

All key secondary endpoints also met statistical superiority in favour of danicopan plus Ultomiris or Soliris, compared to placebo plus C5 inhibition. Results showed significantly more patients treated with danicopan (59.5%) versus placebo (0%) experienced an improvement in haemoglobin of ≥2 g/dL at week 12 in the absence of transfusion (difference in danicopan-placebo: 46.9, 95% CI: 29.2–64.7, p<0.0001).1

Additionally, significantly more patients treated with danicopan avoided transfusion (remaining transfusion-free and not requiring a transfusion as per protocol) through week 12, versus the comparator arm. Improvements in fatigue, as measured by Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-Fatigue) score, and absolute reticulocyte count, another indicator of clinically significant EVH, were also shown.1

Further, change from baseline in lactate dehydrogenase (LDH) at Week 12 was -23.49 [8.29] U/L in the danicopan plus Ultomiris or Soliris arm and -2.92 [11.91] U/L in the placebo arm (p=0.1569), demonstrating effective control of IVH was maintained with C5 inhibition in both arms.

Summary of efficacy resultsi,ii

Danicopan add-on treatment to Soliris or Ultomiris resulted in a statistically significant increase in haemoglobin from baseline to week 12 versus placebo

1. Results analysed comparing danicopan plus Ultomiris or Soliris to placebo plus Ultomiris or Soliris from the Phase III ALPHA trial.
2. ARC, absolute reticulocyte count; D, danicopan; FACIT-Fatigue, Functional Assessment of Chronic Illness Therapy-Fatigue scale (version 4.0); Hgb, haemoglobin; LSM, least squares mean; P, placebo; SEM, standard error of the mean.

†Difference in rates and corresponding 95% CI values were calculated using Miettinen and Nurminen method adjusting for stratification factors.

‡Defined as patients who remain transfusion-free and do not require a transfusion per protocol-specified guidelines.

Results from this Phase III trial showed danicopan is generally well tolerated, and no new safety concerns were identified. The safety analysis set included 49 and 24 participants in the danicopan and placebo arms, respectively. No treatment-emergent adverse events (TEAEs) were Grade 4 or 5. The most common TEAEs were headache (10.2%), nausea (8.2%), arthralgia (8.2%) and diarrhoea (8.2%) in the treatment arm. There were no reported deaths, meningococcal infections or discontinuations due to haemolysis.1

Regulatory submissions for danicopan for adults with PNH experiencing clinically significant EVH 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.2,7,8

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.5,9 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.2,4,5 Patients with PNH with EVH may continue to experience anaemia, which can have various causes, and may require blood transfusions.5,9-11 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.2,8,12,13

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 June 28, 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.1,14

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.

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.

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 Twitter @AstraZeneca.

Contacts
For details on how to contact the Investor Relations Team, please click here. For Media contacts, click here.

References

1. Lee JW, Griffin M, Kim, J, et. al. Danicopan, a First-in-Class Oral Complement Factor D Inhibitor, as Add-On Treatment to Ravulizumab or Eculizumab Improves Hemoglobin Response Versus Placebo in Patients With Paroxysmal Nocturnal Hemoglobinuria and Clinically Significant Extravascular Hemolysis. Presented at: European Hematology Association. Poster #P771.   
2. Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood. 2014;124(18):2804-2811.
3. Griffin M, Hillmen P, Munir T, et al. Significant hemolysis is not required for thrombosis in paroxysmal nocturnal hemoglobinuria. Haematologica. 2019;104(3):e94-e96.
4. Hillmen P, et al. The Complement Inhibitor Eculizumab in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med. 2006;355(12):1233-43.
5. Brodsky RA. A complementary new drug for PNH. Blood. 2020;135(12):884–885. 
6. Kulasekararaj A, Mellow J, Earl L, et al. Prevalence of clinically significant extravascular hemolysis in stable C5 inhibitor-treated patients with PNH and its association with disease control, quality of life and treatment satisfaction. Presented at: European Hematology Association. Abs #PB2056.
7. Hillmen P, et al. Effect of the complement inhibitor eculizumab on thromboembolism on patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007;110(12):4123-4128.  
8. Kulasekararaj AG, Hill A, Rottinghaus ST, et al. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood. 2019;133(6):540–549. 
9. Risitano AM, Marotta S, Ricci P, et al. Anti-complement treatment for paroxysmal nocturnal hemoglobinuria: time for proximal complement inhibition? A position paper from the SAAWP of the EBMT. Frontiers in Immunology. 2019; Jun 14;10:1157.
10. Berentsen S, Hill A, Hill QA, Tvedt TH, Michel M. Novel insights into the treatment of complement-mediated hemolytic anemias. Therapeutic advances in hematology. 2019 Sep;10:2040620719873321.
11. Kulasekararaj AG, Brodsky RA, Hill A. Monitoring of patients with paroxysmal nocturnal hemoglobinuria on a complement inhibitor. American journal of hematology. 2021 Jul;96(7):E232-5.
12. Röth A, Risitano A, Jang JH, et al. Transfusion requirements in adult patients with paroxysmal nocturnal hemoglobinuria naive to complement inhibitors receiving ravulizumab and eculizumab: results from a phase 3 non-inferiority study [abstract]. ECTH 2019. Glasgow, UK ed. Glasgow, UK2019.
13. Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, et al. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood. 2019;133(6):530-539.
14. ClinicalTrials.gov. Danicopan as Add-on Therapy to a C5 Inhibitor in Paroxysmal Nocturnal Hemoglobinuria (PNH) Participants Who Have Clinically Evident Extravascular Hemolysis (EVH)(ALPHA). NCT Identifier: NCT04469465. Available here. Accessed April 2023.