TIDMAZN
RNS Number : 7314Z
AstraZeneca PLC
16 September 2022
16 September 2022 07:10 BST
Danicopan (ALXN2040) add-on to Ultomiris or Soliris met primary
endpoint in ALPHA Phase III trial for patients with paroxysmal
nocturnal haemoglobinuria who experience clinically significant
extravascular haemolysis
Interim results demonstrate statistically significant
improvement compared to placebo in haemoglobin levels from baseline
to week 12
A prespecified interim analysis of the ALPHA Phase III trial
evaluating danicopan (ALXN2040), an investigational, oral factor D
inhibitor, as an add-on to C5 inhibitor therapy Ultomiris
(ravulizumab) or Soliris (eculizumab) showed positive high-level
results in patients with paroxysmal nocturnal haemoglobinuria (PNH)
who experience clinically significant extravascular haemolysis
(EVH).
The trial met its primary endpoint of change in haemoglobin from
baseline at 12 weeks and key secondary endpoints, including
transfusion avoidance and change in Functional Assessment of
Chronic Illness Therapy (FACIT) Fatigue score. Danicopan plus
Ultomiris or Soliris demonstrated superiority compared to placebo
plus Ultomiris or Soliris for this specific patient population,
with statistically significant and clinically meaningful
improvements in haemoglobin levels, transfusion avoidance and FACIT
Fatigue scores from baseline.
PNH is a rare and severe blood disorder characterised by the
destruction of red blood cells, 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.(1-3)
Marc Dunoyer, Chief Executive Officer, Alexion, said : "Alexion
has relentlessly innovated for the PNH community, pioneering with
Soliris, the first treatment for PNH, and establishing Ultomiris as
a standard of care. We are proud of our continued innovation to
advance new ways of targeting the complement cascade to help
address the needs of patients living with this debilitating
disease. These are the first positive Phase III results for an oral
factor D inhibitor and demonstrate the potential for danicopan
add-on therapy to improve signs and symptoms and reduce the need
for transfusions for the limited proportion of people living with
PNH who experience clinically significant EVH."
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: "C5 inhibitors are a proven
treatment option for patients living with PNH, yet a small
percentage may continue to experience anaemia and burden of
transfusion due to clinically significant EVH, however it is not
life-threatening. These data show that danicopan has the potential
to resolve clinically significant EVH while allowing patients to
remain on standard of care treatment with Ultomiris or
Soliris."
Danicopan was generally well tolerated and there were no
clinically meaningful differences in safety results observed
between the danicopan plus C5 inhibitor group and control
group.
Alexion, AstraZeneca Rare Disease, will present these data at a
forthcoming medical meeting and intends to proceed with regulatory
submissions in the coming months.
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) .(1-3)
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.(1) 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.(1, 4, 5)
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. 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.(1,3, 6) PNH patients with EVH may
continue to experience anaemia, which can have various causes, and
may require blood transfusions.(6) 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.
ALPHA
ALPHA is a pivotal, global Phase III trial designed to evaluate
the efficacy of danicopan as an add-on to C5 inhibitor therapy
Ultomiris (ravulizumab) or Soliris (eculizumab) 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 C5 inhibitor therapy for 12 weeks. Prespecified
interim analysis for efficacy was planned once 75 percent (N63) of
participants completed 12 weeks of treatment period 1. At 12 weeks,
patients on placebo plus C5 inhibitor are switched to danicopan
plus a C5 inhibitor and patients on danicopan plus a C5 inhibitor
remain on treatment for an additional 12 weeks.
Patients who complete both treatment periods (24 weeks) have the
option to participate in a long-term extension period and continue
to receive danicopan in addition to C5 inhibitor therapy.
Danicopan (ALXN2040)
Danicopan is an investigational oral medicine in development as
an add-on to C5 inhibitor therapy Ultomiris (ravulizumab) or
Soliris (eculizumab) 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 and orphan designation in the EU 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 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. Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood. 2014;124(18):2804-2811.
2. 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.
3. Hillmen P., et al. The Complement Inhibitor Eculizumab in
Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med.
2006;355(12):1233-43.
4. Hillmen, P., et al. Effect of the complement inhibitor
eculizumab on thromboembolism on patients with paroxysmal nocturnal
hemoglobinuria. Blood. 2007;110(12):4123-4128.
5. Kulasekararaj, A. G., et al. Ravulizumab (ALXN1210) vs
eculizumab in C5-inhibitor-experienced adult patients with PNH: the
302 study. Blood. 2019;133(6):540-549.
6. Brodsky RA. A complementary new drug for PNH. Blood. 2020;135(12):884-885.
Adrian Kemp
Company Secretary
AstraZeneca PLC
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