REG - AstraZeneca PLC - Danicopan Phase III trial met primary endpoint

AstraZenecaAnnouncement

16/09/2022 07:16

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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 (N~63) 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 (https://www.astrazeneca.com/)  and follow the
Company on Twitter @AstraZeneca (https://twitter.com/AstraZeneca) .

 

Contacts
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(https://www.astrazeneca.com/investor-relations.html#Contacts) . For Media
contacts, click here (https://www.astrazeneca.com/media-centre/contacts.html)
.

 

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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