26 February 2024
Voydeya
recommended for
approval in the EU by CHMP as add-on treatment to ravulizumab or
eculizumab for adults with PNH who have residual haemolytic
anaemia
Recommendation of first-in-class, oral, Factor D inhibitor
based on ALPHA Phase III trial results
Voydeya (danicopan)
has been recommended for marketing authorisation in the European
Union (EU) as an add-on to ravulizumab or eculizumab for the
treatment of adult patients with paroxysmal nocturnal
haemoglobinuria (PNH) who have residual haemolytic anaemia.
Voydeya is a
first-in-class, oral, Factor D inhibitor developed as an add-on to
standard-of-care Ultomiris
(ravulizumab) or Soliris
(eculizumab) to address the needs of the approximately 10-20% of
patients with PNH who experience clinically significant
extravascular haemolysis (EVH) while treated with a C5
inhibitor.1,2
The Committee for Medicinal Products for Human
Use (CHMP) of the European Medicines Agency (EMA)
based its positive opinion on results from the pivotal
ALPHA Phase III trial. Results from the 12-week
primary evaluation period of the trial were published in
The Lancet Haematology.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.3-5 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.5-8 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.1-3,9-11
Professor Hubert Schrezenmeier, MD, Medical
Director, Institute of Transfusion Medicine at The University of
Ulm, said: "C5 inhibition with Ultomiris or Soliris is the standard-of-care in
PNH, proven to control IVH and reduce life-threatening thrombotic
events, yet a small portion of patients may experience clinically
significant EVH. In the ALPHA trial, Voydeya as an add-on to Soliris or Ultomiris increased haemoglobin levels
and reduced fatigue, anaemia and transfusion dependence. If
approved, Voydeya may
optimise care for people impacted by this burdensome condition
while allowing patients to maintain disease control with an
established C5 inhibitor."
Marc Dunoyer, Chief Executive Officer, Alexion,
said: "Today's positive CHMP recommendation recognises the promise
of Voydeya as an add-on to
standard-of-care to address signs and symptoms of clinically
significant EVH for this small subset of patients. As we saw in the
pivotal ALPHA Phase III trial, dual complement pathway inhibition
at Factor D and C5 may be an optimal treatment approach for these
patients."
The ALPHA Phase III trial evaluated the
efficacy and safety of Voydeya as an add-on to
Ultomiris or Soliris in patients with PNH who
experienced clinically significant EVH. Results showed that
Voydeya met the primary
endpoint of change in haemoglobin from baseline to week 12 and all
key secondary endpoints, including transfusion avoidance and change
in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue)
score.1
Results from the ALPHA Phase III trial showed
Voydeya was generally well
tolerated, and no new safety concerns were identified. In the
trial, the most common treatment-emergent adverse events were
headache, nausea, arthralgia and
diarrhoea.1
Voydeya has been
granted Breakthrough Therapy designation by the US Food and Drug
Administration and PRIority MEdicines (PRIME) status by the
EMA. Voydeya has also been
granted Orphan Drug Designation in the US, EU and Japan for the
treatment of PNH. Voydeya
was recently
approved in Japan, and regulatory submissions
for Voydeya are
currently under review in additional countries.
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).3-5
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.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.3,9,12
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.13,14 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.3,5,7 PNH patients with EVH may continue to
experience anaemia, which can have various causes, and may require
blood transfusions.13-16 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.3,9-11
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 a C5 inhibitor were switched to
Voydeya plus
Soliris
or Ultomiris, and
patients on Voydeya plus
Soliris
or Ultomiris
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 Voydeya in
addition to Soliris
or Ultomiris. The
open-label period of the study is
ongoing.1,17
Voydeya (danicopan)
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 Japan for certain adults with PNH in combination with C5
inhibitor therapy.
Alexion is also evaluating Voydeya 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
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References
1. Lee JW, et al.
Addition of danicopan to ravulizumab or eculizumab in patients with
paroxysmal nocturnal haemoglobinuria and clinically significant
extravascular haemolysis (ALPHA): a double-blind, randomised, phase
3 trial. The Lancet
Haematology. 2023;10(12):E955-E965.
2. Kulasekararaj AG, 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 (EHA) Hybrid
Congress. 8-11 June 2023; Frankfurt, Germany. Abs
PB2056.
3. Brodsky RA.
Paroxysmal nocturnal hemoglobinuria. Blood.
2014;124(18):2804-2811.
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Significant hemolysis is not required for thrombosis in paroxysmal
nocturnal hemoglobinuria. Haematologica.
2019;104(3):E94-E96.
5. Hillmen P, et al. The
Complement inhibitor eculizumab in paroxysmal nocturnal
hemoglobinuria. N Engl J
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7. Kulasekararaj AG, et
al. Long-term safety and efficacy of ravulizumab in patients with
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pivotal phase 3 studies. Eur J
Haematol. 2022;109(3):205-214.
8. Kulasekararaj AG, et
al. P812: Long-term complement inhibition and survival outcomes in
Patients with paroxysmal nocturnal hemoglobinuria: an interim
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2022;6(Suppl):706-707.
9. Kulasekararaj AG, et
al. Ravulizumab (ALXN1210) vs eculizumab in
C5-inhibitor-experienced adult patients with PNH: the 302 study.
Blood.
2019;133(6):540-549.
10. Lee JW, et al. Ravulizumab
(ALXN1210) vs eculizumab in adult patients with PNH naive to
complement inhibitors: the 301 study. Blood. 2019;133(6):530-539.
11. Röth A, 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.
12. Hillmen P, et al. Effect
of the complement inhibitor eculizumab on thromboembolism on
patients with paroxysmal nocturnal
hemoglobinuria. Blood.
2007;110(12):4123-4128.
13. Brodsky RA. A
complementary new drug for PNH. Blood.
2020;135(12):884-885.
14. Risitano AM, et al.
Anti-complement treatment for paroxysmal nocturnal hemoglobinuria:
time for proximal complement inhibition? A position paper from the
SAAWP of the EBMT. Front
Immunol. 2019;10:1157.
15. Berentsen S, et al. Novel
insights into the treatment of complement-mediated hemolytic
anemias. Ther Adv Hematol.
2019;10:2040620719873321.
16. Kulasekararaj AG, et al.
Monitoring of patients with paroxysmal nocturnal hemoglobinuria on
a complement inhibitor. Am J
Hematol. 2021;96(7):E232-E235.
17. 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 February 2024.
Adrian Kemp
Company Secretary
AstraZeneca PLC