2 April 2024
Voydeya
approved in the
US as add-on therapy to ravulizumab or eculizumab for treatment
of extravascular haemolysis in adults with the rare disease
PNH
Approval
of first-in-class, oral, Factor D inhibitor based on results from
pivotal ALPHA Phase III trial
Voydeya (danicopan)
has been approved in the US as add-on therapy to ravulizumab or
eculizumab for the treatment of extravascular haemolysis (EVH) in
adults with paroxysmal nocturnal haemoglobinuria (PNH).1
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 EVH
while treated with a C5 inhibitor.2,3
The approval by the US Food and Drug
Administration (FDA) was based on positive 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.2
Bart Scott, MD, Professor, Division
of Hematology and Oncology at the University of Washington Medical
Center, and Professor, Clinical Research Division at Fred
Hutchinson Cancer Center, said: "The approval of Voydeya offers this small subset of
PNH patients an add-on therapy designed to address EVH, while
maintaining disease control with Ultomiris or Soliris. Terminal
complement inhibition with Ultomiris can address the
life-threatening complications of PNH, building on the efficacy and
safety of Soliris
established over nearly 20 years."
Marc Dunoyer, Chief Executive Officer, Alexion,
said: "The approval of first-in-class, Factor D
inhibitor Voydeya marks an
important advancement in the treatment of PNH and builds on our
leadership and commitment to bring forward innovation in complement
science. As the ALPHA trial suggests, dual complement pathway
inhibition at Factor D and C5 may be an optimal treatment approach
for this subset of patients with EVH, enabling them to continue
with proven standard-of-care therapy."
The ALPHA Phase III trial evaluated the
efficacy and safety of Voydeya
as 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.2
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.2
Voydeya has been
granted Breakthrough Therapy designation by the US FDA and PRIority
MEdicines (PRIME) status by the European Medicines Agency.
Voydeya has also been granted Orphan
Drug Designation in the US, European Union (EU) and Japan for the
treatment of PNH. Voydeya
has been
approved in Japan and
recommended for approval in the EU.
Regulatory reviews are ongoing 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).4-6
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.4 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.4,7,8
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.9,10 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.4,6,11 PNH patients with EVH may continue to
experience anaemia, which can have various causes, and may require
blood transfusions.9,10,12,13 A small subset of people
living with PNH who are treated with a C5 inhibitor experience
clinically significant EVH, which results in continued symptoms of
anaemia and may require blood
transfusions.4,7,14,15
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 June 28, 2022. At
12 weeks, patients on placebo plus Soliris or Ultomiris were switched to
Voydeya plus Soliris or Ultomiris, and patients on
Voydeya plus Soliris or Ultomiris remained on this 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.2,16
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 the US as add-on therapy to ravulizumab or eculizumab for the
treatment of EVH in adults with PNH.
Voydeya is also
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 70 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
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References
1. Voydeya (danicopan) US prescribing
information; March 2024.
2. 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.
3. 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.
4. Brodsky RA.
Paroxysmal nocturnal hemoglobinuria. Blood.
2014;124(18):2804-2811.
5. Griffin M, et al.
Significant hemolysis is not required for thrombosis in paroxysmal
nocturnal hemoglobinuria. Haematologica.
2019;104(3):E94-E96.
6. Hillmen P, et al. The
complement inhibitor eculizumab in paroxysmal nocturnal
hemoglobinuria. N Engl J
Med. 2006;355(12):1233-1243.
7. 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.
8. Hillmen P, et al.
Effect of the complement inhibitor eculizumab on thromboembolism on
patients with paroxysmal nocturnal
hemoglobinuria. Blood.
2007;110(12):4123-4128.
9. Brodsky RA. A
complementary new drug for PNH. Blood.
2020;135(12):884-885.
10. 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.
11. Kulasekararaj AG, et al.
Long-term safety and efficacy of ravulizumab in patients with
paroxysmal nocturnal hemoglobinuria: 2-year results from two
pivotal phase 3 studies. Eur J
Haematol. 2022;109(3):205-214.
12. Berentsen S, et al. Novel
insights into the treatment of complement-mediated hemolytic
anemias. Ther Adv Hematol.
2019;10:2040620719873321.
13. Kulasekararaj AG, et al.
Monitoring of patients with paroxysmal nocturnal hemoglobinuria on
a complement inhibitor. Am J
Hematol. 2021;96(7):E232-E235.
14. 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.
15. 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.
16. 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 March 2024.
Adrian Kemp
Company Secretary
AstraZeneca PLC