BOSTON--(BUSINESS WIRE)--Alexion Pharmaceuticals, Inc. (NASDAQ:ALXN) today announced that the Phase 3 study of ULTOMIRIS™ (ravulizumab-cwvz), the company’s long-acting C5 complement inhibitor, met its primary objective in complement inhibitor-naïve patients with atypical hemolytic uremic syndrome (aHUS). In the initial 26 week treatment period, 53.6 percent of patients (95% CI [39.6%, 67.5%]) demonstrated complete thrombotic microangiopathy (TMA) response. ULTOMIRIS provided immediate and complete inhibition of the complement C5 protein that was sustained over the entire eight-week dosing interval.
The primary endpoint of complete TMA response was defined by hematologic normalization and improved kidney function. Treatment with ULTOMIRIS resulted in:
- reduced thrombocytopenia, as measured by normalization in platelet count, in 83.9 percent of patients (95% CI [73.4%, 94.4%]),
- reduced hemolysis (the destruction of red blood cells), as measured by normalization in lactate dehydrogenase (LDH) level, in 76.8 percent of patients (95% CI [64.8%, 88.7%]) and
- improved kidney function, as measured by ≥ 25 percent improvement in serum creatinine level from baseline, in 58.9 percent of patients (95% CI [45.2%, 72.7%]). For patients on dialysis at enrollment, baseline was established after they had come off dialysis.
To achieve complete TMA response, patients had to meet all three criteria at the same time at least once. In addition, each of the criteria had to be met for at least 28 consecutive days.
The safety profile was consistent with that observed in two large Phase 3 studies in patients with paroxysmal nocturnal hemoglobinuria (PNH).1,2
“We are very pleased with these data, which demonstrate that ULTOMIRIS can provide clinically meaningful benefits to patients with aHUS,” said John Orloff, M.D., Executive Vice President and Head of Research & Development at Alexion. “The results met the high bar of complete TMA response, defined by hematologic normalization and improved kidney function, and provide confidence that ULTOMIRIS has the potential to become the new standard of care for patients with aHUS. We are preparing regulatory submissions for ULTOMIRIS in aHUS in the U.S., European Union and Japan as quickly as possible.”
Atypical HUS is a severe and chronic ultra-rare disease that can cause progressive damage to vital organs, predominantly the kidneys, leading to kidney failure and premature death. The disease is characterized by TMA (inflammation and blood clotting in small blood vessels throughout the body) that is mediated by chronic, uncontrolled activation of the complement system.3,4,5,6,7
“If left untreated, many patients progress to end-stage renal disease or die during the first clinical manifestations of aHUS or in the first year following these manifestations despite supportive care,” said Spero Cataland, M.D., hematologist at Ohio State University Wexner Medical Center and an investigator in the study. “I am very excited about these data and the potential for an effective new treatment option that can provide hematologic normalization and improved kidney function, including the potential to stop dialysis, when administered every eight weeks.”
The most frequently observed adverse events in this study were headache, diarrhea and vomiting. The most frequently observed serious adverse events were pneumonia and hypertension. In these critically ill patients, there were four patient deaths, none of which were considered related to treatment with ULTOMIRIS. No case of meningococcal infection was observed. Meningococcal infections are a known risk with terminal complement inhibition. To minimize the risk for patients, specific risk-mitigation plans have been established for ULTOMIRIS, based on plans that have been in place for more than 11 years for SOLIRIS® (eculizumab).
Detailed results from this Phase 3 study will be presented at a future medical congress. A Phase 3 study of ULTOMIRIS in children and adolescents with aHUS is currently ongoing.
About the ULTOMIRIS aHUS-311 Study
This global, multicenter,
single arm, Phase 3 study evaluated the safety and efficacy of ULTOMIRIS
administered by intravenous infusion in 56 adults (≥ 18 years of age)
who hadn’t been treated with a complement inhibitor before. The study
consists of an up to seven-day screening period, a 26-week initial
evaluation period and an extension period of up to two years, which is
still ongoing. Patients received a weight-based loading dose (≥ 40 to <
60 kg = 2,400 mg; ≥ 60 to < 100 kg = 2,700 mg; ≥ 100 kg = 3,000 mg) on
Day 1, followed by weight-based maintenance doses (≥ 40 to < 60 kg =
3,000 mg; ≥ 60 to < 100 kg = 3,300 mg; ≥ 100 kg = 3,600 mg) on Day 15
and once every eight weeks thereafter. The primary endpoint was defined
as complete TMA response during the 26-week initial evaluation period,
as evidenced by normalization of platelet count and lactate
dehydrogenase (LDH) level and an improvement in serum creatinine of ≥ 25
percent from baseline. For patients on dialysis at enrollment, baseline
was established after they had come off dialysis. To achieve complete
TMA response, patients had to meet all three criteria at the same time
at least once. In addition, each of the criteria had to be met for at
least 28 consecutive days. Complete C5 inhibition was defined as free C5
levels of <0.5 µg/mL.
About atypical Hemolytic Uremic Syndrome (aHUS)
Atypical
hemolytic uremic syndrome (aHUS) is a chronic, progressive and
debilitating ultra-rare disease that affects both children and adults
and can lead to potentially irreversible damage to kidneys and other
vital organs, sudden or progressive kidney failure (requiring dialysis
or transplant) and premature death.3,4,7,8 aHUS is
characterized by inflammation and the formation of blood clots in small
blood vessels throughout the body (thrombotic microangiopathy [TMA])
mediated by chronic, uncontrolled activation of the complement system,
which is part of the body’s immune system.3,4,5,6,7 TMA
consists of reduced platelet count (thrombocytopenia), hemolytic anemia
(as a result of hemolysis [destruction of red blood cells]) and acute
kidney injury (AKI).5,7,9,10 If left untreated, significant
proportions of adults (46 percent) and children (16 percent) can
progress to end-stage renal disease (ESRD) or die during first clinical
manifestations of aHUS despite supportive care, including plasma
exchange or plasma infusion (PE/PI). One year following clinical
manifestations, 56 percent of adults and 29 percent of children can
progress to ESRD or die, if left untreated.11 Early and
careful diagnosis of aHUS is critical as many coexisting diseases and
events are known or suspected to activate the complement cascade, and as
patients may not necessarily present with the classic TMA triad of
thrombocytopenia, hemolytic anemia and renal impairment12 or
may have less severe renal involvement.13 Available tests can
help distinguish aHUS from other hemolytic diseases with similar
symptoms such as HUS caused by Shiga toxin-producing Escherichia coli
(STEC-HUS) and thrombotic thrombocytopenic purpura (TTP).7
About ULTOMIRIS™
ULTOMIRIS (ravulizumab-cwvz, formerly known
as ALXN1210) is the first and only long-acting C5 inhibitor administered
every eight weeks that works by inhibiting the C5 protein in the
terminal complement cascade, a part of the body’s immune system. The
terminal complement cascade, when activated in an uncontrolled manner,
plays a role in severe ultra-rare disorders like paroxysmal nocturnal
hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and
anti-acetylcholine receptor (AchR) antibody-positive myasthenia gravis
(MG). ULTOMIRIS is approved in the U.S. as a treatment for adults with
PNH. Regulatory authorities in the European Union (EU) and Japan have
accepted and are reviewing applications for the approval of ULTOMIRIS as
a treatment for adults with PNH. In Phase 3 clinical studies in
complement inhibitor-naïve patients with PNH1 and patients
with PNH who had been stable on SOLIRIS® (eculizumab),2
intravenous treatment with ULTOMIRIS every eight weeks demonstrated
non-inferiority to intravenous treatment with SOLIRIS every two weeks on
all 11 endpoints. ULTOMIRIS is also currently being evaluated in a Phase
3 clinical study in complement inhibitor-naïve children and adolescents
with aHUS, administered intravenously every eight weeks. In addition,
Alexion plans to initiate a Phase 3 clinical study of ULTOMIRIS
delivered subcutaneously once per week as a potential treatment for
patients with PNH and aHUS. Alexion is also planning to initiate the
development of ULTOMIRIS, intravenously administered every eight weeks,
as a potential treatment for patients with generalized MG (gMG) and
neuromyelitis optica spectrum disorder (NMOSD).
ULTOMIRIS has received Orphan Drug Designation (ODD) for the treatment of patients with PNH in the U.S. and EU, and for the subcutaneous treatment of patients with aHUS in the U.S.
Please see the full Prescribing Information and Medication Guide for ULTOMIRIS, including Boxed WARNING regarding serious and life-threatening meningococcal infections/sepsis.
Important ULTOMIRIS Safety Information
ULTOMIRIS is a
prescription medicine called a monoclonal antibody. ULTOMIRIS is used to
treat adults with a disease called Paroxysmal Nocturnal Hemoglobinuria
(PNH). It is not known if ULTOMIRIS is safe and effective in children.
ULTOMIRIS is a medicine that affects the immune system. ULTOMIRIS can lower the ability of the immune system to fight infections. ULTOMIRIS increases the chance of getting serious and life-threatening meningococcal infections. Meningococcal infections may quickly become life-threatening and cause death if not recognized and treated early.
Meningococcal vaccines must be received at least 2 weeks before the first dose of ULTOMIRIS if one has not already had this vaccine. If one’s doctor decided that urgent treatment with ULTOMIRIS is needed, meningococcal vaccination should be administered as soon as possible. If one has not been vaccinated and ULTOMIRIS therapy must be initiated immediately, 2 weeks of antibiotics should also be administered with the vaccinations. If one had a meningococcal vaccine in the past, additional vaccination might be needed before starting ULTOMIRIS. Call one’s doctor or get emergency medical care right away if any of these signs and symptoms of a meningococcal infection occur: headache with nausea or vomiting, headache with a stiff neck or stiff back, fever and a rash, muscle aches with flu-like symptoms, headache and fever, fever, confusion, and eyes sensitive to light.
ULTOMIRIS is only available through a program called the ULTOMIRIS REMS.
ULTOMIRIS may also increase the risk of other types of serious infections. People who take ULTOMIRIS may have an increased risk of getting infections caused by Streptococcus pneumoniae and Haemophilus influenzae. Certain people may also have an increased risk of gonorrhea infection. To find out if one is at risk for gonorrhea infection, about gonorrhea prevention, and regular testing, talk to the healthcare provider. Call the healthcare provider right away if one has any new signs or symptoms of infection.
Before one receives ULTOMIRIS, tell the doctor about all of the medical conditions, including if one: has an infection or fever, are pregnant or plan to become pregnant, and are breastfeeding or plan to breastfeed. It is not known if ULTOMIRIS will harm an unborn baby. It is not known if ULTOMIRIS passes into the breast milk. One should not breast feed during treatment and for 8 months after one’s final dose of ULTOMIRIS.
Tell the doctor about all the medicines one takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements. ULTOMIRIS and other medicines can affect each other causing side effects. Know the medications one takes and the vaccines one receives. Keep a list of them to show the doctor and pharmacist when one gets a new medicine.
If one stops receiving ULTOMIRIS, the doctor will need to monitor closely for at least 16 weeks after one stops ULTOMIRIS. Stopping ULTOMIRIS may cause breakdown of the red blood cells due to PNH. Symptoms or problems that can happen due to red blood cell breakdown include: drop in the number of the red blood cell count, tiredness, blood in the urine, stomach-area (abdomen) pain, blood clots, shortness of breath, trouble swallowing, and erectile dysfunction (ED) in males.
ULTOMIRIS can cause serious side effects including infusion reactions. Infusion reactions may happen during one’s ULTOMIRIS infusion. Symptoms of an infusion reaction with ULTOMIRIS may include lower back pain, pain with the infusion, or feeling faint. Tell the doctor or nurse right away if these symptoms develop, or any other symptoms during the ULTOMIRIS infusion that may mean one is having a serious infusion reaction, including: chest pain, trouble breathing or shortness of breath, swelling of the face, tongue, or throat, and feel faint or pass out. One’s doctor will treat the symptoms as needed. The most common side effects of ULTOMIRIS are upper respiratory infection and headache.
Please see the full Prescribing Information and Medication Guide for ULTOMIRIS, including Boxed WARNING regarding serious and life-threatening meningococcal infections/sepsis.
About Alexion
Alexion is a global biopharmaceutical company
focused on serving patients and families affected by rare diseases
through the discovery, development and commercialization of
life-changing therapies. As the global leader in complement biology and
inhibition for more than 20 years, Alexion has developed and
commercializes two approved complement inhibitors to treat patients with
paroxysmal nocturnal hemoglobinuria (PNH), as well as the first and only
approved complement inhibitor to treat atypical hemolytic uremic
syndrome (aHUS) and anti-acetylcholine receptor (AchR) antibody-positive
generalized myasthenia gravis (gMG), and is also developing it for
patients with neuromyelitis optica spectrum disorder (NMOSD). Alexion
also has two highly innovative enzyme replacement therapies for patients
with life-threatening and ultra-rare metabolic disorders,
hypophosphatasia (HPP) and lysosomal acid lipase deficiency (LAL-D). In
addition, the company is developing several mid-to-late-stage therapies,
including a second complement inhibitor, a copper-binding agent for
Wilson disease and an anti-neonatal Fc receptor (FcRn) antibody for rare
Immunoglobulin G (IgG)-mediated diseases. Alexion focuses its research
efforts on novel molecules and targets in the complement cascade and its
development efforts on the core therapeutic areas of hematology,
nephrology, neurology and metabolic disorders. Alexion has been named to
the Forbes list of the World’s Most Innovative Companies seven
years in a row and is headquartered in Boston, Massachusetts’ Innovation
District. The company also has offices around the globe and serves
patients in more than 50 countries. This press release and further
information about Alexion can be found at: www.alexion.com.
[ALXN-G]
Forward-Looking Statement
This press release contains
“forward-looking statements” within the meaning of the Private
Securities Litigation Reform Act of 1995 that involve risks and
uncertainties relating to future events and the future performance of
Alexion, including the following statements relating to: ULTOMIRIS can
provide clinically meaningful benefits to patients with aHUS; ULTOMIRIS
has the potential to become the new standard of care for patients with
aHUS; plans to file regulatory submissions for ULTOMIRIS in aHUS in the
U.S., EU and Japan (and the timing for submitting such filings); the
benefits of ULTOMIRIS for patients, including its potential as an
effective new treatment option that can provide hematologic
normalization and improved kidney function, including the potential to
stop dialysis; plans to issue detailed Phase 3 study results in the
future; future plans to initiate additional clinical trials for
ULTOMIRIS, including trials for intravenous administration every eight
weeks for patients with gMG and NMOSD and trials for subcutaneous
delivery as a potential treatment for patients with PNH and aHUS.
Forward-looking statements are subject to factors that may cause
Alexion's results and plans to differ materially from those expected by
these forward looking statements, including for example: ULTOMIRIS may
not obtain regulatory approval as a treatment for aHUS (due to failure
to meet regulatory requirements); ULTOMIRIS may not gain market
acceptance and/or may not be recognized by patients and physicians as
the standard of care for patients with aHUS; the benefits (including
safety and efficacy) of ULTOMIRIS evidenced in clinical trials are not
witnessed in a broader patient population; any potential post-approval
restrictions that the FDA may impose on ULTOMIRIS; our dependence on
sales from our principal product (SOLIRIS); future competition from
biosimilars and other products; decisions of regulatory authorities
regarding the adequacy of our research, marketing approval or material
limitations on the marketing of our products; delays or failure of
product candidates to obtain regulatory approval; delays or the
inability to launch product candidates due to regulatory restrictions,
anticipated expense or other matters; interruptions or failures in the
manufacture and supply of our products and our product candidates;
failure to satisfactorily address matters raised by the FDA and other
regulatory agencies with respect to product candidates; results in early
stage clinical trials may not be indicative of full results or results
from later stage or larger clinical trials (or broader patient
populations) and do not ensure regulatory approval; the possibility that
results of clinical trials are not predictive of safety and efficacy and
potency of our products (or we fail to adequately operate or manage our
clinical trials) which could cause us to halt trials, delay or prevent
us from making regulatory approval filings or result in denial of
approval of our product candidates; unexpected delays in clinical
trials; future product improvements may not be realized due to expense
or feasibility; the possibility that current rates of adoption of
SOLIRIS in PNH, aHUS, gMG or other diseases are not sustained; the
adequacy of our pharmacovigilance and drug safety reporting processes;
failure to protect and enforce our data, intellectual property and
proprietary rights and the risks and uncertainties relating to
intellectual property claims and challenges against us (including
intellectual property lawsuits relating to ULTOMIRIS brought by third
parties against Alexion); the risk that third party payers (including
governmental agencies) will not reimburse or continue to reimburse for
the use of our products at acceptable rates or at all; failure to
realize the benefits and potential of investments, collaborations,
licenses and acquisitions; delay of collection or reduction in
reimbursement due to adverse economic conditions or changes in
government and private insurer regulations and approaches to
reimbursement; uncertainties surrounding legal proceedings (including
intellectual property suits initiated against Alexion and our products),
company investigations and government investigations, including
investigations of Alexion by the U.S. Securities and Exchange Commission
(SEC) and U.S. Department of Justice; the risk that estimates regarding
the number of patients with PNH, aHUS, gMG, HPP and LAL-D and other
future indications we are pursuing are inaccurate; the risks of changing
foreign exchange rates; risks relating to the potential effects of the
Company's restructurings; and a variety of other risks set forth from
time to time in Alexion's filings with the SEC, including but not
limited to the risks discussed in Alexion's Quarterly Report on Form
10-Q for the period ended September 30, 2018 and in our other filings
with the SEC. Alexion disclaims any obligation to update any of these
forward-looking statements to reflect events or circumstances after the
date hereof, except when a duty arises under law.
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