TARRYTOWN, N.Y., Nov. 27, 2019 /PRNewswire/ --
Nearly 90 percent survival for patients who received REGN-EB3
treatment earlier in the course of their disease; 66.5 percent
survival among all patients who received REGN-EB3
Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) announced today
that the New England Journal of Medicine (NEJM) published
results from the randomized controlled PALM trial showing that
Regeneron's REGN-EB3 and another investigational agent provided the
highest overall survival rates among four investigational
treatments for Ebola virus disease. Monoclonal antibody treatments
REGN-EB3, mAb114 and ZMapp and the small molecule antiviral agent
remdesivir were given to a trial population of 681 patients who had
Ebola during the ongoing outbreak in the Democratic Republic of the Congo (DRC).
REGN-EB3, a triple-antibody cocktail, demonstrated superior
efficacy compared to the ZMapp control arm across multiple
measures, including the primary endpoint of mortality at day 28
(33.5 percent with REGN-EB3 versus 51.3 percent with ZMapp,
p=0.002) and secondary endpoint of reduction of the number of days
until the Ebola virus was no longer detected in the
bloodstream.
The trial was stopped in August
2019 when preliminary results showed that REGN-EB3
crossed the pre-specified superiority threshold for preventing
death compared to ZMapp. Although a second investigational
treatment, mAb114, did not meet this statistical threshold, it had
notable activity, and the decision was made for these two
strongest-performing investigational therapies to continue to be
administered to patients in a trial extension phase.
The REGN-EB3 antibodies were created using Regeneron's novel and
proprietary VelocImmune® platform, which utilizes
a mouse model with a genetically humanized immune system, and
associated VelociSuite technologies that allow for
harvesting and production of specific human antibodies from these
mice. These technologies enable the rapid and efficient generation
of multiple fully-human antibodies against targets such as Ebola
virus, without requiring the identification and utilization of rare
human survivors as sources of such therapeutic antibodies.
"In this study, REGN-EB3 demonstrated a significant survival
advantage over another antibody treatment approach, underscoring
the importance of antibody selection and design. REGN-EB3 was
specifically designed to enhance efficacy, reduce the risk of viral
resistance and mitigate against potential virus evolution. Our
ability to rapidly create and develop these clinically-effective
Ebola-specific antibodies highlights the power and speed of our
VelociSuite human antibody platforms," said Neil Stahl, Ph.D., Executive Vice President of
Research and Development at Regeneron. "We are committed to
continuing to provide this important treatment to patients through
the PALM trial extension trial and 'compassionate use' until the
current outbreak ends. We are also working closely with the U.S.
Food and Drug Administration to gain regulatory approval and with
U.S. and global health authorities to determine appropriate
stockpiling of REGN-EB3, as we believe our triple antibody approach
may have particular utility for future outbreaks."
Ebola outbreaks have
historically resulted in survival rates as low as 10
percent1 and there are no approved treatments for the
disease. Of all patients given REGN-EB3 in this trial setting, 66.5
percent were alive at day 28, compared to 48.7 percent of patients
given ZMapp. Importantly, administration of treatment earlier in
the course of disease (when viral loads are typically lower)
resulted in dramatically higher survival rates with all four
investigational treatments, including 88.8 percent survival at day
28 with REGN-EB3. The greatest reduction in mortality (minus 22.5
percent) across all study groups occurred with REGN-EB3 treatment
in patients who were treated later in the course of their disease,
when risk of dying from Ebola is greatest.
All patients received optimized supportive care (oSOC),
including supportive oral and/or intravenous fluids, electrolyte
replacement, maintaining of oxygen status and blood pressure, pain
management, and antibiotics and antimalarials as indicated. The
paper reported 3 serious adverse events for REGN-EB3, compared to 7
for ZMapp, 9 for remdesivir and 10 for mAb114.
Comparison of 28-day mortality and days to negative PCR by
treatment group
|
All patients
treated with ZMapp + oSOC
(Control arm
for mAb114 and Remdesivir cohorts)
|
Patients treated
with mAb114 + oSOC
|
Patients treated
with Remdesivir + oSOC
|
|
Patients treated
with ZMapp + oSOC after Jan'19
(Control arm
for REGN-EB3 cohort)2
|
Patients treated
with REGN-EB3 + oSOC
|
28-day
mortality
for overall patient
pop.
(No. deaths/Total
No.)
|
49.7%
(84/169)
|
35.1%
(61/174)
|
53.1%
(93/175)
|
51.3%
(79/154)
|
33.5%
(52/155)
|
Mortality difference
vs. ZMapp for overall patient pop.
(95% CI)
|
--
|
−14.6 * (−25.2 to
−1.7)
|
3.4
(−7.2 to
14.0)
|
--
|
−17.8 *
(−28.9 to
−2.9)
|
28-day mortality for
patients who presented early in disease, based on CtNP>22
stratum3
(No. deaths/Total
No.)
|
24.5%
(24/98)
|
9.9%
(10/101)
|
29.0%
(29/100)
|
25.8%
(23/89)
|
11.2%
(10/89)
|
Mortality difference
vs. ZMapp for patients who presented early in disease (95%
CI)
|
--
|
−14.6 (−32.4 to
−2.6)
|
4.5 (−9.1 to
19.1)
|
--
|
−14.6
(−32.6 to
−2.3)
|
28-day mortality for
patients who presented late in disease, based on CtNP£22
stratum
(No. deaths/Total
No.)
|
84.5%
(60/71)
|
69.9%
(51/73)
|
85.3%
(64/75)
|
86.2%
(56/65)
|
63.6%
(42/66)
|
Mortality difference
vs. ZMapp for patients who presented late in disease (95%
CI)
|
--
|
−14.6
(−33.0 to
−0.5)
|
0.8
(−15.3 to 17.2)
|
--
|
−22.5
(−41.8 to −5.1)
|
Median no. of days to
virus clearance (indicated by first negative PCR)
|
27
|
16
|
>28
|
27
|
15
|
*Statistically significant according to
interim monitoring boundary of p<0.034 and p<0.029 for mAb114
and REGN-EB3, respectively.
|
"This trial required an incredible level of cooperation from
international government agencies, non-governmental organizations
and drug developers in order to deliver experimental treatments to
remote, violence-plagued areas of the DRC," said Sumathi Sivapalasingam, M.D., Senior Director,
Early Clinical Development and Experimental Sciences at Regeneron.
"Healthcare workers in the field risked their lives to treat
patients, all while conducting scientifically rigorous and ethically sound
research that will improve the treatment of Ebola in future
outbreaks. We are so grateful for their work and that REGN-EB3 was
able to improve survival for people suffering from this terrible
disease."
About the PALM Trial
The PAmoja TuLinde Maisha (PALM ["together save lives" in
Kiswahili]) clinical trial was a randomized, multicenter,
controlled trial initiated in 2018 to evaluate the safety and
efficacy of three investigational Ebola virus disease therapies:
mAb114, remdesivir and ZMapp. The trial protocol was amended after
the World Health Organization (WHO) held an Ad-Hoc Expert
Consultation to assess all preclinical and clinical data on
available investigational products, and recommended the addition of
REGN-EB3 as a fourth treatment arm. The National Institutes of
Health (NIH) and the Institut National de Recherche Biomédicale
(INRB) in the DRC jointly sponsored and served as co-principal
investigators and are senior authors of the New England Journal
of Medicine publication.
About REGN-EB3
REGN-EB3 (also known as
REGN3470-3471-3479) was invented by Regeneron using its
VelociSuite® technologies, starting with the
VelocImmune® mouse; the therapy combines three
fully-human monoclonal antibodies. REGN-EB3 has received Orphan
Drug designation from both the U.S. Food and Drug Administration
(FDA) and the European Medicines Agency; in early September 2019, REGN-EB3 also received
Breakthrough Therapy designation from the FDA. REGN-EB3 is being
developed, tested and manufactured through contracts awarded in
2015 and 2017 by the Biomedical Advanced Research and Development
Authority (BARDA), under the Assistant Secretary for Preparedness
and Response within the U.S. Department of Health and Human
Services (USG Contract No. HHSO100201500013C and
HHSO100201700016C). REGN-EB3 is currently under clinical
development and its safety and efficacy have not been fully
evaluated by any regulatory authority.
Regeneron's rapid response infectious disease platform has the
potential to accelerate response to future epidemics and pandemics
that may pose a threat to public health. Regeneron and BARDA have
several ongoing research collaborations in addition to the Ebola
program, including efforts to develop antibodies targeting up to 10
pathogens that pose significant risk to public health.
About Regeneron
Regeneron (NASDAQ: REGN) is a
leading biotechnology company that invents life-transforming
medicines for people with serious diseases. Founded and led for 30
years by physician-scientists, our unique ability to repeatedly and
consistently translate science into medicine has led to
seven FDA-approved treatments and numerous product candidates
in development, all of which were homegrown in our laboratories.
Our medicines and pipeline are designed to help patients with eye
diseases, allergic and inflammatory diseases, cancer,
cardiovascular and metabolic diseases, infectious diseases, pain
and rare diseases.
Regeneron is accelerating and improving the traditional drug
development process through our
proprietary VelociSuite® technologies,
including VelocImmune® which uses a unique
genetically-humanized mouse to produce optimized fully-human
antibodies and bispecific antibodies, and through ambitious
research initiatives such as the Regeneron Genetics Center, which
is conducting one of the largest genetics sequencing efforts in the
world.
For additional information about the company, please
visit www.regeneron.com or follow @Regeneron on
Twitter.
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Media
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Inc. ("Regeneron" or the "Company"), and actual events or results
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REGN3470-3471-3479); the extent to which the results from the
research and development programs conducted by Regeneron or its
collaborators may be replicated in later studies and lead to
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potential antibody therapy for the treatment of Ebola; serious
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Regeneron Contacts:
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1 "Ebola virus disease." World Health
Organization.
https://www.who.int/en/news-room/fact-sheets/detail/ebola-virus-disease.
Last accessed November 26,
2019.
2 Administration of remdesivir, mAb114 and ZMapp
began in November 2018, and REGN-EB3
was added as a fourth arm of the trial in January 2019. Therefore, outcomes in the
remdesivir and mAb114 arms and outcomes in the REGN-EB3 arm were
compared to slightly different cohorts of participants in the ZMapp
control group based on time of enrollment. Overall mortality was
very similar in each control group.
3 CtNP refers to "cycle threshold for the
nucleoprotein gene," a measure to determine viral load in the
bloodstream. Patients with higher viral loads will have lower CtNP
values. Viral load generally increases over time without
treatment.
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