Inmazeb is indicated for the treatment of infection caused by Zaire ebolavirus in adult and pediatric patients, including neonates born to a mother who is RT-PCR positive for Zaire ebolavirus infection.
The efficacy of Inmazeb has not been established for other species of the Ebolavirus and Marburgvirus genera
Zaire ebolavirus can change over time, and factors such as emergence of resistance, or changes in viral virulence could diminish the clinical benefit of antiviral drugs. Consider available information on drug susceptibility patterns for circulating Zaire ebolavirus strains when deciding whether to use Inmazeb.
To address emerging or rapidly spreading infectious disease situations, Regeneron has applied our VelociSuite® technologies in a ‘rapid response’ manner that parallel tracks certain steps and speeds hand-offs between groups in order to advance novel antibody treatments in a very expedited manner.
One distinguishing factor of Regeneron’s infectious disease programs is our multi-antibody ‘cocktail’ approach. After generating large pools of virus-neutralizing antibody candidates, our scientists select complementary antibodies that target the virus.
Inmazeb was created using Regeneron’s VelocImmune® platform and associated VelociSuite® technologies. The treatment consists of three monoclonal antibodies of similar structure, atoltivimab, maftivimab and odesivimab, which bind to epitopes on Zaire ebolavirus glycoprotein.
The three antibody combination neutralizes the Ebola virus by blocking the virus from entering into host cells via the glycoprotein and/or enables antibody-dependent effector function by bringing in other immune cells to target infected cells, which is a way for an antibody to get extra help from the immune system in order to clear infected cells from the body.
The three antibodies were carefully selected to have the
following complementary biological properties:
Induces Effector Function
The PAmoja TuLinde Maisha (PALM) clinical trial was a randomized, multicenter, controlled trial initiated in 2018 in the Democratic Republic of Congo (DRC) to evaluate the safety and efficacy of four investigational Ebola virus disease therapies when added to standard of care. The World Health Organization (WHO), 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.
In 2019, the PALM trial was stopped on the basis of a pre-specified interim analysis showing a significant reduction in mortality for people with Ebola virus disease who received Inmazeb compared to investigational control group. As shown in the paper published in the New England Journal of Medicine (Mulangu et al. 2019) and the FDA prescribing information, Inmazeb demonstrated significant efficacy compared to investigational control at reducing mortality at Day 28.
In order to be enrolled, patients needed to have a positive reverse transcriptase-polymerase chain reaction (RT-PCR) for the nucleoprotein (NP) gene of Zaire ebolavirus, could not have received other investigational treatments (with the exception of experimental vaccines) within the previous 30 days. Neonates ≤7 days of age could take part in the study if there was a likelihood that the neonate was infected. Randomization was stratified by reverse transcription-PCR cycle threshold calculated using NP targets (CtNP ≤22.0 vs >22.0; corresponding to high and low viral load, respectively) and Ebola Treatment Unit (ETU) site. All patients received standard-of-care consisting of a minimum of intravenous fluids, daily clinical laboratory testing, correction of hypoglycemia and electrolyte imbalances, and broad-spectrum antibiotics and antimalarials, as indicated.
In the PALM trial, 154 patients were treated with Inmazeb and 153 patients were treated with the control.
Demographics and Baseline Characteristics in PALM Trial
|Mean age (years)||28||31|
|Age <1 month (%)||1 (1%)||2 (1%)|
|Age 1 month to <1 year (%)||4 (3%)||1 (1%)|
|Age 1 year to <6 years (%)||18 (12%)||13 (8%)|
|Age 6 years to <12 years (%)||8 (5%)||4 (3%)|
|Age 12 years to <18 years (%)||8 (5%)||8 (5%)|
|Age 18 years to <50 years (%)||93 (60%)||105 (69%)|
|Age 50 years to <65 years (%)||17 (11%)||18 (12%)|
|Age ≥65 years (%)||5 (3%)||2 (1%)|
|Female (%)||90 (58%)||80 (52%)|
|Positive result on pregnancy testa, n (%)||2/67 (3%)||4/61 (7%)|
|RT-PCR CtNP cycle threshold ≤22, n||66||64|
|Median RT-PCR CtNP (IQR)||22.7 (20.1, 28.1)||22.9 (18.8, 26.4)|
|Median creatinine (IQR)||1.0 (0.7, 4.0)||1.1 (0.7, 3.2)|
|Median AST (IQR)||225.5 (98.0, 941.0)||351.0 (109, 1404.0)|
|Median ALT (IQR)||165.0 (56.0, 418.0)||223.5 (47.0, 564.0)|
|Median days from onset of symptoms to randomization (IQR)||5.0 (3.0, 7.0)||5.0 (3.0, 7.0)|
|Reported Vaccination with rVSV-ZEBOV vaccine, n (%)||34 (22%)||41 (27%)|
|<10 days before ETU admission||20/34 (59%)||21/41 (51%)|
|≥10 days before ETU admission||14/34 (41%)||18/41 (44%)|
|Timing unknown||0/34 (0%)||2/41 (5%)|
a Pregnancy positive test was calculated based on subjects who had pregnancy test result.
CtNP = cycle threshold calculated using NP targets; IQR = interquartile range; AST=Aspartate aminotransferase; ALT=Alanine aminotransferase; ETU=Ebola treatment unit
Each dose was delivered via intravenous infusion by a healthcare professional. Hypersensitivity reactions including infusion-associated events have been reported during and post-infusion with Inmazeb, with approximately 99% of patients receiving Inmazeb completing their dose within three hours. Two subjects who received Inmazeb (1%) did not receive their complete infusion. One of the two subjects did not complete their Inmazeb infusion because of fever elevation. The adverse event profile in adult and pediatric patients treated with Inmazeb was similar. The evaluation of adverse events in patients who received Inmazeb was confounded by signs and symptoms of the underlying Zaire ebolavirus infection.
Adverse Events That Occurred during Inmazeb Infusion in
≥10% of Adult and Pediatric Subjects in the PALM Trial
|Adverse Eventa||Inmazeb (N=154)
|Pyrexia (Elevation in fever)||54||59|
aAdverse events in this table were reported on the day of infusion, and included signs and symptoms that occurred during or immediately after infusion
bAdverse events that were not pre-specified
cInvestigational therapy administered as three separate infusions
Selected Grade 3 and 4 Laboratory Abnormalities, Worsened
to Grade 3 or 4 from Baseline in the PALM Trial
|Laboratory Testa||Inmazeb N=154
|Sodium, high ≥ 154 mmol/L||14 (9)||7 (4)|
|Sodium, low ≥ 125 mmol/L||11 (7)||19 (11)|
|Potassium, high ≥ 6.5 mmol/L||20 (13)||20 (12)|
|Potassium, low < 2.5 mmol/L||14 (9)||13 (8)|
|Creatinine (mg/dL) > 1.8 x ULN||10 (6)||22 (13)|
|Alanine aminotransferase (U/L) ≥ 5 x ULN||16 (10)||24 (14)|
|Aspartate aminotransferase (U/L) ≥ 5 x ULN||33 (21)||30 (18)|
aGraded per Division of AIDS (DAIDS) v2.1
Inmazeb is a combination of three monoclonal antibodies co-formulated in a 1:1:1 ratio of atoltivimab, maftivimab, and odesivimab. The recommended dose of Inmazeb is 50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg (3 mL/kg) diluted and administered as a single intravenous infusion. Please see full prescribing information for additional details on preparation and administration.
In keeping with our mission and values, Regeneron is committed to making this important medicine available to the people who need it. In response to the 2018 Ebola outbreak in the Democratic Republic of the Congo (DRC), we worked with the World Health Organization (WHO), U.S. FDA and other global organizations to offer Inmazeb under a compassionate use protocol and include it in the four-arm PALM Trial. With BARDA support, we continue to provide Inmazeb for free in response to outbreaks in the DRC through the MEURI protocol for compassionate use. Regeneron is actively working with non-governmental organizations and public health agencies to ensure continued access to Inmazeb in low- and middle-income countries.
THANK YOU TO HEALTHCARE PROVIDERS
AND OUR COLLABORATORS
Thank you to the many healthcare workers in the DRC providing care to people suffering from Ebola. You are true heroes and we appreciate your incredible work. Without your courage and dedication, the PALM trial would not have been completed.
Regeneron’s Ebola research and development efforts are supported through collaborations with various governmental and global health organizations, including the BARDA, part of the Office of the Assistant Secretary for Preparedness and Response within the U.S. Department of Health and Human Services (HHS); the WHO; the National Institutes of Health; and the Institut National pour la Recherche Biomedicale in the DRC.
WARNINGS AND PRECAUTIONS
Hypersensitivity Reactions Including Infusion-Associated Events: Hypersensitivity reactions including infusion-associated events have been reported during and post-infusion with INMAZEB. These may include acute, life-threatening reactions during and after the infusion. Monitor all patients for signs and symptoms including, but not limited to, hypotension, chills and elevation of fever, during and following INMAZEB infusion. In the case of severe or life-threatening hypersensitivity reactions, discontinue the administration of INMAZEB immediately and administer appropriate emergency care.
Infusion could not be completed in 1% of subjects who received INMAZEB due to infusion-associated adverse events. The rate of infusion of INMAZEB may be slowed or interrupted if the patient develops any signs of infusion-associated events or other adverse events.
DRUG INTERACTIONS: INMAZEB may reduce the efficacy of live vaccine therefore, avoid the concurrent administration of a live vaccine during treatment with INMAZEB. The interval between live vaccination following initiation of INMAZEB therapy should be in accordance with current vaccination guidelines. The efficacy of INMAZEB among subjects who reported receipt of a recombinant live vaccine prior to their enrollment in the PALM clinical trial was similar to subjects who did not receive a vaccine.
INMAZEB is indicated for the treatment of infection caused by Zaire ebolavirus in adult and pediatric patients, including neonates born to a mother who is RT-PCR positive for Zaire ebolavirus infection.
Limitations of Use: The efficacy of INMAZEB has not been established for other species of the Ebolavirus and Marburgvirus genera. Zaire ebolavirus can change over time, and factors such as emergence of resistance, or changes in viral virulence could diminish the clinical benefit of antiviral drugs. Consider available information on drug susceptibility patterns for circulating Zaire ebolavirus strains when deciding to use INMAZEB.
Please see accompanying full Prescribing Information
WARNINGS AND PRECAUTIONS
Hypersensitivity Reactions Including Infusion-Associated Events: Hypersensitivity reactions including infusion-associated events have been reported during and post-infusion with INMAZEB. These may include acute, life-threatening reactions during and after the infusion. Monitor all patients for signs and symptoms including, but