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Take a look at a selection of our recent media coverage:
5th July 2023
Amlitelimab has met its primary endpoint of an improvement in disease severity of atopic dermatitis in a recent phase 2b dose-ranging trial, its manufacturer Sanofi has announced.
Amlitelimab provided statistically significant improvements in signs and symptoms of moderate-to-severe atopic dermatitis in adults whose disease could not be adequately controlled with topical medications or where topical medications are not a recommended treatment approach.
A non-depleting IgG4 human anti-OX40L monoclonal antibody, amlitelimab’s OX40–OX40L interaction appears to play a central role in the pathogenesis of atopic dermatitis. The drug binds to OX40L and in doing so, blocks its interactions with OX40, thus restoring immune homeostasis between pro-inflammatory and anti-inflammatory T-cells. Consequently, the drug offers a potential first-in-class novel antibody therapy for patients with moderate to severe atopic dermatitis.
Amlitelimab (formerly KY1005) was found in a pharmacokinetic study to reduce skin redness, indicating its potential as a novel pharmacological treatment in immune-mediated disorders. Earlier work revealed how amlitelimab leads to a significant reduction of interleukin-13 levels with a corresponding reduction in dermatitis disease severity. Furthermore, the drug also improves disease severity through targeting interleukin-22.
The latest information released by Sanofi relates to STEAM-AD – a phase 2b, double blind, five-arm study assessing amlitelimab in adult participants with moderate to severe atopic dermatitis. While the company did not provide specific details, it did report that amlitelimab had enrolled 390 people from several countries. The primary endpoint was the percentage change in the Eczema Area and Severity Index score from baseline at 16 weeks.
The detailed efficacy and safety results from the trial are to be presented in a future scientific forum and, as amlitelimab is currently under clinical investigation, the safety and efficacy have not yet been evaluated by regulatory authorities.
Dr Naimish Patel, head of global development, immunology and inflammation at Sanofi, said: ‘While we have made significant strides in the treatment of atopic dermatitis, there are patients who are still in need of new options.
‘We believe that the results from this Phase 2b study with amlitelimab support our perspective that targeting OX40-Ligand has the potential to provide a first and best-in-class treatment option that addresses type 2 and non-type 2 inflammation to meet the individual needs of people living with atopic dermatitis and other chronic inflammatory diseases.
‘We look forward to advancing into a larger Phase 3 clinical development programme and continuing to drive momentum in our immunology pipeline to deliver first or best-in-class treatments.’
23rd November 2022
Gantenerumab which is a fully human monoclonal IgG1 antibody failed to meet the primary endpoint of slowing clinical decline in people with early Alzheimer’s disease (AD) in two randomised, double-blind, placebo-controlled trials according to a release by the manufacturer Roche.
It has been estimated that currently, an estimated 6.2 million Americans aged 65 and older are living with Alzheimer’s dementia. Moreover, the World Health Organisation has estimated that there are more than 55 million people with dementia worldwide and nearly 10 million new cases every year, with Alzheimer’s disease accounting for between 60 – 70% dementia cases. The amyloid cascade hypothesis of AD proposes that deposition of the amyloid-β peptide in the brain is a central event in disease pathology and several drugs have been developed, including gantenerumab which binds with high affinity to aggregated amyloid-β species and removes amyloid-β plaques.
The potential value of gantenerumab came from a small trial in 2012, which revealed that it resulted in a dose-dependent reduction in brain amyloid levels. However, these early findings were called into question after a 2017 randomised trial with the drug in patients with prodromal AD, i.e., mild cognitive impairment, over a 2-year period, was halted early for futility. Despite this, the manufacturer Roche embarked to two global phase III trials, GRADUATE I and II designed to evaluate the safety and efficacy of gantenerumab in people with mild cognitive impairment due to Alzheimer’s and mild Alzheimer’s dementia over 27 months. The primary endpoint of both trials was the change from baseline in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) at 116 weeks, a tool that measures cognitive and functional change across six areas including memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care.
Gantenerumab and Alzheimer’s disease outcomes
According to the press release, 1,965 participants across 30 countries were randomised 1:1 to receive gantenerumab or placebo by subcutaneous injection and titrated to reach a target dose of 510 mg which was administered every two weeks. The results showed that while there was a slowing of clinical decline in GRADUATE I of -0.31 (p = 0.095) and -0.19 (p = 0.29) in GRADUATE II of -0.31 (p=0.0954) from baseline on CDR-SB, neither decrease was statistically significant. Additionally, the level of beta-amyloid removal was also lower than expected.
Commenting on the findings, Levi Garraway, Roche’s Chief Medical Officer and Head of Global Product Development said, ‘While the GRADUATE results are not what we hoped, we are proud to have delivered a high quality, clear and comprehensive Alzheimer’s dataset to the field, and we look forward to sharing our learnings with the community as we continue to search for new treatments for this complex disease.’
Nevertheless, the press release reports that Roche remains committed to Alzheimer’s disease and is continuing to develop and deliver tests to enable early and accurate Alzheimer’s diagnosis and has a pipeline of investigational medicines for different targets, types and stages of the disease.
14th November 2022
The malarial monoclonal antibody CIS43LS has shown a high level of efficacy after 6 months against plasmodium falciparum during the malaria season in Mali according to the findings of a study by researchers from the Mali Malaria mAb trial team.
Malaria is caused by four members of the plasmodium species including Plasmodium falciparum, P. vivax, P. ovale, and P. malariae and is transmitted after being bitten by an infective female Anopheles mosquito producing a febrile illness. Malaria is an extremely common infection and which, according to the World Health Organization (WHO), led to 241 million cases in 2020 (up from 227 million in 2019) and an estimated 627 000 deaths.
The infection disproportionately affects individuals on the African continent and WHO estimates that in 2020, 95% of all malaria cases and 96% of deaths occurred within the region with children under 5 years of age accounting for about 80% of all malaria deaths.
As well as vaccines, a malarial monoclonal antibody, CIS43LS has been developed and which targets the circumsporozoite protein which covers the surface of the infecting sporozoites and has a critical role in sporozoite development in the mosquito, and invasion of hepatocytes necessary for initiation of malaria infection. CIS43LS binds with the circumsporozoite protein, inhibiting its action and is therefore highly effective for passive prevention of malaria. In a phase 1 trial, administration of CIS43LS to adults who had never had malaria infection or vaccination, prevented malaria after controlled infection.
Based on these early and positive findings, researchers undertook a phase 2 trial to assess the efficacy and safety of CIS43LS in healthy adults in Mali during a 6-month malaria season. After an initial dose ranging study, individuals were randomised 1:1:1 to receive CIS43LS doses of either 10 mg/kg/bodyweight, 40 mg or placebo.
The primary efficacy endpoint was the first detection of P. falciparum infection in blood smear examination, and which was checked every 2 weeks for a total of 24 weeks. Prior to the study, all participants were given artemether–lumefantrine for treatment of any existing malarial infection.
Malarial monoclonal antibody efficacy
A total of 330 individuals with a median age of 34.6 years (43% female) were equally randomised to either 10, 40 mg/kg dose of CIS43LS or placebo. At enrolment, plasmodium infection was still present in 12.7% of those receiving 10 mg, 7.3% in the 40 mg group and a similar proportion of placebo participants.
The primary efficacy, i.e., P. falciparum infection, was seen in 35.5% of those receiving 10 mg, 18.2% in the 40 mg group but in 78.2% of placebo participants. At 6 months the efficacy of the 40 mg/kg dose (compared to placebo) was 88.2% and 75% for the 10 mg dose and both comparisons were statistically significant.
In terms of safety, the risk of a moderate headache was 3.3 times as high with the 40 mg/kg dose compared to placebo.
The authors concluded that CIS43LS was effective over a 6-month malaria season and without any evidence of safety concerns.
Citation
Kayentoa K et al. Safety and Efficacy of a Monoclonal Antibody against Malaria in Mali. N Engl J Med 2022
10th August 2022
A malaria monoclonal antibody provides protection against controlled infection in virtually all patients according to the findings of a phase 1 clinical trial by a US research team.
Malaria is an acute, febrile illness caused by Plasmodium falciparum (P. falciparum), a unicellular protozoan parasite, spread through the bites of infected female Anopheles mosquitoes. It is an extremely common disease and the World Health Organisation has estimated that in 2020 there were 241 million cases of malaria, leading to an estimated 627,000 deaths.
While there have been huge efforts directed towards the development of a vaccine, the available data suggests that the RTS,S/AS01 candidate malaria vaccine, has an efficacy of only 36.6%. Some research has shown how antibodies can prevent malaria by neutralising sporozoites (i.e., the infectious form of Plasmodium deposited into the skin when a mosquito bites) before they infect hepatocytes in the liver.
A recognised antibody target is the P. falciparum circumsporozoite protein, that is required for parasite motility and invasion of hepatocytes and in a 2021 study, it was shown that a malaria monoclonal antibody, CIS43LS, which targets this protein, prevented malaria after controlled infection.
For the current phase 1 trial, researchers modified the CIS43LS monoclonal antibody to create a more potent agent, L9LS and described its safety, pharmacokinetics and protective efficacy in health adults who had never been infected with malaria or received a vaccine.
Study participants were given either intravenous LSL9 at doses of 1, 5 and 20 mg/kg or a subcutaneous dose of 5 mg/kg, whereas some did not receive the monoclonal antibody and served as controls. Within 2 to 6 weeks after administration of LSL9, participants were exposed to bites on the forearm from the Anopheles stephensi mosquito which had been infected with P. falciparum.
Parasitaemia (i.e., the detection of parasites in the blood) was assessed after 21 days using a PCR test and for the purposes of the study, participants were considered to be protected by LSL9, if parasitaemia did not develop at this point in time. In cases where parasitaemia did occur, individuals were treated with 1 gm atovaquone and 400 mg of proguanil for 3 days.
Malaria monoclonal antibody and parasitaemia
A total of 27 participants were enrolled with a mean age of 24.5 years (50.3% female), 18 of whom received L9LS (and 9 serving as controls) with 5 receiving the drug subcutaneously. Controlled infection was administered to 23 participants (17 given L9LS and 6 controls).
The results showed the L9LS had dose linearity with the highest mean serum concentration of 914.2 mcg/ml from the 20 mg/kg intravenous dose and the estimated overall clearance was 46.1 ml/day with a half-life of 56 days.
Parasitaemia developed in 2 of the 17 participants given L9LS and all 6 controls (p < 0.001) and did not develop in those given 5 or 20 mg of intravenous L9LS. Interestingly, protection was afforded by serum concentrations of L9LS as low as 9.2 mcg/ml.
The authors concluded that these results indicated that prevention of malaria could be achieved after a single dose of L9LS and that further studies were needed to examine the value of the drug among infants and children.
Citation
Wu RL et al. Low-Dose Subcutaneous or Intravenous Monoclonal Antibody to Prevent Malaria N Eng J Med 2022
22nd December 2021
In a laboratory-based study, third booster sera samples from patients have been shown to produce a four to six-fold reduction in neutralisation against the Omicron COVID-19 variant. This was the finding of a preprint study by researchers from the Aaron Diamond AIDS Research Center, New York, US.
The Omicron COVID-19 variant (B.1.1.529) was first identified in southern Africa and appears to have a high level of transmissibility and will likely cause outbreaks across the globe. A concern with this particular variant is that it contains more than 30 mutations,15 of which are present in the receptor-binding domain region which is the target for neutralising antibodies produced in response to vaccination. It is therefore possible that the Omicron might lead to an increased level of infection despite vaccination although current opinion is that this could be mitigated by a third booster sera sample.
In the absence of clinical data, the US team sought to better understand the extent to which the Omicron variant is able to evade antibody neutralisation, by testing the activity of serum collected from a number of different patient samples. Initially the team created an Omicron pseudovirus and tested this against 10 sera samples collected from the Spring of 2020, which were likely to have been infected with the wild-type (original) COVID-19 virus. While there was a robust response to the wild-type, there was a greater than 32-fold reduction against Omicron and only two samples produced antibody titres above the limit of detection.
Vaccinated samples
The team then turned their attention to both fully vaccinated and third booster sera (TBS) samples. For the two mRNA-based vaccines, BNT162b2 and mRNA-1273, there was a >21-fold decrease in ID50 and > 8.6-fold decrease in boosted sera samples. For the other vaccines, Ad26.COV2.S and ChAdOx1, all samples produced antibody titres below the limit of detection apart from two samples for which the individual had a history of a prior infection.
Using 15 third booster sera samples obtained from BNT162b2 (13) and mRNA-1273, the researchers discovered that although each of these third booster sera produced antibody titres above the limit, there was a mean 6.5-fold drop compared to the wild-type.
Using authenticated Omicron isolates and samples from BNT162b2 and mRNA-1273, there was a greater than 6-fold drop in titres for fully vaccinated and a greater than 4.1-fold drop for boosted samples.
Finally, testing sera with monoclonal antibodies, the researchers found that all four combinations of monoclonal antibodies in clinical use lost substantial activity against Omicron.
Although this was a laboratory-based study and might not be replicated in clinical practice, the authors believed that COVID-19 is potentially only a mutation or two away from being resistant to current antibodies and that it was important to devise strategies that anticipate the evolutional direction of the virus and that future work should focus on the development of agents targeting conserved parts of the virus.
Citation
Liu L et al. Striking Antibody Evasion Manifested by the Omicron Variant of SARS-CoV-2 BioRxiv 2021
12th November 2021
The CHMP positive opinion for regdanvimab marks the first time a monoclonal antibody treatment for COVID-19 has received a recommendation for marketing authorisation from the European Medicines Agency (EMA).
The positive CHMP opinion was supported by data from the global Phase III clinical trial in which Celltrion enrolled more than 1315 people to evaluate the efficacy and safety of regdanvimab in 13 countries including the US, Spain, and Romania. Data showed regdanvimab significantly reduced the risk of COVID-19 related hospitalisation or death by 72% for patients at high-risk of progressing to severe COVID-19.
Rolling review of regdanvimab had been initiated by the EMA in February 2021 and the announcement of the CHMP positive opinion for regdanvimab follows the submission of a marketing authorisation application to the EMA seeking approval of regdanvimab in October 2021.
“The primary benefits of monoclonal antibodies are their high specificity and safety – they are highly specific for a single target, so these monoclonal antibodies rarely cause undesirable side effects,” said Oana Sandulescu, MD, PhD, Associate Professor of Infectious Diseases at the Carol Davila University of Medicine and Pharmacy in Romania. “An infusion of an hour of monoclonal antibodies like regdanvimab can ease COVID-19 symptoms and reduce complications in recently diagnosed, non-hospitalised people at high risk, and thus plays an important role in preventing further spread of the virus.”
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