Making modern medicines Woolfson, Adrian
Science (American Association for the Advancement of Science),
12/2022, Letnik:
378, Številka:
6626
Journal Article
Recenzirano
The business side of drug development comes to the fore in a tale of two blockbuster blood cancer therapeutics
Background
More than one third of Covid‐19 patients at the time of discharge from hospitalization have evidence of cognitive impairment and motor deficits. Patients surviving COVID‐19 are at high ...risk for subsequent development of neurological disease, particularly Alzheimer’s disease.
Method
The clinical Phase 2/3 evaluates the safety and efficacy of NA‐831 alone, and a combination therapy comprises NA‐831 with an anti‐viral drug Atazanavir, NA‐831 with an anti‐inflammatory drug, and a potential synergy between Atazanavir and Dexamethasone.
The Clinical Protocol:
Study Type: Interventional Phase 2/3
Estimated Enrollment: 525 participants
Allocation: Randomized
There will be daily symptom surveys for 14 days, then weekly thereafter for 3 weeks resulting in a total duration of follow up of 36 days.
Status: is recruiting and the study is expected to be completed by December 15, 2023
Result
Primary Outcome Measures
Time from randomization to recovery defined as
1) absence of fever, as defined as at least 48 hours since last temperature ≥ 38.0°C without the use of fever‐reducing medications
2) absence of symptoms of greater than mild severity for 24 hours
3) not requiring supplemental oxygen beyond pre‐COVID baseline
AND 4) freedom from mechanical ventilation or death
Secondary Outcome Measures
1) Brief Cognitive Rating Scale (BCRS) and
2) Clinician’s Interview‐Based Impression of Change plus caregiver input (CIBIC‐plus) after 24 weeks.
Conclusion
The progress of the clinical trials will be presented discussed.
Background
Coronavirus disease 2019 (COVID‐19) is a serious contagious illness caused by the virus strain severe acute respiratory syndrome coronavirus 2 (SARS CoV‐2). Covid‐19 patients are suffered ...from various brain complications, but underlying mechanism is not clear. So far, there is no proper therapeutic strategy against Covid‐19 and its implications on the brain.
Method
Since SARS‐CoV‐2 binds to angiotensin‐converting enzyme 2 (ACE2) for entering into host cells, to target COVID‐19 from therapeutic angle, we designed a hexapeptide corresponding to the ACE2‐interacting domain of SARS‐CoV‐2 (AIDS) that inhibits the association between receptor‐binding domain‐containing spike S1 and ACE‐2. Initially, we have validated the effect of AIDS peptide and the its role in Spike S1 associated neuroinflammatory alteration in mouse primary glia cultures. For in vivo, recombinant spike S1 was administered Intranasally for 14 days. Wild type and mutant AIDS peptide were administered post 5 days treatment of spike S1. Post two weeks treatment, we performed several behavioral assessment and biochemical evaluation
Result
Increased INOS levels and microglia activation was observed by Spike S1 treatment in mice primary microglia. AIDS peptide prominently attenuates Spike S1 associated inflammatory markers in glia cultures. Intranasal intoxication of C57/BL6 mice with recombinant SARS‐CoV‐2 spike S1 led to fever, increase in IL‐6 in lungs as well as in brain, and impairment in spatial learning memory functions and motor disabilities, mimicking some of the important symptoms of COVID‐19. Intranasal treatment with wtAIDS, but not mAIDS, peptide reduced fever, enhanced locomotor functions and cognitive and memory functions in SARS‐CoV‐2 spike S1‐intoxicated mice. Our studies show wtAIDS peptide attenuates Spike S1 inducted cytokine levels in the brain.
Conclusion
Our results illustrated that, selective targeting of ACE2‐to‐SARS‐CoV‐2 interaction by wtAIDS may be beneficial for COVID‐19 associated memory and learning deficits via maintaining the cytokine levels
Background
COVID‐19 results in increased expression of inflammatory cytokines and Alzheimer’s disease (AD) biomarkers of neuronal damage, but inflammation‐targeting clinical trials have yielded poor ...to mixed results. Our studies of other disorders with an inflammatory component, including AD, chemobrain, Down syndrome, normal aging, and West Nile Virus infection, showed that treatment with the ‘pro‐inflammatory’ cytokine granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) in humans or mouse models alleviated clinical, behavioral, and pathological features. Most recently, we completed a Phase 2 clinical trial (NCT01409915) using sargramostim/Leukine (rhuGM‐CSF) in mild‐to‐moderate AD participants, which showed that three weeks of sargramostim treatment improved MMSE scores and improved ATN blood biomarkers of AD pathology (Potter et al., 2021). Therefore, we proposed that human GM‐CSF may be repurposed to promote both the innate and adaptive immune responses in COVID‐19 patients to reduce viral load and mortality.
Method
We investigated GM‐CSF’s effects in eight‐week old male and female human ACE2 (hACE2) transgenic mice infected intranasally with 104 PFU of SARS‐CoV‐2 virus and followed them for 14 days. Mice received daily IP injections of either recombinant murine GM‐CSF or saline. Viral titers, anti‐spike protein antibody levels, and mortality were assessed.
Results
Intranasal inoculation of hACE2 transgenic mice with 104 PFU SARS‐CoV2 virus resulted in high viral titers in lungs and brains and over 85% mortality. GM‐CSF treatment beginning one day post‐infection increased anti‐spike protein antibody titers, lowered mean lung viral titers proportionately (p = 0.0020), and increased the odds of long‐term survival by up to 5.8‐fold (p = 0.0358), compared to saline.
Conclusion
GM‐CSF represents a new approach to the treatment of COVID‐19 by recruiting inflammation and the immune system to attack SARS‐CoV‐2 infection and promote survival.
GM‐CSF is likely to have a significant advantage over current approaches to the treatment of COVID‐19, including anti‐virus monoclonal antibodies, drugs designed to inhibit viral replication, and immunosuppressants, because, unlike short‐term antivirals, it activates the endogenous immune system, with likely long‐term increases in immune memory required for protection against re‐infection,
Based on its mode of action as a natural stimulator of the immune response, GM‐CSF should be effective against all current and future SARS‐CoV‐2 variants.
Abstract
Background
The COVID‐19 pandemic has halted many Alzheimer’s Disease clinical trials, with some forced to re‐start at different points along the trial time‐line with substantial protocol ...amendments and patients dropping out with substantial partial assessments. To align the functional outcomes of these protocol amendments with the original trial design at the individual patient level, we propose to use Physiology‐Based Pharmacokinetic (PBPK) and Quantitative Systems Pharmacology (QSP) Modeling to ‘correct’ the cognitive trajectory of mirror virtual patient population back to the original trail design.
Method
The Virtual Twin approach creates a PBPK computer‐simulated model of each patient with a virtual twin QSP model of trial subjects, with the same co‐medications, common genotype variants affecting metabolism and cognitive outcome; β‐amyloid and tau biomarkers. The QSP platform is a previously ADAS‐Cog calibrated model of key neuronal circuits involved in cognition, allowing to model the effects of CNS active co‐medications based on their pharmacology and genotypes based on imaging studies. In this Virtual Twin approach, the platform will be extensively validated against the actual clinical data from the completer set and the fragmented outcomes of the restarters with their individual protocol amendments, before simulating the cognitive trajectory with the original trial design for those whose trial was interrupted.
Result
Different interruption scenarios in a 24‐month AD study of a bi‐weekly amyloid antibody infusion are simulated with increased anxiolytics and anti‐depressants use after restart. The impact of changes is dependent upon the genotype combination with the 5‐HTTLPR rs 23351 > APOE > COMTVal158Met and different for placebo and active treatment. Anti‐depressants and benzo also differentially substantially affect the cognitive trajectory. We illustrate how to reconstruct the cognitive trajectory of 600 subjects (out of 1200) affected by the interruption.
Conclusion
Combining QSP modeling of the biology with PBPK modeling and extensive validation with the fragmented clinical data available, in principle allows to reconstruct the original cognitive trajectory in patients affected by the COVID‐19 interruption. In this way, the original trial design and statistical analysis plan can be applied to achieve a fair evaluation of the clinical effect of the investigative new drug.
The current standard-of-care for front-line therapy for acute myeloid leukaemia (AML) results in short-term and long-term toxicity, but still approximately 40% of children relapse. Therefore, there ...is a major need to accelerate the evaluation of innovative medicines, yet drug development continues to be adult-focused. Furthermore, the large number of competing agents in rare patient populations requires coordinated prioritisation, within the global regulatory framework and cooperative group initiatives.
The fourth multi-stakeholder Paediatric Strategy Forum focused on AML in children and adolescents.
CD123 is a high priority target and the paediatric development should be accelerated as a proof-of-concept. Efforts must be coordinated, however, as there are a limited number of studies that can be delivered. Studies of FLT3 inhibitors in agreed paediatric investigation plans present challenges to be completed because they require enrolment of a larger number of patients than actually exist. A consensus was developed by industry and academia of optimised clinical trials. For AML with rare mutations that are more frequent in adolescents than in children, adult trials should enrol adolescents and when scientifically justified, efficacy data could be extrapolated. Methodologies and definitions of minimal residual disease need to be standardised internationally and validated as a new response criterion. Industry supported, academic sponsored platform trials could identify products to be further developed. The Leukaemia and Lymphoma Society PedAL/EUpAL initiative has the potential to be a major advance in the field.
These initiatives continue to accelerate drug development for children with AML and ultimately improve clinical outcomes.
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