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This metabolic brain boost revives memory in alzheimer’s mice.

Jon Hamilton

A drug that restores brain metabolism could help treat Alzheimer's

Aging and Alzheimer's leave the brain starved of energy. Now scientists think they've found a way to aid the brain's metabolism — in mice. PM Images/Getty Images hide caption

The brain needs a lot of energy — far more than any other organ in the body — to work properly. And aging and Alzheimer’s disease both seem to leave the brain underpowered.

But an experimental cancer drug appeared to re-energize the brains of mice that had a form of Alzheimer’s — and even restore their ability to learn and remember.

The finding, published in the journal Science , suggests that it may eventually be possible to reverse some symptoms of Alzheimer’s in people, using drugs that boost brain metabolism.

The results also offer an approach to treatment that’s unlike anything on the market today. Current drugs for treating Alzheimer’s, such as lecanemab and donanemab, target the sticky amyloid plaques that build up in a patient’s brain. These drugs can remove plaques and slow the disease process, but do not improve memory or thinking.

The result should help “change how we think about targeting this disease,” says Shannon Macauley , an associate professor at the University of Kentucky who was not involved in the study.

A surprise, then a discovery

The new research was prompted by a lab experiment that didn’t go as planned.

A team at Stanford was studying an enzyme called IDO1 that plays a key role in keeping a cell’s metabolism running properly. They suspected that in Alzheimer’s disease, IDO1 was malfunctioning in a way that limited the brain’s ability to turn nutrients into energy.

So the team used genetics to eliminate the enzyme entirely from mice that develop a form of Alzheimer’s. They figured that without any IDO1, brain metabolism would decline.

The brain makes a lot of waste. Now scientists think they know where it goes

“We expected to see everything [get] much, much, much worse”, says Dr. Katrin Andreasson , a professor of neurology and neuroscience at Stanford. “But no, it was the complete opposite.”

Without the enzyme, the mouse brains were actually better at turning glucose into energy and didn’t exhibit the memory loss usually associated with Alzheimer’s.

“It was such a profound rescue that we sort of went back to the drawing board and tried to figure out what was going on,” Andreasson says.

Eventually, the team found an explanation.

Getting rid of the enzyme had altered the behavior of cells called astrocytes.

Usually, astrocytes help provide energy to neurons, the cells that allow for learning and memory. But when the toxic plaques and tangles of Alzheimer’s begin to appear in the brain, levels of IDO1 rise and astrocytes stop doing this job.

What causes Alzheimer's? Study puts leading theory to 'ultimate test'

“They’re kind of put to sleep,” Andreasson says. So “you’ve got to wake them up to get them to help the neurons.”

And that’s what happened when scientists used genetics to remove IDO1.

Their hypothesis was that high levels of IDO1 were limiting the astrocytes’ ability to produce lactate, a chemical that helps brain cells, including neurons, transform food into energy.

To confirm the hypothesis, the team, led by Dr. Paras Minhas , did a series of experiments. One involved placing a mouse in the center of a shiny white disk under a bright light.

“It really wants to get out of there,” Andreasson says. “But it has to learn where the escape hole is” by following visual cues.

Healthy mice learned how to read those cues after a few days of training, and would escape almost instantly.

“But in the Alzheimer mice, the time to find the escape hole really skyrocketed,” Andreasson says.

That changed when the team gave these mice an experimental cancer drug that could block the enzyme much the way genetic engineering had.

A protein called Reelin keeps popping up in brains that resist aging and Alzheimer’s

The treated mice learned to escape the bright light as quickly as healthy animals. And a look at their brains showed that their astrocytes had woken up and were helping neurons produce the energy needed for memory and thinking.

In the hippocampus, a brain area that’s critical for memory and navigation, tests showed that the drug had restored normal glucose metabolism even though the plaques and tangles of Alzheimer’s were still present.

The team also tested human astrocytes and neurons derived from Alzheimer’s patients. And once again, the drug restored normal function.

Beyond plaques and tangles

The experiments add to the evidence that Alzheimer’s involves a lot more than just the appearance of plaques and tangles.

“We can have these metabolic changes in our brain,” Macaulay says, “but they’re reversible.”

Neurons have long been the focus of Alzheimer’s research. But the new results also show how other kinds of cells in the brain can play an important role in the disease.

The brain is a bit like a beehive, where a neuron is the queen, Macaulay says. But she’s kept alive by worker bees, like astrocytes, which are asked to do more as Alzheimer’s changes the brain.

“Those worker bees are getting unbelievably taxed from all the things they are being asked to do,” Macaulay says. “When that happens, then the whole system doesn’t work well.”

Metabolic treatments that restore astrocytes and other helper cells in the brain could someday augment existing Alzheimer’s drugs that remove amyloid plaques, Macauley says.

And the metabolic approach may be able to improve memory and thinking — something amyloid drugs don’t do.

“Maybe this can make your astrocytes and your neurons work a little bit better, so that you function a little bit better,” Macaulay says.

But first, she says, the promising results will have to be replicated in people.

• Alzheimer's research
• Alzheimer's disease
• Brain research

• Open access
• Published: 02 September 2024

Tilorone mitigates the propagation of α-synucleinopathy in a midbrain-like organoid model

• Qi Zhang 1 ,
• Meng Liu 2 ,
• Juhyung Lee 3 ,
• Brothely Jones 1 ,
• Bing Li 1 ,
• Wenwei Huang 1 ,
• Yihong Ye 3 &
• Wei Zheng 1  

Journal of Translational Medicine volume  22 , Article number:  816 ( 2024 ) Cite this article

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Parkinson’s disease (PD) is a neurodegenerative condition characterized by the loss of dopaminergic neurons and the accumulation of Lewy-body protein aggregates containing misfolded α-synuclein (α-syn) in a phosphorylated form. The lack of effective models for drug screens has hindered drug development studies for PD. However, the recent development of in vitro brain-like organoids provides a new opportunity for evaluating therapeutic agents to slow the progression of this chronic disease.

In this study, we used a 3D brain-like organoid model to investigate the potential of repurposing Tilorone, an anti-viral drug, for impeding the propagation of α-synucleinopathy. We assessed the effect of Tilorone on the uptake of fluorescently labeled α-syn preformed fibrils (sPFF) and sPFF-induced apoptosis using confocal microscopy. We also examined Tilorone’s impact on the phosphorylation of endogenous α-syn induced by pathogenic sPFF by immunoblotting midbrain-like organoid extracts. Additionally, quantitative RT-PCR and proteomic profiling of sPFF-treated organoids were conducted to evaluate the global impact of Tilorone treatment on tissue homeostasis in the 3D organoid model.

Tilorone inhibits the uptake of sPFF in both mouse primary neurons and human midbrain-like organoids. Tilorone also reduces the phosphorylation of endogenous α-syn induced by pathogenic α-syn fibrils and mitigates α-syn fibril-induced apoptosis in midbrain-like organoids. Proteomic profiling of fibril-treated organoids reveals substantial alterations in lipid homeostasis by α-syn fibrils, which are reversed by Tilorone treatment. Given its safety profile in clinics, Tilorone may be further developed as a therapeutic intervention to alleviate the propagation of synucleinopathy in PD patients.

Introduction

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder after Alzheimer’s disease [ 1 ]. It predominantly affects the elderly population and is characterized by the degeneration of dopamine-producing cells in the substantia nigra, leading to decreased striatal dopamine levels, which in turn results in an imbalance of the direct and indirect basal ganglia pathways, causing motor symptoms such as bradykinesia, resting tremor, rigidity, and postural instability [ 2 , 3 ]. Non-motor symptoms, including autonomic dysfunction, sleep disorders, and cognitive impairment, are also significant contributors to PD-associated disability. The etiology of PD is multifaceted, encompassing both genetic and environmental factors. The familial forms of the disease highlight the importance of genes such as SNCA , LRRK2 , and GBA , while environmental factors include exposure to pesticides and a history of traumatic brain injury [ 4 ].

Current therapeutic strategies for PD primarily address symptomatic aspects. A primary pharmacological treatment is dopamine replacement therapy (DRT), which uses levodopa, a dopamine agonist, and monoamine oxidase-B (MAO-B) inhibitors. However, these treatments do not halt or slow the neurodegenerative process and are associated with side effects such as dyskinesia and motor fluctuations [ 5 ]. Thus, there is an urgent need for better PD therapies in clinical application.

A salient pathological hallmark of PD is the presence of intraneuronal proteinaceous inclusions known as Lewy bodies or Lewy neurites in the cell body and processes, respectively, in neurons. Alpha-synuclein (α-syn) is a key critical component of Lewy bodies and Lewy neurites [ 6 ]. In its native state, α-syn is a soluble, misfolding-prone protein predominantly found at presynaptic terminals, although its exact function remains elusive [ 7 ]. It has been implicated in physiological processes, such as synaptic vesicle trafficking and neurotransmitter release [ 8 ].

α-syn undergoes phosphorylation at serine 129, and the modified species is the predominant component in α-syn fibrils that form Lewy bodies in PD. Whether α-syn-containing aggregates is causal to neurodegeneration is unclear. However, α-syn aggregation is enhanced by PD-associated genetic mutations in SNCA , the gene encoding α-syn, and by post-translational modifications such as partial proteolysis [ 9 ]. Importantly, cell-to-cell propagation of α-syn-containing aggregates, a key feature of α-syn-associated PD pathology (also known as synucleinopathy), was observed in patient brains as the disease progressed. These findings led to the hypothesis that the prion-like transmission of α-syn aggregates, during which misfolded α-syn species acts as a template to seed and propagate neurotoxic conformers, might be a key contributing factor to this devastating disease [ 10 , 11 , 12 , 13 ].

In recent years, efforts have been intensified to develop disease-modifying treatments, with antibody-based and gene therapies being a significant focus. Antibodies can promote the clearance of amyloid-like aggregates or block their formation and propagation. Prasinezumab (PRX002) and BIIB054 are antibodies under investigation that target aggregated forms of α-syn. However, they face significant hurdles in clinical trials [ 14 , 15 ]. Gene therapies that target α-syn directly, including strategies to knock down SNCA using antisense oligonucleotides (ASOs), are being tested with promising results observed in rodent and non-human primate models [ 16 , 17 ]. However, these high-risk preclinical studies are time-consuming and resource-demanding. Economic in vitro platforms that allow rapid evaluation of drugs’ syncleinopathy-alleviating potential are urgently needed to accelerate PD drug development.

This study aims to develop a human induced pluripotent stem cell (iPSC)-derived 3D midbrain organoid system as an in vitro drug testing platform. We previously identified Tilorone as a potent inhibitor of heparan sulfate (HS)-mediated α-syn fibril uptake in 2D cell models [ 18 ]. Tilorone is a small molecule used in clinics as a broad-spectrum antiviral agent [ 19 , 20 , 21 , 22 ]. Studies have shown that Tilorone treatment stimulates interferon secretion in mice [ 23 ] and alters lysosome activities in vitro [ 24 , 25 ]. Its newly established role in HS-mediated endocytosis prompted us to test Tilorone’s ability to inhibit α-syn fibril internalization and propagation in mature midbrain organoids, a 3D brain-like system. Our findings demonstrate that Tilorone inhibits effectively the cellular uptake of α-syn fibrils and suppresses fibril-induced endogenous α-syn phosphorylation in these midbrain-like organoids. Proteomic profiling of sPFF-treated organoids indicate that Tilorone can attenuate the abnormal cellular pathways associated with α-syn propagation. In conclusion, these results highlight the potential of Tilorone as a therapeutic agent for PD and underscore the advantages of using human 3D organoids in drug screening and preclinical development.

Materials and methods

Protein purification, labeling, and spff production.

Human α-syn protein was expressed in BL21(DE3) RIL-competent E. coli and purified following an established protocol [ 26 ]. In brief, 1 L of E. coli culture was induced to express α-syn with 0.5 mM isopropyl β-d-1-thiogalactopyranoside at 20 °C overnight. Cells were pelleted by centrifugation at 5,000 rpm for 20 min, then resuspended in high-salt buffer (750 mM NaCl, 10 mM Tris pH 7.6, and 1 mM EDTA) with a protease inhibitor cocktail and 1 mM PMSF (50 mL for 1 L of culture). Resuspended cells were sonicated with a 0.25-inch probe tip at 60% power for a total time of 10 min. Sonicated cell lysate was boiled for 15 min to precipitate unwanted proteins and then cooled on ice for 20 min. The lysate was then centrifuged at 6,000 × g for 20 min. The supernatant containing α-syn was collected and dialyzed in TNE buffer (10 mM Tris pH 7.6, 25 mM NaCl, and 1 mM EDTA) overnight at 4 °C. Proteins were further fractionated using a Bio-Rad NGS chromatography system first through a size exclusion column in TNE buffer, followed by an ion exchange Mono-Q column. Protein was eluted in TNE buffer containing increasing concentrations of NaCl (25 mM to 1 M). Purified monomeric α-syn was dialyzed extensively in PBS, followed by labeling with a threefold molar excess of pH-Rodo Red or Alexa Fluor 596 succinimidyl ester fluorescence dye (Thermo Fisher) for 4 h at room temperature. Unconjugated dye was removed by dialysis in PBS. The labeled α-syn was adjusted to 5 mg/mL in a volume of 500 µL and then placed in a ThermoMixer shaker (Eppendorf) at 1,000 rpm at 37 °C for 7 d to generate α-syn preformed fibrils (sPFF). sPFFs were stained with 3% uranyl acetate and examined by electron microscopy to verify the formation of sPFF. PFFs were then stored in a − 80 °C freezer in small aliquots.

Cells, immunostaining, immunoblotting, and data analyses

Wild-type C57BL/6 mice were obtained from Jackson Labs. The animal study protocol (K117-LMB-20) and ethical review were approved by the NIDDK Animal Research Advisory Committee. C57BL/6 mice were maintained under pathogen-free conditions in the Division of Veterinary Resources of National Institute of Health (NIH). Primary hippocampal neuron cultures were prepared from hippocampi of P0-1 murine pups. To obtain neuronal cells, hippocampi were dissected in Hanks’ balanced salt solution (HBSS) and washed with MEM (Thermo Fisher, 11095080) twice. The hippocampi were incubated with 0.25% trypsin-EDTA (Thermo Fisher, 25300062) containing 100 µg/mL DNase-I (Sigma, 10104159001) at 37 °C for 10 min. Trypsin was then inactivated by addition of MEM containing 10% FBS. After washing with MEM three times, the tissues were dissociated by pipetting several times in MEM containing 100 µg/mL DNase-I. Cells were then centrifuged at 300 x g for 5 min and resuspended in the plating medium (MEM containing 10% FBS, 1 mM sodium pyruvate (Sigma, S8636), 2 mM L-glutamine (Sigma, 59202 C), 100 µg/mL primocin (Invitrogen, ant-pm-05) and 0.6% glucose). The cell solution was passed through a 70-µm strainer (VWR, 76327–100) once to filter out any cell clumps. Cells were seeded into plates or µ-slide 4 well chamber with glass bottom (ibidi, 80,427) pre-coated with 50 µg/ml poly-D-lysine (Sigma, P7280) and 2 µg/mL laminin (Sigma, L2020). Generally, we seed hippocampal neuronal cells obtained from a pup to cover 4 cm 2 or 8 cm 2 of surface area for Immunoblotting and imaging purpose, respectively. We seed cortical cells obtained from a pup to cover 15 cm 2 surface area for immunoblotting. After incubation at 37 °C with 5% CO 2 for overnight, the culture medium was changed to the Neurobasal media (Thermo, 21103049) containing 2% B27 (Thermo, 17504044), 0.5 mM L-glutamine and 100 µg/mL primocin to support the growth of hippocampal neurons. The culture media was replaced with fresh media once a week or when needed.

Anti-mouse phosphorylated α-syn was stained with an antibody obtained from Abcam (catalog number: 51253). Generally, cells were fixed with 4% (wt/vol) paraformaldehyde/4% (wt/vol) sucrose/0.5% (vol/vol) TX-100 in PBS for 15 min, followed by primary antibody incubation overnight.

Anti-human phosphorylated α-syn antibody was obtained from Cell Signaling Technology (catalog number: 23706). Protein extraction was done from 5 to 4 pooled individual organoids using the 350 µl of 1× RIPA buffer (containing 50 mM Tris-HCl pH 7.4, 150 mM NaCl, 0.25% deoxycholic acid, 1% NP-40, 1 mM EDTA, protease inhibitor cocktail (Roche), and 1 x HaltTM phosphotase inhibitor (Thermo Fisher). The lysates were sonicated in the Q125 Sonicators (Thomas Scientific) for 10 cycles of 30 s on (20% output) and 30 s off. Then, samples were spin down at 12,000 g for 5 min at 4 °C. The 180 ul of supernatant were collected, mixed with 4 x loading buffer, and boiled at 95 °C for 5 min. Proteins in the samples were loaded into NuPAGE™ 4 to 12%, Bis-Tris gel (Thermo Fisher), followed by transferred to PVDF membrane. The membranes were blotted with antibody overnight and developed. Band quantifications were performed with Image Lab (Bio-Rad).

Fluorescence confocal images were acquired by a Nikon CSU-W1 SoRa microscope equipped with a temperature control enclosure and a CO 2 control. 3D image reconstructions and analyses were done by Imaris software (Licensed to NIH). Fluorescence intensity was analyzed by open-source Fiji software. To this end, images were converted to individual channels, and regions of interest were drawn for measurement. Statistical analyses were performed using either Excel or GraphPad Prism 8.0 and 9.0. P values were calculated by Student’s t test using Excel or one-way ANOVA by GraphPad Prism 8.0 and 9.0. Linear curve fitting, nonlinear curve fitting, and IC50 calculation were done with GraphPad Prism 8.0 and 9.0. For nonlinear fitting, the inhibitor vs. response–variable slope model or the exponential decay model was used. Images were prepared by Photoshop and Illustrator (Adobe). Data processing and reporting are adherent to community standards.

ATP content cytotoxicity assay in the 96-well format

cells were seeded in white, transparent bottom 96-well microplate (Thermo Fisher Scientific) at 20,000 cells per well in 100 µL/well neuronal medium and incubated at 37 °C with 5% CO2. The medium was carefully removed and 100 µL medium with compounds was added into each well. The plates were then incubated at 37 °C for additional 14 days. After incubation, 50 µL/well of ATPLite (PerkinElmer) was added to assay plates and incubated for 15 min at room temperature. The luminescence signal was measured using a Victor plate reader (PerkinElmer). Data were normalized with wells containing cells but no compound as 100%, and wells containing media-only as 0%.

Midbrain organoid development

Midbrain organoids (MOs) were generated from iPSCs using a published method by Dexorgen, as government contracted service [ 27 ]. Briefly iPSCs were dissociated into single cells with Gentle Cell Dissociation Reagent (GCDR; Cat# 07174, STEMCELL, 100 ml/bottle) and plated into an Aggrewell plate (Stemcell Technologies Inc.) at 3 × 10 6 cells per well. The plate was spun down according to manufacturer’s recommendation in containing midbrain differentiation medium supplemented with 5 µM ROCK inhibitor Y-27,632 (Tocris 1254). Spheroids were collected and transferred into an ultralow attachment 6-well plate (Corning) containing midbrain differentiation medium and placed on an orbital shaker rotating at 120 rpm in an incubator. After 18 days of differentiation, organoids were treated with 0.5 µM AraC for 14 days to stop the organoids from expanding too big. At day 60, organoids were transferred to a 12-well plated and treated with Tilorone (0, 0.5, 2, 4 µM; added 30 min prior to preformed fibrils) and 200 nM preformed fibrils. After 48 h of co-incubation, fresh medium with Tilorone alone was added to the organoids and cultured for an additional 14 days. Fresh medium was changed every other day and organoids were shaken at 120 rpm in an orbital shaker. On day 75, organoids were collected and fixed in 4% PFA and cryosectioned for immunostaining. Samples maintained, sliced and immunostained by Dexorgen, Inc as government contracted service.

qPCR and proteomic analyses

Taq man Parkinson’s disease associated genes array plates were purchased from Thermo Fisher with array ID: PRPRJ2W. Total RNA was extracted from 10 brain organoid per each sample using TriPure reagent (Roche) and purified using RNeasy MinElute Cleanup Kit (Promega) following the standard protocols. The RNA concentration was measured by Nanodrop 2000 UV spectrophotometer, and 1 µg total RNA was converted to cDNA using the iScript Reverse Transcription Supermix (BioRad) system. Samples were analyzed on ViiA 7 real-time PCR system with standard protocol (Table S1 ). For proteomic sequencing, the service was provided by Poochon scientific as government contract service. Generally, 18 frozen organoids pellet samples were received and processed for the study. The preparation of the protein lysates from 18 frozen pellet samples was performed. Protein concentrations were measured using the BCA method. An equal amount of total protein from each sample was processed for MS analysis. In summary, 100 µg of protein from each of the 18 samples was processed for trypsin digestion, followed by TMT-multiplex labeling using one TMT-16plex set. 18 unique TMT tags were used to label 50 µg of trypsin-digested peptides from each of the 18 digests. The LC-MS/MS analysis was carried out using a Thermo Scientific Orbitrap Exploris 240 Mass Spectrometer and a Thermo Dionex UltiMate 3000 RSLCnano System. Each peptide fraction from the set of 24 fractions was loaded onto a peptide trap cartridge at a flow rate of 5 µL/min. The trapped peptides were eluted onto a reversed-phase 25 cm C18 EasySpray nano column (Thermo) using a linear gradient of acetonitrile (3–36%) in 0.1% formic acid. The elution duration was 110 min at a flow rate of 0.3 µL/min. Eluted peptides from the EasySpray column were ionized and sprayed into the mass spectrometer, using an EasySpray Ion Source (Thermo) under the following settings: spray voltage, 1.6 kV, Capillary temperature, 275 °C. The 24 fractions were analyzed sequentially.

The Exploris 240 instrument was operated in the data dependent mode to automatically switch between full scan MS and MS/MS acquisition. Survey full scan MS spectra (m/z 350 − 1800) was acquired in the Orbitrap with 35,000 resolutions (m/z 200) after an accumulation of ions to a 3 × 10 6 target value based on predictive automatic gain control (AGC). The maximum injection time was set to 100 ms. The 20 most intense charged ions (z ≥ 2) were sequentially isolated and fragmented in the octopole collision cell by higher-energy collisional dissociation (HCD) using normalized HCD collision energy at 30% with an AGC target of 1 × 105 and a maximum injection time of 400 ms at 17,500 resolutions. The isolation window was set to 2 and fixed first mass was 100 m/z. The dynamic exclusion was set to 20 s. Charge state screening was enabled to reject unassigned and 1+, 7+, 8+, and > 8 + ions.The set of 24 MS Raw data files acquired from analysis of the 24 fractions were searched against human protein sequences database obtained from the Uniprot KB website using Proteome Discoverer 2.4 software (Thermo, San Jose, CA) based on the SEQUEST and percolator algorithms. The false positive discovery rate (FDR) was set to 1%. The resulting Proteome Discoverer Report contains all assembled proteins with peptides sequences and peptide spectrum match counts (PSM#), and TMT-tag based quantification ratio.

Proteomics data analysis

Foldchanges of protein abundance were calculated as ratio of mean protein expression under compared conditions (Table S2 ). P-values were calculated by Student T test. Proteins with log2Foldchanges > 0.1 and p-values < 0.05 were considered as differentially expressed proteins. R package ggplot2 (version 3.4.0) was used to plot the volcano plot of differentially expressed proteins. R package pheatmap (version 1.0.12) was used to plot all the heatmap figures.

Gene ontology (GO) analysis

Genes with average fold changes ≥ 1.5 were selected for Gene Ontology (GO) analysis of biological pathways (BP) and cellular components (CC) using function enrichGO from R package ClusterProfilter (version 4.2.2). Terms with adjusted p-values < 0.05 were considered as significantly enriched biological terms. Top 30 significantly enriched biological terms ordered by adjusted p-values were displayed. R package aPEAR (version 1.0.0) was used to calculate enrichment networks of the top 30 significantly enriched terms. The GO pathway analyses were obtained from GeneCards ( https://www.genecards.org/ ).

Tilorone inhibits α-syn fibril uptake and fibril-induced endogenous α-syn phosphorylation in primary neurons

Our recent drug repurposing screen identified the antiviral drug Tilorone as a small-molecule inhibitor that blocks cellular uptake of heparan sulfate (HS)-mediated cargos including α-syn sPFF [ 18 ]. The screening, however, was performed using an immortalized cancer cell line. Thus, it is unclear whether Tilorone can inhibit the cell entry of α-syn sPFF in neuronal cells.

To evaluate the effect of Tilorone on neurons, we isolated primary hippocampal neurons from newborn mice and exposed them to fluorescence-labeled α-syn sPFF in the absence or presence of Tilorone at different concentrations for two weeks. Confocal fluorescence microscopy confirmed that Tilorone effectively decreased the uptake of α-syn fibrils by mouse primary neurons in a dose-dependent manner, with maximal inhibition observed at two micromolars (Fig.  1 A, B). Moreover, by immunostaining cells with an antibody recognizing Ser129-phosphorylated α-syn, which is known to be induced by exogenous α-syn fibrils, and is a major Lewy body component and a disease progression marker, we demonstrated that Tilorone could also reduce sPFF-induced endogenous α-syn phosphorylation (Fig.  1 A, C).

Tilorone reduces α-syn fibril-induced phosphorylation of endogenous α-syn in primary neurons. (A) Primary neurons treated with Alexa Flour 594 -labeled preformed human α-syn fibrils (sPFF-A 594 ) (100 nM) for 14 days in the absence or presence of the indicated concentrations of Tilorone (Tilo.) were stained with antibodies specifically against phosphorylated mouse α-syn in green. (B) Quantification of internalized sPFF-A 594 . A.U., arbitrary units. (C) Quantification of phosphorylated α-syn fluorescence intensity. (D) Primary neurons treated with varied doses of Tilorone for 14 days, and the cellular ATP level was measured by an ATPLite luminescence assay. ( n  = 3, Ordinary one way ANOVA analysis, p value not significant for 50 nM sample vs. untreated, 100 nM vs. untreated, 400 nM vs. untreated, 800 nM vs. untreated, p value 0.0001 for 1600 nM vs. untreated, p value 0.0018 for 3200 nM vs. untreated, p value < 0.001 for 6400 nM vs. untreated)

We also assessed the cytotoxicity of Tilorone on these neurons by titrating its concentration from 50 nM to 6.4 µM using an assay monitoring cellular ATP levels (Fig.  1 D). Tilorone did not affect the cellular ATP levels at concentrations below 1 µM. Collectively, these findings indicate that Tilorone can mitigate α-syn fibril uptake and seeding by neurons at concentrations well tolerated by neurons.

An organoid culture system recapitulates PD pathology

The human midbrain-like organoids offers advanced three-dimensional (3D) models that mimic the complex tissue structures formed by different cell types in the human midbrain. Derived from human iPSC, these organoids provide a powerful platform for detailed investigation of mechanisms underlying neurological disorders such as PD.

To develop a midbrain-like PD-relevant organoid model for drug testing, we cultured and differentiated iPSC in 3D. We cultured these organoids for 60 days to achieve sufficient maturation. Immunostaining and confocal microscopy confirmed the developments of dopaminergic neurons and other neuronal cell types at this time point (Fig.  2 A).

Upregulated PD-replated genes in 3D organoids treated with preformed α-syn fibrils. (A) The experiment scheme for assessing the midbrain-like organoids treated with preformed α-syn fibrils and Tilorone (top). The bottom panels show representative images of differentiated organoids immunostained by antibodies against the indicated neuronal markers at different time points. Note that midbrain-like organoids became mature at day 60. (B) A heatmap shows the relative expression levels of 94 PD - associated genes before and after sPFF treatment. (C) Enriched Biological Pathways (BP) or (D) molecular functions (MF) of the upregulated genes ( n  = 75, fold change ≥ 1.5-fold) analyzed by RT-qPCR. GO terms with p-values < 0.05 were considered as significantly enriched terms. Highly enriched terms were displayed in the dot plot (left) with each dot representing an enriched GO term. The size of the dot indicates gene number. The dot color indicates the level of significance. The top 30 highly enriched GO terms were used to identify enriched networks (right). GO terms were clustered based on the similarity of the enriched genes in the terms. GO terms were clustered and connected by lines if they share enriched genes. Shorter lines between GO terms (represented by dots) indicate higher similarity of enriched genes in these terms

We then subjected the organoids to a treatment regime involving sPFF for additional 14 days. We analyzed the expression levels of 94 PD-associated genes by microarray-based quantitative RT-PCR (Fig.  2 A). Significantly altered genes were analyzed to identify interactions based on either biological pathways or molecular functions. These analyses revealed a significant upregulation of several modules such as synaptic formation, synapse structure or activity regulation, and ubiquitin protein ligase binding as molecular signatures altered by α-syn fibrils. These changes might result from an adaptive response to the proteotoxic insult by cells in the organoids to maintain neuronal communications and functions, which may not be entirely successful because our gene expression analysis also suggested a modest elevation in neuronal apoptotic processes following α-syn fibril treatment (Fig.  2 B, C). Thus, the results of our array-based qRT-PCR suggest that organoids exposed to α-syn fibrils do exhibit some features of PD pathology, confirming them as a valuable tool for PD therapeutic evaluation.

Tilorone inhibits α-syn fibrils uptake and fibril-induced α-syn hyper-phosphorylation in human midbrain-like organoids

To investigate Tilorone’s impact on synucleinopathy in midbrain-like organoids, we administered co-treatments involving fluorescence-labeled sPFF and different concentrations of Tilorone. Consistent with our gene expression analyses (Fig.  3 ), immunostaining and confocal microscopy revealed that α-syn fibril treatment accelerated cell death in the organoid’s outermost layers, as shown by the cell death marker Caspase3 (Fig.  3 A). Notably, the distribution of α-syn fibrils within Tilorone-treated organoids diverged significantly from those treated with DMSO control. While control organoids exhibited diffusive α-syn fibril signals in a thick layer of cells, Tilorone treatment resulted in the concentration of fibrils primarily in a thin layer at the organoid’s periphery (Fig.  3 A, B). This suggests Tilorone not only impedes the internalization of fibrils but also restricts their intercellular transmission within the organoid. As expected, 3D confocal microscopy analyses of sliced organoid samples confirmed reduced uptake of α-syn fibrils by the organoids, upon Tilorone treatment (Fig.  3 C).

Tilorone reduces sPFF-induced pathology in midbrain-like organoids. (A) Tilorone reduces cell death induced by added α-syn fibrils. (B) Organoids treated with Alexa Fluor 594 -labeled sPFF (orange) and Tilorone were sliced and stained with antibody targeting tyrosine hydroxylase (Green). Images were taken by 3D super-resolution fluorescence microscopy. (C) The graphs show the quantification of internalized sPFF fluorescence intensity averaged by spot volume (top) and the quantification of internalized sPFF spot number averaged by field ( n  = 2 Ordinary one-way ANOVA analysis, p value < 0.001 for 0.5µM vs. Ctrl, p value < 0.001 for 1µM vs. Ctrl). (D) Tilorone reduces sPFF-induced hyper-phosphorylation of α-syn in 3D organoids as revealed by immunoblotting

We next employed antibodies specific to human α-syn phosphorylated at Ser129 to analyze whole-cell extract samples from organoids exposed to α-syn fibrils in the presence or absence of Tilorone. The results indicated a modest increase in α-syn phosphorylation in organoids treated solely with sPFF compared to the untreated control group. Importantly, Tilorone co-treatment led to a marked reduction of phosphor-α-syn, notably at a concentration of 0.5µM (Fig.  3 D).

Proteomic analyses reveal disease-associated signatures rescued by Tilorone

To have an in-depth understanding of how Tilorone affects the response of organoids to α-syn fibrils, we extracted proteins from untreated, α-syn fibril-treated organoids and those co-treated with α-syn fibrils and Tilorone. We used mass spectrometry to analyze these samples’ whole proteome and compared the relative abundance of the identified proteins. Unlike array-based qRT-PCR analyses (Fig.  2 ), this approach is unbiased and more thorough. Indeed, our analyses revealed a profound change in the whole proteome between untreated and α-syn fibril-treated organoids (Fig.  4 A). Ontology pathway analysis suggested that many proteins related to lipid metabolism (e.g., FABP4, OSBPL7, RINT1, and CAV-1) were upregulated by sPFF (Fig.  4 B-D), strengthening a previously suggested link between lipid deregulation and PD pathology [ 28 , 29 ]. Additionally, several proteins critical for mitochondrial functions are significantly altered by α-syn fibril treatment (Fig.  4 B-D), recapturing the role of mitochondria in PD pathology.

The effect of Tilorone on the global proteome of sPFF-treated organoids. (A) A volcano plot shows the proteins differentially regulated in sPFF-treated organoids. Dashed lines denote the threshold of p-value < 0.05 and Log2 FoldChange > 0.1. Proteins with p-values < 0.05 and Log2 FoldChange > = or < = 0.1 were color-labeled, in red and blue, respectively. (B , C) Heatmaps showing proteins whose abundance was altered by sPFF and Tilorone (Tilo). Proteins with p-value < 0.05 and Log2 FoldChange > 0.1 were considered as differentially regulated. B shows the relative abundance of all differentially regulated proteins. C highlights proteins indicated in the boxed area in B. (D) A Sankey plot showing involved biological pathways of the proteins in C. The Gene Ontology (GO) results for each protein are obtained from GeneCard.

Among proteins affected by α-syn fibril treatment, only a small subset was reversed by exposing α-syn fibril-treated organoids to Tilorone. Notably, the most significant list includes many of the above-mentioned proteins involved in lipid metabolism and mitochondria regulation (Fig.  4 B, C). For example, fatty acid binding protein 4 (FABP4), a fatty acid transporting protein that regulates lipid homeostasis [ 30 , 31 ], was most significantly upregulated by α-syn fibril treatment, and this upregulation was completely abolished by Tilorone co-treatment (Fig.  4 C). Other fibril-induced proteins whose abundance was reduced by Tilorone include OSBPL7, which belongs to the oxysterol-binding protein-like family known for their roles in intracellular lipid transfer at membrane contact sites [ 32 , 33 , 34 ], Caveolin-1 (CAV-1), a caveolae-associated membrane protein widely associated with endocytosis, extracellular matrix organization, and cholesterol distribution [ 35 ], and Rad50 interacting protein (RINT1), which regulates vesicular trafficking between the ER and Golgi apparatus and lipid droplet biogenesis [ 36 ]. Among the identified mitochondria regulators, Acyl-CoA Dehydrogenase Short Chain (ACADS) is crucial for converting short-chain fatty acids into acetyl-CoA, feeding into the citric acid cycle for ATP production at the mitochondria. Glycerol-3-Phosphate Dehydrogenase 1 (GPDA), involved in the glycerol-phosphate shuttling, facilitates the transfer of reducing equivalents (NADH) from the cytosol into the mitochondria, supporting ATP production through oxidative phosphorylation. Mitochondrial basic amino acids transporter (MCATL) carries amino acids, carboxylic acids, fatty acids, and nucleotides across the inner membrane and is crucial for energy conversion [ 37 , 38 ].

Tilorone suppresses neuroinflammation in sPFF-treated organoids

Since previous studies revealed signs of neuroinflammation in sPFF-treated neurons [ 39 , 40 ]and because Tilorone was known to activate interferon production in mice [ 41 ], we examined whether Tilorone could affect neuroinflammation in sPFF-treated organoids. To this end, we re-analyzed the mass spectrometry data, focusing on the expression of a collection of secretory proteins including cytokines and chemokines in midbrain organoids treated with sPFF or with both sPFF and Tilorone. When we compared the protein levels of these treated organoids to these of untreated control organoids, only a few neuroinflammation-related proteins were detected, likely due to efficient secretion. Nevertheless, our analysis showed that these proteins, including complement component 3 (C3), SEMA7A, and CXCL12, were among the most significantly upregulated ones following sPFF treatment (Fig.  5 ), suggesting that sPFF indeed induces neuroinflammation in organoids. Strikingly, in organoids co-treated with Tilorone and sPFF, these proteins were either restored to near-normal levels or further downregulated. Mass spectrometry data also showed that sPFF treatment downregulated a cohort of secretory proteins closely linked to neuronal functions. These include Interleukin-14 (IL-14, also known as α-taxilin), a syntaxin-binding protein known to regulate vesicle fusion and neurotransmitter release [ 42 ], GDF15, a neuroprotective factor [ 43 ], and GDNF (Glial Cell-Derived Neurotrophic Factor), a critical regulator of dopaminergic neuron growth and survival [ 44 , 45 ]. To our satisfaction, Tilorone treatment dose-dependently elevated these proteins, highlighting its role in counteracting the neurodegenerative activities of α-syn fibrils (Fig.  5 ). These findings underscore the potential of Tilorone to regulate key cytokines involved in neuronal health, offering new insights into the therapeutic strategies for PD. Our analyses did not identify interferons even in cells treated with a high dose of Tilorone either by itself or with sPFF (Fig.  5 , Figure S1 ), which might be due to low expression of these factors under non-infection conditions or efficient secretion.

The effect of Tilorone on secretory proteins in sPFF-treated midbrain organoids. A heatmap showing secretory proteins whose abundance was altered by sPFF and Tilorone (Tilo). Proteins with p-value < 0.05 and Log2 FoldChange > 0.1 were considered as differentially regulated

Our study suggests a potential neuroprotective role for Tilorone in mitigating synucleinopathy-associated with PD because it effectively reduces the uptake of α-syn fibrils and the propagation of phosphorylated α-syn in human midbrain-like organoids. This is particularly significant given that phospho-α-syn is a major component of Lewy bodies implicated in a toxic gain-of-function leading to neuronal cell death. The reduction of fibril uptake and α-syn phosphorylation by Tilorone supports it as a therapeutic agent targeting early stages of synucleinopathy-associated neuronal damages.

Tilorone is currently used in clinics as an anti-viral agent in several European countries [ 19 , 20 , 21 , 22 ]. It can be taken orally and has a broad anti-viral spectrum [ 46 ]. It was suggested to act as an immune modulator, inducing the production of anti-viral cytokines such as interferon [ 23 ]. Additional studies suggest that it may also serve as a lysosomotropic agent, altering the pH of endolyososomes to influence viral entry [ 24 , 25 ]. This mode of action is consistent with Tilorone being an α-syn endocytosis inhibitor, underscoring a common mechanism exploiting the vulnerability of a host endocytic system for delivering misfolded protein aggregates and viruses [ 47 ].

The utilization of brain-like 3D organoids to model key aspects of PD pathology provides a new tool in PD therapeutic development. When mature organoids were exposed to α-syn fibrils, we observed a notable upregulation in synaptic maintenance function and ubiquitin ligase-binding activities (Fig.  2 C). These changes suggest an enhanced homeostasis activity in these tissues, potentially as an adaptive response to the proteotoxic stress. Ubiquitin ligases are pivotal in targeting misfolded or damaged proteins for degradation via the proteasome or lysosomes. The increased ubiquitin-binding activity may indicate a cellular attempt to control the accumulation of α-syn fibrils, which are detrimental to neurons. Thus, this upregulation might reflect an intrinsic neuroprotective mechanism to mitigate the potentially harmful effects of fibril accumulation.

Our proteomic analyses also illuminate how 3D brain organoids respond to pathogenic α-syn fibrils and how Tilorone modulates these responses. The most deregulated biological signatures by α-syn fibrils are linked to lipid metabolism and mitochondria functions, which have been implicated in PD pathogenesis [ 48 ]. Specifically, the fatty acid binding protein FABP4 upregulation is associated with microglia-associated inflammation and apoptosis in various cell types [ 49 , 50 , 51 ]. FABP4 was also suggested as one of the plasma biomarkers in early-onset PD patients and PD [ 52 , 53 ]. The modulation of FABP4 by sPFF may disrupt lipid homeostasis to potentiate neuroinflammation. Indeed, our study has revealed the upregulation of several neuroinflammation-related proteins by sPFF, which may depend on FABP4 induction since inhibition of FABP4 was shown to reduce inflammation and apoptosis in models of kidney injury and in cells exposed to lipopolysaccharide [ 54 , 55 ]. Our findings suggest the possibility of using Tilorone to suppress neuroinflammation and restore the decline of the proteostasis network comprised of proteins such as FABP4, OSBPL7, RINT1, and CAV-1, which are integral to lipid homeostasis and cell viability. However, the beneficial effect of Tilorone may depend on its concentration because in organoids treated with Tilorone, a two-fold difference in dosing can result in a drastically different impact on protein levels (Fig.  5 ).

In addition to acting through lipid and protein homeostasis, Tilorone may improve the functional fitness of mitochondria in the context of α-syn seeding and propagation. The observed increase in ACADS and other mitochondria-associated proteins by α-syn fibril treatment may reflect an adaptive mechanism to boost fatty acid oxidation and ATP production, which could support essential cellular functions. However, prolonged fatty acid oxidation may elevate reactive oxygen species (ROS) production, leading to oxidative stress and mitochondrial and cellular damages. It remains to be elucidated whether the molecular signature changes identified in the 3D organoid model can be seen in PD patients, particularly at an early stage of disease development [ 56 , 57 , 58 , 59 ].

Compared to mouse models bearing exogenously administered α-syn fibrils or α-syn transgene, the 3D organoid model as a drug screening platform offers several advantages: (1) Because organoids are derived from human iPSCs, they closely mimic human brain physiology and pathology, offering more relevant insights compared to animal models. (2) Organoids can be produced in large quantities, allowing for high-throughput screening of multiple drug candidates simultaneously, accelerating drug discovery. (3) The development and maintenance of 3D organoids are less expensive and labor-intensive compared to animal models, making it an economical option for preliminary drug testing and evaluation. (4) Using human-derived organoids also reduces ethical concerns associated with animal testing, aligning with the 3R principle (Replacement, Reduction, and Refinement) in scientific research. This system is particularly well-suited for testing candidates from drug repurposing screens, as these agents are typically well-tolerated by humans and possess favorable pharmacodynamics (PD) and pharmacokinetics (PK) properties.

However, the 3D organoid system has limitations, particularly in evaluating long-term toxicity and systemic effects. Organoids do not fully replicate the complexity of an entire living organism. Consequently, they may only capture some of the potential side effects and interactions that a drug might have in a whole-body context. Therefore, to ensure a comprehensive evaluation before advancing to clinical trials, it is essential to test Tilorone’s toxicity and efficacy in animal models after promising results in the organoid model. Animal models provide several essential insights: They help assess long-term exposure to Tilorone, identifying potential chronic toxicity and side effects that may not be apparent in organoid studies at curent time; They can reveal how Tilorone interacts with various organ systems, providing a holistic understanding of its safety profile; They offer information on how Tilorone is metabolized and distributed throughout the body, which is crucial for optimizing dosing regimens; They allow for the evaluation of behavioral and functional outcomes, which are critical for understanding the therapeutic potential of Tilorone in a living organism. Additionally, it is essential to consider other potential benefits of testing Tilorone’s action in animal models. For example, Tilorone was shown to inhibit acetylcholinesterase in vitro [ 41 ]. Since acetylcholinesterase is an enzyme responsible for breaking down acetylcholine, its inhibition may reduce the depletion of this vital neurotransmitter. If present in animals, this mechanism could help slow cognitive decline, which is a significant aspect of PD progression. Future studies delineating Tilorone’s mechanisms of action and effectiveness in vivo and its safety profile over prolonged treatment are required to fully establish its therapeutic potential for PD and related neurodegenerative disorders.

Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Acknowledgements

We thank NIDDK advanced imaging core for assistance in cell imaging experiments.

This work is supported by the Intramural Research Program of NIDDK (Y.Y.) and NCATS (W.Z.).

Open access funding provided by the National Institutes of Health

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Q.Z., W.Z., and Y.Y. conceived and designed the study, M.L. performed bioinformatic analysis, Q.Z. analyzed the data. Q.Z., X. Y., B.L., W.H., J.L. conducted the experiments. Q.Z., and Y.Y. wrote the manuscript. All authors contributed to the editing of the manuscript.

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Zhang, Q., Liu, M., Xu, Y. et al. Tilorone mitigates the propagation of α-synucleinopathy in a midbrain-like organoid model. J Transl Med 22 , 816 (2024). https://doi.org/10.1186/s12967-024-05551-7

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In this PowerPoint templates and icons pack you’ll find a wide array of resources any pharmaceutical business might need. From scientific and medical development to more business-focused templates, this pack will give you a complete set of useful PowerPoint resources.

These Pharmaceutical Industry PowerPoint templates are all available completely for free . You can download them all, and they are ready for you to use straight away. The best thing about the 24Slides’ templates platform is that there is no limit on how many templates you can download. You can mix and match slides from different ones to make your perfect presentation. Whichever topic you’re working on, these pharmaceutical-themed PowerPoint templates will take your presentation to a whole new level.

Here are our best 21 pharmaceutical PowerPoint templates and icons packs, handpicked just for you!

Science Free PowerPoint Templates

Science pharma powerpoint template.

This PowerPoint template is perfect for showcasing pharmaceutical development. Its slides will allow you to show the more scientific parts of the process, while still leaving space for business. It includes several slides with graphs and charts, so you can make all your quantitative data visually engaging.

Playful Science Pharmaceutical PowerPoint Template

There is no reason that science presentations have to be boring. This pharmaceutical PowerPoint template has a beautiful design that will catch your audience’s eye from the first moment. These science-themed slides will give your presentation a clean and polished look that will make it stand out to your potential clients and investors.

Science Graph PowerPoint Template

If you’re looking for some graphs to showcase your information in a fun, engaging way, then this PowerPoint template is for you. It includes 5 slides with different layouts and a green color palette. Its themed slides make this PowerPoint template perfect for the pharmaceutical industry. Whether its product development, a report, or a business plan, these slides will help you make a truly unique presentation.

Science Pie Graph PowerPoint Templates

The Science Pie Graph PowerPoint template is ideal for any pharmaceutical or medical presentation. It includes 3 slides that will complement perfectly any science-based project. Pie Graphs are great for showcasing percentages and data and make easy comparisons between the different segments. You can pick whichever of the three designs fits you best, edit it, and add it to your own presentation in no time.

Science Gantt PowerPoint Template

Gantt charts are amazing tools for any kind of business. They help show your audience time frames for different fields. This is particularly good for project management where there are several tasks and players at the same time. In this case, the 3 slides show each one, three, or twelve months. You can use whichever you find useful, and even mix it with any other of the other pharmaceutical PowerPoint templates on this article.

Science Organisation Presentation Template

Showing your team and your company’s organization can be a huge plus when doing a business presentation. The 3 slides on this pack are specifically focused on organization charts for pharmaceutical and medical industry PowerPoint presentations. You can pick between playful, creative, or corporate style, according to your needs.

Science Lab PowerPoint Template

This PowerPoint template’s design is completely based on science, so it’s a perfect fit for any pharmaceutical presentation tackling product development. But it’s also an easy fit for a business presentation since the images and icons make a great extra to amaze your audience. It includes charts, graphs, and maps, so all you can present easily any information you decide to add.

Free Medical PowerPoint Templates

Pharmaceutical powerpoint template.

This free medical PowerPoint template is a complete take on everything you’ll need for an amazing presentation. All its slides have customized icons concerning the pharmaceutical industry that will give your presentation a clean and polished look.

Creative Animated Pharmaceutical PowerPoint Template

Animations and transitions are amazing tools that PowerPoint offers for making presentations. This pharmaceutical PowerPoint template exploits this feature to make an outstanding presentation. Many people are afraid that using transitions and animations will make them look unprofessional and not take them seriously. But this free medical PowerPoint template is the perfect mix of professionalism and a fun, engaging design.

Health Care PowerPoint Template

For any professional working in the healthcare industry, this PowerPoint template is their perfect match. It has beautiful illustrations, icons, and graphs that will help you showcase all your information in the most visually engaging and eye-catching way.

Medical PowerPoint Template

The medical and pharmaceutical industry is vital for keeping people all around the world healthy and happy. Whatever it is that you want to convey about this topic, this PowerPoint presentation will help you through it.

Sales and Business PowerPoint Templates

Complete business case presentation template.

This 20-slides PowerPoint template is an amazing, all-in-one option for business presentation. It has a blue, sober, and professional design that will help you convey clearly all your ideas to your audience. It has a pretty neutral design, so it’s a great option for pharmaceutical and medical presentations.

Risk Matrix Presentation Templates

When making a business plan, it’s vital to take into consideration the risks it may entail. This pack includes 3 different risk matrix designs that will complement perfectly any of the other pharmaceutical PowerPoint templates.

Project Status Presentation Template

Making reports and keeping track of the progress is as vital in the pharmaceutical industry as in any other. That’s why this template is among those offered in the pharmaceutical PowerPoint templates pack. It’s a straight forward, complete option for showing your audience a business project.

Timeline Pictures Template

This presentation is included in the pharmaceutical PowerPoint templates pack because it’s a great option for showing company profiles. It allows you to show the history and development of your business and company in an engaging, timeline-based design. For those looking for a pharmaceutical company profile template, this one is the perfect choice.

GAP Analysis PowerPoint Template

Gap analyses are a must-have tool for reviewing your business progress. It allows you to compare your current performance with your ideal results, and identify potential improvements. This PowerPoint template is a great business-focused presentation that will be extremely useful for any pharmaceutical or medical company.

Sales Reports Presentation Templates

In order to have a real look at how business is going, sales reports are a must. This pack gives you 3 different designs for a sales report that will complement perfectly any pharmaceutical PowerPoint template.

Extra Resources: Pharmaceutical Icons

Playful pharmaceutical icon.

Icons are the perfect tool for PowerPoint presentations. They are eye-catching and convey complex ideas in very little space. These customized icons will help you make a truly unique pharmaceutical PowerPoint presentation.

Creative Pharmaceutical Icons

If you weren’t feeling the last icon pack, this one might be more to your taste. You can use these icons to turn any PowerPoint template into a pharmaceutical or medical presentation. They’re easy to use and to personalize, so you just have to pick which one you’d like to use.

Pharmaceutical Icons Template Pack

This pharmaceutical icon pack PowerPoint template is the perfect final detail for your presentation. It includes 12 different icons that will give your presentation a little extra. Use them to highlight ideas, mark new topics, and however else you see fit.

Science Icon Template Pack

The last thing the free Pharmaceutical PowerPoint Template and Icon Pack includes is this amazing super pack of science icons. It has 20 different icons with 3 different designs, so you’ll definitely find something that fits your presentations!

You can get access to all these amazing PowerPoint templates, specifically designed and hand-picked for the pharmaceutical industry by clicking on any of them. Whether you’re working on your product development, developing your business plan, creating your company’s profile, or reviewing your sales, a good presentation design can make a difference on getting your audience to hear your message.

If you feel that none of these pharmaceutical PowerPoint templates is exactly what you’re looking for, don’t worry. You can also check out this free healthcare PowerPoint templates . And if that is still not what you were looking for, 24Slides offers a personalized design service that will give you a tailor-made presentation just for you! Our designers will be delighted to help you convey your brand and your message through a beautiful design that will impress your audience.

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Model-Informed Drug Development Paired Meeting Program

The FDA is conducting a Model-Informed Drug Development (MIDD) Paired Meeting Program that will build on the success of the MIDD Paired Meeting Pilot by continuing to advance and integrate the development and application of exposure-based, biological, and statistical models derived from preclinical and clinical data sources in drug development and regulatory review. MIDD approaches use a variety of quantitative methods to help balance the risks and benefits of drug products in development. When successfully applied, MIDD approaches can improve clinical trial efficiency, increase the probability of regulatory success, and optimize drug dosing/therapeutic individualization in the absence of dedicated trials. The MIDD Paired Meeting Program affords sponsors who are selected for participation the opportunity to meet with Agency staff to discuss MIDD approaches in medical product development.  Meetings under the program will be conducted by FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) during fiscal years 2023-2027.

PDUFA legislation has been reauthorized for the MIDD Paired Meeting Program with several significant updates that include:

• Total number of granted submissions per quarter
• Meeting request submission due date
• All meeting packages are due no later than 47 days before the initial (first) meeting and 60 days before the follow-up (second) meeting
• After the initial meeting has been held, the follow-up (second) meeting will be scheduled to occur within approximately 60 days of receiving the meeting package

For more information or questions see the following:

Procedures and Submission Information

Content & format of the meeting information package.

MIDD Meeting Program Email:  [email protected]

Goals of the MIDD Paired Meeting Program

The MIDD Paired Meeting Program fulfills a performance goal agreed to under the seventh iteration of the Prescription Drug User Fee Act (PDUFA VII), included as part of the FDA Reauthorization Act of 2023. 

The MIDD Paired Meeting Program is designed to:

• Provide an opportunity for drug developers and FDA to discuss the application of MIDD approaches to the development and regulatory evaluation of medical products in development, and
• Provide advice about how particular MIDD approaches can be used in a specific drug development program

Under the paired meeting program, FDA will accept 1-2 paired-meeting requests quarterly each year throughout the PDUFA VII period.  Additional proposals that meet the eligibility criteria may be selected depending upon the availability of resources.  For each meeting request granted as part of the paired meeting program, FDA will conduct an initial and follow-up meeting on the same drug development issues.

Eligibility Criteria

• Drug/Biologics development company with an active IND or PIND number for the relevant development program
• Interested consortia or software/device developer should come in partnership with a drug development company
• This excludes statistical designs involving complex adaptations, Bayesian methods, or other features requiring computer simulations to determine the operating characteristics of a confirmatory clinical trial

Selection for Participation

FDA welcomes submissions related to any relevant MIDD topics. However, given that the Agency expects to grant 1-2 meeting requests with additional proposals depending upon the availability of resources per quarter, the Agency will initially prioritize selecting requests that focus on:

• Dose selection or estimation (e.g., for dose/dosing regimen selection or refinement)
• Clinical trial simulation (e.g., based on drug-trial-disease models to inform the duration of a trial, select appropriate response measures, predict outcomes, etc.)
• Predictive or mechanistic safety evaluation (e.g., use of systems pharmacology/mechanistic models for predicting safety or identifying critical biomarkers of interest)

Submission Dates and Decisions

Next Quarterly Due Dates:

Quarterly submissions will now be due on the 1st of the month. FDA will accept requests to participate in the program on a quarterly basis through June 1, 2027.

Submission Process

Meeting requests should be submitted electronically to the relevant application (i.e., PIND, IND) with either “MIDD Program Meeting Request for CDER” (CDER applications) or “MIDD Program Meeting Request for CBER” (CBER applications) in the subject line. Information about providing regulatory submissions in electronic format is available at: Electronic Common Technical Document (eCTD)

In addition, please send an email to [email protected] providing notification your meeting request has been submitted to the relevant application.

Content & Format of the Meeting Request

Include the following information in the meeting request (no more than three to four pages):

• Product name
• Application number
• Chemical name and structure
• Proposed indication(s) or context of product development
• Brief statement of the question in the study or development program (i.e., question of interest) underlying the agenda. The question of interest can be related to dose/dosing, clinical trial simulation, or predictive or mechanistic safety. 
• MIDD approach(es) (e.g., population pharmacokinetic, exposure-response, physiologically-based pharmacokinetic, drug-trial-disease, systems pharmacology/mechanistic modeling) considered for the product under development and how MIDD will be used to address the question of interest (i.e., context of use) and inform regulatory decision-making. The context of use could be, for example: to select or refine dose/dosing regimen, inform trial duration, select appropriate response measures, predict outcomes, predict safety or identify critical biomarkers of interest. 
• Purpose and objectives of the meeting, i.e., what are the specific questions to the Agency about the MIDD approach for the applicable drug development program.

Sponsors whose meeting requests are granted as part of the paired meeting program should submit a meeting information package electronically with either “MIDD Program Meeting Package for CDER” (CDER applications) or “MIDD Program Meeting Package for CBER” (CBER applications) in the subject line. Meeting Packages are due no later than 47 days before the initial (first) meeting. After the initial meeting has been held, the follow-up (second) meeting will be scheduled to occur within approximately 60 days of receiving the meeting package. 

Meeting background packages should include the following information:

• Background section that includes a brief history of the development program and the events leading up to the meeting, and the status of product development
• Proposed agenda, including estimated times needed for discussion of each agenda item
• Questions for discussion with a brief summary of each question explaining the relevance to the MIDD approach and how the Agency can help guide any next steps relative to the regulatory decision-making process. 
• Details pertaining to the question of interest and the context of use.  State whether the model will be used to inform future trials, to provide mechanistic insight, or in lieu of a clinical trial.
• Assessment of model risk, including the rationale for the model risk level. Model risk assessments should consider the weight of model predictions in the totality of data used to address the question of interest (i.e., model influence) and the potential risk of making an incorrect decision (i.e., decision consequence). 
• Information and data imperative to support discussion (e.g., a description of the data used to develop the models and how the model will be validated, model development, simulation plan, results).

Meeting Summaries

A meeting summary will be sent to the requester within 30 days of each meeting

Submission Assistance

For more information, contact FDA at [email protected] with “MIDD Program Meeting Package for CDER” (CDER applications) or “MIDD Program Meeting Package for CBER” (CBER applications) in the subject line. 

Learn More about Model Informed Drug Development from CDER Researchers – In Their Own Words:

• Raj Madabushi, Ph.D. Video
• David Strauss, M.D., Ph.D. Video
• The US Food and Drug Administration's Model‐Informed Drug Development Meeting Program: From Pilot to Pathway - Madabushi - Clinical Pharmacology & Therapeutics - Wiley Online Library

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Medication PowerPoint Template

The Medication PowerPoint Template is a set of vector images of oral drugs and their use. These PowerPoint shapes are design variations of pills, tablets, capsules, as well as labeling diagrams. The healthcare professionals benefit from these PowerPoint templates that serve as a tool kit for making medical presentations. The vector graphics of medication, along with other medical templates can support the contents of healthcare presentations. The SlideModel catalog provides a range of healthcare PowerPoint templates, assisting professionals to create a convincing health-related presentation.

The medicine PPT templates demonstrate oral medicinal products for physical and mental well-being. The slides include shapes of prescription drugs, dosage, and medicine formula. Additional slides present scene illustrations clipart of person taking medicine and sick person to represent symptoms. The PowerPoint also contains weekly planner templates to explain the daily medication schedule. These daily medicine charts are useful to keep track of treatment courses.

The pharmaceutical instructor professionals can market their products to investors using these engaging graphics of medical drugs. The shapes of pill bottles and a person taking medicines can also represent overdose in presentations of drug misuse.

The slides of medication vectors allow customization of desired colors, shades, and shape effects. These read-made graphics let users complement an existing slide or create one from scratch. The Medication PowerPoint Template presents healthcare theme layouts with an option to add the company logo at the left corner.

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Model‐Informed Drug Development Approaches to Assist New Drug Development in the COVID‐19 Pandemic

1 Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Science, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring Maryland, USA

Jianghong Fan

Eliford kitabi, xinyuan zhang, manuela grimstein, yuching yang, justin c. earp, yaning wang.

Leveraging limited clinical and nonclinical data through modeling approaches facilitates new drug development and regulatory decision making amid the coronavirus disease 2019 (COVID‐19) pandemic. Model‐informed drug development (MIDD) is an essential tool to integrate those data and generate evidence to (i) provide support for effectiveness in repurposed or new compounds to combat COVID‐19 and dose selection when clinical data are lacking; (ii) assess efficacy under practical situations such as dose reduction to overcome supply issues or emergence of resistant variant strains; (iii) demonstrate applicability of MIDD for full extrapolation to adolescents and sometimes to young pediatric patients; and (iv) evaluate the appropriateness for prolonging a dosing interval to reduce the frequency of hospital visits during the pandemic. Ongoing research activities of MIDD reflect our continuous effort and commitment in bridging knowledge gaps that leads to the availability of effective treatments through innovation. Case examples are presented to illustrate how MIDD has been used in various stages of drug development and has the potential to inform regulatory decision making.

Coronavirus disease 2019 (COVID‐19) is an ongoing global pandemic, causing more than 613,000 deaths in the United States alone as of August 2021. Scientists from industry, academia, and regulatory agencies have been working collaboratively to fight against this disease and improve patient care for other diseases during the pandemic. The mutual goal is to shorten the drug development cycle to make promising therapies that meet regulatory requirement available as soon as possible and save people's lives. Several key questions have been raised that remain critical to the development of safe and effective treatments of COVID‐19. The first question is how to identify promising candidate compounds, especially from the existing compound pool, for treating COVID‐19. The second question is how to fill in knowledge gaps in clinical development programs for new treatments, knowing that the clinical development programs may be more abbreviated as compared with routine programs due to time constraints and limited resources. The third question is how to safely provide sufficient treatments for patients with diseases other than COVID‐19 who require long‐term medical care where there is a shortage of medical resources and treatment at facilities may increase the risk of viral infections in patients.

Model‐informed drug development (MIDD) is well suited to tackle these critical questions. MIDD represents the application of a broad range of quantitative models to facilitate new drug development and regulatory decision making. It allows an integration of the current knowledge of disease, pharmacology, and patient characteristics. In a nutshell, MIDD provides a unique platform to leverage findings from different sources to address critical questions in drug development. During the COVID‐19 pandemic, emergency use authorization (EUA) is a unique pathway to make promising therapeutic interventions available to the public when evidence suggests that it is “reasonable to believe” that the product “may be effective” in treating the disease or condition identified in an emergency declaration by the Secretary of the Department of Health and Human Services. MIDD is playing an important role in the review process when clinical trials do not have a full coverage for proposed doses, indications, or populations for EUA. In the following sections, recent experiences utilizing MIDD to address the aforementioned key questions are outlined. In sharing these cases, it is the authors’ intention to inform and illustrate tools that have been and will continue to be useful for informing therapeutic interventions of COVID‐19.

UNDERSTANDING THE POTENTIAL EFFECT FOR CANDIDATE COMPOUNDS FOR TREATING COVID‐19

COVID‐19 is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). SARS‐CoV‐2 is a single‐strand RNA virus and highly contagious in humans. When the pandemic started, no molecule was known to have an antiviral effect against SARS‐CoV‐2. A first response from the scientific and pharmaceutical community was to identify potential candidates from the existing compound pool. Some development programs that applied MIDD approaches are presented below to highlight the key evidence and considerations in curating prior knowledge to assess the potential antiviral effect of the candidate compounds.

Hydroxychloroquine

Hydroxychloroquine sulfate is approved by the US Food and Drug Administration (FDA) for prophylaxis and treatment of malaria, treatment of lupus erythematosus, and rheumatoid arthritis. The FDA authorized hydroxychloroquine sulfate for EUA to treat certain patients hospitalized with COVID‐19 in March 2020; based on additional data, including MIDD analyses, the FDA revoked the authorization in June 2020. 1

In view of the importance of translating in vitro antiviral activity to in vivo efficacy in informing drug development and clinical management for COVID‐19, in May 2020, the FDA’s Office of Clinical Pharmacology published a scientific article discussing the key aspects in translating in vitro antiviral activity to appropriate clinical dosing regimens using hydroxychloroquine sulfate as a case example. 2 The discussion was based on a thorough literature review and evaluation of the reported mechanism of action, clinical pharmacology, in vitro antiviral and prophylactic activity testing, animal tissue data, modeling and simulation, and proposed dosing regimens which were believed to be safe and effective. It is important to note that the in vitro half maximal effective concentration (EC 50 ) values used in the literature reports were based on the drug concentrations in the cell culture media (extracellular concentration). Thus, the rationale of significantly higher total lung concentrations relative to the in vitro EC 50 value, which several publications relied on to support hydroxychloroquine sulfate as potentially efficacious against SARS‐CoV‐2 at the proposed dosage, was not substantiated. Rather, the free extracellular lung concentration (the level of which is close to the free plasma hydroxychloroquine sulfate concentration) should be used to compare with the in vitro EC 50 /EC 90 (90% maximal effective concentration) values. The misuse of concentrations for comparison could lead to the wrong conclusion regarding in vivo efficacy because there is a considerable difference between total lung concentrations and free extracellular lung concentrations resulting from a substantial intracellular accumulation. In our article, translating the in vitro antiviral activity to the in vivo setting for hydroxychloroquine sulfate was detailed. Schematically, the developed hydroxychloroquine sulfate physiologically‐based pharmacokinetics (PBPK) model was used to first simulate the free plasma exposure of hydroxychloroquine sulfate, then to estimate the free lung extracellular concentration achieved with the proposed hydroxychloroquine sulfate dosing regimens. Under the assumption that in vitro accumulation is similar to in vivo , the calculated free lung concentrations that resulted from the proposed dosing regimens were well below the in vitro EC 50 values. Therefore, it was concluded the antiviral effect of hydroxychloroquine sulfate against SARS‐CoV‐2 could not be achieved with a safe oral dosing regimen. Randomized clinical trials evaluating hydroxychloroquine sulfate as a treatment for COVID‐19 failed to confirm that the drug is effective for this use, which is consistent with our analysis. 3 , 4 This effort highlights the essential contribution of MIDD to COVID‐19 drug repurposing.

Remdesivir, a phosphoramidate ester of a C‐adenosine analog, is a prodrug which was developed for the treatment of human Ebola virus. It is the first drug approved by the FDA for the treatment of COVID‐19 in hospitalized patients. Before the outbreak of COVID‐19, remdesivir was being evaluated for the treatment of other human coronavirus diseases caused by SARS‐CoV and Middle East respiratory syndrome coronavirus (MERS‐CoV). Antiviral activities against these coronaviruses were anticipated based on in vitro to in vivo translation in that human plasma concentrations after a 100‐mg daily dose were above the in vitro IC 50 . 5 In animals infected with the coronaviruses, prophylactic or treatment doses of 25 mg/g twice daily (in mice) and 5 or 10 mg/kg/day (in rhesus macaque) prevented the disease and the reduced lung viral load after lethal SARS‐CoV and MERS‐CoV inoculations. 6 , 7 Consequently, after the COVID‐19 outbreak, remdesivir was a logical choice against SARS‐CoV‐2 and underwent preclinical anti–SARS‐CoV‐2 tests and treatment trials for COVID‐19. However, uncertainty still existed as to whether the in vitro activity could translate to effective antiviral activities in human lungs. Pharmacokinetic (PK) bridging from the effective animal dose to the human dose for COVID‐19 was based on rhesus macaque infection models and PK studies in healthy subjects. It was observed that plasma and peripheral blood mononuclear cell concentrations of remdesivir and GS‐443902 (the active nucleotide triphosphate metabolite), respectively, in rhesus macaques after a 5‐mg/kg/day dose were comparable to the corresponding concentrations in humans after a 100‐mg/day dose. Additionally, the plasma concentration of GS‐441524, the main circulating metabolite, was comparable between humans (20‐ mg first dose followed by 10‐ mg/day dose) and macaques (10‐mg/kg/day dose) for 28 days. 6 Based on the PK bridging analysis and safety profiles from the Ebola trial, the remdesivir dosages of 200 mg on Day 1 followed by 100 mg/day intravenous (i.v.) for 5 to 10 days were considered appropriate for the treatment of COVID‐19 and showed clinical effectiveness in hospitalized adults in the Adaptive COVID‐19 Treatment Trial (ACTT)‐1, which supported the EUA and subsequent full approval. 5

DOSE DETERMINATION FOR NEUTRALIZING ANTIBODIES TARGETING SARS‐CoV‐2

Neutralizing antibodies (nAbs) are designed to reduce viral entry of SARS‐CoV‐2 into host cells, thereby reducing the severity of COVID‐19 and risk of hospitalization. While vaccinations are considered to be the cornerstone in the arsenal to combat COVID‐19, protection largely relies on the capacity and magnitude of the host immune response to inoculation. For people who are not fully vaccinated, not expected to mount an adequate immune response to vaccination (e.g., immunosuppressed individuals), or not willing/able/eligible to be vaccinated, nAbs offer potential for treatment, and in one case, prophylaxis. To address urgent needs, MIDD approaches were used to provide timely support for a reduced dose of nAbs with pending clinical outcomes, allowing for more people to have access when the supply is limited and assess efficacy periodically for variant strains in this emerging, rapidly evolving pandemic.

Bamlanivimab and etesevimab

Bamlanivimab and etesevimab are both recombinant human immunoglobulin G1 kappa monoclonal nAbs that can bind to the spike protein on SARS‐CoV‐2 and block viral entry into host cells to reduce the extent of host infection. Bamlanivimab monotherapy of 700 mg i.v. for the treatment of COVID‐19 was granted an EUA in December 2020 based on the totality of the scientific evidence available, including evidence from virology, symptomology, and hospitalization. In February 2021, the FDA issued an EUA for bamlanivimab and etesevimab administered together based on data that demonstrated significance in clinical end points, formation of fewer treatment‐emergent variants, and additional viral load reduction compared with bamlanivimab alone. 8 However, at the time of the February 2021 EUA, a lower dose in the treatment regimen (700 mg bamlanivimab and 1,400 mg etesevimab i.v.) with pending clinical results was proposed instead of the substantive dose (2,800 mg of each nAb) to expand the utility given the limited supply. Notably, dose selection for each nAb in the regimen is based on individual receptor‐binding characteristics, considering the two nAbs cover different but overlapping epitopes on receptor binding domain of viral S‐protein. A pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the relationship between plasma concentrations of the two nAbs and changes in viral load collected from nasal swab over time. Due to the lack of clinical data for different doses of etesevimab, the in vivo plasma EC 50 values were estimated under the assumption of threefold antiviral potency of bamlanivimab relative to etesevimab derived from in vitro studies. Simulations using the PK/PD model suggested a comparable antiviral efficacy with the proposed dose. In efforts to address the concern for the relative antiviral potency assumption as the ratio varied among viral isolates (twofold for Washington isolate to sevenfold for Italy isolate), we performed a sensitivity analysis to independently estimate the EC 50 of etesevimab without such an assumption. Despite uncertainties arising from the single‐dose data, the EC 50 estimate of etesevimab converged within a reasonable range. The proposed dose of bamlanivimab and etesevimab is expected to provide sufficient coverage for 28 days based on concentrations over the highest EC 90 value. This conservative margin provided further support for the antiviral efficacy of the reduced dose, which was later confirmed with the virology data in the Blaze‐4 (NCT04634409) study. 9 , 10

With the increasing prevalence of emerging variants, efficacy was reevaluated in view of potential resistance to treatment regimens of bamlanivimab alone and two nAbs used together. The exposure margin over the EC 90 of the prevalent variants with reduced susceptibility can provide qualitative assessment based on various extrapolation approaches, such as scaling up the estimated in vivo EC 90 by fold shift of the in vitro EC 50 /EC 90 of the variant relative to the wild type for comparison with serum concentrations and/or estimating lung concentrations by an expected percentage of lung penetration for comparison with the in vitro EC 90 . Clinical data for the variants, though limited, were also evaluated if available. Bamlanivimab alone is not favorable due to an increased frequency of resistant variants, and thus the EUA for this regimen was revoked in April 2021. 11

PEDIATRIC EXTRAPOLATION OF DRUGS APPROVED/AUTHORIZED TO TREAT COVID‐19

Traditionally, the approval of a pediatric indication is supported by clinical trials conducted in pediatric patients to characterize the PK/PD profiles and/or to demonstrate effectiveness and safety. There can be a significant delay between the approval in adults and labeling in pediatric patients. 12 MIDD in recent years has been commonly applied for dose selection and optimization to facilitate pediatric drug development based on the exposure matching principle. 13 Given the urgent need for effective treatments of COVID‐19 and limited time for pediatric development, MIDD approaches with limited PK data were used to best leverage the knowledge from various sources to support the use of approved or authorized COVID‐19 therapies in pediatric patients. Pathogenesis, the course of the disease, and the effect of the drug product were assumed to be similar between pediatric patients and adults for efficacy extrapolation, and safety data from adult clinical studies were used as supportive information in pediatric assessment. 14 , 15

Remdesivir received FDA approval in October 2020 for the treatment of COVID‐19 in adults and pediatric patients 12 years and older and weighing at least 40 kg who require hospitalization. 16 Data related to remdesivir use in pediatric patients were limited, and PK data in pediatric patients were not available at the time of approval. The same dosing regimen of remdesivir used in pediatric patients and adults was supported by PBPK modeling and population PK analyses. Applying the modeling analyses to simulate exposures, the recommended dosing regimen is expected to result in comparable steady‐state plasma exposures of remdesivir and its metabolites in adolescents as observed in healthy adults. 5 Such analyses relied on the current understanding of enzyme maturation in adolescents and the experience of allometric relationships in PK across pediatric age groups. Remdesivir use in the approved pediatric population was based on extrapolation of pediatric efficacy from well‐controlled studies in adults, and safety data available in adults weighing 40–50 kg and a limited number of pediatric subjects who received remdesivir in a compassionate use program in patients with Ebola. 16

For pediatric patients less than 12 years of age and weighing at least 3.5 kg, remdesivir is available through an EUA. A weight‐based dosing regimen (a single loading dose of 5 mg/kg followed by 2.5 mg/kg/day i.v.) was recommended by PBPK modeling to derive an expected exposure range of remdesivir and plasma metabolites in this age group within the adult steady‐state exposure range. Of note, the predicted pediatric exposure would not exceed exposures observed in healthy adults who received 14 daily doses of 150‐mg remdesivir. Additionally, before starting and during remdesivir administration, laboratory testing for renal and hepatic functions and prothrombin time is a measure implemented to monitor potential safety risks in patients, including this vulnerable population. The PBPK‐informed dose for this age group would include uncertainties such as knowledge gaps on enzyme maturation rates in younger children. 17 , 18 The impact of these uncertainties on the exposure of remdesivir and plasma metabolites in younger pediatric patients needs to be verified when the clinical data become available. Nonetheless, the dosage was derived with a reasonable level of confidence to provide access to the drug for patients less than 12 years of age during the pandemic. Confirmatory PK, supportive efficacy, and safety information are being collected in an ongoing pediatric clinical trial.

Baricitinib

The FDA originally issued an EUA for baricitinib, in combination with remdesivir, for the treatment of suspected or laboratory‐confirmed COVID‐19 in hospitalized adults and pediatric patients 2 years or older requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation in November 2020. The EUA was based on a randomized, double‐blind, placebo‐controlled clinical trial (ACTT‐2). 19 Baricitinib is a Janus kinase inhibitor and approved for the treatment of rheumatoid arthritis (RA) in adults. 20 For COVID‐19, baricitinib is expected to improve clinical outcomes through modulating inflammatory response and preventing a hyperinflammatory state, and it can now be used alone based on the revised EUA issued in July 2021. 21 , 22 During the EUA review, one of the key clinical pharmacology questions was the appropriateness of the dosing recommendation for pediatric patients 2 years or older. The PK of baricitinib in adult and pediatric patients with COVID‐19 was unknown, and the dose in adults was recommended based on the dose used in the clinical trial ACTT‐2. It was known that the baricitinib exposure in patients with RA is approximately twofold of that in healthy volunteers. Therefore, PK may vary by health status and diseases. The dose recommendation for pediatric patients with COVID‐19 was established by applying the dose ratio of pediatric patients to adults rather than the pediatric dose obtained from other indications. PK in pediatric patients with juvenile idiopathic arthritis, atopic dermatitis, and type I interferonopathies have been evaluated, hence exposure comparison of baricitinib between pediatric patients and adults with the same disease was made to determine the dose ratio. PBPK modeling and simulation in healthy pediatric patients and adults, adult patients with RA, and pediatric subjects with juvenile idiopathic arthritis confirmed similar exposure using the proposed dose ratio. The effectiveness and safety of baricitinib in pediatric patients are continuously being evaluated in ongoing clinical trials.

Bamlanivimab and etesevimab are authorized to be administered together for the treatment of mild to moderate COVID‐19 in adults and pediatric patients (12 years and older weighing at least 40 kg) with positive results of direct SARS‐CoV2 viral testing, and who are at high risk for progressing to severe COVID‐19 and/or hospitalization. Dosing of these agents across the age range was informed by MIDD methodology. Applying the population PK modeling that accounts for the difference in body size with weight allometry, the mean of simulated area under the concentration‐time curve (AUC) in pediatric patients is anticipated to be ~ 25% higher than that in adults. 9 Given a linear PK and available adult safety data from higher dose cohorts, the adult dose is considered appropriate for pediatric patients 12 years and older weighing at least 40 kg. The efficacy of these nAbs is determined by their neutralizing capacities to the virus; thus the effect in these pediatric patients as authorized was expected to be comparable to adults given near‐maximal antiviral activity would be achieved based on a large predicted‐exposure margin over in vivo EC 90 .

DOSE INTERVAL PROLONGATION OF THERAPEUTIC PROTEIN DRUG AMID THE PANDEMIC

During the pandemic, it is critical to ensure patients with diseases other than COVID‐19 can receive their needed treatments safely where there is a shortage of medical resources and an increased risk of viral infection in medical facilities. Frequent visits to hospitals or infusion centers for a chronic treatment may increase the risk of patients contracting SARS‐CoV‐2. The issue may be more prominent for oncology patients whose immune system is generally compromised due to the treatment received (e.g., radiotherapy or chemotherapy). As shown below, MIDD approaches were used to support less frequent dosing in these patients in order to minimize the risk of viral infection.

Pembrolizumab

In April 2020, FDA approved an alternative dosing regimen of 400 mg every six weeks (Q6W) for pembrolizumab, a monoclonal antibody that binds to the PD‐1 receptor, under the accelerated approval pathway. Results of MIDD analyses provide the pivotal evidence in support of the approval of pembrolizumab Q6W dosing regimen. Modeling and simulation based on PK data from 4,687 subjects across multiple tumor types suggest a significant overlap in concentration‐time profiles and comparable exposures between 400 mg Q6W and efficacious dosing regimen 200 mg Q3W or 2 mg/kg Q3W. The predicted trough concentration for 400 mg Q6W is 34% lower than that of 200 mg Q3W, which was suggested to have a minimal effect on the efficacy based on exposure response analyses. The three dosing regimens were expected to achieve a similar efficacy profile. The predicted peak concentration for 400 mg Q6W was substantially (~60%) lower than that of 10 mg/kg Q2W dose, which was tested to be tolerable in the clinical trial.

Other monoclonal antibodies for oncology patients

Similar MIDD approaches were also applied in the approval of less frequent dosing for nivolumab, 23 atezolizumab, cetuximab, and adalimumab, and the development of subcutaneous injection for nivolumab and pembrolizumab to offer a convenient and effective alternative dosing regimen. The availability of the alternative measures for administering these monoclonal antibodies are expected to decrease the number of clinic visits and reduce the chance of patients contracting SARS‐Cov2.

RESEARCH ACTIVITIES IN CLINICAL PHARMACOLOGY FOR COVID‐19–RELATED THERAPIES

In addition to supporting new drug application and EUA reviews, MIDD approaches have been widely used to address various questions relating to COVID‐19 through our research projects that might be critical in different development programs. The following examples reflect our continuous efforts in assisting new drug development amid the COVID‐19 pandemic.

Anti–SARS‐CoV‐2 repurposing drug database: Clinical pharmacology considerations

In light of the analyses we conducted for hydroxychloroquine regarding in vitro to in vivo anti–SARS‐CoV‐2 activity extrapolation, we expanded the analyses to a large number of molecules/repurposed drugs whose in vitro anti–SARS‐CoV‐2 activity was reported and developed an “Anti–SARS‐CoV‐2 Repurposing Drug Database.” This database includes in vitro anti–SARS‐CoV‐2 activities, in vivo PK data (peak plasma concentration (C max )), unbound fraction in plasma ( f up ), as well as equations comparing in vitro antiviral activities and in vivo exposures. There are more than 100 drugs/compounds with both PK and EC 50 data available, and ~ 80 compounds with EC 50 data only. Variability exists in both PK and EC 50 values. Reasons that can cause difference in EC 50 values are manifold: methods of how virus was quantified, types of cell lines used, in vitro experiment conditions, etc. In evaluation of the potential in vivo antiviral activity, both the EC 50 range and relevance should be considered. Currently, the variability in PK (i.e., C max and f up ) was not inquired in the database. The C max of only the highest relevant dose level was provided. The value of f up was collected from the labels or publications or assumed to be 1 when no data are available. The highest possible C max and f up were used to maximize the unbound exposure with the intent to capture as many molecules as possible for further evaluation regarding in vivo antiviral activity. This database highlights the clinical pharmacology considerations and can further be used by drug developers as a screening tool for evaluating an anti–SARS‐CoV‐2 drug. 24 The database was developed based on the in vitro studies published prior to November 2020. As research on COVID‐19 is still evolving, the database should be actively updated and maintained, for example, to include the emerging data for the new variants. With the publication of the database, we rely on scientists in this area to keep updating the database.

PBPK modeling for remdesivir

As a nucleoside analog prodrug, remdesivir undergoes intracellular multistep activation to form its pharmacologically active species, GS‐443902, which is not detectable in the plasma. A question arises whether and which of the observed plasma exposures of remdesivir and its metabolites (GS‐704277, GS‐441524) would correlate with or be informative of the exposure of GS‐443902 in tissues. In this study, we focused on the exposure prediction in two organs: lung and liver. Lung, as the main organ involved in the SARS‐CoV‐2 infection, is considered to be one of the target sites of remdesivir's action, while the active metabolite generated in the liver is generally regarded as the attribute of the liver‐related adverse events in patients and healthy subjects who receive remdesivir. A whole‐body PBPK modeling and simulation approach was utilized to elucidate the disposition mechanism of remdesivir and its metabolites in the lung and liver and explore the relationship between plasma and tissue PK of remdesivir and its metabolites in healthy subjects. In addition, the potential alteration of plasma and tissue PK of remdesivir and its metabolites in patients with organ dysfunction was explored. The global sensitivity analysis results indicated that (i) no correlation is expected between the plasma exposure of GS‐704277 and the lung or liver exposure of GS‐443902 because metabolic activation of remdesivir in other tissues instead of the liver and lung may be the major contributor to the plasma exposure of GS‐704277; (ii) the plasma exposure of GS‐441524 is highly correlated with the liver exposure of GS‐443902, which could contribute to the liver‐related adverse events; (iii) remdesivir levels in the plasma are expected to be correlated with the liver or lung exposure of GS‐443902, under assumptions that the relative lung/liver enzyme expression levels and lung physiology and anatomy remain unaltered by COVID. In addition, our simulation results indicated that the intracellular exposure of GS‐443902 was decreased in the liver and increased in the lung in subjects with hepatic impairment relative to the subjects with normal liver function. In subjects with severe renal impairment, the exposure of GS‐443902 in the liver was slightly increased, whereas the lung exposure of GS‐443902 was not impacted. 25 These predictions along with the organ impairment study results may be used to support decision making regarding the remdesivir dosage adjustment in these patient subgroups. The modeling exercise illustrated the potential of whole‐body PBPK modeling to aid decision making for nucleoside analog prodrugs, particularly when the active metabolite exposure in the target tissues is not available.

Evaluation of the QT prolongation potential of hydroxychloroquine

It is important to understand the mechanism and the extent of a QT prolongation effect of COVID‐19 treatments in order to apply appropriate safety monitoring procedures in patients. Both chloroquine and hydroxychloroquine sulfate were once considered potential treatments for COVID‐19. The effect of chloroquine on the corrected QT (QTc) interval has been evaluated in a QT study submitted to the FDA, and the relationship between QTc interval changes and chloroquine concentrations was estimated via modeling approach. 26 Given the structural similarity, we applied a relative potency between chloroquine and hydroxychloroquine sulfate on the concentration‐QT relationship of chloroquine to predict QT effect by hydroxychloroquine sulfate treatment. This relative potency was obtained from an in vivo experiment using isolated rabbit ventricular wedge system, the method of which was previously described by Liu et al . 27 Hydroxychloroquine sulfate concentrations at different clinically evaluated doses were predicted with a population PK model developed using PK data submitted to the FDA. This approach enables us to evaluate the QT effect of hydroxychloroquine sulfate in patients with COVID‐19. The analysis suggested a significant, concentration‐dependent QT prolongation effect driven by the accumulation of hydroxychloroquine sulfate in patients with COVID‐19 and supported close electrocardiographic monitoring in this patient population (unpublished data).

CONCLUSIONS

Successful applications of different MIDD approaches have improved the efficiency of drug development and informed regulatory decision making, thus expanding the toolbox in the fight against the COVID‐19 pandemic. The multiple MIDD approaches/examples highlighted herein have been shown to be efficient tools that integrate various sources of information to streamline new drug development, especially under urgent situations such as the COVID‐19 pandemic. MIDD approaches can be applied to identify potential compounds during drug discovery and early development, allowing the community to target promising candidates. In late clinical development, MIDD approaches may be used to fill in knowledge gaps, such as the potential loss of efficacy against variant strains when clinical data are limited, and the landscape of emergent variants is rapidly changing. Under various situations, such as efficacy against variants of concern and dose interval change for well‐studied therapeutic proteins, MIDD approaches may alleviate the need for additional clinical trials, which is extremely valuable when the development time is restricted, and there is a high unmet medical need.

No funding was received for this work.

CONFLICT OF INTEREST

The authors declared no competing interests for this work.

This article reflects the views of the authors and should not be construed to represent the views or policies of the US Food and Drug Administration. Any mention of commercial products is for clarification and not intended as an endorsement.

ACKNOWLEDGMENTS

The authors would like to thank Stefanie Kraus, Carol Bennett, Kimberly Bergman, and Shiew‐Mei Huang for their helpful suggestions and edits for this manuscript.

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Perspective on model-informed drug development

Affiliation.

• 1 Center for Pharmacometrics and Systems Pharmacology, University of Florida College of Pharmacy, Lake Nona, FL, USA.
• PMID: 34404115
• PMCID: PMC8520742
• DOI: 10.1002/psp4.12699

Model-informed drug development (MIDD) is a process intended to expedite drug development, enhance regulatory science, and produce benefits for patients. Quantitative modeling and simulation-principally by population pharmacokinetics (PK), exposure-response, and physiologically based pharmacokinetic (PBPK) analysis-is the technology that provides the capability to deploy MIDD across a range of applications. MIDD was codified in the 2017 Prescription Drug User Fee Act Reauthorization 1 (PDUFA VI, 2018-2022) and a performance goal was a MIDD pilot program to hold 2 to 4 industry-U.S. Food and Drug Administration (FDA) paired meetings quarterly through 2022.

© 2021 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

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Conflict of interest statement

The author declared no competing interests for this work.

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