This achievement and other advances, which Qubit says raise hopes of a near-term practical application of hybrid high performance computing (HPC)-quantum computing to drug discovery, has led to the company and the Sorbonne receiving €8 ($8.7) million in funding under the France 2030 national plan for the further development of Hyperion-1.

With this proof of concept, the teams note that they have demonstrated that the routine use of quantum computers coupled with high-performance computing platforms for chemistry and drug discovery is much closer than previously thought. Nearly five years could be gained, they add, bringing researchers significantly closer to the era when quantum computers (noisy or perfect) could be used in production within hybrid supercomputers combining HPC, AI, and quantum. The use of these new computing powers will improve the precision, speed, and carbon footprint of calculations, the researchers point out.

Soon to be deployed on noisy machines

To achieve this breakthrough, teams from Qubit Pharmaceuticals and Sorbonne University developed new algorithms that break down a quantum calculation into its various components, some of which can be calculated precisely on conventional hardware. This strategy enables calculations to be distributed using the best hardware (quantum or classical), while automatically improving the complexity of the algorithms needed to calculate the molecules’ properties. In this way, explain the researchers, all calculations not enhanced by quantum computers are performed on classical GPUs.

As the physics used allows the number of qubits required for the calculations, the team, by optimizing the approach to the extreme, has managed to limit GPU requirements to a single card in some cases, according to the scientists. As this hybrid classical/quantum approach is generalist, it can be applied to any type of quantum chemistry calculation, and is not restricted to molecules of pharmaceutical interest, but also to catalysts (chemistry, energy) or materials, notes Robert Marino, PhD, CEO of Qubit Pharmaceuticals.

“This work clearly demonstrates the need to progress simultaneously on hardware and software development,” says Jean-Philip Piquemal, PhD, professor at Sorbonne University and director of the theoretical chemistry laboratory (Sorbonne University/CNRS), co-founder and CSO of Qubit Pharmaceuticals. “It is by making breakthroughs on both fronts that we will be able to enter the era of quantum utility for drug discovery in the very short term.”

The post Qubit Number to Simulate Molecules Reportedly Reduced by the Sorbonne and Qubit Pharmaceuticals appeared first on GEN - Genetic Engineering and Biotechnology News.

Characterizing clonal evolution in blood cancers like acute myeloid leukemia (AML) is critical for understanding their mutational histories and how cell populations change during disease development.

In this GEN webinar, Robert Bowman, PhD, will discuss his lab’s approaches for modeling clonal evolution in mouse models of disease. His group deploys multi-recombinase models to study the stepwise acquisition of mutations seen in AML. These approaches allow for the evaluation of how mutation order impacts disease development. They have characterized the hierarchy of cellular differentiation using flow cytometry and single cell RNA sequencing, recently integrating the ScaleBio Single Cell RNA Kit into their workflow. He will discuss a specific study focusing on FLT3-mutant AML, present data comparing genetic deletion versus chemical inhibition with FDA-approved tyrosine kinase inhibitors, and finally, his plans to further deploy models of oncogene-dependency.

A live Q&A session will follow the presentation, offering you a chance to pose questions to our expert panelist.

Webinar produced with support from:

The post Modeling Clonal Evolution in Hematopoietic Malignancies appeared first on GEN - Genetic Engineering and Biotechnology News.

“We sought to gain insight into a fundamental question: How does genetic variation determine our ‘chemical individuality’—the inherited differences that make us biochemically unique?” said Eric Gamazon, PhD, associate professor of medicine in the Division of Genetic Medicine at Vanderbilt University Medical Center. Gamazon is senior and co-corresponding author of the team’s published report in Nature Genetics, which describes the development of GeneMap and the initial application of the platform.

Kivanç Birsoy, PhD, at the Rockefeller University, is co-senior and co-corresponding author. In their paper, titled “Metabolic gene function discovery platform GeneMAP identifies SLC25A48 as necessary for mitochondrial choline import,” the investigators stated, “… we developed the GeneMAP platform for discovery of metabolic gene function that leverages genetic models of gene expression and quantifies the gene-mediated genetic control of metabolites.”

Metabolic reactions play critical roles in nutrient absorption, energy production, waste disposal, and synthesis of cellular building blocks including proteins, lipids, and nucleic acids, the authors explained. “Given these critical processes, approximately 20% of protein-coding genes are dedicated to maintaining the intracellular chemical landscape and include small-molecule transporters and enzymes.” And while decades of research have revealed the functions of many of these genes, “the exact molecular substrates for many metabolic components remain elusive.”

Abnormalities in metabolic functions are associated with a range of disorders including neurodegenerative diseases and cancers. But, as Gamazon explained, “Despite decades of research, many metabolic genes still lack known molecular substrates. The challenge is in part due to the enormous structural and functional diversity of the proteins.” The authors continued, “Such gaps in our understanding arise partly from diverse tissue-specific expression patterns, functional redundancies, and the metabolic promiscuity of these elements, complicating efforts to define their precise physiological roles.”

The researchers developed the GeneMap platform to discover functions for orphan transporters and enzymes—proteins with unknown substrates. They used datasets from two independent large-scale human metabolome genome-wide/transcriptome-wide association studies (GWAS) and demonstrated with in silico validation that GeneMAP can identify known gene-metabolite associations and discover new ones. They explained, “To identify gene–metabolite relationships, we conducted transcriptome-wide association studies (TWAS) in two independent genomic studies of the human metabolome from the Canadian Longitudinal Study on Aging (CLSA) and the Metabolic Syndrome in Men (METSIM) Study.” In addition, they showed that GeneMAP-derived metabolic networks can be used to infer the biochemical identity of uncharacterized metabolites.

To experimentally validate new gene-metabolite associations, the researchers selected their top finding (SLC25A48-choline) and performed in vitro biochemical studies. SLC25A48 is a mitochondrial transporter that did not have a defined substrate for transport. Choline is an essential nutrient used in multiple metabolic reactions and in the synthesis of cell membrane lipids.

The researchers showed that SLC25A48 is a genetic determinant of plasma choline levels. “Given that SLC25A48 is a member of the SLC25A family that encompasses mitochondrial small-molecule transporters, we hypothesized that SLC25A48 may regulate the availability of choline or its downstream metabolites in mitochondria,” they commented. The investigators then conducted radioactive mitochondrial choline uptake assays and isotope tracing experiments to demonstrate that loss of SLC25A48 impairs mitochondrial choline transport and synthesis of the choline downstream metabolite betaine. “Altogether, our results suggest that SLC25A48 is necessary for mitochondrial choline import and is a key determinant of de novo betaine synthesis in mammalian cells,” they stated.

They also investigated the consequences of the relationship between SLC25A48 and choline on the human medical phenome (symptoms, traits, and diseases listed in electronic health records) using the large-scale biobank resources, UK Biobank and BioVU, Vanderbilt’s DNA biorepository linked to extensive clinical data. These investigations identified eight disease associations.

“What’s exciting about this study is its interdisciplinarity—the combination of genomics and metabolism to identify a long-sought mitochondrial choline transporter,” Gamazon said. “We think, given the extensive in silico validation studies in independent datasets and the proof-of-principle experimental studies, our approach can help identify the substrates of a wide range of enzymes and transporters, and ‘deorphanize’ these metabolic proteins.”

In their paper, the authors concluded, “We developed GeneMAP, a platform for predicting metabolic gene function, and demonstrated its ability to render accurate and replicable results … Because many metabolic enzymes and transporters still do not have identified physiological substrates, GeneMAP provides a unique platform for deorphanizing these genes. This will open up an avenue for understanding the underlying basis of disease as well as development of therapeutics.”

The post Metabolic Proteins “Deorphanized” with Gene-Metabolite Association Prediction Tool appeared first on GEN - Genetic Engineering and Biotechnology News.

Angelman syndrome is caused by mutations in the maternally inherited copy of the UBE3A gene. Paternal UBE3A is epigenetically silenced by a long non-coding antisense (UBE3A-ATS) in neurons. Therefore, when the maternal copy is mutated, UBE3A protein in the brain is eliminated. However, the reactivation of paternal UBE3A is a possible approach for treating AS.

Now, researchers have identified a small molecule that could be safe, non-invasively delivered, and capable of turning on the dormant paternally-inherited UBE3A gene copy brain-wide, which would lead to proper protein and cell function.

This work is published in Nature Communications in the paper, “Ube3a unsilencer for the potential treatment of Angelman syndrome.”

Together with colleagues, Hanna Vihma, PhD, a postdoctoral research fellow in the Philpot lab at UNC School of Medicine, screened more than 2,800 small molecules from a Pfizer chemogenetic library to identify one that could activate paternal UBE3A in mouse models with Angelman syndrome.

Researchers genetically modified mouse neural cells with a fluorescent protein to indicate activation of UBE3A. After treating the neurons with more than 2,800 small molecules for 72 hours, researchers compared their cells with those treated with topotecan, a small molecule known to turn on paternal UBE3A. (Topotecan lacks therapeutic value in animal models of the condition.)

(S)-PHA533533, a compound that was previously developed as an anti-tumor agent, was found to act “through a novel mechanism to significantly increase paternal Ube3a mRNA and UBE3A protein levels while downregulating Ube3a-ATS in primary neurons derived from AS model mice.”

Researchers were able to confirm the results using induced pluripotent stem cells derived from humans with Angelman syndrome. Additionally, researchers observed that (S)-PHA533533 has excellent bioavailability in the developing brain. The authors add that, “peripheral delivery of (S)-PHA533533 in AS model mice induces widespread neuronal UBE3A expression.”

“We previously showed that topotecan, a topoisomerase inhibitor, had very poor bioavailability in mouse models,” said Vihma. “We were able to show that (S)-PHA533533 had better uptake and that the same small molecule could be translated in human-derived neural cells, which is a huge finding. It means it, or a similar compound, has true potential as a treatment for children.”

“This compound we identified has shown to have excellent uptake in the developing brains of animal models,” said Ben Philpot, PhD, professor of cell biology and physiology at the UNC School of Medicine and associate director of the UNC Neuroscience Center. “We still have a lot of work to do before we could start a clinical trial, but this small molecule provides an excellent starting point for developing a safe and effective treatment for Angelman syndrome.”

Although (S)-PHA533533 shows promise, researchers are still working to identify the precise target inside cells that causes the desired effects of the drug. Philpot and colleagues will also conduct further studies to refine the medicinal chemistry of the drug to ensure that the compound—or another version of it—is safe and effective for future use in the clinical setting. “This is unlikely to be the exact compound we would take forward to the clinic,” continued Philpot. “However, this gives us a compound that we can work with to create an even better compound that could be moved forward to the clinic.”

The post Small-Molecule “Unsilencers” Show Promise against Angelman Syndrome appeared first on GEN - Genetic Engineering and Biotechnology News.

MORF-057 is a selective oral small molecule inhibitor of α4β7 integrin developed using the company’s Morphic Integrin Technology (MInT) platform. MORF-057 is now under study in two Phase II trials in ulcerative colitis (UC), and a third in Crohn’s disease.

In releasing first quarter results in April, Morphic said it was enrolling patients in the Phase IIb EMERALD-2 trial (NCT05611671) assessing MORF-057 in ulcerative colitis, and anticipated dosing its first patient during the second quarter in the Phase II GARNET trial (NCT06226883) evaluating MORF-057 in patients with moderate-to-severe Crohn’s disease.

Morphic is expected to disclose additional details on the studies when it releases second quarter results later this summer. The company had not announced a release date at deadline.

Should MORF-057 generate positive data and win approvals, it could potentially challenge Takeda Pharmaceutical’s already-marketed intravenous, subcutaneous, and injector pen versions of its injectable drug Entyvio^® (vedolizumab), an integrin receptor agonist indicated for moderately and severely active UC and Crohn’s. For the fiscal year ending March 31, Entyvio generated blockbuster sales of ¥800.9 billion ($4.986 billion), up 14% from ¥702.7 billion ($4.375 billion) a year earlier.

Another α4β7 integrin receptor antagonist, Biogen’s Tysabri (natalizumab), carries indications in Crohn’s disease as well as muscular sclerosis. Tysabri generated $464.7 million last year, down nearly 5% from $488.4 million in 2022.

“Morphic has always believed that the immense potential of MORF-057 to benefit patients suffering from IBD could be optimized by the ideal strategic partner. Lilly brings unparalleled resources and commitment to the inflammation and immunology field,” Morphic CEO Praveen Tipirneni, MD, said in a statement.

Added Daniel Skovronsky, MD, PhD, Lilly’s chief scientific officer: “Oral therapies could open up new possibilities for earlier intervention in diseases like ulcerative colitis, and also provide the potential for combination therapy to help patients with more severe disease.”

“We are eager to welcome Morphic colleagues to Lilly as this strategic transaction reinforces our commitment to developing new therapies in the field of gastroenterology, where Lilly has made significant investments to deliver first-in-class molecules for the benefit of patients,” added Skovronsky, who is also president, Lilly Research Laboratories and president, Lilly Immunology.

Investors and at least one analyst shared Lilly’s enthusiasm for the deal. Morphic shares traded on Nasdaq zoomed 75% today, to $55.74, while Lilly shares barely budged, inching up 0.4% to $918.00.

“A good outcome”

Michael Yee, an equity analyst with Jefferies, wrote today in a research note that he viewed the deal favorably since Morphic won’t have Phase IIb data to read out on MORF-057 till the first half of next year, and would need “significant” additional capital to run costlier Phase III studies and commercialize the drug worldwide.

“We see this as a good outcome for holders as it provides nearly full value of the Phase IIB data ahead of having to go through the up/down risk of data in H1:25,” Yee wrote. “MORF has prev[iously] spoken about a global partnership or strategic options. We think this is a good outcome and would have been where the stock probably would have traded up to if data were positive in H1/25 (approx[imately] up 50–100%).

In such a scenario, Yee explained, Morphic’s shares would be consistent with Jefferies’ 12-month price target of $60 and “Buy” rating on the stock: “Overall we think it’s a good deal for MORF shareholders.”

Yee added that because Morphic’s pipeline showed little overlap with that of Lilly, he did not foresee a challenge to the deal from the U.S. Federal Trade Commission (FTC), which has opposed some recent biotech merger and acquisition (M&A) deals on antitrust grounds.

Morphic’s pipeline also includes four preclinical programs:

• MORF-088, a family of small molecule αVβ8 integrin inhibitors being developed for myelofibrosis and a combination immuno-oncology approach to treat solid tumor indications.
• A family of small molecule α5β1 inhibitors with potential indications in severe pulmonary hypertensive disease, including pulmonary arterial hypertension, based on research showing that fibronectin integrin inhibition suppresses pulmonary arterial smooth muscle cell proliferation.
• A family of small molecule candidates targeting non-integrins including TL1-A and IL-23, which according to Morphic have potential as treatments for IBD through monotherapy and possibly in combination with other IBD treatment mechanisms including α₄β_7.
• A family of next generation α4β7 inhibitors for gastrointestinal indications using the MInT platform. The next-gen candidates have enhanced selectivity, potency, and pharmacokinetic profiles compared with first-generation inhibitors like MORF-057.

Lilly immunology pipeline

Lilly’s immunology pipeline is headed by mirikizumab (LY3074828), an interleukin 23 (IL-23) inhibitor under regulatory review as a treatment for Crohn’s disease. Mirikizumab is now marketed under the name Omvoh (mirikizumab-mrkz) as a treatment for moderately to severely active ulcerative colitis in adults, after winning FDA approval last October.

Lilly has not furnished sales figures for Omvoh, instead lumping the drug with four other products in a “New Products” category that nearly quadrupled its combined sales during Q1, from $600 million to $2.39 billion—a jump driven by its tirzepatide-based diabetes and weight loss drugs Mounjaro^® and Zepbound^®.

Also in Lilly’s immunology pipeline are seven Phase II candidates in five key indications (atopic dermatitis, hidradenitis suppurativa, multiple sclerosis, psoriasis, and rheumatoid arthritis), as well as three Phase I candidates for undisclosed autoimmune diseases.

Lilly plans to acquire via tender offer all outstanding shares of Morphic at $57 a share, a 79% premium over Morphic’s closing stock price Friday of $31.84 a share—and an 87% premium to the 30-day volume-weighted average trading price of Morphic’s common stock ending Friday.

The boards of Lilly and Morphic have approved the transaction, which is expected to close in the third quarter subject to customary closing conditions, including the tender of a majority of outstanding shares of Morphic’s common stock.

Lilly said it would reflect the Morphic acquisition in upcoming financial results and financial guidance after it determines whether to account for the deal as a business combination or an asset acquisition, including any related acquired in-process research and development charges, according to Generally Accepted Accounting Principles (GAAP) upon closing.

“My deepest thanks go to the entire Morphic Team for their expertise, creativity and tenacity. We are also grateful to the investigators and patients who have contributed to the success of MORF-057 thus far, and we eagerly anticipate the path forward for MORF-057 and other integrin medicines under Lilly’s stewardship,” Tipirneni added.

The post Lilly to Acquire Morphic for $3.2B, Adding Phase II IBD Programs appeared first on GEN - Genetic Engineering and Biotechnology News.

Professors Susruta Majumdar, PhD, Washington University, Brian K. Kobilka, PhD, Stanford University, and Jay P. McLaughlin, PhD, University of Florida collaborated on the project to identify compounds that enhance naloxone’s potency and longevity following treatment. Their team identified a compound that fits these criteria while also reducing withdrawal symptoms in the mice test subjects, even at low doses.

“Naloxone is a lifesaver, but it’s not a miracle drug; it has limitations,” said Majumdar. “Many people who overdose on opioids need more than one dose of naloxone before they are out of danger. This study is a proof of concept that we can make naloxone work better—last longer and be more potent—by giving it in combination with a molecule that influences the responses of the opioid receptor.”

Opioids like oxycodone and fentanyl function by binding to the opioid receptors in the brain to reduce pain perception. Concurrently, with pain reduction, opioids can also induce euphoria, and reduce breathing rate. Overdosing usually occurs as a result of too slowed breathing.

Naloxone reverses opioid overdoses by blocking the ability of the opioid to bind to receptors in target cells. It is fast acting at reversing opioid effects, but it wears off more quickly than many stronger opioids take to be cleared from the blood stream, allowing the overdose symptoms to return. Even when overdose is reversed successfully, withdrawal symptoms can often be so severe that opioid use may restart.

In the current study, the team screened 4.5 billion molecules to identify compounds that can improve the function of naloxone. One of the most promising compounds is a negative allosteric modulator (NAM), simply dubbed compound 368.

“The compound itself doesn’t bind well without naloxone,” said lead author Evan O’Brien, PhD, postdoctoral researcher at Stanford University. “We think naloxone has to bind first, and then compound 368 is able to come in and cap it in place.”

While compound 368 is ineffective on its own, when combined with naloxone, the opioid receptor is blocked from binding to opioids for at least ten times longer than naloxone treatment alone. The combination also results in naloxone being 7.6 times more effective in inhibiting the opioid receptor activation. O’Brien pointed out that “compound 368 is able to increase the binding of naloxone and turn the receptor off more completely.”

Importantly, the team didn’t find any off-target effects from the compound. “We don’t see anything happen to the mice even when we inject a massive amount of compound 368,” O’Brien shared. This adds promising data to support future clinical trials in humans.

“We have a long way to go, but these results are really exciting,” McLaughlin said.

Majumdar concurred, adding, “Developing a new drug is a very long process, and in the meantime new synthetic opioids are just going to keep on coming and getting more and more potent, which means more and more deadly. Our hope is that by developing a NAM, we can preserve naloxone’s power to serve as an antidote, no matter what kind of opioids emerge in the future.”

The team will continue their work with compound 368 and other molecular candidates that may be NAMs of the opioid receptor. O’Brien points out that “allosteric modulators are not common yet, and they’re a lot more difficult to discover and to work with.”

The eventual goal is to bring a naloxone enhancing product to market. “We’re still working on optimizing the compound’s properties for those longer-lasting effects,” O’Brien said. “But first showing that it works cooperatively with these low doses of naloxone suggests that we’re on the right track.”

The post Naloxone’s Ability to Reverse Opioid Overdoses Enhanced by NAMs appeared first on GEN - Genetic Engineering and Biotechnology News.

The findings are published in PLOS Biology in an article titled, “The evolution of antimicrobial peptide resistance in Pseudomonas aeruginosa is severely constrained by random peptide mixtures.”

“The prevalence of antibiotic-resistant pathogens has become a major threat to public health, requiring swift initiatives for discovering new strategies to control bacterial infections,” the researchers wrote. “Hence, antibiotic stewardship and rapid diagnostics, but also the development, and prudent use, of novel effective antimicrobial agents are paramount. Ideally, these agents should be less likely to select for resistance in pathogens than currently available conventional antimicrobials. The usage of antimicrobial peptides (AMPs), key components of the innate immune response, and combination therapies, have been proposed as strategies to diminish the emergence of resistance.”

A recent GEN article highlighted antibiotic-resistant bacteria and a weakness to help overcome antibiotic resistance.

In the new study, researchers investigated whether antimicrobial peptide mixtures synthesized in the lab could reduce the risk of the pathogen P. aeruginosa from evolving antimicrobial resistance, compared to exposure to a single antimicrobial peptide. They found that using antimicrobial peptide mixtures carried a much lower risk of the bacteria developing resistance. The mixtures also helped prevent the bacteria from developing cross-resistance to other antimicrobial drugs, while maintaining—or even improving—drug sensitivity.

Overall, the findings suggest that the use of antimicrobial peptide mixtures is a strategy worth pursuing in the search for new, longer-lasting treatments for bacteria. The researchers suspect that using a cocktail of multiple antimicrobial peptides creates a larger set of challenges for bacteria to overcome, which can potentially delay the evolution of resistance, compared to traditional antibiotics. Furthermore, these cocktails can be synthesized affordably, and previous studies have shown them to be nontoxic in mice.

“Even after four weeks of exposure, a usual treatment duration for Pseudomonas infections, we could not find resistance against our new random peptide, but against other antimicrobials,” added lead author Bernardo Antunes.

The post Antimicrobial Peptide Cocktail Leave Bacteria Shaken Up appeared first on GEN - Genetic Engineering and Biotechnology News.

To see splicing modulation more clearly, scientists at the Istituto Italiano di Tecnologia (IIT) in Genoa and the European Molecular Biology Laboratory (EMBL) in Grenoble have zoomed in on the conserved active site of an RNA splicing machines, specifically, the self-splicing group II introns, the bacterial and organellar ancestors of the nuclear spliceosome. This work, which spanned enzymatic, computational, and crystallographic studies, has uncovered mechanistic details that could inform the rational design of splicing modulators through structure-based strategies.

The scientists presented their work in Nature Communications, in an article titled, “Targeting the conserved active site of splicing machines with specific and selective small molecule modulators.”

“Integrating enzymatic, crystallographic, and simulation studies, we demonstrate how [the self-splicing group II introns] recognize small molecules through their conserved active site,” the article’s authors wrote. “These RNA-binding small molecules selectively inhibit the two steps of splicing by adopting distinctive poses at different stages of catalysis, and by preventing crucial active site conformational changes that are essential for splicing progression.

“Our data exemplify the enormous power of RNA binders to mechanistically probe vital cellular pathways. Most importantly, by proving that the evolutionarily conserved RNA core of splicing machines can recognize small molecules specifically, our work provides a solid basis for the rational design of splicing modulators not only against bacterial and organellar introns, but also against the human spliceosome, which is a validated drug target for the treatment of congenital diseases and cancers.”

Cells rely heavily on the ability to finely control gene expression, a complex process by which the information contained in DNA is copied into RNA to eventually give rise to all the proteins and most of the regulatory molecules in the cell. This process includes splicing, a vital and ubiquitous reaction that ensures the correct maturation of transcribed genes in all forms of life.

Splicing, as the name suggests, involves “cut and paste” operations. These are necessary to create mature versions of RNA that can perform coding or noncoding functions.

“Studying the RNA splicing process is very complex due to the chemical reactions and the molecular actors involved, such as RNA, proteins, ions, and water molecules,” said Marco De Vivo, PhD, principal investigator of the Molecular Modeling and Drug Discovery Lab, associate director for computation at IIT in Genoa, and one of the paper’s senior authors. “Thanks to modern molecular simulation techniques, we have acquired a detailed understanding of what happens, and how to intervene to modulate splicing. Our study has already enabled us to synthesize new drug-like molecules capable of modulating splicing in a new, specific, and highly effective way.”

Indeed, IIT and EMBL researchers, with the support of EMBLEM—EMBL’s technology and knowledge transfer branch—and IIT’s patent office, have recently also deposited a patent that describes novel chemical compounds acting as splicing modulators. In the future, by further improving these compounds, it may become possible to regulate the production of specific proteins linked to defective or mutated genes.

The paper’s other senior author, Marco Marcia, PhD, group leader at EMBL Grenoble, remarked, “Visualizing splicing modulation at the near-atomic level is breathtaking. It allows us to control one of the most fundamental reactions in life. In the future, we will consolidate the successful integration of our biological experimental studies with the chemical and computational studies of our collaborators, aiming at an ambitious goal: to develop new drugs, such as antibacterials and antitumor agents.”

The researchers led by De Vivo and Marcia investigated the small molecule modulation of RNA splicing by integrating the EMBL’s and the Partnership for Structural Biology’s expertise in biochemistry, biophysics, and structural biology, and by using the automated MASSIF-1 beamline jointly operated by EMBL and the European Radiation Synchrotron Facility (ESRF) to obtain X-ray crystallographic structures of intron-ligand complexes. The researchers also leveraged IIT’s molecular dynamics simulation technology, which allowed for the study of the physico-chemical interactions of the molecules involved.

The study lays the groundwork for the future identification of potential drugs that act directly on genetic mutations or modifications which alter the process of gene expression, thereby targeting the onset of tumors or genetic diseases.

The post RNA Splicing Visualized, Easing the Design of Small-Molecule Modulators appeared first on GEN - Genetic Engineering and Biotechnology News.

Kisunla is the first amyloid plaque-targeting therapy with evidence to support stopping therapy when amyloid plaques are removed, which according to Lilly can reduce both the number of infusions needed as well as the treatment cost.

The FDA based its approval of Kisunla on positive data from the Phase III TRAILBLAZER-ALZ 2 trial (NCT04437511), in which people least advanced in the disease showed the strongest results 18 months after receiving the drug. Treatment with Kisunla significantly slowed clinical decline in two groups: Patients with low to medium levels of tau protein, and patients mirroring the overall population, which also included participants with high tau levels.

According to Lilly, patients treated with Kisunla who were less advanced in their disease showed a significant slowing of decline of 35% compared with placebo on the integrated Alzheimer’s Disease Rating Scale (iADRS), which measures memory, thinking, and daily functioning. In the overall population, a statistically significant 22% showed response to treatment based on the iADRS.

Among the two groups analyzed, participants treated with Kisunla had up to a 39% lower risk of progressing to the next clinical stage of disease compared with placebo patients. And among patients in the group mirroring the overall population, Kisunla reduced amyloid plaques on average by 61% at six months, 80% at 12 months, and 84% at 18 months compared to the start of the study.

“Very meaningful results”

“Kisunla demonstrated very meaningful results for people with early symptomatic Alzheimer’s disease, who urgently need effective treatment options. We know these medicines have the greatest potential benefit when people are treated earlier in their disease, and we are working hard in partnership with others to improve detection and diagnosis,” Anne White, executive vice president and president of Lilly Neuroscience, said in a statement.

The positive data led to a recommendation in favor of the drug last month by the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee. Through two 11–0 votes, the advisory panel unanimously concluded that it was effective in treating patients with mild cognitive impairment, based on available data—and that the benefits of the drug outweighed its risks.

Lilly had been pursuing FDA approval for Kisunla since July 2022. The pharma giant initially expected a decision in the first quarter of this year, only to be told in May the agency would decide after hearing from the advisory committee.

Akash Tewari, an equity analyst with Jefferies, has projected peak annual sales for Kisunla of $2.9 billion—below the $4.6 billion projected by a consensus of analysts, asserting that Leqembi has shown an incrementally better risk-benefit profile in early AD patients. Tewari expects a commercial launch for Kisunla in the fourth quarter of this year.

Lilly has set a list price of $695.65 per vial for Kisunla, or about $32,000 for a year of treatment. That’s about 21% above the $26,500 annual list price in patients of typical weight for Leqembi^® (lecanumab-irmb), an Alzheimer’s treatment marketed by Eisai and Biogen which gained full approval four days short of a year ago (Leqembi received accelerated approval in January 2023). The costs for patients needing six and 18 months of treatment have been set at, respectively, $12,522 and $48,696.

“Duration of Kisunla regimen will differ across pts [patients],” Tewari wrote in a research note, “so we’ll need to see how real-world data w/ Kisunla looks.” He noted that the average time to negative amyloid beta level was ~47 weeks in the TRAILBLAZER-ALZ2 trial.

Alzheimer’s has been a notoriously difficult indication for drug developers. Only a handful of drug successes have ever reached the market, most of which have merely slowed progression of symptoms by six to twelve months.

A 2014 Cleveland Clinic study found a 99.6% failure rate of clinical trials for AD drug candidates between 2002 and 2012. That study found high attrition rates for AD treatments, with 72% of agents failing in Phase I, 92% failing in Phase II, and 98% failing in Phase III.

Reshaping AD drug landscape

Kisunla is also the second new drug in as many years that is expected to reshape the AD drug landscape following decades of failures by big pharmas and small biotechs alike. The other is Leqembi, a recombinant humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody designed to treat Alzheimer’s by targeting aggregated soluble and insoluble forms of amyloid beta (Aβ).

The FDA is reviewing Eisai’s Supplemental Biologics License Application (sBLA) for a monthly intravenous maintenance dosing form of Leqembi, with the agency setting a Prescription Drug User Fee Act (PDUFA) target action date of January 25, 2025.

Leqembi is one of two amyloid-targeting Alzheimer’s drugs from Eisai and Biogen to win FDA approval in recent years. The other is Aduhelm^® (aducanumab-avwa), which won a controversial but historic FDA accelerated approval in 2021 as the first therapy indicated for reducing clinical decline in AD patients and the first therapy to tie improved clinical outcomes to removing amyloid beta. Aduhelm became the first treatment approved with an Alzheimer’s indication since 2003.

However, in January Biogen ended commercialization of Aduhelm following disappointing sales and the failure of the drug to gain reimbursement from the Centers and Medicaid and Medicare Services. The latter triggered Biogen’s initial rounds of cost-cutting in 2022, as well as the departure of the company’s previous CEO Michel Vounatsos, since succeeded by current CEO Christopher Viehbacher. Biogen said it would instead shift resources to commercialization of Leqembi and development of other pipeline candidates designed to treat Alzheimer’s.

The disruption caused by Aduhelm, Leqembi and now Kisunla has fueled development of new Alzheimer’s therapies by other biopharma giants, and several smaller biotechs—including Alzheon, which last month completed a $100 million Series E financing, and Cognition Therapeutics, which has shown clinical success for its lead candidate CT1812.

Howard Fillit, MD, co-founder and chief science officer for the Alzheimer’s Drug Discovery Foundation (ADDF), hailed the FDA approval of Kisunla.

“It’s promising to see that some patients essentially enter remission, where they achieve full amyloid clearance with no resurgence in substantial plaque buildup for several years to follow,” Fillit stated. “This approval is emblematic of the new era of Alzheimer’s research where we now have the first class of disease-modifying drugs that will eventually be used in combination with novel therapies—based on the biology of aging—that target all the underlying complexities of this disease.”

“This milestone will not only catalyze the next generation of therapies, but also reframe how we deliver treatments,” Fillit added.

The post FDA Approves Lilly’s Amyloid-Targeting Kisunla for Early Alzheimer’s appeared first on GEN - Genetic Engineering and Biotechnology News.

A new spatial biology is in sight—literally. It is a more vivid, more detailed, and ultimately more informative spatial biology. It can distinguish between cell types that were once indistinguishable, and it can do so while capturing their spatial context. It can even pinpoint the subcellular locations of individual molecules. And it can accomplish these tasks with unprecedented precision because technology is now available that opens a new dimension beyond the usual three spatial dimensions. This new dimension may be called the “plex” dimension.

Plex refers to the number of fluorescence markers that are used with microscopy and other cell analysis platforms. Conventional platforms may accommodate just a handful of markers, constraining investigations of complex biological phenomena. But such investigations may require many markers.

Unfortunately, using more and more markers—and thereby shifting from low-plex to high-plex spatial biology—has been too difficult for most laboratories. They’ve balked at the need for special expertise, complicated workflows, and instrument upgrades. Fortunately, these difficulties can be overcome with new multiplex imaging technologies. For example, there are antibody panels that are compatible with streamlined workflows and automated imaging systems.

To learn more about these technologies, consult the articles in this eBook—especially the article describing organ mapping antibody panels. Also, be sure to read the articles that describe the kinds of spatial biology applications that are bound to become more common as high-plex technology becomes more accessible. Indeed, this technology is democratizing spatial biology.

 Sponsored by:

The post Spatial Biology Colors Outside the Lines appeared first on GEN - Genetic Engineering and Biotechnology News.