Nucleic Acid Insights’ Post

Hemophilia, a genetic disorder primarily affecting males, is characterized by deficiencies in clotting factors VIII (Hemophilia A) or IX (Hemophilia B). This deficiency impairs the blood's ability to clot and effectively seal wounds. Recent advances in treatment, including gene therapy, long-acting clotting factor replacements, and small molecule drugs, are revolutionizing care for hemophilia patients. Gene therapy shows exceptional promise by using viral vectors to introduce normal clotting factor genes into patients, potentially providing long-lasting therapeutic effects. Further research is targeting additional regulatory factors in the coagulation pathway, aiming to further enhance treatment outcomes. To aid in these advancements, we have carefully curated a list of over 20 essential targets and related reagents specifically for hemophilia research. https://bit.ly/3Q5Es4Z

Presentation of the first clinical results for GNT0004 gene therapy for Duchenne Muscular Dystrophy: These results obtained with our drug candidate GNT0004 for Duchenne Muscular Dystrophy are very encouraging, particularly in patients treated at the highest dose, both in terms of microdystrophin expression and functional improvement. They enable us to prepare for the pivotal phase of the trial, and demonstrate how this innovative technology can provide solutions to one of the most complex genetic diseases. I would like to pay tribute to the expertise of our researchers and experts who have made these initial results possible.

STAT+ article out this morning on Pfizer’s Duchenne data from World Muscle ~two weeks back. “Perplexing results from Duchenne muscular dystrophy trial raise questions about gene therapies: Pfizer results showed boys did not improve even though target was achieved.” It’s behind a paywall, so quick summary: + Recall, Pfizer’s gene therapy showed no statistically significant improvement in a Phase III Duchenne trial in primary or secondary endpoints BUT it did show an improvement in the microdystrophin production that should, hypothetically, predict a slowing of Duchenne progression.  + Microdystrophin is a surrogate biomarker intended to predict clinical efficacy and was critical to Sarepta’s pathway to market. + The STAT+ authors conclude that this finding may not damn all microdystrophin, but rather the specific version that Pfizer used, still leaving the door open for Sarepta’s microdystrophin to have power (even though it failed its EMBARK primary endpoint) + What does this finding say about using proxies to predict clinical results vs. the clinical results themselves? + And what are the implications for Accelerated Approval for others like RegenxBio and Solid whose planned filings leverage forms of microdystrophin: “The Pfizer data casts doubt on Marks’ nearly unilateral decision. Data presented at the World Muscle Society meeting showed boys who received the drug had produced almost as much microdystrophin on average as healthy individuals produce dystrophin. Yet there was no muscle benefit.” + This one is a bit of a head-scratcher, but STAT goes into strong details about variables in construction, trial length, muscle uptake, and measurement that could lead to Pfizer’s results (or lack thereof). #sarepta #raredisease #duchenne #elevidys #acceleratedapproval #genetherapy

#genetherapy #hemophilia Liver-directed gene transfer eliminates pre-existing antibodies to target proteins Researchers discovered a potential breakthrough in gene therapy for genetic disorders, possibly including autoimmune diseases. This two-pronged approach was inspired by studies on hemophilic animals twenty years ago. The studies showed that delivering genes to the liver could both introduce the missing protein and create immune tolerance to it, overcoming a major hurdle in gene therapy. Further research using hemophilia A dogs confirmed this approach could eliminate pre-existing antibodies to the therapeutic protein. Finally, a recent human trial successfully replicated these findings, demonstrating the potential of this strategy in people with hemophilia A. This exciting new approach tackles the root cause of the genetic disorder while simultaneously removing the immune barrier that has limited gene therapy in the past. References: 1. Safety and efficacy of valoctocogene roxaparvovec in participants with active and prior FVIII inhibitors: Preliminary results from GENEr8-INH, a phase 1/2 study https://lnkd.in/gS7D8fNU 2. Immune tolerance induction by hepatic gene transfer: First-in-human evidence https://lnkd.in/gAN7pd2X BioMarin Pharmaceutical Inc. Guy Young Margareth C Ozelo Mingjin Li Urooj Imtiaz, MD Konstantia-Maria Chavele

Gene&Cell Therapy >> Pfizer’s Duchenne muscular dystrophy gene therapy fails Phase 3 trial: Pfizer’s Duchenne muscular dystrophy gene therapy failed to meet the primary and key secondary endpoints in a Phase 3 study, pointing to a bleak future for the program. The gene therapy failed to significantly improve motor function at one year in boys with Duchenne, measured using a 17-item scale that evaluates various aspects of mobility called the North Star Ambulatory Assessment. The therapy also did not significantly improve secondary endpoints such as 10-meter run/walk velocity and time-to-rise-from-floor velocity compared to placebo. “Pfizer will continue to closely monitor all participants enrolled in the study and is evaluating appropriate next steps for the program,” the company said Wednesday in a statement. Known as CIFFREO, the study enrolled 99 boys aged 4 through 7 with Duchenne muscular dystrophy, according to the federal clinical trials database. The participants received Pfizer’s fordadistrogene movaparvovec or placebo. There have been two patient deaths in Pfizer’s Duchenne gene therapy clinical studies. In May, Pfizer disclosed that a boy enrolled in a Phase 2 study for the therapy passed away, and it was investigating the patient’s death. As a result, the company paused the administration of the gene therapy to boys who had originally been in the placebo arm of the Phase 3 study. In 2021, Pfizer disclosed a boy in a Phase 1b study of the gene therapy died and later said he “had more advanced disease with underlying cardiac dysfunction.” The FDA granted accelerated approval last June to Sarepta Therapeutics’ Duchenne muscular dystrophy gene therapy for boys aged 4 to 5. Within the narrow group of patients eligible for Elevidys, demand has been high. The FDA is expected to decide by June 21 on whether to expand the eligible population based on mixed results from a confirmatory study. Last year, Pfizer took a step back from developing early-stage gene therapies, selling a suite of preclinical programs to AstraZeneca. #lucidquest #genetherapy #celltherapy

Single-cell omics and CRISPR technologies are two topics that are given plenty of attention in the current market, but haematology as a whole doesn't get quite the same level of consideration. The latest review on erythropoiesis gives an interesting overview on where we stand in the mechanisms of red blood cell formation. Aside from looking into findings around transcription factors and epigenetic modifications relating to erythropoiesis, the review highlights how this knowledge could result in novel approaches to rare diseases like Diamond-Blackfan anemia. Gene therapy for β-thalassemia is highlighted as one example of a potential way forwards, but as of February 2024 there are only 38 FDA approved CGT products on the market. This review gives me hope that innovations in single-cell omics and CRISPR technologies could mean more CGT products getting approval and seeing more haematology-focused businesses in the world. Do you see CGT as the future of biotech too? Are there any other therapeutic areas you'd want to see more focus on? Let's connect to talk about all things Omic!

Inherited retinal diseases (IRDs) stem from genetic mutations that result in vision impairment. #genetherapy shows promising therapeutic potential, exemplified by the encouraging initial results with voretigene neparvovec. The advent of in vitro-transcribed (IVT) #mRNA has broadened the possibility of new ocular gene therapies. Synthetic mRNA achieves higher translation efficiency without nuclear translocation, poses no genomic integration risks, is transiently expressed, and its production is cost-effective, making therapies more accessible globally. #genetherapies #mRNAtherapeutics #RNAtherapeutics . https://lnkd.in/duZvYdmn

In the evolving gene therapy landscape, the slow rollout of treatments highlights the need for partnerships that tackle challenges like cost, starting with critical raw materials. Anemocyte stands out by delivering technical solutions while prioritizing both sustainability and quality. Get in touch to learn more! #Anemocyte #plasmidDNA #pDNA #mRNA

Gene&Cell Therapy >> Prime Medicine whittles down pipeline, signs gene editing deal with Bristol Myers: Prime Medicine announced Monday morning that it is cutting its pipeline, and it signed a T cell therapy partnership with Bristol Myers Squibb for $110 million upfront. The gene editing company, which once boasted a pipeline of at least 18 disclosed programs, is now focusing on five programs, including the new T cell collaboration with Bristol Myers. With the BMS deal, Prime could receive more than $3.5 billion in milestones. The duo is developing cell therapies for immunological diseases and cancer. As a result of the deal and the pipeline cuts, Prime now expects its cash runway to last into the first half of 2026. Its stock ($PRME} was up about 14% in premarket trading on Monday. Prime’s programs include its lead asset for chronic granulomatous disease, for which the company began clinical studies earlier this year. It’s also developing a follow-on program for a different form of the disease known as X-linked chronic granulomatous disease and treatments for Wilson disease and cystic fibrosis. This is a developing story.  #lucidquest #genetherapy #celltherapy

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