William van der Touw

Let’s hope this is a big step forward by anticipating and addressing potential regulatory backlog given the inflection of #cellandgene therapy and #AI approaches. The logic being that a standardized framework for development platforms could take less assessment time and offer #biotech swifter approvals and reduced development costs. #innovation #medicine #pharmaceutical #

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Advancing Delivery of AAV Vector-Based Gene Therapies Using Bispecific Antibodies (ASGCT 2024) There are several challenges that the viral vector field has been facing over the past few decades, noted Sven Moller-Tank, PhD, director of Viral Delivery Technologies, Regeneron Genetic Medicines, Regeneron, in an interview with BioPharm International® at the American Society of Gene and Cell Therapy’s (ASGCT’s) 27th Annual Meeting, which is occurring May 7–11, 2024 in Baltimore, Md. The first challenge is pre-existing immunity because people have naturally been exposed to adeno-associated virus (AAV) and have developed immune responses. This makes it a challenge to run clinical trials, when patients have pre-existing immunity, Moller-Tank stated. The second challenge has been delivery; as a whole, it has been extremely difficult to get enough virus to the peripheral tissues, as opposed to the liver, where it can cause issues with your immune response, and thirdly, there has always been an issue with cargo capacity, he explained. “AAVs can only package about 4.7 kb, and [many] therapeutic genes really don't fit into that capacity,” he said. A fourth challenge dealing with viral vectors would be sustained expression, Moller-Tank added. “The idea with AAV gene therapies generally is that it's a one-and-done therapeutic. However, there [are many] unknowns about how long it's going to express. We're now seeing [in] clinical trials [that] it can indeed last a long time, but it's really unknown for maybe more junior populations, children, where they're going to grow over time, and, after receiving a therapeutic, they may lose expression,” he observed. https://lnkd.in/eBTf8YXG

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Chimeric Antigen Receptor or CAR T cells are cell-based #genetherapies that have revolutionized the disease trajectory for some cancer patients that have few other treatment options left. What's more, CAR T cells hold immense future promise for many additional patient populations, including cancer patients that are earlier in their disease trajectory, patients with other types of cancers (including solid tumors), and even patients beyond #oncology. Unfortunately, CAR Ts are not without risks including the risk of secondary malignancies; today's FDA announcement requiring boxed warnings for all BCMA and CD-19 directed CAR Ts emphasizes one key point - the question of long-term follow-up. In today's announcement, #FDA recommends lifetime follow-up of all CAR T patients for secondary malignancies. This is a contentious issue for essentially all #genetherapies; as outlined by FDA, the length of follow-up should be risk-based, but as the example of CAR Ts clearly shows, our understanding of the risks associated with gene therapies continues to evolve. Following any patient over their lifetime is by no means an easy task, in particular in the U.S.'s fragmented healthcare system. To complicate things further, some CAR Ts are approved for #pediatric uses - adding the complexities of pediatric to adult care transition and a lifespan that hopefully far exceeds the 15 years of long-term follow-up #FDA usually requires for the 'highest-risk' genetherapies.

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Can antibodies get us the highest insights to biology, through large content proteomics, we need to take predictive and precision medicine to where it needs to be? Does not seem like it. ”In conclusion, the field of proteomics is expanding rapidly and thousands of proteins, particularly those in higher abundance, can be measured with great precision. We identified substantial differences in precision within and across the latest large-scale proteomic platforms available. Expanding the coverage of human plasma proteomic profiling retains precision with SomaScan’s aptamer-based technology. In contrast, newly added antibodies on the latest Olink platform often yielded imprecise values below the LOD of the assay in human plasma.” ”…indicate that precision of these two leading platforms in human plasma has diverged as the number of included proteins has increased.”

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Today in @ScienceMagazine, together with my former colleagues at the Novartis Institutes for BioMedical Research, we report the discovery and characterization of first molecular glue degraders of the WIZ transcription factor (TF) for fetal hemoglobin derepression and therapeutic consideration in Sickle Cell Disease. Chemical Biologists may appreciate the CRBN-directed glue degrader library, here used in phenotypic screening of erythropoietic progenitors for HbF induction w/o effect on viability or differentiation. WIZ was discovered by proteomic study of hits and validated by CRISPR. Globin Biologists will enjoy the discovery of WIZ as a repressor of fetal hemoglobin (HbF). This biology has been intently studied, and here we find WIZ loss derepresses HbF by a local decrease in repressive H3K9me2, attributable to the association of WIZ and EHMT1/2. Medicinal chemists will appreciate the potent and selective activity of dWIZ-1 and dWIZ-2, the excellent drug-like properties, oral bioavailability and importantly the excellent tolerability in rodents and monkeys. For Biochemists, we show recruitment to CRBN as dependent on WIZ zinc finger 7, and biophysically characterize association by surface plasmon resonance. The CRBN:dWIZ: WIZ ternary complex buries 413 sq-A of surface area. Drug hunters like me might reflect on molecules that potently target a transcription factor with no pockets – effectively no tertiary structure predicted by @AlphaFold. This chemistry targets instead targets the ZnF secondary structure – truly marking the conceptual end of “undruggable” (if still in doubt). Hematologists will enjoy pharmacologic target validation in multiple pre-clinical models, a relatively selective impact on gene expression, the wide open therapeutic index, and the ease of end-game medicinal chemistry to produce investigational agents. Most importantly, for patients with Sickle Cell Disease. The advance of CRISPR-edited stem cells for transplantation, from our group and others, is a major advance. But patients need more accessible, safe, oral medicines especially in Sub-Saharan Africa. We welcome your feedback on this study, and hope dWIZ-1 and dWIZ-2 immediately prove valuable tools to the community and an inspiration for targeting disordered proteins. Finally, I thank all former colleagues in the NIBR TPD Initiative, and in particular this program’s true champion – Dr. Pamela Ting. Pam, working with you on this brave idea and on the collaborative assembly of the manuscript this last year are treasures I will always cherish, like our friendship. Article: https://lnkd.in/es6k87up Perspective: https://lnkd.in/ewn4eZNT

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The potential of human gene editing to change the lives of those with genetic diseases cannot be understated. With substantial growth in therapies utilizing GE technologies, the FDA released a draft guidance on human gene therapy products in January 2024. In our latest Regulatory Navigator blog, we discuss key takeaways from the FDA's guidance on nonclinical assessment for investigational GE products. These include important considerations for future GE product development, such as using surrogates for testing, evaluating on- and off-target editing events, and characterizing toxicities.

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Genentech Wins FDA Approval for First Adjuvant Therapy for ALK-Positive, Early NSCLC The FDA on Thursday greenlit the use of Genentech’s Alecensa (alectinib) for the adjuvant treatment of patients with early-stage, anaplastic lymphoma kinase-positive non-small cell lung cancer who have undergone tumor resection. With the approval, Alecensa is now the “first and only” ALK inhibitor approved for this indication and patient population, according to Genentech. Thursday’s regulatory win is backed by data from the Phase III ALINA trial, a randomized, active-controlled and open-label study comparing adjuvant Alecensa with platinum-based chemotherapy. The study enrolled 257 patients with Stage IB to IIIA tumors who had undergone resection and tested positive for anaplastic lymphoma kinase (ALK) using an FDA-approved test. Results from ALINA, which the company released in October 2023, showed that Alecensa could cut the risk of disease recurrence or death by 76% versus platinum-based chemotherapy. This treatment effect was highly significant and yielded a p-value of less than 0.0001. The ALK blocker also led to a significant improvement in central nervous system-disease-free survival, according to an exploratory analysis of ALINA. Genentech CMO Levi Garraway in a statement on Thursday called ALINA’s disease-free survival data “unprecedented,” adding that “Alecensa significantly improves upon the standard of care for people with early-stage ALK-positive lung cancer.”

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Biotech weekly news roundup! All of the weeks biggest topics in one place: Illumina enters into $750M agreement with JP Morgan to fund Grail Divestment! https://lnkd.in/gFwA-2Dp Ultragenyx gets the green light to seek FDA approval of Gene Therapy! https://lnkd.in/gTTwKezi Follow / connect with me to keep up to date with all the latest developments in the space! #biotech #bioinformatics #news

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This introductory webinar described #FDA's #IVD classification scheme and registrational path based on perceived product "risk." This is distinct from licensed professional #CLIA activities which are subject to regulatory oversight related to "complexity," with high complexity tasks requiring qualified personnel licensure by California Dept of Public Health's Laboratory Field Services [CDPH LFS] in this state. The CLIA section of LFS serves as CA's designated CMS partner for overseeing CLIA lab operations. Pathologist medical directors and other qualified specialists are licensed by the state of CA and operate under guidance, inspections and proficiency testing by professional organizations such as College of American Pathologists (CAP) and the Medical Board of CA. #Pathologists--who are trained, board certified and licensed in laboratory #medicine--routinely develop and validate tests used in CLIA laboratories, regardless of whether they are FDA IVDs or LDTs, assessing the accuracy and reproducibility of tests performed and overseeing a wide range of quality assurance activities for CLIA #laboratories. In my opinion, this is all part of the "practice of medicine" we should enhance, not encumber.

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💲 Neuroscience biotech LB Pharmaceuticals, Inc. is prepping for an IPO...as the antipsychotics #competitive space ramps up its developments. ❔ What is LB's differentiator? From Endpoints News: 💊 "LB is in mid-stage testing with an #oral treatment candidate for #schizophrenia. Named 'LB-102', the company has described it as a new and improved version of the decades-old medicine amisulpride, a D2 and D3 antagonist that has been sold in many countries but never approved in the US as an antipsychotic. LB has previously said it expects to run multiple Phase 3 trials in 2025 and ask for FDA approval in 2028. It could also test the drug candidate in patients with depression, bipolar depression and other indications." #Antipsychotics #MDD #Schizophrenia #IPO #BipolarDisorder #Biotech #RegulatoryAffairs #Pharma #Healthcare

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Some #cell and #genetherapies have fundamentally rewritten disease trajectories for the #raredisease patients and families that were able to benefit from them, allowing patients to live longer, fuller lives and, in some cases, offering #children with rare diseases a precious chance to reach adolescence. But, the long-term #risks and #benefits associated with these #innovative treatments remain incompletely understood. Pair this with the often substantial treatment costs, the fragmented U.S. healthcare system, and FDA's increasing use of the somewhat controversial (albeit largely unjustifiably so!) #acceleratedapproval pathway to approve these products, and it is no surprise why long-term follow-up of gene therapy patients is front and center on #FDA's mind (and why payers from the Centers for Medicare & Medicaid Services #CMS and state #Medicaid offices to private payers have a HUGH stake and role to play)! Following anyone, or anything, for up to 15 years (!) or more is no small feat, let alone following each individual patient as they move across state lines, health systems, and the pediatric-to-adult transition in care. This is exacerbated by a host of largely unresolved questions, from who should be responsible for follow-up if the #drugsponsor can no longer do so (or is simply no longer around; think of the long list of household brands that ceased to exist over the past decade alone) to what data elements to collect for long-term #safety and #effectiveness (and how to do this in a standardized and rigorous way that can integrate (more or less) seamlessly into routine clinical practices and does not make the development of #cell or #genetherapies so prohibitively expensive that it kills the promising pipeline of innovative products), to how to appropriately analyze and pool sparse data across therapies that use the same delivery vector (or other relevant therapy aspect, such as the type and duration of myeloablative therapy for #CAR-Ts), to who owns the data (and who can see and analyze it). Our community HAS to come together and figure this out to benefit patients, the healthcare providers that serve them, and ultimately all of us. As FDA has repeatedly stated, and the recent Pink Sheet article explains, rare disease families deciding whether to try a new, experimental gene therapy at the risk of unknown side effects and possibly being precluded from later, potentially more effective treatment options or dosing regimens, are making nearly impossible choices, and they deserve data-driven answers to be able to make the choices that are right for them. The healthcare providers that care for gene therapy patients deserve better than being faced with the risk of decades of arduous unfunded mandates around long-term follow-up; and payers, drug sponsors, and all of us deserve robust long-term efficacy data. https://lnkd.in/e-n4iV3u

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Biologics are driving exceptional advances in patient care across a range of conditions and more life changing biologic medicine innovations are on the horizon. To fully realize their potential, it's essential to set guidelines, best practices, and standards that establish quality expectations. By doing this, biologics innovators have the clarity they need to develop new medicines. Standard also will enhance regulatory predictability and therefore reduce risks. They also build trust among patients and healthcare practitioners. Public standards, like the standards developed at USP, enable resources to flow to where they are most needed. For instance, an agreed-upon set of analytical methods for biologics would allow manufacturers to focus on developing and manufacturing innovative therapies rather than creating in-house testing methods. Standards also facilitate consistent and predictable product manufacturing and assessment and reduce time to market. Removing barriers to testing biosimilars, whether through reference standards, analytical methods, or quality guidelines, is crucial. USP is prioritizing the development of state-of-the-art analytical tools to accelerate the advancement of biologics and biosimilars. This supports continuous innovation, reduces barriers to market access for quality medicines, and provides solutions available to stakeholders across the global supply chain. Because of our longstanding work with manufacturers and regulators ensuring the quality of medicines, USP uniquely positioned and eager to partner with government agencies, including the FDA, to remove obstacles and build solutions to bring biosimilars to patients faster. Go to https://lnkd.in/eEMki9rc to learn more. 

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We are hiring a manufacturing lead for HelixNano, a clinical stage startup building next-gen mRNA tech to augment the immune system. You'll be perfecting our manufacturing processes/strategy and removing blockers. Here are some problems you might need to solve in the next year: * R&D develops a therapeutic that involves complex (~1e3) libraries of mRNA, and wants to make large batches for preclinical toxicology and NHP efficacy studies. You are tasked with rapidly adapting the existing manufacturing process to to enable multiplexing, including identifying and fixing methods that generate unacceptable biases, and finding or developing library-compatible QC strategies for DNA, mRNA, and LNP-formulated mRNA. * You have built an internal system for managing reagent inventory both internally and across all partners involved in product manufacturing. However, you notice that a specific team at a CDMO partner instead uses their own internal tool, syncing with the HelixNano tool too rarely to be useful (every ~2 months). You need to address by first figuring out why they are not using the HelixNano system, in case this identifies gaps in our system or processes and we need to tweak them. Similarly, you need to check whether any processes are breaking down at the CDMO, and advise them on how to address this.n * You are deploying a more automated, computer-vision-based robotics process in GMP manufacturing. You end up having to liaise with OSHA to ensure that the system is safe for the technicians working in the clean room. If this sounds exciting, find out more at https://lnkd.in/gQG73AuP.

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Umoja Biopharma Announces Publication in Blood Highlighting Successful Generation of In Vivo CAR T-cells in Non-Human Primate Modeling First landmark, peer-reviewed publication of successful in vivo CAR T-cell data in an immune competent NHP model Data validate the VivoVec™ platform in a translationally relevant model and support its transition into human clinical testing, offering a potential paradigm shift in the field of CAR T-cell therapies Key Study Findings VivoVec particles (VVPs) incorporating CD80 and CD58 costimulation proteins exhibit enhanced capacity for in vivo CAR T-cell generation and produce CAR T-cells with increased antitumor functionality compared to those produced from VVPs displaying anti-CD3 scFvs alone. Combining the anti-CD3 scFv together with the ligand binding domains of CD80 and CD58 into a single multi-domain fusion (MDF) protein markedly augments the particles’ ability to bind, activate, and transduce T-cells. VVPs incorporating MDF compatible with NHP T-cell activation and costimulation potently generate anti-CD20 CAR T-cells in vivo, comprising up to 65% https://lnkd.in/eqsSTKjf

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FDA has a different 'Peter principle' problem: poorly articulated, idiosyncratic decision-making. In a BioCentury Inc. Editor's Comment, my colleague Steve Usdin argues that FDA's full approval last week of Sarepta Therapeutics' DMD gene therapy Elevidys exposed management failures at the agency. Steve says the approval: *is misguided, and contravenes the fundamental purpose of science-based decision-making *disregards the competence of long-serving staff *means there may never be definitive evidence about efficacy in patients age 6 & up *& leaves other biopharmas guessing as to what standards CBER will apply in the future "Even those who applaud the conversion of accelerated approval of Elevidys to a full approval should be concerned about the process." Read the op-ed in #BioCentury https://lnkd.in/gKi4CUeN #biotech #pharma #regulation #FDA #DMD #genetherapy #BioCenturyThisWeek podcast

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Every time I hear Iván Godinez talk about CITE-seq, I learn something new! 💡 Register below so you don't miss next week's workshop on how to get more holistic CITE-seq data by adding intracellular profiling to your experiment. #singlecell #singlecellsequencing #CITEseq #proteomics #transcriptomics #genomics

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This cool new animation on www.pirche.com pretty much summarizes what #PIRCHE is all about. Donor HLA-derived peptides bound in recipient HLA (i.e. PIRCHE) are presented to naive recipient's T cells. Activation of such T cells elicits Tfh cells that support B cells to form a sound antibody response towards the donor antigen. Consequently it appears beneficial to transplant donor-recipient pairs with lower PIRCHE scores. #TransplantDiagnostics #NewWebsite #bioinformatics

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AAV continues to demonstrate utility as a vector for human gene therapy. However, there is a significant cost associated with production scales required to meet late-stage and/or commercial demands (>1,000L). Defining processes that enhance AAV titers during production can aid in the application of these virus to treat diseases. By leveraging DoE studies and implementing a perfusion system, AAV titers increased resulting in overall reduced production costs. This work also highlights the importance of analytical assays for the quantification of CQAs. Collaborations between PD and AD teams are crucial for overcoming production challenges. This ensures scalable, cost-effective productions are developed to achieve success. #AAV #analyticaldevelopment #processdevelopment

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