Philipp Beck’s Post

🧼Which surfactant for your #genetherapy #formulation? #P188 vs #Tween 20/80? 𝗠𝘆 𝗹𝗲𝗮𝗿𝗻𝗶𝗻𝗴: a little 𝗘𝗗𝗧𝗔 doesnt hurt any formulation! It comes in handy to 𝗰𝗮𝗽𝘁𝘂𝗿𝗲 𝗮𝗻𝘆 𝗺𝗲𝘁𝗮𝗹 𝗶𝗼𝗻𝘀 that otherwise might contribute to degradation. 𝗜̲ ̲𝘄̲𝗮̲𝗻̲𝘁̲ ̲𝘁̲𝗼̲ ̲𝗵̲𝗶̲𝗴̲𝗵̲𝗹̲𝗶̲𝗴̲𝗵̲𝘁̲ ̲𝘁̲𝘄̲𝗼̲ ̲𝗿̲𝗲̲𝗰̲𝗲̲𝗻̲𝘁̲ ̲𝘀̲𝘂̲𝗿̲𝗳̲𝗮̲𝗰̲𝘁̲𝗮̲𝗻̲𝘁̲ ̲&̲ ̲𝗳̲𝗼̲𝗿̲𝗺̲𝘂̲𝗹̲𝗮̲𝘁̲𝗶̲𝗼̲𝗻̲-̲𝗿̲𝗲̲𝗹̲𝗮̲𝘁̲𝗲̲𝗱̲ ̲𝗮̲𝗿̲𝘁̲𝗶̲𝗰̲𝗹̲𝗲̲𝘀̲:̲ ▶1️⃣ #Poloxamer188 𝗰𝗼𝗻𝘁𝗿𝗶𝗯𝘂𝘁𝗲𝘀 𝘁𝗼 𝘃𝗶𝘀𝗶𝗯𝗹𝗲 𝗽𝗮𝗿𝘁𝗶𝗰𝗹𝗲 𝗳𝗼𝗿𝗺𝗮𝘁𝗶𝗼𝗻 𝘁𝗵𝗮𝘁 𝗰𝗼𝗻𝘀𝗶𝘀𝘁 𝗼𝗳 𝗮𝗴𝗴𝗿𝗲𝗴𝗮𝘁𝗲𝗱 𝗣𝗿𝗼𝘁𝗲𝗶𝗻 + 𝘀𝗶𝗹𝗶𝗰𝗼𝗻𝗲 𝗼𝗶𝗹 𝗳𝗿𝗼𝗺 𝘁𝗵𝗲 𝘀𝘁𝗼𝗽𝗽𝗲𝗿! “𝘔𝘦𝘤𝘩𝘢𝘯𝘪𝘴𝘮 𝘰𝘧 𝘗𝘳𝘰𝘵𝘦𝘪𝘯–𝘗𝘋𝘔𝘚 𝘝𝘪𝘴𝘪𝘣𝘭𝘦 𝘗𝘢𝘳𝘵𝘪𝘤𝘭𝘦𝘴 𝘍𝘰𝘳𝘮𝘢𝘵𝘪𝘰𝘯 𝘪𝘯 𝘓𝘪𝘲𝘶𝘪𝘥 𝘝𝘪𝘢𝘭 𝘔𝘰𝘯𝘰𝘤𝘭𝘰𝘯𝘢𝘭 𝘈𝘯𝘵𝘪𝘣𝘰𝘥𝘺 𝘍𝘰𝘳𝘮𝘶𝘭𝘢𝘵𝘪𝘰𝘯” (Link in the comments.) ▶▶2️⃣ #Tween #Polysorbates 𝗱𝗲𝗴𝗿𝗮𝗱𝗲 𝗾𝘂𝗶𝘁𝗲 𝗳𝗮𝘀𝘁 𝗶𝗻 𝘁𝗵𝗲 𝗽𝗿𝗲𝘀𝗲𝗻𝗰𝗲 𝗼𝗳 𝗶𝗿𝗼𝗻(𝗜𝗜) 𝗹𝗲𝗮𝗰𝗵𝗮𝘁𝗲𝘀 𝗳𝗿𝗼𝗺 𝗽𝗹𝗮𝘁𝗶𝗻𝘂𝗺-𝗰𝘂𝗿𝗲𝗱 𝘁𝘂𝗯𝗶𝗻𝗴 𝗺𝗮𝘁𝗲𝗿𝗶𝗮𝗹 𝘁𝗵𝗮𝘁 𝗶𝘀 𝗳𝗿𝗲𝗾𝘂𝗲𝗻𝘁𝗹𝘆 𝘂𝘀𝗲𝗱 𝗶𝗻 𝗳𝗶𝗹𝗹𝗶𝗻𝗴 𝗹𝗶𝗻𝗲𝘀. “𝘐𝘮𝘱𝘢𝘤𝘵 𝘰𝘧 𝘵𝘶𝘣𝘪𝘯𝘨 𝘮𝘢𝘵𝘦𝘳𝘪𝘢𝘭 𝘰𝘯 𝘴𝘵𝘢𝘣𝘪𝘭𝘪𝘵𝘺 𝘢𝘯𝘥 𝘧𝘪𝘭𝘭𝘪𝘯𝘨 𝘢𝘤𝘤𝘶𝘳𝘢𝘤𝘺 𝘰𝘧 𝘣𝘪𝘰𝘭𝘰𝘨𝘪𝘤 𝘥𝘳𝘶𝘨 𝘱𝘳𝘰𝘥𝘶𝘤𝘵” (Link in the comments.) 𝗙𝗿𝗼𝗺 𝘁𝗵𝗲 𝗮𝗯𝘀𝘁𝗿𝗮𝗰𝘁: “To avoid the impact on PS80 oxidation the potential remediations presented in the article are to avoid any trace of iron or to add a chelating agent, or to discard the vials having experimented a filling stop (> 5 min).“ Philipp Hebestreit Francois du Plessis John Carpenter

🚨🚨🚨 NEW AAV APPROVAL 🧬 Pfizer's HemB-therapy BEQVEZ got FDA-approved today. Congrats! Please find the updated cheat sheet below. Download & share it within your teams. No surprises overall: 0.001% #Poloxamer 188 180 mM NaCl Pretty bad stability profile though... Here is the link to the label, which still sits on Pfizer's servers somehow... https://lnkd.in/dtTqiubR

🚨🚨🚨 NEW: April 2024 Edition of the #AAV #Formulation Cheat Sheet 🧬💊 Pfizer’s #Beqvez against #Hemophilia B got approved by the Health Canada | Santé Canada authorities in late December 2023. 🎉 🏷𝗣𝗿𝗶𝗰𝗲𝘁𝗮𝗴: 𝟰.𝟴 𝗺𝗶𝗹𝗹𝗶𝗼𝗻 𝗖𝗮𝗻$ We are awaiting FDA approval within the first half of 2024, so stay tuned for precise formulation information (which is not contained in the documents provided by Health Canda but will be in the FDA’s label) Link to the canadian label in the comments! 𝗕̲𝗲̲𝗾̲𝘃̲𝗲̲𝘇̲ ̲𝗵̲𝗶̲𝗴̲𝗵̲𝗹̲𝗶̲𝗴̲𝗵̲𝘁̲𝘀̲:̲ ▶ 𝟭𝗘𝟭𝟯 𝘃𝗴/𝗺𝗟 (pretty standard nowadays) ▶ 𝗣𝗼𝗹𝗼𝘅𝗮𝗺𝗲𝗿 𝟭𝟴𝟴 is the surfactant of choice (no concentration known yet) ▶ Handling of thawed drug is pretty limited: 𝟮𝟰𝗵 only, so better no hiccups in the hours before treatment. 𝗡̲𝗼̲𝘁̲𝗮̲𝗯̲𝗹̲𝗲̲ ̲𝗶̲𝘀̲ ̲𝘁̲𝗵̲𝗲̲ ̲𝗮̲𝗱̲𝗺̲𝗶̲𝗻̲𝗶̲𝘀̲𝘁̲𝗿̲𝗮̲𝘁̲𝗶̲𝗼̲𝗻̲ ̲𝗽̲𝗿̲𝗼̲𝗰̲𝗲̲𝗱̲𝘂̲𝗿̲𝗲̲:̲ ▶  𝗕𝗲𝗾𝘃𝗲𝘇 𝗶𝘀 𝗱𝗶𝗹𝘂𝘁𝗲𝗱 𝗯𝗲𝗳𝗼𝗿𝗲 𝗶𝗻𝗳𝘂𝘀𝗶𝗼𝗻 𝘁𝗼 𝟮𝟱𝟬 𝗺𝗟 𝗶𝗻 𝟬.𝟵% 𝘀𝗮𝗹𝗶𝗻𝗲 𝘄𝗶𝘁𝗵 𝟬.𝟮𝟱% 𝗵𝘂𝗺𝗮𝗻 𝘀𝗲𝗿𝘂𝗺 𝗮𝗹𝗯𝘂𝗺𝗶𝗻 (𝗛𝗦𝗔). 💡𝗪𝗵𝗲𝗻 𝗮𝗿𝗲 𝘁𝗵𝗲 𝗻𝗲𝘅𝘁 𝗔𝗔𝗩 𝗮𝗽𝗽𝗿𝗼𝘃𝗮𝗹𝘀 𝗱𝘂𝗲? Have a look at my previous post about the 2024 timeline for new AAV approvals here: https://lnkd.in/ddgx5PCr #genetherapy #atmp #gmp #manufacturing

Are you wondering how Verve Therapeutics pivot to #GalNAc-#LNP will play out? 🧬💊 I cannot answer this question, but I can provide you with Kallanthottathil G. Rajeev, PhD ("Rajeev") excellent presentation from the TIDES 2021 conference, where he presented the background work. I did a fair bit of #mRNA GalNAc-LNP science myself and I was impressed by how straightforward they made it look. Slides 12-20 show the key breakthroughs & I will explain why: 1️⃣ 𝗟𝗶𝗴𝗮𝗻𝗱 𝗱𝗲𝘀𝗶𝗴𝗻 (𝘀𝗹𝗶𝗱𝗲 𝟭𝟮/𝟭𝟰): design 2 bears easier chemistry both for manufacturing but also early on during R&D for quick iteration of different linker stem-lengths (lysine & derivatives). Surprisingly (at least to me), design 2 resulted in slightly better liver editing when tested in vivo in mice. 2️⃣ 𝗦𝗽𝗮𝗰𝗶𝗻𝗴 & 𝗹𝗶𝗽𝗶𝗱 𝘁𝗮𝗶𝗹 (𝘀𝗹𝗶𝗱𝗲 𝟭𝟱-𝟭𝟳): a longer linker between GalNAc and lipid had a huge impact! Likewise, the lipid type was very influencial: DSG outperformed cholesterol and simple C20-alkyl. 3️⃣ 𝗚𝗮𝗹𝗡𝗔𝗰-𝗱𝗲𝗻𝘀𝗶𝘁𝘆 𝗼𝗻 𝗟𝗡𝗣 𝘀𝘂𝗿𝗳𝗮𝗰𝗲 (𝘀𝗹𝗶𝗱𝗲 𝟭𝟵): Key was to look at editing in the LDLR -/- double knock-out mice: 0.05 mol% of GalNAc-lipid is ideal, even showing some robustness: 5-fold less/more GalNAc-lipid resulted in similar editing efficiencies. Congrats to opening another door to the liver #Verve Team! Your work was inspiring to all (especially for myself) who tried & failed to improve LNPs by adding GalNAc. Thanks Sekar (Sek) Kathiresan for your clear communication on BiotechTV Christian Dohmen Christian Dubiella Volker Fehring #genetherapy #genediting

𝗣𝗲𝗿𝗳𝘂𝘀𝗶𝗼𝗻 𝗽𝗿𝗼𝗰𝗲𝘀𝘀 𝗮𝗽𝗽𝗹𝗶𝗰𝗮𝗯𝗹𝗲 𝘁𝗼 #𝗔𝗔𝗩 manufacturing? 🧬 I just listened to the latest episode (39) of the Smart Biotech Scientist podcast by David Brühlmann, PhD where he interviewed Jochen B. Sieck, PhD, MBA from Merck Life Science on balancing perfusion process & sustainability. Link: https://lnkd.in/dPtTE9xg Notably, Jochen stressed that perfusion processes are not a new thing: they have been used in the past for instable & low-yield biopharmaceuticals like Factor VIII (which was launched using perfusion processes!) Then, the industry went to fed-batch processes: yields increased, easier to operate, better performing media. 𝘕𝘰𝘸 𝘵𝘩𝘦 𝘪𝘯𝘥𝘶𝘴𝘵𝘳𝘺 𝘪𝘴 𝘭𝘰𝘤𝘬𝘦𝘥-𝘪𝘯 𝘪𝘯𝘵𝘰 𝘧𝘦𝘥-𝘣𝘢𝘵𝘤𝘩 𝘱𝘳𝘰𝘤𝘦𝘴𝘴𝘦𝘴 😒 𝗕𝗨𝗧 𝗕𝗨𝗦𝗜𝗡𝗘𝗦𝗦 𝗗𝗥𝗜𝗩𝗘𝗥𝗦 𝗳𝗼𝗿 𝗣𝗘𝗥𝗙𝗨𝗦𝗜𝗢𝗡/𝗖𝗢𝗡𝗧𝗜𝗡𝗨𝗢𝗨𝗦 𝗽𝗿𝗼𝗰𝗲𝘀𝘀: ▶𝘂𝗻𝗸𝗻𝗼𝘄𝗻 annual demand/patient population ▶you have a 𝗺𝘂𝗹𝘁𝗶-𝗽𝗿𝗼𝗱𝘂𝗰𝘁 enterprise ▶if 𝘆𝗶𝗲𝗹𝗱 𝗶𝘀 𝗹𝗼𝘄 (or restricted by cell density) ➡💡 𝘀𝗺𝗮𝗹𝗹 & 𝗳𝗹𝗲𝘅𝗶𝗯𝗹𝗲 𝗳𝗮𝗰𝗶𝗹𝗶𝘁𝘆 𝗶𝘀 𝗯𝗲𝘁𝘁𝗲𝗿 𝘀𝘂𝗶𝘁𝗲𝗱, since it is not overloaded with large CAPEX investment. However, is a perfusion process applicable for an #AAV process? We have seen some progress e.g. by Ultragenyx at #ESGCT2023. They showed that higher cell density inhibited productivity. Thus, they used a perfusion process 1-2 hours post-infection. The majority of rAAV product remains intracellular --> waste was removed without loosing product. Perfusion was stopped at 48 hrs & batch was harvested, since after 48 hrs rAAV starts to get released into the media.

Prefilled syringe! Finally 👏 I wonder if Moderna added a #surfactant like #Poloxamer 188 or #PS80 #PS20 to their drug product formulation & new presentation (pre-filled syringe). Looking forward to their "Vaccines Day" event tomorrow.

🧬𝗔𝗔𝗩 𝗰𝗹𝗶𝗻𝗶𝗰𝗮𝗹 & 𝗿𝗲𝗴𝘂𝗹𝗮𝘁𝗼𝗿𝘆 𝗿𝗮𝗱𝗮𝗿 𝘂𝗽𝗱𝗮𝘁𝗲 𝗳𝗼𝗿 𝟮𝟬𝟮𝟰💊 A lot is going on this year! In January we already saw 2024's first #AAV approval for Pfizer's Beqves AAV.rh74 against HemB in Canada. Six AAV products have phase I/II/III readouts this year and Pfizer's Beqvez has a PDUFA date scheduled sometime in Q2-2024. Short-form: REGENXBIO Inc. ➡ 𝗛𝘂𝗻𝘁𝗲𝗿 𝗦𝘆𝗻𝗱𝗿𝗼𝗺𝗲 (AAV9) Ultragenyx ➡ 𝗪𝗶𝗹𝘀𝗼𝗻'𝘀 𝗗𝗶𝘀𝗲𝗮𝘀𝗲 & 𝗚𝗦𝗗𝟭𝗮 (AAV9 & AAV8) Pfizer ➡ 𝗛𝗲𝗺𝗔, 𝗛𝗲𝗺𝗕 & 𝗗𝗠𝗗 (AAV2/6, AAV.rh74, AAV9) Please don't nail me down on the "market" row - patient numbers are rough estimates. #genetherapy #GMP #manufacturing #formulation

🌄 Day 1 of #DGGT2024 was #LNP-heavy, but … #AAV made a great comeback during this day’s last talk: Laura Sepp-Lorenzino, Ph.D. Keynote address (swipe pictures!) Here are my 4 most memorable takeaways: ▶1️⃣ My favourite talk from today was that of Laura Sepp-Lorenzino, Ph.D. from Intellia Therapeutics, Inc., who showcased not only the impressive data from their clinical programs. Laura also highlighted Intellia’s gene insertion platform that combines #mRNA/LNP (to precisely create an insertion site) with insertion template-loaded #AAV (without promoter). The template is stably inserted in the albumin locus and provides durability advantage over conventional AAV episomes. Great data! 🚨🚨🚨 little caveat: if the #AAV would be redoseable, this would be even better. Laura mentioned that they are working on this 😊 ▶2️⃣ #miRNA – the underdog strikes back: Stefan Engelhardt (TUM) presented RNATICS macrophage-targeted miR-21 conjugate. Their lead canditate "RCS-21" is a trimannose-conjugated locked nucleic acid antimir-21 that is administered via nebulization into the lung to prevent exaggerated inflammatory responses that are driven by macrophages. I loved the chemistry behind RCS-21 molecule (driven by baseclick CEO Thomas Frischmuth), but this was as “small molecule” as we got on this day. Start of Phase 1 clinical trial testing RCS-21 is 2024! ▶3️⃣ Olivia Merkel showed a spray-dried, T cell-targeted transferrin-PEI #siRNA particle approach to target lung tissue via inhalation. I asked Olivia whether the transferrin-siRNA conjugate wouldn’t be perfectly fine without PEI (just as GalNAc-siRNA), but she highlighted that this is indeed not the case in the lung environment with the mucus barrier. ▶4️⃣ Christian Plank presented Ethris lipid nanoparticles that not only have a better stability profile compared to e.g. the Covid vaccines, but also have the attribute of staying on target after administration with minimal to none spreading into other tissue. Without doubt: Ethris technology is world-leading spanning over multiple areas: RNA, LNP and nebulization. Looking forward to day 2!

🧬🌈Today, #DGGT24 annual conference in Munich begins! Here is a collection of some of the #AAV presentations. Looking forward to meet new and old colleagues: - Marco Radukic provides the answer to all questions - Samuel Theuerkauf grafts #DARPins on AAVs -will you join this week, Christian Jost? - Tarik Bozoglu targets #AAV9 with affinity peptides - Dirk Grimm lets AAV flex its muscles I'll provide some takeaways after the talks for our #genetherapy colleagues who cannot join Matt Edwards Francois du Plessis

💡🧬Formulation-people! I'm genuinely interested: can you answer this question without checking any resource first? Surfactants are an important excipient in #AAV #genetherapy formulations. Poloxamer 188 is used in most AAV products on the market. But: the most stable formulation (#HEMGENIX) contains the more labile Polysorbate 20. Please comment below this post to get into a deep discussion about surfactants 😁 Here is a link to the #AAV #formulation #cheatsheet https://lnkd.in/duFvKbJP