ARW's ATMP Manufacturing Must-Reads (2024 NEW YEAR'S RESOLUTIONS EDITION!)

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

Day-in and day-out, I write, read, listen to, and watch as much content as I can about CGT and RNA therapy manufacturing, in particular, and/or other ATMP industry-related topics that you should at least be aware of in the manufacturing facility. Once a month, I compile the articles and industry updates I think are most worthy of your time into an unconventional newsletter format (below) and send them out via email.

As this was the first must-reads of 2024, it only seemed fitting that we embrace the “new year, new goals” mentality. Because one of my “resolutions” was to be more generous in the new year, I’ve taken the liberty of grouping your must-reads together in accordance with some resolutions I’ve drafted just for you! I know, I know — I shouldn’t have. And you’re very welcome.  

Resolution #1: I will be a champ and subscribe to ARW’s new publication, Advancing RNA.

• Oh my gosh you are TOO kind.
• You can sign up here.

Resolution #2: I will finally get in shape and run a 4-minute mile!
[RNA 2024 OUTLOOK]

• And I, ARW, will be the first to send you flowers when you’re admitted to the hospital.
• Even better, reading my latest Q&A on how to break RNA’s 4-minute mile featuring CEOs and CSOs from Ethris, Replicate, Orbital, and Combined Therapeutics will most likely not require you to add any physical therapists to your speed dial in the new year.
• My Q&A above may be a quick sprint, but if you’re looking for more of a marathon read, this long-form article in Nature by several of our friends at Pfizer does a very thorough job exploring the past, present, and future of coding and non-coding RNA therapeutics. Stay hydrated.

Resolution #3: I will not expect people to immediately recognize and celebrate the wonder that is me.
[ATMP 2024 OUTLOOK]

• But if they don’t, it was “nice” to know them.
• The holidays may be over, but it’s still the season to look beyond ourselves and to take stock of the predictions and expectations for the broader ATMP space in 2024, starting with:
  • This Biopharma Excellence consultant’s no-nonsense break down of the problems we face and how we’re tackling them for AAV, LNP-mRNA/RNA, CAR-Ts, and gene editing therapies.
  • This LinkedIn post from Carl Schoellhammer of DeciBio giving us predictions for oligos, mRNA, AAV, and cell therapies. If you want some more, he expands upon these highlights in his recently published article on Advancing RNA.
  • My colleague Erin Harris put together a 2024 Outlook article for Cell & Gene on the future for some of the lesser-sung viral vectors — namely anelloviruses and lentiviral vectors.
  • My other colleague, Louis Garguilo, reached out to some of his Outsourced Pharma board members to get their perspectives on how the biggest 2023 outsourcing “speed bumps” might flatten out in 2024 and what innovations or challenges we may encounter in the process.

Resolution #4: I will pay off my debt and start saving more money this year.
[MONEY]

• Thank Christ for scratch-off tickets.
• ... And also for this new private life sciences growth fund. Goldman Sachs announced its entrance into life sciences investing with the close of West Street Life Sciences. The fund’s initial fundraising efforts brought in $650 million and will be doled out on early- to mid-stage therapeutics, tool providers, and diagnostics companies, specializing in precision and genetic medicines, cell therapies, immunotherapies, synthetic biology, and AI.

Resolution #5: I will educate all my family and friends about the importance of global access to ATMPs.
[MARKET ACCESS]

• But in case that doesn’t work, any chance you have a connection to Oprah?
  • “You get a CGT — and you get a CGT!”
• IQVIA came up with “7 key indicators of progress in the life sciences sector” for its blog. #1 is worth noting, but I’d particularly direct your attention to #3, which homes in on the recent sickle cell gene therapy approvals. In particular, Murray Aitkin argues that a key progress marker for the life sciences space in 2024 will be reaching more than 2% of the sickle cell patient population (i.e., 2,000+ patients) with the newly approved sickle cell disease CGTs.
• Continuing along those lines, I thought this MIT Technology Review article was a great companion piece to the IQVIA article above — this time presenting a patient’s perspective of what it was like to participate in Vertex/CRISPR’s exa-cel clinical trial. Though the experience/therapy changed his life for the better, the process wasn’t all sunshine and roses, either. There’s a lot to chew on here.

Resolution #6: I will finally accept that self-regulation is just not a thing I was put on this earth to do.
[REGULATORY]

• Exhibit A: This newsletter.
• Fortunately for us, there’s also no holding my colleague Erin at Cell & Gene back. It’s only January and she has already snagged both Peter Marks and the FDA’s new Super Office Director, Nicole Verdun, to join her for a free CGT Regulatory Outlook panel discussion on Jan. 25 from 12:45-1:30 PM ET. Register here!
• In recent weeks, the FDA published two draft guidances:
  • The Advanced Manufacturing Technologies Designation Program (comments due by Feb. 12, 2024), and;
  • Potency Assurance for CGT Products (comments due by March 27, 2024). This is a revision aiming to replace the CGT “potency tests” guidance from 2011.
• As you can imagine, the potency assay guidance garnered quite a bit of attention across the industry. I particularly appreciated Raz Eliav’s thoughts on LinkedIn & this write-up in RAPS about what this revision is setting out to accomplish and how it differs from the previous version.
• Speaking of guidance, the FDA is looking for feedback on how it could improve/streamline issuing guidances for industry. Scroll down to section II to see the list of questions they have for us about our desired scope, format, category, and public commentary needs (etc.,) for future guidances.
• For those of us hoping to launch our therapies in the UK, the MHRA’s new International Recognition Procedure is now in effect, enabling applicants to receive swifter market authorization for therapies previously approved by partner regulators (e.g., FDA/EMA/TGA, etc.).

Resolution #7: I will FINALLY start that sci-fi novel I’ve been planning since I was 14.
[mRNA ‘-ICITIES’ & ‘-ILITIES’]

• And my heart is telling me it needs to be a series of at least four books, starting with:
• mRNA & The Chamber of Designability:
  • Several of our friends from Moderna penned a review article outlining what we know about mRNA stability and activity and how these factors can influence our mRNA design decisions. [Institutional access required]
• mRNA & The Sorcerer’s Stability:
  • Greenlight Biosciences experts have gifted us this article highlighting their thermodynamic analysis of a 4,000 nucleotide-long mRNA and which factors positively or negatively impacted its length, stability, and integrity.
  • Several researchers at University of Wisconsin-Madison have identified mineral coatings that could enable freeze-dried mRNA (DS only) to be stored at room temperature for up to six months.
• mRNA & The Goblet of Immunogenicity:
  • Moderna is back, this time with a histological analysis quantifying protein expression levels and site(s) of expression for their mRNA vaccine in rodents and NHPs.
  • This Molecular Cell publication does a deep dive into the world of endogenous dsRNA — namely, how they came to be, how they’re processed (or ignored), and how they degrade.
  • A study in Nature revealed that modified mRNA vaccines unintentionally “inspire” cells to encode “small amounts of unintended proteins.” This is a much more approachable write-up explaining about why this isn’t necessarily bad news but remains an important consideration as we explore chronically dosed therapies.
  • This team from Corner Therapeutics have published an article exploring the immunogenicity benefits of co-immunization with mRNA/LNP vaccines (e.g., antigen + additional protein[i.e., cGAS∆N]).
• mRNA & The Prisoner of Reactogenicity:
  • In this Advancing RNA guest column, Noxopharm’s CSO outlines “more tunable” alternatives beyond base modifications to minimize reactogenicity of mRNA vaccines.

Resolution #8: I will be less litigious in 2024.
[LEGAL ISSUES]

• Unless your name rhymes with “Karepta”or “Bregenex.”
• In which case, buckle up: A district court in Delaware has invalidated Regenxbio’s/Upenn’s '617 Patent' protecting host cells containing certain AAV sequences. Sarepta, who was accused of infringing this patent with its AAV DMD gene therapy, has emerged triumphant. (An appeal is most likely forthcoming.)