ARW's CGT + RNA Manufacturing Must-Reads (FORTUNE COOKIE 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. Every two weeks, 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.

The day this newsletter was sent was “practice being psychic day.” But instead of trying to come up with elaborate predictions of my own — which would no doubt reveal that practice does NOT make ARW perfect or psychic — I’ve turned to the second-best option. Each section of must-reads below will be joined by a particularly appropriate (and bite-sized) piece of fortune cookie wisdom.

If that still feels like a cop-out, please refer to the prophecy I received recently from a fortune cookie: “It could be better, but it’s good enough.”  Enjoy mediocrity.

Only listen to fortune cookie; disregard all other fortune telling units.
[OUTSOURCING]

• Unless those “fortune telling units” are named Adam Haskett & Joe Graskemper — in which case, disregard “fortune cookie” and listen to everything they have to say.
• In particular, you can catch up on the latest installment — part 3 of 4 — in our series on outsourcing. Here, these two gurus continue to dispense their immense outsourcing wisdom, this time sharing how they approach risk-sharing in their outsourcing partnerships while also being sensitive to arising and background IP.

Don’t panic.
[REGULATORY]

• It’s just the FDA.
• The FDA recently finalized its guidance on Benefit-Risk Assessment for New Drug & Biological Products. As we already know well, the Risk-Benefit ratio has become a central pillar of every CGT regulatory discussion. For some quick high-level takeaways of this guidance’s scope, check out this informative write-up in RAPS.
• While the guidance above is quite benign, this article — Pharma Could Lose Some Commercial Info Protections As Part of FDA’s Misinformation Campaign — suggests our industry could face discomfort in the future as the FDA discusses altering certain procedures to improve transparency and confront misinformation.
  • I’d argue the last section on “communicating uncertainty” is and has been particularly relevant to all ATMP regulatory decision making. In fact, it will be interesting to observe the FDA’s communication strategy and response moving forward in relation to Sarepta’s DMD gene therapy, which, as the news reported this week, did not meet its primary endpoint in its pivotal study.
  • As I profiled in recent weeks, Sarepta’s therapy received an accelerated approval, but raised a number of scientific and manufacturing-related questions.

Catch on fire with enthusiasm and people will come for miles to watch you burn.
[MARKET UPDATES]

• Well, this took an extremely dark turn... but also, I kind of want S’mores now?
• Two of my colleagues recently put their “stop-drop-and-roll” technique to the test by attending ARM’s Meeting on the Mesa, where it sounds as though enthusiasm for the future of the industry remains high (but also fire-proof). If you missed the meeting yourself, be sure to check out:
  • Tyler Menichiello’s top 5 quotes/takeaways from MOTM — my favorite highlight being a quote from the newly appointed Director of the FDA’s OTP, Nicole Verdun; and
  • Erin Harris’ article homing in on the costs and ethics of gene therapy. For those of us outsourcing, check out her third takeaway on what’s top of mind for biotechs/CDMO partnerships these days.
  • Both Erin and Tyler focus on the role ethics play in our field, but if you’re interested in a longer article that goes a bit longer on the topic of ethics as it was discussed during MOTM, I liked this one from GEN: Without Ethics, CGTs Will Fail.
• Obviously, lack of access remains one of the biggest ethical problems we face as an industry. In turn, NIIMBL has set its sights on standardizing the development of viral vectors to make them more “broadly available” for use across the industry. This month, they announced their new Viral Vector Program, which will comprise two workstreams — one on process and one on analytics — and will culminate in a shared-access platform.
  • NIIMBL will also build a workforce training program to accompany this future platform.
• DeciBio will be hosting a webinar next week, November 8, on the future of the cell therapy manufacturing sector. In particular, they’ll be showcasing growth in the supportive tools industry and addressing gaps where more innovation may be needed.

You don’t have to be faster than the bear; you just have to be faster than the slowest guy running from it.
[CELL THERAPY TURN-AROUND TIME]

• Unless you’re a cell therapy maker — in which case we expect you’ll be faster than the cheetah that is chasing the bear.
• Speaking of speeding things up, this article profiling oncology hospital leaders’ current perspectives on the commercially available cell therapies is well worth a read (and then some). Frankly, these leaders do not mince words when comparing and contrasting what commercialized cell therapies bring to the table or don’t bring to the table, thanks to their still-unreliable manufacturing processes. Some meaningful tidbits from this article include:
  • Access remains tenuous. For example, Sloane Kettering is only able to treat 2-3 patients out of the 10 it would like to treat per-month given limited manufacturing slots for cell therapies.
  • Of the products referenced in the article, Yescarta’s 16-day process is a leader in terms of turn-around time.
  • Out-of-spec products are still a big problem. Upon reaching the commercial market, one product (Carvykti) has encountered higher than the 18 percent failure rate seen in clinical trials.
  • Out-of-spec products can be used under special protocols without payer coverage. But this requires additional administration protocols/safety information for physicians. In turn, companies should consider implementing a program or a pathway to help physicians provide out-of-spec products when deemed appropriate/necessary.

Enjoy yourself while you can.
[COMPLIANCE/ANNEX 1]

• "Too late." Sincerely, Annex 1
• To be clear, this BioPhorum whitepaper — CGT Aseptic Process Simulation Reflections — was written before Annex 1 went into effect at the end of August. But I daresay those of us in MSAT or QC (or fellow multi-disciplinary nerds) can and will still enjoy reading this document which explains current regulatory landscape/guidance on APS implementation and provides recommendations on how to navigate the challenges in applying said guidance to ATMP processes.

Something wonderful is about to happy.
[LNPs]

• We successfully delivered LNP-mRNA to the brain!
  • Ahh — typo! I meant to the liver.
• At least when the co-founder of Moderna speaks on LinkedIn about new LNP-mRNA research, we can at least trust it’s legit. In a recent post, Kenneth Chien shares a recent study demonstrating that mRNA/LNP optimization is just as important as guide RNA and nuclease selection when exploring in vivo gene modification via base or prime editing.
  • The study he references can be found here: Genotoxic Effects of Base & Prime Editing in Human HSCs
• This article on 4 Major Trends in LNP Research is both the introduction to and doorway into LNP-Narnia. In addition to summarizing high level trends, this article provides us with the opportunity to go deeper into a database comprising ongoing LNP research from 2020-2023.
• We can expect to see more from ISPE on LNP-mRNAs moving forward. In addition to sharing a recording of a recent ISPE ATMP community of practice town hall, this LinkedIn post from Erich Bozenhardt shares that mRNA-LNPs were one of the most in-demand topics for further discussion and future ISPE ATMP projects.