Will 2022 be the year that blew our minds?

I’ve been thinking lately about what place this year, 2022, may ultimately hold in our memories. By this time next year when we have the benefit of some hindsight, will we be referring to it as the first post-pandemic year of the twenty-twenties? Will it be the year in which biotech stocks rebounded from their crushing 2021 downturn?, or will it be the first time on record in which biotech experiences a bear market two years in a row?

And what role will 2022 ultimately play in the world of cell and gene? An inflection point in sales would always be a fascinating narrative, but of course we already saw the first billion dollar drug in C&GT, last year. Luckily, there are many other possibilities that intrigue me just as much that we’ll be able to look forward to in the near future.

It appears likely that 2022 will become the year in which the field moves from treatment options only for “no options” patients to earlier indications, thus allowing C&GT to compete with traditional therapies. There’s also significant potential for it to be the year of the first T cell product approval in solid tumors, and/or the year of the most approvals to date. And a bit of a longer shot, but one close to my heart, is the possibility that it will become known as the year in which allogeneic cell therapies finally generated compelling clinical proof-of-concept data.

Let’s go through these one at a time in more detail.

First, based on clinical data released over the last few months, it seems likely that 2022 will be the year that the field moves from therapies being approved to treat only “no options” patients to those same therapies being approved for earlier indications. Such approvals would allow C&GT to begin competing with traditional/established therapies. Earlier indications will ultimately have an extraordinary impact on patient survival and quality of life, which is the purpose that drives nearly everyone who works in this field. So, what are the possible 2022 paths towards this monumental shift?

The path that we will know about first is that by which two autologous, CD19 targeted CAR-T products could be indicated for second-line treatment of large B-cell lymphoma (LBCL).

The first of these, Kite/Gilead’s Yescarta®, yielded positive data in the ZUMA-7 study of second-line relapsed or refractory LBCL, which was announced in June of last year. Yescarta showed impressive improvements in both event-free survival (8.3 months vs 2 months, p<0.0001) and objective response rate (83% vs 50%) compared to standard of care chemotherapy. In September of 2021, Gilead submitted the sBLA for this expanded label. Approval seems likely, given this compelling data and the fact that the CMC package for Yescarta has been reviewed previously. The PDUFA date is set for…wait for it!…momentarily: on April 1, 2022.

BMS’s Breyanzi® is running close behind, with positive topline data from the TRANSFORM study announced (without details) last June, impressive details elaborated on in December, sBLA acceptance and Priority Review announced in February, and a PDUFA date upcoming this June 24th.

To continue the trend of good things in our field coming in batches of two at the moment, the second path towards this same turning point would be to see one or both of the two AAV gene therapies for Hemophilia get the nod. If approved, both products would be replacing an established therapy (enzyme replacement) in a severe subset of Hemophilia patients as opposed to treating a “no option” population.  Both sponsors are expected to file in 1H’22 with potential for approval before year end and both will be in play in both Europe and the US.

BioMarin’s RoctavianTM (previously known as ValRoxTM) is a treatment for Hemophilia A: in Europe, we can expect CHMP’s opinion on BioMarin’s MAA this upcoming Q2. In the US, we saw the January announcement of favorable two-year data and a planned BLA resubmission (also in Q2). BioMarin has indicated that they anticipate a six-month review timeline, which would potentially mean an approval before year-end.

Turning towards Hemophilia B, Uniqure/CSL Behring’s etranacogene dezaparvovec is expected to file in both regulatory markets during 1H’22 following the announcement of favorable data last December.

Approval of these two gene therapies during 2022 seems less certain than the two second line CAR-T approvals, given both the tighter timelines for approval before year-end and the fact that neither product is already approved in another indication. That said, there does seem to be real potential for as many as four C&GT products to be competing head-to-head with prior standards of care before the year is over.

Now, on to the next possibility I mentioned: what if this year hands us the first T cell product approval in solid tumors?

This is a quick and easy one to consider, but certainly no less exciting or promising! Iovance are currently indicating that in the first half of this year we can expect filing of their long-delayed Lifileucel BLA in melanoma. Those of you who follow the space will recall that Iovance’s BLA has been repeatedly delayed by inability to obtain concurrence from FDA with their potency strategy: an unfortunately common point of failure in the space. Should they meet this deadline, I would expect the strength of their clinical data and the unmet need in this indication to support Priority Review, which would mean a PDUFA date before year-end.

Given that I’ve already highlighted the potential for five groundbreaking approvals this year, my next point of consideration should come as no surprise: that 2022 also has potential to set a record for the most C&GT approvals in a single year. Remember that in 2017, the original turning-point year for C&GT, we saw three approvals, all of new products: Kymriah®, Yescarta, and Luxturna®. 2018 saw only one: a line extension for Kymriah. 2019 and 2020 each gave us one new product: Zolgensma® and TecartusTM, respectively. Last year, in 2021, we saw momentum building up noticeably, with six approvals (five of which were for new products): Tecartus got a line extension and the five new products were Breyanzi®, AbecmaTM, Stratagraft®, Imlygic®, and Rethymic®. That makes 2021 the year to beat, and based on the information we’re tracking in-house, the makings of another record-breaking year are certainly there.

I’ve discussed two potential line extensions above: Yescarta and Breyanzi…and also in the works is a new indication in FL for Kymriah (with a PDUFA date possibly near April). That brings us to three line extensions to watch for in 2022 and, remember, two of these three are nothing short of revolutionary when we consider that they’re for earlier (second-) lines of therapy.

What about the new products awaiting approval this year? In addition to Lifileucel, Roctavian (ValRox), and etranacogene dezaparvovec as mentioned above, Bluebird brings in two that I haven’t mentioned yet: beti-cel in TDT and eli-cel in CALD. Add to that February’s approval of Janssen/Legend’s CarvyktiTM in multiple myeloma, and we’re up to six possible new product approvals this year! Lastly, and I should note that this one could possibly be a stretch considering prior delays relative to announced benchmarks: PTC’s PTC-AADC, for which the sponsor has indicated we should expect a CHMP opinion in Europe in April and a US BLA filing in 1H’22.

That makes for a possibility of ten or more approvals this year: seven of which would be new products and three of which would be line extensions. It’s quite the statement of extraordinary potential for this year that my summation of ten or more possible approvals this year should show up this far into my article, isn’t it?

But wait, there’s more!

2022 may well also become the year in which allogeneic therapies experience their long-awaited turning point.

Tl;dr: this is a market segment whose time is likely to come very soon; will data results expected this year be resounding? Consistent? At Dark Horse we’re closely tracking at least 21 companies with data coming out this year. That’s…a lot.

I’ve saved my discussion of allo until last, in part because it is a bit more of a reach; recent developments suggest a true inflection in this space may yet be delayed another year or more. That said, it is particularly close to my heart given my own personal work history at companies rooted in allogeneic approaches before joining Dark Horse.

Back in late 2018, a colleague and I published “the long road to affordability,” in which we used publicly available data to estimate the likely cost of goods sold (COGS) for autologous CAR-T manufacturing and speculated on paths to improving costs in this critical class of therapies. To quote ourselves in the conclusion of this article, “… while significant improvements in COGS are feasible, ultimately more substantial changes such as transitioning to allogeneic platforms may be necessary to make C&GT products affordable for very large indications…”

So, what to watch for this year in the world of allogeneic cell therapies? Well, first and foremost, Atara is poised for Q4 EMA approval of the first-ever allogeneic T cell therapy (Tab-cel®). The US BLA for the same has been delayed, though, due to a need for further discussion with the FDA.

Multiple companies are expected to release clinical data from gene-edited allogeneic αβ T cell products this year and we’ll be watching them closely. Given the early data from Allogene, CRISPR, and Precision, all announced in the past 6 months, though, it appears likely that further modifications to product design, dosing schedule and/or conditioning regimen will be required to demonstrate durable clinical responses.

2022 milestones I’ll be watching especially closely in this space will be whether either (i) the addition of an HLA-E transgene to evade NK cell rejection in Precision’s 2nd generation PBCAR19B (program update expected mid-year) or (ii) the PD-1 knockout employed in Caribou’s CB-010 (initial data in the ANTLER trial to be reported at ‘at a medical meeting in 2022’) can overcome the persistence issues observed in those first-generation allogeneic αβ T cell approaches.

Although early, data in the NK cell space potentially shows more promise. Back in 2020, data from the Rezvani lab at MD Anderson (umbilical cord-derived NK cells with a CD19 CAR and IL-15 armoring) showed 8 of 11 (73%) response rate in a highly pretreated mixed NHL/CLL population, with 7 of those 11 (64%) being complete responses, and a median durability of 13.8 months. The program (which partnered with Takeda in 2019) appears to have initiated a Phase 2 study in 2021; however, it is unclear if we can expect any interim data updates in 2022.

Similarly, data reported in December from Fate Therapeutic’s FT516 (iPSC-derived NK cells expressing a high affinity, non-cleavable CD16 construct) trial in relapsed/refractory B cell lymphoma showed very early promise of improved durability vs. allogeneic gene edited αβ T cell approaches. Additional data is expected in 2022 from this program as well as from Fate’s FT596, FT538, and FT576 programs, beginning with this February ’22 press release.

Other ongoing clinical trials of NK cell products that may potentially report interim data during 2022 include Artiva’s AB-101, Nkarta’s NKX101 and NKX019, and Celularity’s CYNK-001 and CYNK-101 (although most of these trials are scheduled to complete in 2023 according to clinicaltrials.gov).

Another orthogonal approach to allogeneic cancer immunotherapy is gamma delta T cells. It’s admitted too early to tell if the inherent allogeneic potential of these cells will help overcome the persistence issues encountered for gene edited αβ T cell approaches, but Adicet’s ADI-001 (CD20 targeted γδ T cells) showed promising response rates in initial clinical data reported in December. Just the other day, IN8bio announced three durable remissions in its ongoing Phase 1 trial of INB-100 in AML, although given that INB-100 was given in patients undergoing HSCT, it’s hard to know how much to make of this data. Additional data is expected this year from both programs, as well as IN8bio’s INB-200 program in Glioblastoma.

Not to go too far afield, but I must also note that there are, of course, allogeneic therapies that aren’t cancer immunotherapies. While most of these remain further removed from clinical proof-of-concept, two I’ll be watching this year are Vertex’s diabetes program, which reported very promising data (albeit in one patient) in October, and Viacyte’s competing program in collaboration with CRISPR therapeutics which announced first dosing in February.

There you have it: my official guide on what to watch in 2022. Any one of these prospects (earlier indications/competing with traditional therapies, T cell product approval in solid tumors, the most approvals ever in one year, and/or strong allo proof-of-concept data) would be noteworthy, ground-breaking, and cause for celebration in the cell and gene world. And if more than one of these prospects is simultaneously realized this year…well, 2022 would then certainly go down in the cell and gene record books as a year to remember.

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