2022 thus far

September 30, 2022
DHC COO Katy Spink at work in her home office|

by Katy Spink, DHC’s COO and Managing Partner

Welcome to the end of Q3’22, a time that feels like an excellent opportunity for an update on my thoughts from earlier this year regarding what 2022 could mean for cell and gene. The year is looking strong so far, if not quite in the category of ‘mind blowing’ relative to the high level of expectations I’ve come to have for this space in recent years!

My original piece considered the possibilities that 2022 could be the year in which at least one of these major steps forward for cell and gene therapy (CGT) would likely take place:

  1. Moving from approved labels only for “no options” patients to indications in which CGTs compete with traditional therapies;
  2. The first cellular immunotherapy product approval in solid tumors;
  3. The year of the most major market approvals to date; and/or
  4. The possibility that 2022 could become known as the year in which allogeneic cell therapies finally hit their long-awaited inflection point of generating compelling clinical proof-of-concept data.

To steal my own punchline a bit, I’d say that as of today both #1 and #3 are ‘done deals’ (with potential for more), while #2 and #4 are inflections points that are likely to come soon, but not this year. Let’s review in more detail, starting with those that are coming to fruition this year and then considering those to watch in 2023.

First, I mentioned back in Q1 that there was, “real potential for as many as four CGT products to be competing head-to-head with prior standards of care before the year is over.” That high water mark remains within reach.

As anticipated, the first of these were earlier line approvals for two autologous, CD19 targeted CAR-T products. 1H’22 saw both of these (Kite/Gilead’s Yescarta® on April 1st and BMS’s Breyanzi® on June 24th) approved by FDA as second-line treatment of large B-cell lymphoma (LBCL).

Second-line approvals in Europe are pending but still looking possible before year-end. Breyanzi's EU application is under review as of June 20th and Kite/Gilead recently announced a positive CHMP opinion for Yescarta’s EU second-line submission. Whether these will clear in late 2022 or spill over to early 2023 is currently too close to call.

The other two products with potential to propel CGT past this milestone were two AAV gene therapies for Hemophilia: BioMarin’s RoctavianTM (previously known as ValRoxTM) for severe Hemophilia A, and Uniqure/CSL Behring’s EtranaDez (etranacogene dezaparvovec) in Hemophilia B. So far this looks like a mirror image of the LBCL therapies, in that European approvals are making it in before US approvals.

Roctavian's European green light came in Q3 but the US response is not expected until sometime in early 2023. BioMarin just met their September BLA resubmission deadline so the possibility of hearing back in 2023 assumes that FDA agrees on the appropriateness of an accelerated six-month review cycle and that there are no clock resets for additional info requests.

And, if all goes smoothly for EtranaDez, both European and US approval are still possible this year. Also of interest, ICER just released their report on cost-effectiveness of these therapies, concluding that both were likely to be cost effective at a modeled price-point of $2.5M.

In summation, of the eight (four European and four US) decisions we were watching for this year for point #1, we’ve seen zero rejections.

The count currently stands as three yes’s (Yescarta US, Breyanzi US, Roctavian EU) with a possibility for up to four more (Breyanzi EU, Yescarta EU, and EntranaDez in both US and EU), with only Roctavian’s US approval looking certain to roll to 2023.

This image sums up the 2022 CGT products that are approved/being approved to compete with current standard of care. The count currently stands as three yes’s (Yescarta US; Breyanzi US; Roctavian EU) with a possibility for up to four more (Breyanzi EU, Yescarta EU, and EntranaDez in both US and EU), with only Roctavian’s US approval looking certain to roll to 2023.

Now let’s consider point #3: the prospect for the most major market approvals in a year, which remains an interesting point of consideration. We aren’t blowing 2021 out of the water, but we are seeing steady growth globally, and particularly in the markets that traditionally hold the highest bar for approval: the EU and US.

As an indication of the steady progress we’ve been making in this field, 2021 is the year to beat, with six approvals, including four new products (AbecmaTM in both US and EU; Breyanzi, Stratagraft®, and Rethymic® in the US) and two line extensions (Yescarta, which added follicular lymphoma and TecartusTM, which added adult B-cell ALL, both in the US)1.

With the US approval of eli-cel (SKYSONA1) earlier this month, we have already surpassed those record-breaking numbers from 2021 with a total of eight major market approvals so far this year. This includes three products approved for a first indication and first geography (CARVYKTI™ in the US and EU as well as Japan, plus Roctavian and UpstazaTM in the EU), two approved for the first time in the US after prior approval (and withdrawal) in the EU (ZYNTEGLO® and SKYSONA), and three line extensions (Follicular Lymphoma for Kymriah®, plus the aforementioned 2nd line indications for Yescarta and Breyanzi). And 2022 may not stop there…as I discussed above, EtranaDex has opportunities to be approved in both the US and EU this year. Not only that, but Atara has set expectations for EU approval of Tab-cel® in the final quarter of 2022. If both of those products get the ticket this year, 2022 will go on record as having the most new CGT products approved in a single year, as well as the most overall approvals.

What does all this mean for 2022’s place in the evolution of cell and gene therapies? While eight to ten new approvals this year is perhaps not quite ‘mind-blowing’ when compared to last year’s total of six, it’s certainly indicative of a mind-blowingly rapid growth in our expectations if we take a longer angle view compared to, for example, the three approvals that initially lit this field on fire back in 2017.

Now, let’s take a look at points #2 and #4: those which are not going to hit in 2022 but give us something exciting to look forward to in 2023.

#2 is a quick one to consider. I had posed the question, “What if 2022 delivers us the first T cell product approval in solid tumors?” We now know the short answer: it won’t. So, let’s move this into the 2023 column. 1H 2023 is currently the best case scenario for Iovance’s Lifileucel if their BLA is completed by end of this year (Iovance initiated rolling BLA submission in August, citing Q4 as the goal date for completion) and if there are no further hiccups for this previously fraught therapy in the review process. In fact, it’s looking like we’ll have at least two shots on goal for this milestone in 2023, as Adaptimmune have indicated that they anticipate a BLA submission for Afami-cel (for treatment of rare sarcomas) by year end, with a likely PDUFA data in mid-2023.

Lastly, point #4: “Will 2022 be the year in which allogeneic therapies hit an inflection point?” All signs now point to no compelling inflection here in 2022. Although it’s worth noting again the likelihood that Atara’s Tab-cel could obtain the first approval for an allogeneic cellular immunotherapy with EMA clearance in Q4, none of the broader platform approaches mentioned in my earlier article have demonstrated the type of transformative data that would suggest we’ve reached a turning point for allogeneic therapies, and there’s no compelling reason to expect that the last few months of the year will change that. To summarize this year’s key developments in the three key allogeneic immunotherapy sub-sets highlighted in my original article:

In the gene edited (αβ)CAR-T space, Allogene, Precision BioSciences, and CRISPR continue to push forward with their first generation ALLO-501A, PBCAR0191, and CTX110 programs. In particular, Allogene has reported a likely Phase 2 initiation for ALLO-501A still to come this year, as well as updates on the Phase 1 ALPHA, ALPHA2 trials promised before year-end. So far, however, we’ve not seen any reason to believe that these approaches will overcome the durability issues that were evident in their early clinical readouts. In my original article, I highlighted the potential for the addition of a PD-1 knockout in Caribou’s CB-010 to potentially overcome this durability issue; sadly, data from the ANTLER trial reported in June and updated in August would suggest CB-010 is also currently demonstrating low durability, at least for dose level 1. An update on dose level 2 is promised by year-end; I’ll keep my fingers crossed for better durability in that cohort. As for the other 2nd generation approach mentioned in my prior article, Precision’s PBCAR19B (which adds an HLA-E transgene in hopes of evading NK cell-based rejection) appears unlikely to release new data this year beyond what we saw over the summer.

While NK cells remain a space to watch, 2022 has yet to bring any transformative developments. Nkarta’s response rates look intriguing, but durability remains to be seen. None of Fate Therapeutics’ programs have released a substantive data update yet this year. Century’s CNTY-101, which just received IND clearance in August, will certainly be a product to watch in 2023, but I wouldn’t expect data this year.

And finally, the early clinical data on Adicet’s γδ T cell program ADI-001 suggests impressive response rates but appears to hint at similar durability problems to other allogeneic immunotherapy programs so far, at least in lower dose cohorts.

So, we’ll hand the lion’s share of allogeneic expectations over to the year 2023 or beyond. Also for 2023, let’s remember the possibility for the first—or first and second?!—T cell product approval in solid tumors (Iovance’s Lifileucel and/or Allogene’s Afami-cel) and the US approval of Roctavian.

A handful of other notable approvals to watch for in ‘23 include:

There will be more to come from me over the next year with regards to 2023’s place in the field, of course. Meanwhile, I’ll remain attuned and interested to see how many more exciting milestones are realized by the end of this year

1Note:  SKYSONA was approved in 2021 in the EU but was voluntarily withdrawn by the company that same year, so I’m not counting that towards the 2021 total.

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