Bracing for a hematology faceoff: CARs vs. bispecifics

After a challenging period, bispecific antibodies (bsAbs) are making a comeback in hematology as they become a prominent drug class and a major threat to CARs.

Historically, excitement around bsAbs peaked in 2012 following the Amgen (AMGN)/Micromet acquisition but gradually faded due to disappointing results for Amgen’s Blincyto and other bsAbs. Blincyto (a CD19xCD3 T cell engager) is designed to kill tumor cells by simultaneously binding T cells (via CD3) and leukemia cells (via CD19), bringing them in close proximity and triggering a T cell response. The drug was approved in 2014 and is a growing product ($85M in Q3/19) but it remains the only FDA-approved bispecific T cell engager and uptake has been hampered by safety issues and the need for continuous administration. Replicating Blincyto’s success with other targets proved challenging and other programs based on Micromet’s or competing platforms have not generated attractive data until recently.

With bsAbs not living up to expectations, investors turned to CARs that provided an alternative to T cell engagers. The idea was similar (mounting a potent and specific T cell response) but instead of recruiting T cells in vivo, CARs are engineered ex-vivo and then re-infused to patients.

The CAR space exploded in 2014-2018 based on exciting data in liquid tumors, especially ALL/DLBCL (CD19) and multiple myeloma (BCMA). CARs generate high response rates and are potentially curative in some indications. The graphs below from Yescarta’s pivotal trial in DLBCL demonstrates this potential: Despite the relatively modest PFS of 6 months, 40% of patients were still in remission after more than two years. BCMA CARs are equally impressive with response rates of 80-100% with a median PFS of 12-18 months.

Yescarta - PFS-OS - Locke 2019Lancet Oncol. 2019 Jan;20(1):31-42.

Bispecifics strike back

Recent data readouts from multiple clinical trials have made bsAbs the hottest segment in hematology. At ASH 2019, companies presented results in DLBCL (CD20) and multiple myeloma (BCMA).

On the CD20 front, data from Roche, Regeneron (REGN), Xencor (XNCR) and others demonstrated strong efficacy and an acceptable safety profile with agents that can be given weekly or less frequently. Response rates in DLBCL are in the 38-58% range, including CRs. Durability is still premature but most CRs appear durable, up to 2 years, and importantly, re-treatment upon relapse can lead to subsequent responses.

Mosunetuzumab

BCMA bispecifics are 1-2 years behind CD20 programs with BMS (BMY) in the lead following recent update for CC-93269. At the higher doses, response rate and CR rates were 88.9% and 44.4%, respectively, with most responses ongoing at the time of cut off.

cc93269

These results come on the heels of Amgen’s AMG420 data at ASCO 2019, which demonstrated a 70% response rate at the relevant dose. In contrast to CC-93269, AMG420 is a classic BiTE like Blincyto and has to be given via continuous infusion. Amgen is now focusing on a half-life extended BCMA program, AMG701, which should be at a similar stage to that of CC-93269 but no clinical data have been published. Regeneron presented preliminary (7 patients) data for its BCMA bsAb (REGN5458) demonstrating a 57%-75% response rate.

These data are preliminary and need to be corroborated by larger studies but definitely make BCMA bsAbs a promising class for multiple myeloma, together with BCMA CARs and BCMA ADCs (see below a table from Nature Reviews Drug Discovery). At ASH 2020, investors should expect more mature data from several BCMA programs that are still in dosing optimization.

BCMA landscape

Nat Rev Drug Discov. 2019 Jul;18(7):481-484

Threat to CARs

Recent data with bsAbs put them on a collision course with CARs, especially in DLBCL and multiple myeloma, where data look promising for both classes. While both are designed to induce T cell responses against cancer cells, they represent very distinct approaches and product profiles. CARs are personalized living therapies typically given once, with complex logistics. Bispecifics are simple off-the-shelf products that are administered repeatedly.

Looking at the parameters in the table below, it is easy to see why physicians and patients would prefer bsAbs over CARs. They are readily available, logistically simpler (no cell collection, no conditioning, no patient-specific shipments, no waiting periods, no production failures etc.). They also allow dosing flexibility (dose titration, treatment holidays etc.) and their manufacturing cost is low. One potential advantage CARs have is the fact they don’t require chronic treatment.

But what about efficacy, especially long term remissions? Both CD19 and BCMA CARs lead to very high response rates including a long survival tale in a significant portion of patients with CD19 CARs. It will be challenging for bsAbs to match response rates seen with CARs and durability is still an open question, but so far there appear to be multiple cases of long term remissions with CD19 bsAbs even after patients are taken off treatment.

In addition, clinical data for CARs are confounded by the fact that they do not include “technical failures”, (patients who could not receive treatment due to technical and clinical issues). These technical failures occur in 10-30% of cases based on pivotal studies and real-world failure rate is probably higher. Including these cases in the data set will significantly diminish CARs’ efficacy metrics.

CARs vs. bsAbs

While the burden of proof is still on bsAbs, I personally think bsAbs will capture a significant market share even if they are less efficacious than CARs, especially in community centers where the majority of patients are treated. The two classes are not mutually exclusive as patients who fail one treatment modality may receive the other after relapse and this has been reported with both modalities with successful outcomes. Allogeneic CARs address some logistical issues but their clinical profile is still unclear (especially persistence) and as a cell therapy they will always be more complex, expensive to manufacture and administer (including conditioning). It will be interesting to see data for several allogeneic CARs in 2020, which could shed light on CARs’ potential to become a widespread treatment option.

bsAbs for solid tumors

So far success with bsAbs has been limited to hematology. Solid tumors are less accessible and have a challenging immune suppressive mileu, which makes it challenging for current T cell engagers to have an effect at tolerable doses. Other efforts to target two “oncogenic” targets (VEGFxAng2, VEGFxDLL4…) or immune checkpoints (PD1xLAG3, PDL1xTGFb…) either failed or are too early to assess.

The most successful bispecific program in solid tumors I am aware of is Zymeworks’ (ZYME) ZW25 (HER2xHER2), which demonstrated encouraging single agent activity but with somewhat limited durability.While ZW25 has clear potential in HER2 expressing GI tumors, the more attractive program in the company’s pipeline is ZW49, an ADC based on ZW25. Targeting two sites on the same receptor may increase potency without having an effect on off-target toxicity, thus expanding the therapeutic window, which is ADC’s main problem. Who knows, perhaps bispecific antibodies could become an important enabling technology for ADCs and vice versa…

Portfolio updates

I am selling Spark (ONCE) and Audentes (BOLD) following their respective acquisitions. I am also selling a portion of Xenon (XENE) given its disproportional weight (15%) in the portfolio and adding positions in Madrigal (MDGL) and Viking (VKTX). Cash is now almost a third of the portfolio as it has been challenging for me to find new stocks at attractive valuations.

Portfolio holdings – Jan 19, 2020 

portfolio - 19-1-2020 after changesbiotech etfs - 19-1-2020

 

 

112 thoughts on “Bracing for a hematology faceoff: CARs vs. bispecifics

  1. thanks a lot Ohad for your new blog!

    Ohad, I was wondering whether you have any current take on

    AMRN (failure of AZ CVOT, failure of ACST, only one w CVOT!)

    EIGR (rare and ultra rare diseases, main value driver HDV programs)

    MIRM (rare liver diseases, current focus on pediatric, with pretty clear route to market in ALGS, followed by PIFC2)

    thanks!
    Christian

    Like

  2. Dear Chad,

    Thanks for the update and the insight into Bispeficics…. what about for bispecifics for solid tumors – and non-BCMA targeting agents? How does that competitive landscape look like, and do you think that drugs like Perception will give way to bispecifics? especially ADCs?

    Regarding your comment… companies with interesting valuations are hard to find–what about the following:
    TRIL (resent surge / but compared to FTSV
    KZR
    MBIO
    CGEN
    MGEN
    GNCA
    CYCN
    ABEO
    STML
    AGTC
    CARA
    TRVN – for migraine program

    Like

  3. Sorry, Ohad!
    spellchecker changed your name…
    also, what is your view on XENE– is your the decision to sell part of holding only a portfolio rebalance decision?
    Thanks!
    Dan

    Like

  4. Also, what is your take on KRTX given the stellar ph2, the multiple indications they are going after, and the size of the addressable market? Their valuation still much lower than SAGE and it seems that their MOA is clearer than SAGE, making it in my view a more derisked investment.
    Dan

    Like

  5. Ohad
    You are reducing your GT exposure!?!
    Before selling BOLD and ONCE, the GT was 24%, now is only 17%.
    2 years ago you said your goal is to make GT 30% of the portfolio, bc it’s disruptive technology. Why change of heart?
    So far your GT investment was very successful – 4 nice acquisitions
    BOLD, NITE, ONCE, AVXS, which proves your initial vision about the field.
    Is there any reason to become disappointed in GT, for us to be worry about?

    Like

  6. @Dan I think it’s not appropriate to ask Ohad in one post for 12 companies. If everybody is acting like this we will get no answers. Currently Ohad has not answered the questions of the last blog “Portfolio updates – Biotech M&A valuations and ADCs”.

    Like

  7. Ohad. You do such a good disciplined job on cancer company analysis. You should join us on the other side as drug developer.

    Private Oncology CEO

    Like

  8. Thanks for the update. You should write more even if it’s not related to your portfolio. Maybe on trends you notice or the things you have been reading

    Like

  9. Hi Ohad
    Thanks for another nice post – any BsAb platform you prefer ?

    Whats your view on Sutro Biopharmas cell free protein synthesis technology XpressCF – they claim its disruptive? You mentioned their site specific conjugation programs in your last post (CD74 and FolRalpha plus a BCMA ADC with BMS). Two new INDs this year and a exciting collaboration with Merck on cytokine derivatives (of couse they mentioned Nektar and Synthorx).
    So with a market cap of only 275 million dollars it looks cheap and “just” need some positive clinical data to get things going.

    BR
    Jens

    Like

  10. I’ve posted links to two Google spreadsheets on my Twitter account. One contains a list of companies working on biospecific antibodies, and the other has a list of companies working on CAR-T therapies.

    Biospecific Antibodies:

    CAR-T:

    Like

  11. @toby

    Thanks for the tip… so you want to become moderator of Ohad’s blog?
    😉

    I do not expect any answers from Ohad and I am super grateful when he does! I have been following his blog for more than 4 years now 😉 and like everyone here appreciate every post by Ohad and his insightful replies to everybody else’s questions, and also value the community of readers who. One here and ask questions and share opinions!

    Thanks!
    Dan

    Like

  12. Abivax – what do you think of Abivax and their drug ABX-464? Seems to have shots in UC, CD and perhaps RA.

    CCXI – had a brilliant presentation at JPM20. What do you think about their drug Avacopan? Is it a pipeline in a drug like some people say? Could it become a blockbuster?

    Like

  13. Ohad , you previously indicated you would add to your position in Chma if it remained at these levels once their nda was accepted by the fda. Is that still the plan?

    Like

  14. Dear Ohad, thank you for your work. I am interested in your recent view on TGTX. They are at 52h and up more than +100% this year. I remembered you were not very keen on it in the past, given the latest presentation at JP Morgan, i was wondering if you have changed your mind and what do you expect it will go related the data to be released in a few days/weeks
    Most analyst PT are very favorable with lots of upside from todays price and they closed recently an offering they did only for 1 investor (great point partners)
    thank you,

    Like

  15. Hi Ohad
    Thanks again for your great blog!
    Any thoughts on MGNX? They list three bi-specifics and should have data for ASCO in at least one of them. Their enterprise value is less than $300M.
    Thanks in advance
    Declan

    Like

  16. Hi Ohad blog followers
    interesting July call activity / volume at NERV. One can have a nice return w/o a lot of risk by selling calls. Here it is how it may work.
    Buy 1,000 shares NERV at $8.40. Total $8,400.
    Sell 10 contracts -NERV200717C12.5CALL JUL 17 $12.5 at $3.60
    Instant $3600 (75%) gain.
    If in July NERV is <$12.5, you keep the $3,600 premium and the shares.
    If above – your 1000 shares will be called at $12.50 and will have a total gain of $7,700 or 160% from the initial $4,800 investment.
    Risk – NERV fails miserably below $4.80 before July 17 2020.
    I've have never seen such high call premium since, I guess, before the acquisition of LOXO in Jan 2019.

    Hope it's helpful.

    Like

  17. Hello Ohad
    is AUPH a reasonable candidate for m/a ?
     andre – I have zero experience with call & put.
    what is the worst case scenario for a lose?
    Thanks

    Like

  18. Christian (AMRN) – Looks like the starts are aligning for them, still hard for me to assess upside potential from here…

    EIGR – Sorry, not following them.

    MIRM – Looks very interesting with good underlying biology, need to dig deeper into that one.

    Dan-

    So far bispecifics have generated positive results primarily in liquid tumors. I think that in order to move into solid tumors CD3 engagers will require additional technologies to prevent systemic side effects like capping/masking. I am also optimistic about bsADCs like ZW49 but we’ll have to wait to ASCO to find out.

    XENE – It’s purely based on resource allocation, that position became too large following the recent run up.

    KRTX – Not familiar wit the story but looks like data are solid.

    andre – I still like GTx as a field and have high hopes for it even though the past year demonstrated the challnges AAV based therapies are experiencing. I didn’t intentionally reduce my exposure, it was due to the acquisitions and it is hard to find GTx players with reasonable valuations. For example, FOLD and RARE both have interesting programs but valuations are high.

    Toby – I answered the questions from the previous post, hope I didn’t miss anything.

    tedy (IGMS) – Let’s see, I prefer to wait for data given the high valuation.

    Anon – Thanks, I try to do my best on the other side of actual oncology drug development as part of my day job but for some reason it is harder than writing blog posts… 😉

    Jens Bjørn – That’s a good question… so far most IgG based platforms look comparable in terms of clinical profile but it’s early days. bsADCs is a very promising approach IMO but let’s wait for ZW49’s data.
    STRO – Agree with your assessment. They clearly have strong technologies and capabilities, a single clinical success will have a dramatic impact, fingers crossed for their FRa program, CD74 looks too toxic imo.

    Mike – (Abivax/CCXI) – Sorry, not very familiar with them.

    Paul (CHMA) – Yes, still plan on adding, not sure when.

    lgonber (TGTX) – So I think their drugs are active, I am just concerned about their chances of getting market share in a crowded market dominated by strong players.

    Declan (MGNX) – I am following them closely, waiting to see updated AML data for the CD123 program, not very optimistic about the other two (IO) but let’s see.

    Alex (ESPR) – From what I recall their PDUFA date is next month. From that point it’s a launch story and in 2022 CV outcome data.

    Richard Baker (MGNX) – I don’t think Marg is a viable product, many other HER2 alternatives and list is only getting bigger. I prefer to wait for clinical data from the other programs, so far nothing stands out but it’s still early.

    andre (NERV) – Thanks, not a big options expert.

    Alex (AUPH) – I think so, haven’t been following the story closely but data look good and safety profile is attractive.

    Ohad

    Like

  19. I think main “issue” with AUPH is patent life. 2027 is short, and for 2037, well not sure how strong those new patents are and whether they go into the label. This point is probably not easy for an acquirer, though hope/think M&A will happen.

    Like

  20. MGEN up 100% today on no news… seems many microchip biotech with low valuations such as TRIL and MGEN are making moves.
    I am also following CAPR and SYBX

    Ohad, you said before that you were not a big fan of CAPR – could you share mode detail regarding this? Valuation is at a paltry $7M.

    Dan

    Like

  21. hi Dan, TRIL did have some news recently, showing some nice single agent activity. tox profile a bit less a concern than before (but still..). they did a huge raise in relative terms yesterday – more than market cap. so financial problem solved for now… people looking at FTSV market cap which is way higher despite drug did not show much single agent activity, so the sharp price rise seems “rational”.

    Like

  22. Hello Ohad,

    Any thought on Affimed (AFMD). Bispecifics to NK cells. Low market cap.

    Fate, also in NK space high valuation, looks interesting.

    Scott

    Like

  23. You mentioned conditioning several times in your article. Are they are pre-conditioning platforms you favor at this point in time? Several companies come to mind: MGTA, MTEM, FTSV, Jasper

    Like

  24. Hi Ohad,

    VKTX, MDGL and other NASH plays are declining at an alarming rate. You continue to add… Is it just the timeframe for results driving them lower as you have indicated they are derisked.

    Like

  25. Exicure $xcur has a drug in phase 2 that has a market cap of less than 250 million with promising sna technology. They have already done a raise and they have an innovative approach to treat cancer using sna technology. Have you ever heard of this approach to treat cancer.

    Like

  26. Hi Ohad,

    Could you take a look at CYDY, truly remarkable news today. They treated 3 late stage triple negative breast cancer patients and the cancers are almost cured. They just applied for BReakthrough therapy and request a emergency FDA meeting to include 50 more patients. Is it a scam? I couldn’t resist and bought a bunch of shares. Would really appreciate your opinion for this stock.

    Like

  27. For Jinyu-
    Like you say, truly remarkable news (CYDY), but I would caution to take a quick look at the company’s balance sheet (consolidated Nov 30, 2019)- where their cash position is $409,000 but their (current) accounts payable is in excess of $18 million. One has to wonder which is more shocking: their current ratio, or the “stunning” results.
    Just my thoughts.

    Like

  28. @Lawrence,CYDY will issue 16M share Monday, the most important thing is whether the report for the 4 stage 4 mTNBC treatment is true, if so, it will be huge, next thing to watch is the FDA type C meeting and breakthrough therapy, both should move the stock tremendously.

    Like

  29. Hi Jinyu–
    While you are waiting for Ohad’s input…
    With regard to CYDY–some potential caveats:
    –it is quite unusual to cite efficacy in terms of circulating tumor cells rather than response of measurable metastatic lesions. Given the patients have stage IV disease, that would be the usual metric for efficacy. Circulating tumor cells could respond to the carboplatin alone, and are more likely to respond than solid tumors due to steric factors etc.
    –It is unusual for Abs to have CNS responses due, once again, to steric factors and the BBB. For example, Herceptin versus tucatnib in her 2+ breast cancer.
    In any event, best of luck!

    Like

  30. CYDY market cap $640m? For otc stock? Seems very high

    DEAR Ohad,
    What in your mind makes enhertu, the daiichi ADC Grigore and technology, so much better and efficacious than other ADCs? What is the key innovation? And do you think ZW-49 has a chance of competing, and what gives you hope (from technological perspective / tech/ MOA) that this might be the case?
    Thanks!
    Dan

    Like

  31. FYI
    just from googling a bit CYDC was home based in Santa Fe NM 2003
    then in Lutz FL(no date) then in 2012 Lake Oswego OR and now in Vancouver WA.

    Like

  32. Alex (AUPH) – Just a matter of valuation (2B) and digging into the data, which admittedly I didn’t have time for…

    Karlo (AGTC) – Results are underwhelming imo.

    John (KURA) – It’s never a good thing when someone leaves but I don’t know if this is based on anything fundamental.

    Dan (CAPR) – I just don’t like products with an iffy mode of action, especially cell therapies.

    Scott – So NK are clearly a hot space right now especially for CAR, less so in bispecifics where CD3 engagers are generating better data.
    AFMD – I prefer to wait for more clinical data as so far results have been disappointing.
    FATE – They made a lot of technical progess and they clearly are pioneer in allo IPS derives products but I am very nervous about companies whose valuation is based on a single “super responder”, preer to wait for more data especially at this valuation. A lot of allo NK programs out there, not sure they have the right one…

    Tim (MGTA, MTEM, FTSV) – So I like MGTA because they take a holistic systemic approach. FTSV – I am still not buying the hype there around MDS/AML data regardless of other programs they have.

    Alex (STML) – Either a marketing problem or a small market… nobody ever targeted BPDCN.

    Les (VKTX/MDGL) – I guess the long horizon isn’t helping but I still like the stories there, oral drugs, good efficacy, same MOA, safety is clean so far.

    Ohad

    Like

  33. ABEO – is it a good buy at this time to add more or invest new. How is it different from it’s competitors in a better or worse way ?

    Like

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