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. Hello Ohad,

    Have you looked at Aptose Biosciences (APTO) at all. Just listened to their KOL “dog and pony show” today. Seems like they have a very compelling case for their lead candidate (CG-806) which is a FLT-BTK selective inhibitor. Early data is showing a very clean safety profile yet seems to have broader coverage for FLT mutations than quizartinib & gilteritinib. There is also is pre-clinical evidence of synergy in combination with venetoclax. Current market cap is around 500 million. Any thoughts that you or others have would be much appreciated. Thanks!

    Like

  2. Hi Ohlad, regarding Madrigal, if you look at their current data against the FDA primary endpoint for P3, based on pathology scores, fibrosis was reduced by ≥ 1
    point in 29% of resmetirom treated patients vs. 23% in placebo. Whille it is statistically significant, the numbers are fairly close. Any concerns here for P3>

    Like

  3. hi Mark
    for Madrigal phase 3 NASH study
    Primary endpoint will be “NASH resolution with at least a 2-point reduction in NAS, no worsening of fibrosis”
    “At least a 1 stage reduction in fibrosis with no worsening of NAS” is a secondary endpoint
    I like their phase 2 data, but Ohad is the expert 🙂

    Like

  4. Hi Ohad, any thoughts on new IPO this week BEAM?
    Belongs to the CRISPr class but with a more precision technology. Early days but hot space and less overpriced than older peers.
    Is a new Zhang company (EDitas founder too)
    Still reluctant to get into Febe edition?
    Thank you for your insight
    L.

    Like

  5. Hi Ohad, the next 2 to 3 weeks would be interesting for ESPR since 2 FDA approvals are due, do you think ESPR at $60 right now is still worthy to buy? Some say it would reach ~$100 if the 2 approvals achieved. Thanks!

    Jinyu

    Like

  6. Ohad,
    HRTX has a pdufa on Mar 26 for post op pain. In the past you said you follow this program.
    What are the market opportunity and is 2b marker cap justified.
    ESPR starting moving up in expectation of two pdufa in February. Crossing finger they don’ t tank after the approval. I saw an analysis giving then +5-10% on approval and -20-30% on not. Not good odds for holding through pdufa. What you think?

    Like

  7. Ohad
    Another question if I may, is 50% gain in INSM justified for good but not perfect ph 2 data – higher dose didn’t meet some of the secondary end points

    Like

  8. Alex
    i can’t post links, but go to SY Investing on twitter, scroll down to Feb 5, 2020.
    Table Key binary #biotech events in Feb ’20 from Cowen.
    Cowen gives +5-10% vs -25-40% for ESPR
    Interesting to see some of the other predictions – good track record so far
    e.g. ADVM +/-20% for cohort 2 data. So far the stock is + 30%
    INSM +/-20% on Ph 2 data: so far +40%
    BIIB +/-10% on Tecfidera IP: so far +20%

    Like

  9. ” has been challenging for me to find new stocks at attractive valuations.”
    what about ACAD AUPH EXEL? all of them have a chance to be acquired..

    Like

  10. Hi Ohad

    From what I read you like MGTA a lot and are excited about its potential capabilities in the conditioning field – it didn’t have a big run up yet, what holds you back from adding it to your portfolio?

    Many thanks
    Ron

    Like

  11. Ohad
    RVMD – it looks the drug is active, single agent activity in lung cancer. What you think of their approach – SHP2. I am surprised that AE a low

    Like

  12. curiousperson (ABEO) – No strong opinion there at the moment , investors are waiting for more clinical data.

    Frank (ALEC) – So the approach is novel backed by some very interesting genetic data in humans but as we just saw with beta amyloid mAbs, it doesnt guarantee success. I don’t think valuation is justified without clinical POC.

    Adam (APTO) – Wow, they made a nice move, didn’t see new clinical data though. My primary concern here around inhibiting too many targets is still there until they demonstrate a good clinical profile.

    Karlo (QURE/SRPT/RGNX) – I don’t have plans to add these names given valuations. RGNX is very diversified but their AMD program is still not de-risked enough especially following the ADVM data. I think RARE became more attractive following recent GSD1a data.

    AGTC – I prefer to wait for more data, my primary focus is XLRP.

    Mark (MDGL) – From what I understand 1ry endpoint in their P3 is NASH resolution (2 points improvement) without fibrosis worsening, where the data look strong and based on other studies placebo response rate should be 5-10%. Agree the fibrosis reduction effect doesn’t look great based on pathology score but this can be explained by the limited follow up (36 weeks). So yes, I am always concerned but the metabolic effect on liver and blood markers is quite strong.

    lgonber (BEAM) – Cool technology but as always, I prefer to wait for clinical data with these valuations.

    Jinyu (ESPR) – I plan on holding. I think BA will get approved but that won’t be a huge surprise, curious to see launch in the absence of CVOT data… The Zetia combo pill should provide an attractive statin-free oral option but let’s see…

    Andre-
    HRTX – I think they have a superior product to that of PCRX in post-op pain. Definitely on my watchlist.
    ESPR -See above

    andre (INSM) – Not sure… still didn’t have a chance to look at the data.

    Ohad

    Like

  13. Great move on XENE and nice article on SeekingAlpha indicating target of $25 by end of 2020.

    Hi Ohad (and folks on the blog) – Have you looked at SYBX? Price to Book is at .47 and nice investors & partnerships supporting it.

    Like

  14. Hey Ohad,
    Any views on MTEM (molecular templates) and their engineered toxic bodies, as they call them. Their toxins moa (which they claim is distinct from competing drugs) is ribosomal inactivation. They have a few candidates in ph2 and a new one targeting her2.

    Dan

    Like

  15. Alain (AVRO) – Overall a good data set in P2 Fabry update IMO. Of course, small numbers and limited follow up but I like the fact they see stabilization or near stabilization across all parameters (enzyme, substrate and VCN), they now have 12 and ~16 month durability in the first two patients which means they passed the 6-12 month “challenging” period based on their P1. Of course, we need more follow up to see how things hold up. The cystinosis data were very preliminary but looks like there is a clear efficacy signal.

    Richard Baker (SRRA) – Not following them closely but would be careful given momelotinib’s history but the new fundraising was impressive with good names. Warrants will burden the stock for sure in the foreseeable future…

    Ron (MGTA) – Honestly, I just don’t feel I know the space well enough but I think they are on to something.

    andre (RVMD) – After looking at the data in the S1 I find the profile underwhelming with a narrow therapeutic window (which isn’t that surprising given what we know about other MAPK inhibitors). This is clearly seen in teh exposure data and the need to use intermittent dosing, biology makes sense but they simply can’t hit the target hard enough IMO. There was only one confirmed PR in KRAS+ NSCLC and the breakdown to mutation type isn’t clear to me as I would guess that all mutations should be sensitive. Bottom line, prefer to wait for more data at this valuation.

    Jonathan (SRPT) – I think their DMD program carries much more risk than the market assigns, prefer to stay on the sidelines with this valuation.

    Alex (ZGNX) – Sorry, don’t know them well.

    Les (SYBX) – Very high risk bet but valuation reflects this. I always prefer to wait for more clinical data especially in fields like microbiome that have no validation in humans.

    Ohad

    Like

  16. I would like to post a thank you to:

    Ohad..I have learned so much from his posts. I think I know science and medicine well, but he has taught me several critical lessons–my top picks 🙂
    —pay attention to market cap and market opportunity-regardless of the merits of the science
    —look for derisked drugs or opportunities
    –pay attention to cash and share offerings
    –be wary in rising markets where everything is rising..make sure the science and POC/phase of trial matches the valuation

    Ohad reminds me of a Buffett or Bogle–ruthlessly applying simple principles systematically and, like all the great ones…he makes it look easy.

    I would also like to thank the commenters as well. It is one of the few blogs where the comments are incredibly insightful and thoughtful. A particular thank you today to Andre, whose comment on BTAI near the holidays made me look into and purchase it. They are having a good day today and are probably overbought, but the main point is he used many of Ohad’s principles…market cap/derisked stock…when making his comment.

    I feel as a group we are giving capital to companies that will use it to better the world and avoiding hyped companies that will just squander it or siphon it to their executives.

    Sorry for the long post but given the effort that is put into this blog by Ohad, I just wanted to personally say how much it has meant to me.

    Like

  17. Thanks, Garry, I think it’s fair to say your post resonates with everyone here, I owe Ohad a good part of my fortune and for taking a special interest in this sector.

    Side Note: I think we were long time virtual members of the IMGN boards, nice reporting today. I also recall you were fighting your own battles with illness so I am glad to you here years later

    Like

  18. Ohad, you last looked at KPTI on 2/6/19. “anxious to see data with their next generation compounds” – would you please give them another look ? (add them to your portfolio ? > the catalyst large pharm use before buying : ) : )

    Gary, gonna call your beautiful post ‘our’ valentine gift to Ohad (ha : )

    Thank you.

    Like

  19. Thanks Garry, I’m flattered.
    But you put a lot of pressure on me to post only spotless questions.
    Now anything short of 300-400% in 3-4 months would be considered below par 😦
    So, for the time being I digress.
    Andre

    Like

  20. Ohad

    XENE has had stellar return over the last year. With add’l data on 1101 later this year, does it seem like a company that may not independent for more than another year if data is positive

    Like

  21. Ohad

    GNCA (Genocea) claims to have developped the “next wave” of immuno-
    therapies with its inhibigens / inhibitory antigens.
    Is this in your opinion something worthwhile to pursue ?
    TIA

    Like

  22. Ohad
    Are you still under embargo about BTK?
    What do you think about brain-penetrating BTK inhibitor? Sanofi recently reported that they met the primary endpoint of Phase 2 trial in MS.
    The technology is from PRNB, which has Ph 3 in BTK for some sort of Autoimmune Skin-blistering Disease. Solid Ph 2 data – 25% CR 55% SD and virtually no AE. Plus two other Ph 2 programs.
    They claim they are the leader in oral reversible covalent BTK.
    Do you agree?

    Like

  23. Hi All,

    After the run-up for XENE, is it still at a reasonable market cap for an entry point? I had it a few years ago, but had rotated into a few other stocks I liked. I have some capital available again, so am thinking about buying some XENE. Any thoughts on their current market cap relative to potential would be much appreciated.

    Thanks,

    Adam

    Like

  24. Hello Ohad,

    inteteresting that SGEN has licensed monoclonal antibodies from FPRX today. So FPRX is still alive preclinical respectively has substantial research. They have some readouts this year. Maybe a buy at the low marketcap?

    Like

  25. Ohad

    $HRTX Pdufa delayed 3 months. You mentioned it was on your watch list. Tomorrow should give a buying opportunity to buy a bit cheaper for what you labeled as “a superior product to PCRX in post op pain”. They said there was a positive outcome from the FDA reinspection of the HTX-011 contract mfg facility. Do you have any cause of concern from the CRL? Seems like a buying opportunity

    Like

  26. Hi Ohad, fellow followers :),

    Will really appreciate your thoughts on HEPA. early stage NASH company but results are better than 4 other competitors. To quote: Hepion’s drug candidate, CRV431, prevented experimentally induced liver fibrosis to a greater extent than four other leading NASH drug candidates: obeticholic acid (“OCA”, an FXR agonist), elafibranor (a PPAR/ agonist), resmetirom (a THR- agonist), and Aramchol (an SCD1 inhibitor). These results support the potential for CRV431 to exert potent antifibrotic activity in NASH. Also yesterday’s results show multi-organ, condition applicability. Market Cap just $18M.

    Like

  27. Dear Ohad,

    Any opinions on MTEM- the stock been steadily rising as the company seems to be validating its technology ETB (engineered toxic bodies).

    Also, regarding APTO: do you think there will be a next phase to drug development where technology is advanced enough to design cancer-agnostic drugs that target several disease pathways/targets selectively while sparing other targets that are known to cause safety concerns – it seems that this is the only way to prevent mutations – invruvica is an example of this – targeted therapy but 2-3 years down the road many patients relapse with cancer mutation- I guess my question is are the like of ZYME and others techs going to enable design of mutation-agnostic drugs that an achieve durability of 5plus years? Or are you skeptical about this? And is this the path forward, as APTO managers and scientific advisers seem to be indicating (they still have to prove safety, though)

    Ric

    Like

  28. Adam, XENE had an offering at the market recently at $16. So institutions have invested at that price. I added to my core position at that price too while Ohad was reducing his position to balance his portfolio. Let’s see :).

    Like

  29. Alex
    Elevated liver enzymes warning is the same for Lipitor.
    It is down bc ESPR had a nice run preapproval – mid 30s to 70s.
    Let’s see the drug price on Monday call – I guess it will be $4-5K /year. If lower, the stock will go even further down.

    Like

  30. RE ESPR
    they said they’d price NEXLETOL at same price as lipitor – so 3 to 3.5K per year.
    it will be interesting to see price of combo pill (approval decision 26 feb).
    The name NEXLETOL not that good: sounds like NEXT to LETAL.

    Like

  31. Sold SAGE and took the losses. Holding strong on AXSM and OVID. Reduced holdings across biotech – took profits and losses. Bought quite a bit of BIS. I’m thinking the bottom is at 22000 points on the DOW. Or 18000 if Coronavirus does not quit easily. Difficult to hold large positions through this messy situation.

    Like

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