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…… Quite a reaction this week to a potential pandemic. I took a position in PREVAIL , based on the science,leadership,and the collaborations they have. As you know they are now after the recent sell-off,about 25% below their IPO price. I have been unable to find any news to explain and justify this correction. If I remember correctly, PONTIFAX was involved and you could not comment. If that is still the case,could you possibly refer me to any source that might provide me with some kind of prospective !

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  2. Hello Ohad,
    Can you comment further about SGMO, esp after this latest partnership with Biogen. It just seems to me that they have so many good deals- that they nearly seem cheap. Am I missing something ? Is there something that Pfizer, Sanofi, Gilead, Takeda, and now Biogen – see in their science… that is being under appreciated by the market? Your opinion mean a lot, thank you.

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  3. ATNM

    do you like their product IOMAB-B in P3? and how do you see the current valuation at EV 25m? should be worth much more? what does market not like at this company?

    Thank you for your assessment.

    Peter

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  4. Hey Les,

    what portion of your portfolio is in BIS? Anybody else wants to share their thinking regarding current situation and what could happen for market and economy this year? I have sold some positions, some also for a loss. Seems that in event of larger epidemic, the strain on healthcare systems and economy might slow down everything, including running of clinical trials.

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  5. Hi Dan,
    Here’s two cents worth.
    • Overall Markets were priced to maintain 2% growth in the West and 6% in the East…Helped by low and lower interest rates.
    • the current Covid-19 disruption is clearly going to lower growth and earnings. It’s interesting that the Bond Market is only inverted on the short term. Longer out (2yr versus 10yr or 30 year ) despite drops, a steeper curve and steeper still this week.
    That implies the market thinks this is a short ( 2 Quarter) disruption.
    • the above fits the theory that Covid-19 will disappear by Summer.
    • What spooks me is that Covid-19 seems to have a R0 infectivity close to influenza. High infection rate is supported by the clusters seen in Wuhan, Yokohama Cruise, South Korea, Iran and Italy. What’s scarier, the mortality rate is unclear to date because each countries approach to screening, reporting is different. As of this past week Italy had screened 12,000 ….compared to 900 in the USA. So there’s a lot still to be revealed about this virus and whether it settles into an endemic state. That uncertainty will foster the fear we’re seeing. Fear based reductions in consumer buying and confidence, a disruption in the global daisy chain for production, strains on real-time inventory approaches ( especially for health care) will further this process.
    That could extend the negative growth effect for way longer then 2 Quarters.
    • I’m only buying Ohad recommendations that I’m happy to add to or initiate and hold onto for awhile. I’m NOT buying BIS as it’s tough to time an exit. Steering clear of viral vaccine stocks as if Covid 19 does fade out their sadly won’t be any funding ( as happened after SARS) to run trials etc. I think Oncology trials are safe. Unless it’s a biotech that needs to raise capital in the next 6 months, I’m basing investments, like Ohad on the Long play.

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  6. Hello Ohad,

    $FENC seems like an interesting and pretty derisked story here at $6.80 (MC about $135m).

    PEDMARK is for the prevention of cisplatin-related ototoxicity in pediatric patients, and should have peak sales potential of about $100m. Approval should happen this year. In the US, they’ll have 7.5 years market exclusivity (pediatric orphan drug designation), in Europe potentially 10 years.
    Cash is a bit low (about $15m) but they have access to a senior debt facility of $12.5m upon approval of the drug in the US. R&D costs will be very low going forward and marketing costs should not be excessive. A big chunk of the company (about 17%) is held by insiders, about 50% held by institutions.

    There is a pretty good SA-article explaining the investment thesis, see “Fennec Pharmaceuticals: Market Fatigue Due To A Lack Of Catalysts Has Created A Mispricing”

    Do you and others have any opinion on them?

    I well understand that this won’t be a $1b company, but I am also ok with doubles 😉

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  7. hi Dan,

    I also increased my cash ratio during last week so that i can sleep better, and bought SQQQ on Monday (LABD I have been holding from before).

    The only “Corona-investment” I made is in German company Drägerwerk (in the common shares – they also have preferred shares). Valuation is still low (well below book value) and they should have a good order book for some time for their PPE (personal protective equipment). In the US, some of these companies “exploded” due to the Corona-hype, see e.g. APT the last few days. Don’t expect the same for Drägerwerk, but some % should be possible…

    I am happy to have some cash on the side, because I think some good buying opportunities might come along during the next few weeks. My guess is that the correction is not yet finished here.

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  8. Hi Frank,

    Thanks for your thoughts on the matter – I appreciated your 2 cents. I think the long play is smart when considering the volatility and uncertainty right now. As far as Ohad “recommendations” like Chiasma, Xenon, Viking, and Madrigal – nothing has fundamentally changed. I see this as an opportunity to add to my position at a discounted rate and within my own risk tolerance.

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  9. Les – my concern with AXSM is that their Dextromethorphan/bupropion combo can be replicated by physicians to avoid high drug costs. Both are cheap medications that are easily accessible. While their trials are very promising, it may not translate to sales. Speaking with psychiatrists, more than one has expressed this sentiment – it is only a matter of them figuring out the dosing.

    My two cents on the matter. I thought I would contribute because this community is pretty great, and I appreciate everyone’s contributions.

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  10. Thank you Ohad and every one here on ARQL and BOLD . It’s convenient to have some proceeds from them in current market condition.

    I had also been reducing my bio holdings the last 6 months. As I’m not able to monitor market movements for the next few weeks, I also choose not to be in BIS.
    Will wait and see for further dips in prices.

    It’s probably good to buy shares at different months to “diversify”, dollar average down.

    Clinical trials in China have taken a back seat as hospitals are tied up with Covid 19. I’m wondering how large the effect will be as Covid 19 is hitting more countries and regions, including Western US. I’m anticipating that a lot of Clinical Trials may have outside-visit-window cases as patient visits, measurements etc will get disrupted as the outbreak spreads. Data readouts may be delayed? Data analyses may become a lot messier with missing data, when some patients not coming in for their Week X, Month Y visits.

    Recent news that caught my attention was this, https://www.sciencemag.org/news/2020/02/united-states-badly-bungled-coronavirus-testing-things-may-soon-improve

    It made me curious how South Korea and China could test a lot more cases much more quickly than the US.

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