Genomic Medicine 2021: (Happy To) Turn The Page

Summary

• 2021 was a painful year for genomic medicine investors. Investor enthusiasm waned as valuations were stripped of hype premiums.
• Allogeneic cell therapy relapses, chromosome abnormalities and preliminary variable or ineffective data outweighed some positive announcements.
• Delivery remains an obstacle - especially for CNS indications.
• The promise of genomic medicines remains strong and within the Gartner Priority Matrix.

PhonlamaiPhoto/iStock via Getty Images

Abstract

Biotechnology (XBI) performance was terrible in 2021. Goldman Sachs determined (Exhibit 10 confidential analyst report) the 52% February-to-December drawdown compared to the S&P 500 was the longest and largest since inception. The nascent subsector of gene and cell therapy or GCT underperformed the XBI, driven by a negative news flow and deflated investor expectations. This article summarizes some of the events that led to the GCT selloff in the context of the Gartner Hype Cycle for genomic medicine. Gene editing companies Beam (BEAM), Cellectis (CLLS), CRISPR (CRSP), Editas (EDIT), Intellia (NTLA) and Sangamo (SGMO) are the primary focus given their importance to this sector. The promise of GCT disruptive innovation is still intact though the realization of this promise is still years away.

Source: Finviz

Terminology

Readers less familiar with GCT may benefit from reading the 2018 article: Genomic Medicine: Catch The Gene Therapy Wave. The following conventions were used to avoid confusion for the rest of this article.

• Gene Therapy – The Alliance for Regenerative Medicine or ARM describes gene therapy as seeking to modify or introduce genes into a patient with the goal of treating, preventing and curing disease. The American Society of Gene + Cell Therapy defines gene therapy as the introduction, removal, or change in the content of a person’s genetic code with the goal of treating or curing a disease. Gene therapy or GT is also the term used to describe medicines that transplant functional genes to counter or replace malfunctioning genes that are at the root cause of certain diseases. The rest of this article will use the term gene therapy to describe medicines relying on the functional transplant method which does not involve any gene editing.

• Cell Therapy – Cell Therapy or CT involves infusing live cells into a patient with the intent to cure or mitigate disease symptoms. Cells that originate from the patient are called autologous. These cells are removed, edited ex vivo (outside the body) and reinfused. Cells that come from donors are called allogeneic (or universal). These cells are edited ex vivo to mitigate the immune response to incompatible (non self) antigens.

It's not ready for prime time yet, but we hope it will be in the not too distant future.

Christi Shaw, Kite CEO, June 2021 panel

• Gene Editing – Gene editing changes the DNA encoding process within cells linked to specific diseases. Gene editing includes gene (expression) regulation or GR (activation, increase, decrease or knock out). Ex vivo editing enables both autologous and allogeneic CT. Gene editing or GE done in vivo can be considered its own therapeutic modality.

..regulators will now bring increased scrutiny to the question of whether or not your cutting creates something untoward.

Fyodor Urnov, Dec 2021 Nature

GCT programs

Gene and cell therapy is still a nascent life science sector. There have been seven FDA approved medicines (Table 1). The five autologous CT products combined to generate less than 1% of the oncology drug tracking group (Table 2) in 2020.

Consistent with prior biotechnology modality eras, program approvals have triggered M&A activity with six of the seven approved therapy companies bought by pharma. The exception was a UPenn collaboration.

We have yet to see any acceleration in the approval process with only four approvals over the past four years. This slow progress is the result of a combination of issues highlighting the need for assays, biomarkers, expanded manufacturing, process development, analytical models, etc.

Commercial success has been limited (Table 2). Only Zolgensma has achieved annual revenues of $1 billion. All others are lagging projections used for acquisition valuation purposes. Autologous cell therapy for oncology indications combined to generate a little over $1 billion in 2020 (Table 3) or less than 1% of my tracking group.

ARM supplies a useful summary of unique clinical programs in their annual and half-year reports (Table 4). The 2021 1H report showed a mere 1% increase in unique GCT trials. The 2020 full year grew by 39%. The decline in Phase 3 trials for the first half of 2021 appears to reflect the pandemic slowdown.

The ASGCT trial finder supplies a tool to explore all trials for GCT including registry, baseline, lead-in, and follow up trials (Table 5). 25% of all trials are active but not recruiting and 12% that have yet to start recruiting. Similar to prior years, the majority of these trials are for oncology indications.

Genomic Medicine News

It seemed that a disproportionate number of news releases from the sector was negative last year contributing to the selloff. However, a look at the BIO survey of clinical results predicts an early-stage clinical pipeline is dominated by disappointing rather than successful updates. Given the 7.9% likelihood of approval or LoA for phase 1 programs sector weighting toward early clinical programs, the news cycle may well continue into 2022.

Allogeneic CT has been a primary focus as the sector aims to evolve beyond autologous therapies which are expensive and require protracted treatment processes. Allogeneic approach concerns were expressed at the 30-minute mark of an Intellia and Sangamo panel discussion at the October 2020 Meeting on the Mesa.

Cell therapy has become very much an engineering and optimization problem. There is a future where allogeneic cells will be every bit as good as autologous cells. Currently I don’t think the allogeneic nut has been cracked. I do think that in two, four or six years down the road, we are going to look backward and say our tool kit was so primitive back then.

Andrew Schiermeier, Intellia COO, October 2020

In 2021, the pursuit of allogeneic CT met resistance due to the lack of durable response. Manufacturing constraints and processes continued to hamper progress.

• The entire Allogene (ALLO) pipeline was put on hold while investigating chromosomal abnormalities.
• Allogene and CRISPR announced patients treated with allogeneic CAR-T have begun to relapse after initial promise. Precision BioSciences (DTIL) announced similar results.
• Manufacturing challenges led to FDA action for BioMarin (BMRN) and bluebird bio (BLUE).
• Pricing issues led bluebird to wind down European operations.
• Generation Bio (GBIO) disclosed disappointing preclinical nonviral gene therapy data.
• Gilead (GILD) allogeneic CT pipeline has stalled with no guidance or explanation.
• Collaboration partnerships at Voyager (VYGR) were terminated by Sanofi (SNY) and AbbVie (ABBV) in the past 2 years.
• CNS challenges continue following uniQure (QURE) AMT-130 variable and inconclusive data release.

Meme investing a metaphor for the Gartner Hype Cycle

Meme - derivative of the Greek work mimeme - means that which is imitated. Meme stocks are shares of a company that have gained a cult-like following which became a dominant theme in 2021. This theme impacted the GCT sector with increased awareness of CRISPR gene editing. Consider the Gartner Hype Cycle for genomic medicines (Figure 1). The graphic was modified (see arrows) to show where Gartner places GCT in 2020 as well as their July 2021 update.

The graphic was also modified to show some history for cloud computing. Cloud computing was at the peak of inflated expectations in 2010 (#1) and expected by Gartner to mature in 2-to-5 years. In 2014 the cloud hype had dropped close to the trough of disillusionment. By 2020, the cloud had begun to approach the plateau of productivity. The impact of this cycle relative to sector valuations can be seen by reviewing the stock price for Microsoft (MSFT) over this period.

Cell & gene therapy or CGT platforms are systems designed to help collect, analyze and distribute biological samples and to turn them into therapies for patients. As per the priority matrix in the Hype Cycle for Life Science Commercial Operations 2020, Gartner predicts that cell and gene therapy platforms will have high priority for life science organizations in five to ten years.

Source: Gartner website

Source: Gartner with author modifications

A proxy for the GCT Hype Cycle is Cathie Wood and the ARK Genomics ETF (ARKG) which is focused on disruptive innovation in genomic medicines.

Source: Finviz

ARK has correctly named many attributes of this disruption cycle including artificial intelligence, predictive diagnostics, machine learning and image recognition. Quantitative systems pharmacology or QSP predictive modeling is expected to accelerate clinical trials and improve early phase results. There was a significant increase in the number of FDA submissions incorporating QSP models (Figure 2) in the last two years.

Figure 2: Quantitative systems pharmacology submission trend

Source: Landscape analysis of regulatory submissions to the US Food and Drug Administration

Sanofi has licensed technology from Julia Computing and others. Their 2021 ASH poster presentation included expected improvement (Figure 3) from the next four participants based upon the updated manufacturing process being used.

Figure 3: Sanofi QSP model for sickle cell

Source: Sanofi ASH presentation

Gene Editing Platforms

Beam Therapeutics

Pros

• Base editing considered CRISPR 2.0. Single base integration with no double strand break
• Clearer intellectual property franchise than other CRISPR editors
• First program approved for clinic

Cons

• Valuation is still close to hype cycle peak of inflated expectations
• No platform validation or human data
• Lead programs for sickle cell have lagged competitors with potential curative data

Cellectis

Pros

• Partner with Allogene has accelerated development effort
• 70% selloff in 2021 provides a bounce opportunity subject to Allogene clearance of hold
• Not caught up in CRISPR hype cycle

Cons

• Insufficient cash runway has potential for highly dilutive equity offering in 2022
• Reliance on allogeneic CAR-T at a time the sector is trying to resolve duration and FDA holds
• Talens editing has limited endorsement in the sector

CRISPR Therapeutics

Pros

• Potential first and best in class for sickle cell CT product. Potential approval in 2023 with large Total Available Market or TAM
• Relationship with Vertex (VRTX), who will lead manufacturing and commercialization effort, increases potential of acquisition premium on first program approval
• Cash balance represents over 5-year runway and 43% of current market cap

Cons

• Three of five clinical programs are allogeneic. Durability of allogeneic programs is suspect
• Termination of Research and Development head Tony Ho may signal undisclosed unwelcome news
• The CRISPR intellectual property landscape lacks clarity

Editas Medicines

Pros

• The hype premium has declined after valuation dropped from $4.5 billion to $1.8 billion
• Progress with Cas12a reduces reliance on Cas9
• The cash runway is over 4 years

Cons

• AbbVie terminated the Allergan collaboration
• Brilliance preliminary study data raised doubts about efficacy and safety. Remaining pipeline is early stage
• The CRISPR intellectual property landscape lacks clarity

Intellia Therapeutics

Pros

• Regeneron (REGN) collaboration
• Data on multiplex editing in 2020 and GE in 2021 was exceptional
• Cash runway suggests limited dilution risk for 2022

Cons

• Valuation was not affected by sector selloff in 2021, leaving it closer to hype cycle peak
• The CRISPR intellectual property landscape lacks clarity
• Pipeline behind clinical programs is primarily still in research phase

Sangamo Therapeutics

Pros

• Likely to have three phase 3 programs within 12-24 months including Fabry GT and sickle cell CT
• Pipeline includes leadership in emerging T regulatory CT and CNS gene regulation (no cutting)
• Sangamo began building out their in-house manufacturing sites in California and France 2 years ago. This is now largely complete while the other gene editing platform companies are currently in catch-up mode
• Only editing platform company reportedly using machine learning and artificial intelligence per Deep Pharma 2021 report. Sanofi is using for process development modifications for Sickle Cell and Takeda (TAK) is using to design gene regulation clinical trial for TAK-686

Cons

• History of terminated programs including 3 GE in 2019-2020 and beta thalassemia CT in 2021
• Hemophilia A GT on hold for protocol change. May lead to delays versus BioMarin
• Breadth of pipeline requires funding from milestone achievements to avoid dilution

Summary

Market performance for genomic medicine was abysmal in 2021. There were only two new approved therapies to generate enthusiasm, which was not enough to offset the number of datasets showing waning or insignificant durability. Clinical holds or delays due to chromosome abnormalities, toxicity and manufacturing issues added to the pall. Novel delivery remains both a need and research in progress. This news flow combined with the pandemic, a severe biotechnology correction reduced investor enthusiasm triggering 50% or greater valuation drops.

The future of GCT remains bright and now the sector has removed much of the hype premium from valuations. The time frame to routine medicine approvals may be a few years away, but the negative sentiment is likely to shift relatively soon as molecular engineering, analytical method and delivery tools evolve.

Figure 4

Source: Deep Pharma Intelligence AI for Drug Discovery

I do think that in two, four or six years down the road, we are going to look backward and say our tool kit was so primitive back then.

Andrew Schiermeier, Intellia COO, October 2020

Analyst’s Disclosure: I/we have a beneficial long position in the shares of ALLO, PFE, SGMO either through stock ownership, options, or other derivatives. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

Comments

[Marty Chilberg]

Small cap gene therapy companies continue to get hammered by the inflation/Fed Funds rate cycle. Clearly investors want to participate in the upside of drug discovery but have rotated into Vertex and Regeneron to do so given their balance sheet and cash flows. While I continue to track the gene therapy space, I have been reluctant to publish anything given this backdrop. Hope everyone is conserving capital for when it ends. Remain modestly invested in a couple names but over 40% cash for over a year as I wait out this cycle.

[tkarl]

@Marty Chilberg If by "cycle" you mean macro, I think we are close. For years I've been monitoring my own investment returns, and when I compare to previous cycles, this one seems close to the end. With everyone sitting on 40% cash, once FOMO kicks in, things are going to pop quickly. Question now is, what's worth buying?

[Marty Chilberg]

@tkarl Hope you are right. I've felt we were close a few times in past several months but not the case. Everyone wants to talk about inversion and Fed funds rate hike cycle in historical terms but we've never had the context of negative/zero bond interest rates, quantitative easing/tightening and worldwide imbalance in commodity supply/demand curves that has influenced the macro over the past 3 yrs.

When to buy continues to define my thesis which remains unclear. What to buy after the when is clearer will be a welcome change in perspective. I'll likely publish something once I start putting money back to work but today I remain focused on preservation of capital. The market hopium about Fed rate cuts beginning soon is not my view. The ISM numbers indicate a rapidly slowling economy and the likely Fed response will be to pause the hike cycle but cuts seem only a possible response to further negative shifts such as SVB.

[charged]

@Marty Chilberg i had forgotten about this article. Just read again. As usual had no idea how early we were on this tech. My first investment was crsp which i dumped and bought vrtx. Many may have done. My 2nd sgmo…waiting for update on base editor. They have a march poster presented at conference 3/20 not released to public. I went to 47% cash yesterday. Cut investments i could sell in tax free or deferred accounts. Not going to pay taxes until i need cash.

[Marty Chilberg]

Added some info on CGT trajectory in at tweet stream

twitter.com/...

[Marty Chilberg]

A few news tidbits so far in Jan:
- Allogene had their hold for all allogeneic CAR-T clinical programs lifted. No findings that that chromosome abnormality in patient was due to any AlloCAR T product, Mfg process or TALEN editing
- Pfizer updated clinical register for HemA to modify Primary Completion date to Sept 2023 from Jan 2023. No update on Hold but suggests filing to FDA has been made and impact determination made.
- Atara has sold their in house ATOM AAV vector manufacturing facility and staff To FujiFilm to reduce forward operating expenses and provide $100m cash infusion. Combination extends cash runway to CYE23
- Homology sold their in house AAV vector manufacturing facility and staff to Oxford Biomedica for $130m cash infusion.

[itamarro]

Thank you for the solid overview.

[olddompat]

@Marty Chilberg - great update on what was a disappointing year. I remember reading your 2018 article several times.

What are your thoughts on Precision Bio [DTIL]? Despite the bad year, it seems their market cap of ~$400MM is still well below peers? Any thoughts on a target price?

[Marty Chilberg]

@olddompat I had them on my buy list but with the allo issues, I'm no longer a buyer. These editing platform companies either get valued based upon the technology/IP capabilities or the programs. Crispr and base editing get the benefit of belief in approach so the programs can be further out. Talens, ZFN and Arc are all not viewed as competitive so they need to have program progression today to get credit. Doesn't make it right but that's the market today IMO. When DTIL had allo issues it stripped that value down because of a higher risk of failure. Once the dust settles and bios are back in favor, I'll take another look but not until then

[olddompat]

@Marty Chilberg thx for reply - hope bios are back in favor in 2022

[Marty Chilberg]

3 decades and counting for beta thal cell therapy

www.mskcc.org/...

[Marty Chilberg]

Sanofi signs new AI drug discovery deal

endpts.com/...

[Marty Chilberg]

Intellia announced some program updates this morning. They called out an allogeneic program which may indicate allo is overcoming the challenges described in article. Look forward to hearing more

P/R

NTLA-3001 for AATD-associated lung disease: NTLA-3001 is Intellia’s wholly owned CRISPR-mediated in vivo targeted gene insertion development candidate. It is designed with the aim to precisely insert a healthy copy of the SERPINA1 gene, which encodes the alpha-1 antitrypsin (A1AT) protein, with the potential to restore permanent expression of functional A1AT protein to therapeutic levels after a single dose. This approach seeks to address alpha-1 antitrypsin deficiency (AATD)-associated lung disease and eliminate the need for sub-optimal weekly IV infusions of A1AT augmentation therapy or lung transplant in severe cases.
Intellia is conducting Investigational New Drug (IND)-enabling activities for NTLA-3001 with plans to file an IND or IND-equivalent in 2023. The Company also continues to explore additional editing strategies for AATD.

They also announced a new collaboration for allo

ir.intelliatx.com/...

[TarsTarkis]

I really enjoy reading your work. Very insightful for me, as I generally am a value investor. I had a large percentage of my IRA in biotech for long-term growth. Only down 12% in 2021, so I should consider myself lucky.

I have followed Perceptive Advisors for many years. They have a good long-term track record. They got crushed in 2021. I think Cathy and the ARK funds got way too much money with retail and mo-mo investors riding her wave. Wondering if Perceptive got redemptions and have been forced to sell positions in 2022.

Question on SGMO? You have a price target of $14. Is that a 3-5-10 year target?

[Marty Chilberg]

@TarsTarkis Hi Tars-appreciate the comment and kind words. Can't say I follow Perceptive very closely. Not surprised with any results in C21 bio. Congrats on limiting losses to 12%.

My valuation is always current value not future. I use it for personal trade decision making. Today when SNY dropped SCD, my price dropped by $2.50 to $11.50 but the SCD haircut may be mitigated if they can find a way forward. Surprised but have to say that autologous is not the way forward in CT as has been seen with the plodding growth of approved therapies and the overall cost of treatment.

[TarsTarkis]

@Marty Chilberg Thank You. Any comments on XBI. My average cost is $114, but looking to add, just not sure where bottom is. Could the washout be this week? Any technical help would be appreciated.

[Marty Chilberg]

@TarsTarkis The 100 level was the top in 2018 and resistant until May 2020 when it broke free and ran.

The last rally was from 80 to around 160 (mth closes). The 50% retrace didn't hold. The 62% took it to 110 so I'm looking at 100 as stronger support.

The Q you have to have an opinion on is inflation. If the consensus is accurate that the rate will revert to around 2% in 2H then you should be a buyer. If you think the Fed waited too long and they will need to raise over 3x this year then 100 may not hold.

[Marty Chilberg]

SNY discontinuing the SCD program effective Jun 2022. Final patients to be dosed in 3Q. SGMO working to find a transition plan and new collab partner. SNY indicates this is an internal change of direction away from Auto CT to Allo going forward.

This program represented 17% of my SOTP valuation or $2.50 per share. New PT is $11.50. Milestone fcst for C22 was $10m. 1H opex no impact. 2H22 opex to be determined as SNY participation will end

[MikeFromNZ]

A veritable tour de force, as usual; I have no material disagreements.

[egga]

What would you consider attractive valuation for BEAM? Their single base technology stands out and may be able to do what other editing companies cant. Maybe..

[Marty Chilberg]

@egga I put my own price target ($40) in Table 7. That was the price toward end of C20 before the buying craze hit all the editing stocks on virtually no data. Beam is my preferred Crispr play but not at these levels given the 5-8 years it will take to get a product to market. Will reassess based upon cash levels/raises and hopefully some collabs that offload some risk.

[mlnovillo]

Marty, don't you think it's curious that SGMO hasn't raised (despite spikes to $18 and $11 in the last 12 months or so) and that they haven't secured any new partnerships (despite repeatedly noting they are approached all the time to do so)?

With 3 drugs going into Ph3 i don't see how this company doesn't get bought. Only impediment in my opinion is the depressed share price (the BOD isn't going to sell SGMO for $15 or what not)

[Marty Chilberg]

@mlnovillo Interesting Q. I do think they missed an opportunity on the spike at end of C20. The cash they brought in from collabs from BIIB and NVS may have convinced them to let the price ride but clearly was a missed opportunity. Perhaps the CFO departure and initial uncertainty about replacement impacted it. Fully expect to see a new collab in C22 for a Treg indication to increase the runway. This may be enough unless the HemA milestones are pushed out from hold.

M&A likely won't be triggered by HemA status given the exit from GT. Same for Fabry as the typical M&A premium is driven up by follow on pipeline following POC and there is none for GT. We may see Fabry get collaborated with a 50/50 split of commercial which could bring in some cash.

Hard to say about SCD triggering some M&A interest. I could see it but an interested party may want to wait for some Treg data first given that is the majority of CT pipeline preclinic. I'd bet they will eventually get acquired but tied to G/R or Treg interest which suggests a window in C23-4 after more is known about approach, allo editing and delivery. Definitely later than I thought a year ago, but I believed they would file IND for Alz last year per R&D day comments.

[mlnovillo]

@Marty Chilberg

Thank you, that's very thorough.

I'm not sure how M&As work logistically, but maybe you can clarify something for me: I'd think that -- if a purchaser offered lets say 4-5B for the Company -- the BOD would be under a significant amount of pressure to sell, given the share price action over the last few years. What would be the BOD's fiduciary duties at that point? Could they just reject such an offer without any kind of disclosure to the shareholders or repercussions? Do they have free reign to reject offers like that (I understand this may be a question for a lawyer).

I agree about the partnership you foresee, I just hope it's not accompanied by a hugely dilutive equity grant a-la Biogen (17% or what not) given the share price.

Thank you for all your insight as always.

[Marty Chilberg]

@mlnovillo What a great Q in today's world. The BOD has various duties at which come into play in any review or exercise of an M&A transaction. The 3 primary ones are:
- Duty of care- to make decisions in good faith
- Duty of loyalty- which requires decisions to be in the best interests of the corporation ignoring personal economic conflict
- Duty of good faith-honesty in their conduct during the process

I read something a while back that said approx 97% of all transactions approved by the BOD trigger a lawsuit to try to get more. That and numerous other issues is one reason why the BOD and companies should always lay out long term strategy in specific enough detail to inform investors of long term intent. If a transaction fits that strategy it becomes evidence in favor of a deal. OTOH if a transaction goes against stated strategy it becomes evidence that the deal should/could be contrary to the stated interests of the company.

Just the tip of the iceberg and I'm no lawyer. Suffice it to say that if a compelling opportunity is presented the BOD will definitely seriously consider it weighing the interest of all stakeholders.

There is probably a line that once crossed in a negotiation/discussion would lead to disclosure Frequently early disclosure is a strategy to increase the valuation. That's why acquirers almost always expect a no shop clause.

[charged]

Great article as usual. Crispr crash was inevitable as so much hype. Interestingly it has still been a good investment. Technology just an infant. Btw my biomarin did ok. Sgmo hurting at moment. Brainstorm in als simple little tech about to file bla.

[Marty Chilberg]

@charged Thanks. It's a shame that Seeking Alpha doesn't encourage this type of article. I do the research for myself and publish occasionally but unless an author writes about a single stock, there really is no incentive to do so. Anyway, thx for read/comment and agree that we have a long road ahead. Hope BMRN works out for you. i can't get comfortable with Fuchs so avoid

[doctahJonez]

i keep looking back at SGMO but just can't decide, the whole sector just feels too dicey right now. nice writeup, ty!

[Marty Chilberg]

@doctahJonez My concern is tied to inflation risk which is likely another primary catalyst for the selloff last year. With rising rates expected for at least this year, the market rotation is risk-off moving monies out of cash burn or high multiple stocks and into value/yield vehicles. Early stage bios need cash to fuel development for years which makes me focus on the cash runway. SGMO has a ton of potential but the HemA milestone nut is being questioned due to the durability and P3 hold. If the hold is quickly lifted and the P3 readout is good, I'm likely to add but not until then.

[William Frey]

@Marty Chilberg now or not being questioned?

[Marty Chilberg]

@William Frey Sorry but I don't understand the Q

[Murphy2013]

Well done ,thank you, however , wish it were better news for this holder of CRSP and EDIT ..!

[Marty Chilberg]

@Murphy2013 It was definitely a hard year. Wishing us all better luck this year but the real returns are still a ways off.

[charles1222]

Nice overall summary of this biotech area. At this stage, hard to determine the winners and you make that clear. I will follow you.

[Marty Chilberg]

@charles1222 Thanks for follow. Personal view is that 10 yrs from now Crispr editors will dominate the global lab landscape, but any editor that has clinical success will lead to strong investment returns tied to fundamental traction.

[thucydides123]

Long VRTX and REGN to play CRSP and NTLA indirectly.