Thread by @Biotech2k1

The #CRISPR Report:

I am going to build this thread all day as I go through all the public CRISPR companies. Make sure you keep up with it as I add each company as the day goes along.

1/ CRISPR Therapeutics $CRSP

This is a Swiss-American company based in Switzerland and R&D in Cambridge US. They are the most developed company with their first therapy exa-cel submitted for FDA approval. This is for Sickle Cell disease.

2/ The company trades at about $4 billion valuation. They have just under $2 billion cash. The burn rate is over $700 million per year. That is an excessive amount of cash burn. I don't see how they sustain that even with commercial sales starting later next year.

3/ CRISPR Tx is using the original CAS9 enzyme which does double stranded breaks. This is older technology which works great for ex-vivo cell editing where edits can be verified. It also works fine for in-vivo to do gene knockout. I don't see it ever doing insertions.

4/ I was a huge fan of CRISPR Tx early on, but sold all of it back in 2021 because I felt their sole focus on SCD caused them to lose the innovative spirit. Their R&D day consisted of just copying every program from every other company in this space.

5/ Their lead drug is exa-cel for treatment of SCD which is a very big indication. There are 90k patients in US and another 300k outside US. Their limit will be set by their ability to manufacture these complex therapies.

6/ Capacity is expected to be around 1,000 doses a year at commercial launch. That puts sales somewhere around $2.5 billion based on price, of which, Vertex gets 60% and CRISPR Tx gets only 40%. That is about $1 billion and barely covers cash burn.

7/ Their CAR-T programs have been just absolutely tragic. They have some of the lowest efficacy data across the industry and the lowest durability data at around 6 months. I don't see how any of these programs compete commercially.

8/ Their last program is around Diabetes, but their current approach is expected to fail. They need to do a lot of work to catch up to their competitors in creating beta cells for Diabetes.

9/ Overall, there is plenty of potential here, but most of it seems outdated and behind competitors. I expect they will be commercial with $1 billion sales and still struggling to keep up with cash burn and the science.

10/ Intellia Therapeutics $NTLA

This company is located in Cambridge US. They struggled early on with management and vision. Then they got a new CEO and everything changed. He has brought Intellia to the leadership position in the CRISPR field.

11/ They company trades at $3.8 billion valuation. They have about $848 million cash. Their burn rate is about $450 million per year. That leaves them with a low cash position. They will need to raise sometime soon.

12/ They are the only other company using the original CAS9 enzyme. This does the infamous double stranded breaks. They are using it wisely to do in-vivo gene knock out in the liver. This puts them as competitors with RNAi therapies.

13/ Their fist therapy is for hATTR which is a genetic disease. They are knocking out the gene in-vivo in the liver. So far the data has been very impressive with over 90% gene knockdown. Long term safety will be necessary to give this advantage of other chronic therapies.

14/ Their second therapy is for HAE which is a genetic disease. Their approach shows over 90% knock down of plasma Kallikrein. They will need to establish that long term Kallikrein knockdown stops HAE attacks for patients. This program will have far less competition.

15/ They have an allogeneic program around cell therapies for T cells. They worked on it for a while then dropped the program to come up with a newer approach. I looked at this newer approach and expect it wont work any better than the last one.

16/ They did buy a company called Rewrite which gives them some technology to develop their own base editor or prime editor. That gives them more tools beside the limited CAS9 enzyme.

17/ I think there is a lot of potential for these first 2 programs assuming they compete well against other available therapies in their space. I think each one could do $1 to $2 billion each making this already bigger in potential that other companies in this space.

18/ Editas Medicine $EDIT

This is one of the original 3 CRISPR companies. They are located in Cambridge US. They have been struggling for many years with bad management and weak science. I have been extremely harsh on this company, and its been right for many years.

19/ The company trades at $790 valuation with $470 million in cash. They burn over $200 million per year. That makes them a very cheap valuation, but it has been so for good reason thus far.

20/ They are using the CAS12 enzyme. This dose double stranded breaks much like the original CAS9 enzyme. It does have a few benefits like different PAM site and staggered cuts.

21/ Their lead program is around LCA10 an inherited eye disease. Their early data in this program from spring was very weak and the stock got crushed. They have an update coming soon which may help if the data improves.

22/ Their second program just read out data in Rhodopsin associated RP. The data showed only a 30% correction of the RHO protein. I really wonder if that will be significant enough to prove any therapeutic benefit. Only more data will tell.

23/ Their next program is an ex-vivo editing program for SCD and Beta Thal. They had data in their original program a few years ago and it was really bad. They dropped the program trying to fix the HbB gene and move to the Fetal Hb approach. We have no data here yet.

24/ They do have a decent cell therapy platform where they are working on alpha/beta T cells, gamma/delta T cells and iPSC NK cells. The problem here is the progress has been painfully slow. I can't even remember the last time they had any good updates.

25/ Overall, Editas is a very high risk pick in the CRISPR space that has a ton of potential should it ever get past the long history of bad management and weak data. Their use of AAV in the eye is completely legacy science that seems to be very weak.

26/ Personally, I would not touch it until they start showing a series of good data readouts to prove they are turning this wreck around.

27/ Beam Therapeutics $BEAM

They are located in Cambridge US along with all the other CRISPR companies. This will be the first company we will look at with the Second Generation of CRISPR editing. I think they have one of the best management teams in this space.

28/ The company trades at $3 billon valuation. They have over $1 billion in cash as of Q2. They are burning about $250 million a year. There valuation looks expensive based on market cap, but they have multiple partnerships that add value.

29/ They get 50% of the first 2 programs from Verve and 35% from the third program. They have a deal with Apellis for complement disorders. They get nice royalties and milestones on those programs. They even have a license and deal with Prime for prime editing.

30/ Their major partner is Pfizer where they are using base editing and LNP delivery in combination with Pfizer's mRNA technology to focus on rare diseases. They are entitled to milestones and royalties on all these programs.

31/ Their first program of their own is all about SCD. They have a program just enrolling phase 1 for the ex-vivo Fetal Hb approach. They are working on improving the conditioning with safer CD117 antibodies. They are even working toward in-vivo editing of the SCD mutation.

32/ Their second program is for in-vivo editing in the liver in Glycogen Storage Disease. This currently in IND enabling studies and could be in the clinic in 2023. Their last program is around editing T cells for cell therapies.

33/ This is a fairly small program they are working on. It was recently put under clinical hold by the FDA. The press release suggests the FDA just wanted more data to show the safety of multiplex editing from chromosomal rearrangements.

34/ Overall, Beam is still in very early stage development for a new generation of CRISPR base editing that has no data yet int the clinic to validate the technology. There is some NPH data from Verve and Beam that does suggest this will be successful.

35/ I think the potential here is unlimited as they are the only company that holds all the patents for base editing. They have unlimited use of the tech for themselves. Anyone who uses their tech in partnership pays a big royalty to do so.

36/ Verve Therapeutics $VERV

This company is located in Cambridge US. They are the second company using 2nd generation base editors. I think they have a great management team, but I have some concerns with their indications they have chosen.

37/ They trade at a $1.88 billion market cap. They have $595 million in cash as of the Q2 report. They burn about $125 million per year. Their valuation is still a bit expensive based on their level of development. Other CRISPR companies offer much better value.

38/ They are using base editing which they are licensing from Beam. They have a license for 4 key gene targets of which they selected their first 3 and only released 2 of them. The first 2 are for PCSK9 and ANGPTL3. They pay Beam 50% of the US revenues of these programs.

39/ They just picked their 3rd target from Beam and they pay 35% on that undisclosed target. They also have a license for CAS12 they got from the Broad Institute. This comes from the same source as Editas license. I am not sure what use they have with it though.

40/ Verve's first program is for PCSK9. This is where I have issues with their programs. They claim to be curing all cardiovascular disease. The data at only 69% for the highest dose in NHP is only on par with already very effective and cheap.

41/ I don't see them getting anything but a very small market share as a therapy of last resort unless their human data improves significantly. Their second program in ANGPTL3 showed about 95% to 98% protein reduction in NHP data. That one needs more data, but looks better.

42/ They do have a partnership with Vertex for developing therapies in the liver. Little is known about this partnership if they are able to sublicense base editing or if they are doing this with the CAS12 they got from Broad. We will have to wait and see.

43/ Overall, I think Verve is a great company, but has a very expensive valuation due to the excitement over the size of the cardiovascular market size. The issue for them is they are taking on some of the most competitive spaces in biotech with very strong competing therapies.

44/ Many of the therapies they are up against like Statins are very cheap and genetic at $15 per month. Some of the already commercial PCSK9 therapies are very powerful and are very inexpensive at $1,500 a year like Repatha. Its is going to be a long upward battle for them.

45/ The excuse of lack of compliance by patients does not justify the cost of these therapies. I don't see insurers paying a huge premium for these therapies just because patients won't take their cheaper medications regularly.

46/ Prime Medicines $PRME

This company is located in Cambridge US. They just recently went public so the amount of information on them is more limited. I would classify them as a 3rd generation company. Not because their tech is better than base editing. It just came after.

47/ As matter of fact, I have voiced many concerns that makes me think that Prime Editing could fail. There is a high rate of errors in the Reverse Transcriptase that drives Prime Editing. Then there is the chance of Indels that are created from the repair of the flaps.

48/ Honestly this tech is just way too new and unvalidated to have gone public so soon. It could be years before it is ready for clinical trials and you are stuck funding the bill. That is assuming it works at all to reach clinical trials.

49/ The efficiency data from the S-1 was really weak for this technology compared to CRISPR programs. They did a great job hyping the tech with a pipeline page showing like 18 indications.

50/ This would not be bad for a really high risk tolerant investor if the valuation wasn't so massively bubbly. They trade at nearly $2 billion valuation with only about $300 million in cash. Not sure what kind of cash burn they will see as a public company yet.

51/ This is an extremely over hyped technology with very little data that doesn't look even ready for clinical development. One that may never even work.

52/ Graphite Bio $GRPH

Graphite is located in San Francisco. They are the last because I don't think there science is going to work at all. They use a CAS enzyme to make a double stranded break. They then use an AAV to deliver a template strand of DNA for HDR repair.

53/ There is just so much that could go wrong with this technology with double stranded breaks and indels. Then there is the issue with distribution with 2 vectors delivering 2 parts of the therapy. Not all cells will get both parts.

54/ Their first indication is to use the tech ex-vivo in stem cells to correct SCD. This is a good place to start as these cells can be sequenced to ensure they are of good quality before they are put into patients. I would suspect this shows chromosomal rearrangements.

55/ There are plenty of investors out there willing to gamble on this one as a lottery ticket should the tech work. The early efficiency data was really low. Like below 50% editing low. I don't think qualifies as investment grade.

56/ Caribou Biosciences $CRBU

I missed this company as I often classify them as a cell therapy company. They are located in Berkley California. They are the only company in CRISPR who isn't using the technology for editing genetic diseases.

57/ They are solely focused on cell therapies for oncology. They are working on a few programs around ex-vivo allogeneic CAR-T with CD19 and BCMA programs. They are working on some of the most innovative edits with PD-1 knockout, HLA knockout and HLA-E inserts.

58/ They have another program around iPSC NK cells. This is a very exciting program as stem cells can endure many edits and yield near perfect cell lines for cell therapies. We haven't seen any data from these programs yet.

59/ They do have some early data for CB-010 which had 100% ORR and 80% CR rate after just 1 dose. They even have promising range of durability. We will need to see more data to see if that robust activity continues.

60/ Caribou uses CAS12 enzyme for editing which puts it in the same class as Editas with first generation CRISPR editors. Their claim to fame is their chRDNA technology. They develop their guides using a combination of DNA and RNA nucleotides.

61/ This enhances their binding to the DNA and increases efficiency while reducing off target effects. It has data that shows that chRDNA also decreases chromosomal rearrangements by 5 fold over other version of editing.

62/ The company itself is very cheap trading at just $568 million valuation. They have $366 million cash as of Q2 report. They are only burning about $100 million per year for cash burn.

63/ They are actually very capital efficient picking only a few programs to take to commercial. They can do many other programs once they are profitable with the program they have are making money.