CRISPR (NTLA, EDIT, CRSP + CRBU) + BEAM (added 10/21)

[PeteD01]

Monday morning, I bought three different individual stocks.
Generally not a good idea, I know, but this time it might be different.

Friday June 25th, Intellia Therapeutics Inc announced "Landmark Clinical Data Showing Deep Reduction in Disease-Causing Protein After Single Infusion of NTLA-2001, an Investigational CRISPR Therapy for Transthyretin (ATTR) Amyloidosis"

This is the first ever successful application of a CRISPR based therapeutic intervention via systemic infusion of the biologic.

I believe that it is possible to invest in the entire sector (CRISPR in human therapeutics) with just three stocks (NTLA, EDIT, CRSP).

I see this as a long term investment and bought $1000 worth of each.

There is so much more to say about this but let me just say that it is potentially as big of a deal as the mRNA technology but seems to have not gotten the attention it deserves.

Have fun researching this and let us know what you think!

Disclaimer: This is not a penny stock scheme at all

[HPstache]

Yes, strongly considering getting in to this sector as well.  Feels a little too late, but still could be plenty early.  Wish I had taken action when NTLA was mentioned multiple times in the "moonshot" and "shoot I stock picked" threads...

[PeteD01]

Yes, strongly considering getting in to this sector as well.  Feels a little too late, but still could be plenty early.  Wish I had taken action when NTLA was mentioned multiple times in the "moonshot" and "shoot I stock picked" threads...

Too late maybe for a short term speculative investment but just right for a long term speculative investment considering the glacial speed at which drugs move through the pipeline to market unless something really disruptive happens (COVID and mRNA).

[mckaylabaloney]

One of the reasons I don't invest in individual stocks is that I'm a securities lawyer. My whole job revolves around the fact that companies frequently lie, or more commonly simply mislead . Consequently, I've seen enough instances of biopharm companies announcing "landmark" data that turns out to be merely okay, or that gets disproven in later studies, to be inherently skeptical of announcements like this.

That said, I'm no scientist. So I don't understand all the nuances in this announcement, and I'm not equipped to evaluate the science. But a few things stand out immediately, including that: (1) this is just interim data from a Phase 1 trial; (2) there are only six patients; and (3) the initial efficacy data doesn't appear to provide a huge clinical benefit in TTR reduction compared to existing treatments (i.e. the main benefit seems to be that it would require fewer treatments -- maybe this is a huge deal on its own, I genuinely don't know). That's a lot of runway for things to change.

It's totally possible that none of these things will turn out to be concerns, and later trials will validate all of this initial data, and that this will be a huge deal (and if the tech really is life-changing for people, I hope that's the case!) and you'll make lots of money on these on these investments. It's also possible that this initial data will turn out to be a fluke, and/or that the companies are overstating the benefits, or the FDA will deny approval due to other issues, or whatever, and the stocks will fall. Sounds like you haven't invested very much so you'll be fine either way. (Worst case scenario, maybe you'll be a class member in one of my cases someday.) Personally, I'll avoid the risk and accept that if these stocks do skyrocket, I'll see only a sliver of the benefits in my index funds.

[PeteD01]

One of the reasons I don't invest in individual stocks is that I'm a securities lawyer. My whole job revolves around the fact that companies frequently lie, or more commonly simply mislead . Consequently, I've seen enough instances of biopharm companies announcing "landmark" data that turns out to be merely okay, or that gets disproven in later studies, to be inherently skeptical of announcements like this.

That said, I'm no scientist. So I don't understand all the nuances in this announcement, and I'm not equipped to evaluate the science. But a few things stand out immediately, including that: (1) this is just interim data from a Phase 1 trial; (2) there are only six patients; and (3) the initial efficacy data doesn't appear to provide a huge clinical benefit in TTR reduction compared to existing treatments (i.e. the main benefit seems to be that it would require fewer treatments -- maybe this is a huge deal on its own, I genuinely don't know). That's a lot of runway for things to change.

It's totally possible that none of these things will turn out to be concerns, and later trials will validate all of this initial data, and that this will be a huge deal (and if the tech really is life-changing for people, I hope that's the case!) and you'll make lots of money on these on these investments. It's also possible that this initial data will turn out to be a fluke, and/or that the companies are overstating the benefits, or the FDA will deny approval due to other issues, or whatever, and the stocks will fall. Sounds like you haven't invested very much so you'll be fine either way. (Worst case scenario, maybe you'll be a class member in one of my cases someday.) Personally, I'll avoid the risk and accept that if these stocks do skyrocket, I'll see only a sliver of the benefits in my index funds.

I think you have comprehensively stated the risks associated with this speculative investment.

Without these risks the potential rewards would not exist.

I am a physician and familiar with CRISPR. My decision did not come out of the blue.
Systemic administration of a CRISPR based therapeutic and subsequent detection of dose dependent decreased synthesis of the target protein in a human subject is a very big deal.

[BicycleB]

Yes, strongly considering getting in to this sector as well.  Feels a little too late, but still could be plenty early.  Wish I had taken action when NTLA was mentioned multiple times in the "moonshot" and "shoot I stock picked" threads...

Exactly!!

Personally, never bought individual stocks until recently. Probably my getting into it is a bubble-y sign. Have been interested in CRISPR (and CRSP specifically) for months; kicking myself a bit. Quite the learning experience.

[bwall]

Gene editing stocks today are like oil companies in 1890. Or semi-conductor stocks in 1984. Or Apple in 2004. They may have been cheaper a couple of years prior, but there is plenty of room left to run. YOU HAVEN"T MISSED ANYTHING! ! IMHO.

I'm not a scientist, but my wife worked in a cancer research department at the local university. They did lots of studies and she got a lot of experience of looking at the research. I knew the markets and she knew the science. I've talked about NTLA, CRSP and TWST (synthetic dna sequencing) here on these boards since 2019, which is when I first found them.

I'd read some phrases in biopharma press releases like "we're serving the great unmet need of fourth line cancer treatment." If you don't know the science (like I didn't), then it sounds like the product has potential. My wife laughed when she read that--'Fourth line means fourth in line. They must dose the other three treatments first. By then you're either cured or dead. Not too many potential patients. If the treatment was any good, it'd be first line.' Therefore un-investible.

I'd strongly suggest enrolling in a genetics class at your local university to understand about DNA, CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) and gene editing. As a side note, IMO, at a minimum you need to know what CRISPR stands for before investing in gene editing stocks. And what the Cas-9 protein does. Once you have this information, you are much, much better qualified to invest in these stocks. You will earn much more money by enrolling in that genetics class and using your acquired knowledge to invest than you will at your day job. Or, at least that was the case for us.

My conservative estimate is that these stocks can all be $50b market cap each in the next few years. My bullish estimate is +/- $250b, about the size of today's pharma giants, b/c, well, gene editing can cure cancer (in theory). They could also be bought out at any time from one of these pharma giants at a nice premium, even from these levels.

BEAM can also to be added to the list of gene editing stocks.

[PeteD01]

Gene editing stocks today are like oil companies in 1890. Or semi-conductor stocks in 1984. Or Apple in 2004. They may have been cheaper a couple of years prior, but there is plenty of room left to run. YOU HAVEN"T MISSED ANYTHING! ! IMHO.

I'm not a scientist, but my wife worked in a cancer research department at the local university. They did lots of studies and she got a lot of experience of looking at the research. I knew the markets and she knew the science. I've talked about NTLA, CRSP and TWST (synthetic dna sequencing) here on these boards since 2019, which is when I first found them.

I'd read some phrases in biopharma press releases like "we're serving the great unmet need of fourth line cancer treatment." If you don't know the science (like I didn't), then it sounds like the product has potential. My wife laughed when she read that--'Fourth line means fourth in line. They must dose the other three treatments first. By then you're either cured or dead. Not too many potential patients. If the treatment was any good, it'd be first line.' Therefore un-investible.

I'd strongly suggest enrolling in a genetics class at your local university to understand about DNA, CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) and gene editing. As a side note, IMO, at a minimum you need to know what CRISPR stands for before investing in gene editing stocks. And what the Cas-9 protein does. Once you have this information, you are much, much better qualified to invest in these stocks. You will earn much more money by enrolling in that genetics class and using your acquired knowledge to invest than you will at your day job. Or, at least that was the case for us.

My conservative estimate is that these stocks can all be $50b market cap each in the next few years. My bullish estimate is +/- $250b, about the size of today's pharma giants, b/c, well, gene editing can cure cancer (in theory). They could also be bought out at any time from one of these pharma giants at a nice premium, even from these levels.

BEAM can also to be added to the list of gene editing stocks.

Correct me if I am wrong, but I am under the impression that NTLA, EDIT, CRSP are the only companies working on translational projects (from ¨"bench to bedside" or drug development) using CRISPR.
These companies deal with the regulatory and safety issues generally in collaboration with big pharma and that makes them interesting in my mind at this point in time.


BEAM does not do clinical projects.

[HPstache]

I've been researching quite a bit this morning.  I have noticed that some people recommend investing in ARKG as an index of sorts for the Genomic Revolution.  Does anyone have any thoughts of doing this to try and let the professionals do the picking and catching the rising tide rather than the moonshot?

https://ark-funds.com/wp-content/fundsiteliterature/holdings/ARK_GENOMIC_REVOLUTION_MULTISECTOR_ETF_ARKG_HOLDINGS.pdf

[PeteD01]

I've been researching quite a bit this morning.  I have noticed that some people recommend investing in ARKG as an index of sorts for the Genomic Revolution.  Does anyone have any thoughts of doing this to try and let the professionals do the picking and catching the rising tide rather than the moonshot?

https://ark-funds.com/wp-content/fundsiteliterature/holdings/ARK_GENOMIC_REVOLUTION_MULTISECTOR_ETF_ARKG_HOLDINGS.pdf

I got some thoughts on this:

I would never invest in something with "genomic revolution" in the name - it simply is meaningless to me.
Would you invest in something with ¨the marvels of chemistry" in the name? I thought so.
There is so much garbage in that sector (as others have pointed out) that "catching the rising tide" is a rather unpleasant thought to be honest.
I do not think that the sector can be invested in without detailed knowledge in some part of it.
There isn`t even anyone who understands all the different things going on at a level required to make the right call.

I do know enough about CRISPR and drug development to make this particular call for myself after realizing that there are only three companies active in translational research.
I do disagree with other assessments by saying that a systemically delivered (intravenous infusion of a nonspecific liposomal delivery mechanism similar to the new COVID vaccines), targeting (a programmable RNA-based intracellular homing mechanism) therapeutic resulting in a dose-dependent knockout of a pathologic gene in several human subjects is a VERY BIG DEAL.
And that`s why I put my money there and not somewhere else in the sector where I have not the slightest idea about what¨s going on there.

[bwall]

Correct me if I am wrong, but I am under the impression that NTLA, EDIT, CRSP are the only companies working on translational projects (from ¨"bench to bedside" or drug development) using CRISPR.
These companies deal with the regulatory and safety issues generally in collaboration with big pharma and that makes them interesting in my mind at this point in time.

BEAM does not do clinical projects.

I think you're correct on both counts.

I had to go to BEAM's website and check their pipeline, as I was sure they did clinical projects with named treatments (BEAM-101, BEAM 102, etc). Sure enough, it only says Investigational New Drug (IND), then Phase III. No Phase I or Phase II.

You write: "These companies deal with the regulatory and safety issues generally in collaboration with big pharma and that makes them interesting in my mind at this point in time."

Do you mind if I ask your thinking behind this statement? I'm not doubting it or questioning the thought process, I'm just trying to learn more and it seems like you have some good insight.

[PeteD01]

Correct me if I am wrong, but I am under the impression that NTLA, EDIT, CRSP are the only companies working on translational projects (from ¨"bench to bedside" or drug development) using CRISPR.
These companies deal with the regulatory and safety issues generally in collaboration with big pharma and that makes them interesting in my mind at this point in time.

BEAM does not do clinical projects.

I think you're correct on both counts.

I had to go to BEAM's website and check their pipeline, as I was sure they did clinical projects with named treatments (BEAM-101, BEAM 102, etc). Sure enough, it only says Investigational New Drug (IND), then Phase III. No Phase I or Phase II.

You write: "These companies deal with the regulatory and safety issues generally in collaboration with big pharma and that makes them interesting in my mind at this point in time."

Do you mind if I ask your thinking behind this statement? I'm not doubting it or questioning the thought process, I'm just trying to learn more and it seems like you have some good insight.

Clinical research and drug development is an intensely regulated environment and is really the business big pharma is in (apart from producing and marketing drugs), There are no new players in that field given that moat.
NTLA, EDIT, CRSP are working in that field in addition to tweaking CRISPR tech and developing delivery methods.

To put it differently, NTLA, EDIT, CRSP or their big pharma partners are the entities showing up at the clinical researcher conferences to develop clinical research protocols and later at doctor´s conferences to sell their wares.
Companies like BEAM show up at NTLA, EDIT, CRSP conferences and workshops to sell their newest developments to them.

BEAM is much closer to basic research than NTLA, EDIT, CRSP which are doing translational research.

As a physician, my interest in BEAM is limited.
On the other hand, I would potentially enroll my own patient in a clinical trial with the new Intellia therapeutic. That´s how close this is to the clinical arena.

[bwall]

Clinical research and drug development is an intensely regulated environment and is really the business big pharma is in (apart from producing and marketing drugs), There are no new players in that field given that moat.
NTLA, EDIT, CRSP are working in that field in addition to tweaking CRISPR tech and developing delivery methods.

To put it differently, NTLA, EDIT, CRSP or their big pharma partners are the entities showing up at the clinical researcher conferences to develop clinical research protocols and later at doctor´s conferences to sell their wares.
Companies like BEAM show up at NTLA, EDIT, CRSP conferences and workshops to sell their newest developments to them.

BEAM is much closer to basic research than NTLA, EDIT, CRSP which are doing translational research.

As a physician, my interest in BEAM is limited.
On the other hand, I would potentially enroll my own patient in a clinical trial with the new Intellia therapeutic. That´s how close this is to the clinical arena.

Fascinating!

How do you recognize the difference between BEAM and the other three? Again, I'm not doubting you, I just know what I see on the websites and the difference isn't readily apparent to me.

For example, it would never occur to me that BEAM is interested in selling their treatments/drugs/developments, etc. to the big boys rather than doing their own clinical trials.

And, as a follow up question, why do you prefer one over the other?

Thanks for helping me learn more.

[PeteD01]

Clinical research and drug development is an intensely regulated environment and is really the business big pharma is in (apart from producing and marketing drugs), There are no new players in that field given that moat.
NTLA, EDIT, CRSP are working in that field in addition to tweaking CRISPR tech and developing delivery methods.

To put it differently, NTLA, EDIT, CRSP or their big pharma partners are the entities showing up at the clinical researcher conferences to develop clinical research protocols and later at doctor´s conferences to sell their wares.
Companies like BEAM show up at NTLA, EDIT, CRSP conferences and workshops to sell their newest developments to them.

BEAM is much closer to basic research than NTLA, EDIT, CRSP which are doing translational research.

As a physician, my interest in BEAM is limited.
On the other hand, I would potentially enroll my own patient in a clinical trial with the new Intellia therapeutic. That´s how close this is to the clinical arena.

Fascinating!

How do you recognize the difference between BEAM and the other three? Again, I'm not doubting you, I just know what I see on the websites and the difference isn't readily apparent to me.

For example, it would never occur to me that BEAM is interested in selling their treatments/drugs/developments, etc. to the big boys rather than doing their own clinical trials.

And, as a follow up question, why do you prefer one over the other?

Thanks for helping me learn more.

BEAM does not have a single clinical trial going on. They can talk and write about it all day long but getting a clinical trial approved and up and running is a very difficult thing to do. Talk is cheap, on the other hand, maybe they are going to announce a clinical trial and once it is underway, I would consider them involved in translational research and look at them very differently. The problem is all these companies talk all day long about the clinical implications of their work because that´s where the money is. I do not believe a thing until they have actually enrolled patients into their own study. Until then, their only marketin medicine is other companies doing their own clinical research.

You can search for clinical trials by putting the company name under "Other terms":

https://clinicaltrials.gov/

If it doesn´t come up it doesn´t exist.


I don´t prefer one over the other because I wouldn´t know on what basis. I bought equal $$ amount of each NTLA, EDIT, CRSP.

[bwall]

I've been researching quite a bit this morning.  I have noticed that some people recommend investing in ARKG as an index of sorts for the Genomic Revolution.  Does anyone have any thoughts of doing this to try and let the professionals do the picking and catching the rising tide rather than the moonshot?

https://ark-funds.com/wp-content/fundsiteliterature/holdings/ARK_GENOMIC_REVOLUTION_MULTISECTOR_ETF_ARKG_HOLDINGS.pdf

I've given Cathy Woods' funds a look. She plays with an open hand which is very sporting of her. I think that she has some great picks, some good picks and some trash.

But, who am I other than just some random guy on the internet? How can I compete with her researchers who know more about these science fields than I do? She (presumably) pays them very well for their work and I'm just an average guy posting stuff for free in a small forum in an obscure corner of the internet. How can I compete with a paid professional?

This is what I'd do; look at her top picks. The ones she has the most money in. Research the companies; what do they do? Pedigree of top management? Total addressable market? How much cash on their balance sheet? High short interest? (built in future demand). Insider buying activity? (the Holy Grail). 
Analyze how big you think the companies can grow to become (and how big they are now). Keep in mind there will be dilution as they issue more stock in the coming years. Keep in mind there might be early buyouts. Make your choice of two or three stocks. Go big or go home. Watch the company very closely. Sleep well at night. Wait for the stock to rise. Know your exit strategy and stick to it. 
*it's highly advisable to take some college level classes on genomics if attempting this investment strategy.

[bwall]

Clinical research and drug development is an intensely regulated environment and is really the business big pharma is in (apart from producing and marketing drugs), There are no new players in that field given that moat.
NTLA, EDIT, CRSP are working in that field in addition to tweaking CRISPR tech and developing delivery methods.

To put it differently, NTLA, EDIT, CRSP or their big pharma partners are the entities showing up at the clinical researcher conferences to develop clinical research protocols and later at doctor´s conferences to sell their wares.
Companies like BEAM show up at NTLA, EDIT, CRSP conferences and workshops to sell their newest developments to them.

BEAM is much closer to basic research than NTLA, EDIT, CRSP which are doing translational research.

As a physician, my interest in BEAM is limited.
On the other hand, I would potentially enroll my own patient in a clinical trial with the new Intellia therapeutic. That´s how close this is to the clinical arena.

Fascinating!

How do you recognize the difference between BEAM and the other three? Again, I'm not doubting you, I just know what I see on the websites and the difference isn't readily apparent to me.

For example, it would never occur to me that BEAM is interested in selling their treatments/drugs/developments, etc. to the big boys rather than doing their own clinical trials.

And, as a follow up question, why do you prefer one over the other?

Thanks for helping me learn more.

BEAM does not have a single clinical trial going on. They can talk and write about it all day long but getting a clinical trial approved and up and running is a very difficult thing to do. Talk is cheap, on the other hand, maybe they are going to announce a clinical trial and once it is underway, I would consider them involved in translational research and look at them very differently. The problem is all these companies talk all day long about the clinical implications of their work because that´s where the money is. I do not believe a thing until they have actually enrolled patients into their own study. Until then, their only marketin medicine is other companies doing their own clinical research.

You can search for clinical trials by putting the company name under "Other terms":

https://clinicaltrials.gov/

If it doesn´t come up it doesn´t exist.

That makes perfect sense. Thank you for the reply.

Until a trial is up and running, it's just hot air and waaayyyy too risky. Which is why I sold 900 shares of Intellia in late 2019 and swapped into CRSP. I lost confidence in them. I still got 6x with CRSP, but today it would've been 12x with NTLA. High quality regrets, I guess.

[PeteD01]

FYI

https://www.nejm.org/doi/full/10.1056/NEJMoa2107454?query=TOC&cid=NEJM%20eToc,%20July%201,%202021%20DM126402_NEJM_Non_Subscriber&bid=526588250

[Metalcat]

As someone with a rare genetic illness, I'm not quite as excited as a lot of other medical colleagues are about this.

It's VERY cool, of course. However, there are a ton of genetic diseases where we're still eons away from isolating causal genes AND being able to deliver CRISPR effectively to the necessary tissues. Even the article posted above commented that CRISPR delivery is very challenging, and that the liver was a good target because of its propensity to suck up everything injected into the body.

In addition, genetic diseases with clearly identified, isolated genes aren't all that common. Even my genetic illness has multiple genes errors associated with it and no one actually knows if those are the specific genes are directly causing the illness.

Basically, even with these moves forward with CRISPR, as exciting as they are, for a lot of genetic conditions like mine, we're still sci-fi levels of advancement away from practical treatment.

Now that's not to say that we aren't on the precipice of multiple clinical uses. I'm just not convinced that the patient population will be large enough of a market to have a huge explosive impact on the drug market.

I mean, look at biologics. The population of migraine sufferers vastly outnumbers specific gene diseases, and yet the new migraine biologics, which work well, haven't moved the needle on drug profits from what I've seen.

So if I'm not even jazzed about the possibility of a CRISPR treatment for my own genetic illness, then I'm certainly not hyped that so many people will need whatever CRISPR treatments are in the near future that I would stake my investments on them.

A drug can be a revolutionary miracle, but if there aren't enough sick people to use it on, it's not going to make much of a dent in the broader market. Besides, isn't there a huge chance any of these companies just get swallowed up, Valient-style if they start actually making money? And then they just become part of the larger portfolio of mega drug companies who make the bulk of their profits off of erection pills and antidepressants?

Perhaps I'm wrong, but I'm not dumping my money into a bet on mostly very rare diseases. Maybe I'll miss some explosive growth and look back on this in 10 years, but if that's the case, I'll also likely be cured, so I win either way.

Again, I'm not an expert on this. I don't really understand how pharmaceutical investing works, so maybe I'm way off. But I'm also a medical professional and a former research scientist, and I guess I just don't see the big money play here.

If you're already a stock picker, then that's a different matter. This seems like as good a stock pick as any other. But for a passive investor like myself, I don't see this as *the* super performing exception to break the rule for.

Again though, feel free to educate me how I could be missing something big.

[PeteD01]

As someone with a rare genetic illness, I'm not quite as excited as a lot of other medical colleagues are about this.

It's VERY cool, of course. However, there are a ton of genetic diseases where we're still eons away from isolating causal genes AND being able to deliver CRISPR effectively to the necessary tissues. Even the article posted above commented that CRISPR delivery is very challenging, and that the liver was a good target because of its propensity to suck up everything injected into the body.

In addition, genetic diseases with clearly identified, isolated genes aren't all that common. Even my genetic illness has multiple genes errors associated with it and no one actually knows if those are the specific genes are directly causing the illness.

Basically, even with these moves forward with CRISPR, as exciting as they are, for a lot of genetic conditions like mine, we're still sci-fi levels of advancement away from practical treatment.

Now that's not to say that we aren't on the precipice of multiple clinical uses. I'm just not convinced that the patient population will be large enough of a market to have a huge explosive impact on the drug market.

I mean, look at biologics. The population of migraine sufferers vastly outnumbers specific gene diseases, and yet the new migraine biologics, which work well, haven't moved the needle on drug profits from what I've seen.

So if I'm not even jazzed about the possibility of a CRISPR treatment for my own genetic illness, then I'm certainly not hyped that so many people will need whatever CRISPR treatments are in the near future that I would stake my investments on them.

A drug can be a revolutionary miracle, but if there aren't enough sick people to use it on, it's not going to make much of a dent in the broader market. Besides, isn't there a huge chance any of these companies just get swallowed up, Valient-style if they start actually making money? And then they just become part of the larger portfolio of mega drug companies who make the bulk of their profits off of erection pills and antidepressants?

Perhaps I'm wrong, but I'm not dumping my money into a bet on mostly very rare diseases. Maybe I'll miss some explosive growth and look back on this in 10 years, but if that's the case, I'll also likely be cured, so I win either way.

Again, I'm not an expert on this. I don't really understand how pharmaceutical investing works, so maybe I'm way off. But I'm also a medical professional and a former research scientist, and I guess I just don't see the big money play here.

If you're already a stock picker, then that's a different matter. This seems like as good a stock pick as any other. But for a passive investor like myself, I don't see this as *the* super performing exception to break the rule for.

Again though, feel free to educate me how I could be missing something big.

What you wrote supports the notion that there are high risks involved with this investment but that is just the flip side of the potential reward.

But here are the things to consider>

It is not by accident that there are only three companies involved in clinical research in CRISPR application in human disease among likely hundreds involved in CRISPR research in one way or another, directly and indirectly. The difficulty of bringing therapeutics into the clinical arena serves as a very strict filter most contenders are not able to pass. That makes a concentrated bid possible.

I cannot overemphasize how strong I feel about the fact that the intracellular targeting mechanism (guide RNA) of CRISPR is programmable. In addition, the COVID mRNA vaccine success has forced the regulators to grapple with the difficulty of approval of therapeutics which can be subtly altered to allow real time responses to evolutionary challenges. This is a concrete effect of the pandemic and not some diffuse sentiment that COVID is going to turbocharge biotech or other meaningless stuff.

Single gene disorders will always be the first to be investigated in genetic disease research because they are model diseases. Also the market for single gene diseases is not exactly small (I think hemophilia is rather big).

What I am seeing here is a situation not dissimilar to the early days of the PC. I do not think that it is worthwhile to jump on every new fantastic gadget coming to the biotech market, unless you are a short term speculator, but to look for the companies involed in the development of the infrastructure of the clinical research framework, which includes the regulators, within which marketable therapeutics are going to be developed.
These companies might not always select the ultimately best technology but will determine what is going to be successful in the market. 

As you can see, my investment is not so much a bet on CRISPR tech (which is actually rather mature), but a long term bet on companies bringing programmable therapeutics to the bedside and who are actually doing the difficult work of establishing the framework, in collaboration with the regulators, in which to do such a thing.

I had to put some money on this to not have regrets in the future. And if I lose it all I would be confirmed in my opinion that I have no business in investing in single stocks - so it is a win win anyway.

[Metalcat]

Okay...not a lot of that answered my questions.

I see your point about a "concentrated bid", but are you expecting that these three companies, moving forward, will be the driving forces in the pharmaceutical industry on this front? Are the big enough to even do that?

I mean, it's a huge step from developing the core technology for a therapy to making money from mass produced, marketed products. Many times in history the inventors of tech did not end up the folks profiting the most from the tech.

From my understanding, as I already stated before, a good chunk of Pharm development among the big guys comes from acquisitions. So your companies you invest in might get swallowed up by juggernauts the moment they produce anything even remotely valuable, and their value then gets diluted among the value of other drugs and tech within the Juggernauts, thus neutralizing your "concentrated bid".

This brings me back to market share. How big of a market are you anticipating for gene editing? Just how much of the population has identifiable gene mutations that are confirmed to be causal of their symptoms? Genuine question. From my experience, few doctors are even familiar with most single gene, genetic illnesses because they're so rare.

I mean, if it was licensed for cosmetic genetic alterations, like eye colour, hair colour, and balding etc, that would be an ENORMOUS market $$$$$$. Still, even if this did ever get approved, I don't see the original research companies being the entity to commercialize this particular use, plus the timelines could be bonkers.

Again, as stock picks go, I don't think this is a bad one, and I think you will probably make money. I'm just failing to see the potential for these companies being giant moon shot investments. The advent of a new technology does not always show a clear path for investment success based on that tech.

Unless I'm missing something, of course.

[PeteD01]

Okay...not a lot of that answered my questions.

I see your point about a "concentrated bid", but are you expecting that these three companies, moving forward, will be the driving forces in the pharmaceutical industry on this front? Are the big enough to even do that?

I mean, it's a huge step from developing the core technology for a therapy to making money from mass produced, marketed products. Many times in history the inventors of tech did not end up the folks profiting the most from the tech.

From my understanding, as I already stated before, a good chunk of Pharm development among the big guys comes from acquisitions. So your companies you invest in might get swallowed up by juggernauts the moment they produce anything even remotely valuable, and their value then gets diluted among the value of other drugs and tech within the Juggernauts, thus neutralizing your "concentrated bid".

This brings me back to market share. How big of a market are you anticipating for gene editing? Just how much of the population has identifiable gene mutations that are confirmed to be causal of their symptoms? Genuine question. From my experience, few doctors are even familiar with most single gene, genetic illnesses because they're so rare.

I mean, if it was licensed for cosmetic genetic alterations, like eye colour, hair colour, and balding etc, that would be an ENORMOUS market $$$$$$. Still, even if this did ever get approved, I don't see the original research companies being the entity to commercialize this particular use, plus the timelines could be bonkers.

Again, as stock picks go, I don't think this is a bad one, and I think you will probably make money. I'm just failing to see the potential for these companies being giant moon shot investments. The advent of a new technology does not always show a clear path for investment success based on that tech.

Unless I'm missing something, of course.

Yes you are missing something.

This is not a bid on a new technology - which is not that new anyway.
This is a bid on the three companies which are in the business of shaping the regulatory environment in which programmable therapeutics are brought to market.
This is much more like a bid on an operating system than on a hardware manufacturer.

You missed a hidden reference to cancer tx: "therapeutics which can be subtly altered to allow real time responses to evolutionary challenges"
But the biggest miss is that you are trying to pin down the obvious way how the big bucks will be made in the future. If that were possible it would be common knowledge and be fully priced in.

To repeat myself, I am doing this because I can see a potential which could not possibly be realized or even be quantified in the time frame professional stock pickers operate and therefore cannot be priced in. (And you are actually eloquently making the case for this)

I am really doing only two things: 1. identify the possibility of of a concentrated bid without having to bid on a winner 2. invest for a time frame which doesn´t allow the pros to price anything in (using the only advantage we individual investors have )

[Metalcat]

Makes sense, thanks for clarifying.

[MustacheAndaHalf]

This is not a bid on a new technology - which is not that new anyway.
This is a bid on the three companies which are in the business of shaping the regulatory environment in which programmable therapeutics are brought to market.
This is much more like a bid on an operating system than on a hardware manufacturer.

The performance of these stocks during the pandemic has been impressive - something is definitely being priced in.  CRSP is up over +250% since Mar 1 2020.  NTLA is up 5x since October 1 2020.  I think people saw mRNA vaccines and searched for similar technology, which is why these stocks jumped by multiples recently.  If they're undiscovered, why are they up 3x and 5x in a short time period?

What about the risk of a privately funded new competitor?  If a competitor takes market share from the 3 you invested in, and you can't invest in that competitor, it could be a problem.  Do you feel confident of your ability to monitor for upcoming competitors?

[bwall]

I've enjoyed reading the conversation between @Malcat , bringing the bear case, and @PeteD01, with the bull case. Thank you to both.

Some comments on the bear case: As these three companies progress, the stock price increases and the market cap grows. Today CRSP & NTLA are about $10b each, EDIT is just under $4b. In order to buy up these companies, a large premium would have to be paid, say in the 30-40% range. So, we'd be talking $13-14b range for the two that are furthest along. That's big money for a research/clinical trial, even for big pharma. Most big pharma buyouts that I've seen are in the $3-9 billion range for companies whose new drug had just received FDA approval. Now, overlap the bear case on to this and you'll see that there are no buyouts coming soon. It might well be the case that by the time these new drugs receive FDA approval, the companies will have a market cap of $20-30 billion, and you're still looking at a fat premium for a takeover.

One other fact to consider is that a company can only be bought out if management wants to do it. Perhaps the leadership of these three companies isn't motivated by money anymore? CRSP & NTLA 's founders shared last year's Nobel Prize and they're well on the way to becoming billionaires, if not already. Maybe they want to be the ones credited with XXXX ? Maybe they want to do further research and be spoken of in the same breath as Crick & Watson? If that's their goal, offering them billions of dollars in a buyout won't be nearly as attractive as keeping the company. To be fair, it's impossible to know what management wants.

As to the total addressable market concern brought out in the bear case. Yes, it's small today. But, over time this changes. CRSP announced early this year that they are starting to work on juvenile diabetes (only). As time goes by, I expect the list to get longer, either as more simple gene fixes are identified OR as the science develops ways to cure complex fixes.

[bwall]

This is not a bid on a new technology - which is not that new anyway.
This is a bid on the three companies which are in the business of shaping the regulatory environment in which programmable therapeutics are brought to market.
This is much more like a bid on an operating system than on a hardware manufacturer.

The performance of these stocks during the pandemic has been impressive - something is definitely being priced in.  CRSP is up over +250% since Mar 1 2020.  NTLA is up 5x since October 1 2020.  I think people saw mRNA vaccines and searched for similar technology, which is why these stocks jumped by multiples recently.  If they're undiscovered, why are they up 3x and 5x in a short time period?

What about the risk of a privately funded new competitor?  If a competitor takes market share from the 3 you invested in, and you can't invest in that competitor, it could be a problem.  Do you feel confident of your ability to monitor for upcoming competitors?

@MustacheAndaHalf : new drug development is incredibly expensive, on the order of hundreds of millions of dollars, maybe even over a billion and it takes many years; think 10 years or so. With this cost and turn around time, most sponsors of clinical trials eventually have to turn to the stock market for funding.

My personal lay-person opinion is that discovering CRISPR is on par with Columbus' discovery of the New World. It took Iberians decades (!) to figure out exactly what they'd found. But once they did, the world changed forever.

So it is with CRISPR; discovered and named in 2012 (though observed earlier, as the Vikings had also landed in the New World before Columbus), here it is now almost a decade later and we've still done nothing with it. Yet.

[RunningintoFI]

Small disclaimer to start this - I work for a Biotechnology company that plays heavily within this industry.  Don't use that as some sort of indicator that you should or should not invest in a certain way - just acknowledging that I have a certain bias that others may not.

That being said, CRISPR is just one of many potential gene editing techniques in development today - there are no guarantees the CRISPR technique itself is the ultimate gene editing winner but I do think the industry as a whole is in it's infancy and we cannot comprehend the full potential of the technologies for positive or negative reasons.   

I don't think rare and ultra-rare diseases are where the money is within gene editing from an investors perspective - the process is extremely expensive for individual cases with longer time horizons to application.  When gene editing can reliably start to solve aging, heart disease, baldness, etc. then I think you are looking at more explosive growth. 

From a non-investor perspective, the things that I hear about give me hope for a future where more people have a chance at a better life and that makes every day at work just a little bit more worthwhile. 

[PeteD01]

This paper gives a good overview of "programmable nucleases" and explains the revolutionary impact of CRISPR tech in the field.
The issue of off-target site cleavage is also explained in some detail.
Off-target site cleavage is essentially the common mechanism of treatment toxicity and monitoring this is going to be a very, if not most, important aspect of any gene editing therapies and standardization of this is, in my opinion, an area regulators will be heavily involved in.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4798875/pdf/nihms736118.pdf

[Metalcat]

Small disclaimer to start this - I work for a Biotechnology company that plays heavily within this industry.  Don't use that as some sort of indicator that you should or should not invest in a certain way - just acknowledging that I have a certain bias that others may not.

That being said, CRISPR is just one of many potential gene editing techniques in development today - there are no guarantees the CRISPR technique itself is the ultimate gene editing winner but I do think the industry as a whole is in it's infancy and we cannot comprehend the full potential of the technologies for positive or negative reasons.   

I don't think rare and ultra-rare diseases are where the money is within gene editing from an investors perspective - the process is extremely expensive for individual cases with longer time horizons to application.  When gene editing can reliably start to solve aging, heart disease, baldness, etc. then I think you are looking at more explosive growth. 

From a non-investor perspective, the things that I hear about give me hope for a future where more people have a chance at a better life and that makes every day at work just a little bit more worthwhile.

Agreed.

I don't want any of my posts to suggest that I don't see huge potential here in terms of future treatments, I just can't quite grasp the moonshot investment angle or a workable timeline for large scale marketing of commercial products. At least not for any substantial amount of investment.

If it's just some fun money for playing with stock picking, that's a different matter.

[MustacheAndaHalf]

What is the timeline for CRISPR proving itself?

Two years ago, Moderna (MRNA) was priced at $13-$15 per share, and it's currently $234/share.  That +1500% increase in 2 years came from the pandemic, and a successful mRNA vaccine for Sars-cov-2.  In that same time period, CRSPR went up +200%, suggesting the market thinks Moderna is much more valuable than CRSPR stock.

I suspect that CRSPR and similar gene editing techniques will be valuable.  But I do not think CRSPR will have a monopoly on the technique and the profits.  They simply can't pursue every disease by themselves.  If CRSPR licenses it's technology to other companies, those other companies will profit off the drugs they discover.  If CRPSR won't do that, other companies will seek similar techniques that aren't covered by CRSPR's patents.  I don't think CRSPR will have a monopoly on the profits from gene editing, and the price of MRNA vs CRPSR stock suggests the market thinks that as well.

[PeteD01]

I have been trying to prove @bwall wrong but have been unsuccessful.
It really does appear to require some formal education in molecular genetics to recognize the impact of CRISPR technology on biology.
I did find one review article for the more general reader. It does a good job in explaining the disruptive nature of CRISPR and how CRISPR has dramatically lowered the barriers to entry in the tool development arena which has led to an exponential increase in publications in the field, while at the same time exposing the formidable barriers to obtaining regulatory approval for therapeutic interventions.
It also gives a good outline of the potential of CRISPR in therapeutics, which goes far beyond single gene disorders.
The article does not mention the impact of AI on solving the problem of off-target cleavage, however.

Here is a quote from the article:

"Room for Improvement
As versatile and powerful as CRISPR/Cas technology may already be, many aspects of the technology still need to be improved, understood, or both, for therapeutic application. Whereas for research applications, suboptimal aspects of CRISPR/Cas technology will become an inconvenience or a significant cost factor, for therapy these same aspects will prevent regulatory approval for clinical application or may turn a trial into a tragedy. The issues that remain to be addressed may be divided into aspects of safety, efficiency and utility, with some overlap between the categories."
 

https://link.springer.com/article/10.1007/s40291-019-00391-4

 

[bwall]

What is the timeline for CRISPR proving itself?

Two years ago, Moderna (MRNA) was priced at $13-$15 per share, and it's currently $234/share.  That +1500% increase in 2 years came from the pandemic, and a successful mRNA vaccine for Sars-cov-2.  In that same time period, CRSPR went up +200%, suggesting the market thinks Moderna is much more valuable than CRSPR stock.

I suspect that CRSPR and similar gene editing techniques will be valuable.  But I do not think CRSPR will have a monopoly on the technique and the profits.  They simply can't pursue every disease by themselves.  If CRSPR licenses it's technology to other companies, those other companies will profit off the drugs they discover.  If CRPSR won't do that, other companies will seek similar techniques that aren't covered by CRSPR's patents.  I don't think CRSPR will have a monopoly on the profits from gene editing, and the price of MRNA vs CRPSR stock suggests the market thinks that as well.

Here is my understanding of the situation. There are many people on these boards that know more about this than I do, so please correct anything I get wrong. 

Timeline: CRSP has a clinical trial that is scheduled to finish in May, 2022. I believe it is the first one scheduled to be completed. 
https://clinicaltrials.gov/ct2/show/NCT03745287

Once the clinical trial is finished, data must be collated, reviewed and forwarded to FDA for their review. The FDA then has time to ask questions or request more data. Request more data is code for 'continue the trial'. The FDA then will (or won't) grant approval.

Then and only then will they have a therapy (not a drug, but perhaps a cure) that they can market for ten's of thousands of dollars each to hundreds of thousands of people in the USA. Add in Europe and the market potentially doubles. Gene editing stocks are working to have a full pipeline; doing multiple studies at the same time, staggered over a couple of years so that every couple of years they should have a new treatment coming online.

Moderns's stock price has skyrocketed because of COVID and the vaccine they developed. They are now earning money because of COVID. I don't think that CRISPR stocks were attempting any COVID solutions. They are all still in the clinical trial phase and have no income. So, using the stock performance of pre-COVID Moderna to draw sweeping conclusions might be a bit premature.

Drawing again on the comparison of CRISPR to the discovery of the New World; in 1501, nine years after discovery, no one had any idea of the Aztec riches to be found in Mexico City in 1519. In the same vein, we don't know how the discovery of CRSIPR with change the world in 18 years. My money is on the power of science, human ingenuity and the US stock market's ability to allocate capital.

[MustacheAndaHalf]

Moderns's stock price has skyrocketed because of COVID and the vaccine they developed. They are now earning money because of COVID. I don't think that CRISPR stocks were attempting any COVID solutions. They are all still in the clinical trial phase and have no income. So, using the stock performance of pre-COVID Moderna to draw sweeping conclusions might be a bit premature.

Pfizer and Moderna's vaccines are both around 95% effective in preventing Covid, less so with the Delta variant.  Both are mRNA vaccines targeting the spike protein of Sars-cov-2.  I think it's fair to say there isn't a significant difference between these two vaccines.

Yet Moderna's stock is up 13x, adding $88 billion to it's market cap (after 20% share dilution).  Pfizer, meanwhile, has lost market cap since Jan 2019.  If Moderna is only going up $88 billion from Covid vaccines, how do you explain Pfizer's stock performance?

[PeteD01]

Yet Moderna's stock is up 13x, adding $88 billion to it's market cap (after 20% share dilution).  Pfizer, meanwhile, has lost market cap since Jan 2019.  If Moderna is only going up $88 billion from Covid vaccines, how do you explain Pfizer's stock performance?

Pfizer does not own the BioNTech vaccine - BioNTech owns it and has a collaboration agreement with Pfizer.

[bwall]

Pfizer and Moderna's vaccines are both around 95% effective in preventing Covid, less so with the Delta variant.  Both are mRNA vaccines targeting the spike protein of Sars-cov-2.  I think it's fair to say there isn't a significant difference between these two vaccines.

Yet Moderna's stock is up 13x, adding $88 billion to it's market cap (after 20% share dilution).  Pfizer, meanwhile, has lost market cap since Jan 2019.  If Moderna is only going up $88 billion from Covid vaccines, how do you explain Pfizer's stock performance?

Wow! I didn't realize that Moderna had a market cap of $94 billion. That's quite a bit and it shows the potential of the mRNA based solutions. It's gone up 11x since their IPO in late 2018. Amazing. To me, it showcases the potential of other disruptive biopharmas and where their market caps can be. Keep in mind, though, that without COVID, Moderna's market cap wouldn't be anywhere near where it is today.

I'm not sure why Pfizer hasn't performed as well. As best I can see, they are flat over the last two years. Perhaps they should get involved in the gene editing space? They're a large pharma company, more involved in production and swallowing the innovators, as outlined by Malcat upthread.

[PeteD01]

Pfizer and Moderna's vaccines are both around 95% effective in preventing Covid, less so with the Delta variant.  Both are mRNA vaccines targeting the spike protein of Sars-cov-2.  I think it's fair to say there isn't a significant difference between these two vaccines.

Yet Moderna's stock is up 13x, adding $88 billion to it's market cap (after 20% share dilution).  Pfizer, meanwhile, has lost market cap since Jan 2019.  If Moderna is only going up $88 billion from Covid vaccines, how do you explain Pfizer's stock performance?

Wow! I didn't realize that Moderna had a market cap of $94 billion. That's quite a bit and it shows the potential of the mRNA based solutions. It's gone up 11x since their IPO in late 2018. Amazing. To me, it showcases the potential of other disruptive biopharmas and where their market caps can be. Keep in mind, though, that without COVID, Moderna's market cap wouldn't be anywhere near where it is today.

I'm not sure why Pfizer hasn't performed as well. As best I can see, they are flat over the last two years. Perhaps they should get involved in the gene editing space? They're a large pharma company, more involved in production and swallowing the innovators, as outlined by Malcat upthread.

BioNTech has a market cap of 54B and they developed and manufacture the Pfizer/BioNTech vaccine. IPO was in late 2019 at $15 - now about $220.

[MustacheAndaHalf]

Yet Moderna's stock is up 13x, adding $88 billion to it's market cap (after 20% share dilution).  Pfizer, meanwhile, has lost market cap since Jan 2019.  If Moderna is only going up $88 billion from Covid vaccines, how do you explain Pfizer's stock performance?

Pfizer does not own the BioNTech vaccine - BioNTech owns it and has a collaboration agreement with Pfizer.

Ah, how sloppy of me to think of it as the Pfizer vaccine - it's the "Pfizer BioNTech" vaccine, as you point out, with BioNTech holding the rights.  BioNTech (BNTX) is up about 8x since Jan 2020, adding about 47 billion to it's market cap.  Both stocks have significant gains from their COVID vaccines.

Yet BioNTech has about half the market cap gains ($47B) compared to Moderna ($88B).  There's still a mystery there, but at least it's a smaller one.

[PeteD01]

Yet Moderna's stock is up 13x, adding $88 billion to it's market cap (after 20% share dilution).  Pfizer, meanwhile, has lost market cap since Jan 2019.  If Moderna is only going up $88 billion from Covid vaccines, how do you explain Pfizer's stock performance?

Pfizer does not own the BioNTech vaccine - BioNTech owns it and has a collaboration agreement with Pfizer.

Ah, how sloppy of me to think of it as the Pfizer vaccine - it's the "Pfizer BioNTech" vaccine, as you point out, with BioNTech holding the rights.  BioNTech (BNTX) is up about 8x since Jan 2020, adding about 47 billion to it's market cap.  Both stocks have significant gains from their COVID vaccines.

Yet BioNTech has about half the market cap gains ($47B) compared to Moderna ($88B).  There's still a mystery there, but at least it's a smaller one.

Look at their pipelines, especially infectious disease vaccines.
Also, Moderna was apparently able to deal with the regulators on their own and BioNTech needed a collaborator.

[bwall]

I have been trying to prove @bwall wrong but have been unsuccessful.
It really does appear to require some formal education in molecular genetics to recognize the impact of CRISPR technology on biology.
I did find one review article for the more general reader. It does a good job in explaining the disruptive nature of CRISPR and how CRISPR has dramatically lowered the barriers to entry in the tool development arena which has led to an exponential increase in publications in the field, while at the same time exposing the formidable barriers to obtaining regulatory approval for therapeutic interventions.
It also gives a good outline of the potential of CRISPR in therapeutics, which goes far beyond single gene disorders.
The article does not mention the impact of AI on solving the problem of off-target cleavage, however.

Here is a quote from the article:

"Room for Improvement
As versatile and powerful as CRISPR/Cas technology may already be, many aspects of the technology still need to be improved, understood, or both, for therapeutic application. Whereas for research applications, suboptimal aspects of CRISPR/Cas technology will become an inconvenience or a significant cost factor, for therapy these same aspects will prevent regulatory approval for clinical application or may turn a trial into a tragedy. The issues that remain to be addressed may be divided into aspects of safety, efficiency and utility, with some overlap between the categories."
 
https://link.springer.com/article/10.1007/s40291-019-00391-4

Thank you for the link and for trying to find something at the layman's level. I'll need to carve out some time to read and understand it. BTW, off-target cleavage is a new phrase for me. I will probably come back with questions/comments later.

Re: he advantages accruing to the three companies already involved in gene editing trials that you mentioned upthread; Even after reading that it wasn't readily obvious to me, even after you spelled it out. I asked my wife, who knows the science/regulation end better than I do, and she immediately agreed. It's a big deal for these three companies.

It never occurred to me that AI might be used to solve the myriad genetic mysteries still existing. But, yeh, wow. This could be bigger than I imagined.

[PeteD01]

I have been trying to prove @bwall wrong but have been unsuccessful.
It really does appear to require some formal education in molecular genetics to recognize the impact of CRISPR technology on biology.
I did find one review article for the more general reader. It does a good job in explaining the disruptive nature of CRISPR and how CRISPR has dramatically lowered the barriers to entry in the tool development arena which has led to an exponential increase in publications in the field, while at the same time exposing the formidable barriers to obtaining regulatory approval for therapeutic interventions.
It also gives a good outline of the potential of CRISPR in therapeutics, which goes far beyond single gene disorders.
The article does not mention the impact of AI on solving the problem of off-target cleavage, however.

Here is a quote from the article:

"Room for Improvement
As versatile and powerful as CRISPR/Cas technology may already be, many aspects of the technology still need to be improved, understood, or both, for therapeutic application. Whereas for research applications, suboptimal aspects of CRISPR/Cas technology will become an inconvenience or a significant cost factor, for therapy these same aspects will prevent regulatory approval for clinical application or may turn a trial into a tragedy. The issues that remain to be addressed may be divided into aspects of safety, efficiency and utility, with some overlap between the categories."
 
https://link.springer.com/article/10.1007/s40291-019-00391-4

Thank you for the link and for trying to find something at the layman's level. I'll need to carve out some time to read and understand it. BTW, off-target cleavage is a new phrase for me. I will probably come back with questions/comments later.

Re: he advantages accruing to the three companies already involved in gene editing trials that you mentioned upthread; Even after reading that it wasn't readily obvious to me, even after you spelled it out. I asked my wife, who knows the science/regulation end better than I do, and she immediately agreed. It's a big deal for these three companies.

It never occurred to me that AI might be used to solve the myriad genetic mysteries still existing. But, yeh, wow. This could be bigger than I imagined.

https://medium.com/swlh/solving-the-problem-of-off-target-effects-with-ai-14055406abc8

[bwall]

Thank you for the link and for trying to find something at the layman's level. I'll need to carve out some time to read and understand it. BTW, off-target cleavage is a new phrase for me. I will probably come back with questions/comments later.

Re: he advantages accruing to the three companies already involved in gene editing trials that you mentioned upthread; Even after reading that it wasn't readily obvious to me, even after you spelled it out. I asked my wife, who knows the science/regulation end better than I do, and she immediately agreed. It's a big deal for these three companies.

It never occurred to me that AI might be used to solve the myriad genetic mysteries still existing. But, yeh, wow. This could be bigger than I imagined.

https://medium.com/swlh/solving-the-problem-of-off-target-effects-with-ai-14055406abc8

Great link! Thanks. The article quickly moves from basics to complex ideas. Turns out, I'd heard of off-target cleavage before, but never by that name, just 'editing at the wrong place' or 'inaccuracy', or another less precise phrase. It did seem to be a bit of a tricky problem to me, but directing AI at this problem seems like a viable solution.

The market caps of BioNTech ($54b) and Moderna ($94B) are staggering. Both these companies were practically unknown two years ago and today they are huge. Granted, COVID pulled their development forward immensely. I guess that for me this confirms my analysis of potential future market caps for the CRISPR stocks. There's a lot that has to happen still for the CRISPR stocks to get there, but it is certainly in the realm of possibility that one day they have similar market caps.

[RunningintoFI]

This may intrigue those of you in this thread for future consideration.  Note that I am not aware of any commercial application of this YET but I do think this holds some gene editing promise for the future.  The best technology is likely still yet to come.

https://www.longevity.technology/rise-of-the-retrons-a-new-gene-editing-technique/

[bwall]

I have been trying to prove @bwall wrong but have been unsuccessful.
It really does appear to require some formal education in molecular genetics to recognize the impact of CRISPR technology on biology.
I did find one review article for the more general reader. It does a good job in explaining the disruptive nature of CRISPR and how CRISPR has dramatically lowered the barriers to entry in the tool development arena which has led to an exponential increase in publications in the field, while at the same time exposing the formidable barriers to obtaining regulatory approval for therapeutic interventions.
It also gives a good outline of the potential of CRISPR in therapeutics, which goes far beyond single gene disorders.
The article does not mention the impact of AI on solving the problem of off-target cleavage, however.

Here is a quote from the article:

"Room for Improvement
As versatile and powerful as CRISPR/Cas technology may already be, many aspects of the technology still need to be improved, understood, or both, for therapeutic application. Whereas for research applications, suboptimal aspects of CRISPR/Cas technology will become an inconvenience or a significant cost factor, for therapy these same aspects will prevent regulatory approval for clinical application or may turn a trial into a tragedy. The issues that remain to be addressed may be divided into aspects of safety, efficiency and utility, with some overlap between the categories."
 
https://link.springer.com/article/10.1007/s40291-019-00391-4

Thanks for the link. My brain was full after reading it. I didn't understand most of it, but some sentences did manage to sink in after reading and thinking.

Here are two that stuck out:

Brief Instructions for the Toolkit
The current momentum of novel discovery and developments of and around CRISPR/Cas suggests that the tools we have in hand after barely 6 years of research into tailored RGNs are all but the tip of the iceberg. However, these tools already provide a veritable arsenal of possible treatment strategies for genetic diseases.

And

A Lever to Move the Medical World
Based on these CRISPR/Cas-based technologies, therapy development for many human diseases, including infectious diseases, cancers and monogenically inherited diseases, is underway.

So, huge potential that we might not even be able to grasp now. Also; it's gonna take time. No quick fixes, which might explain why NTLA has retreated off the highs in the past week or two. And, no quick buyouts w/o FDA approval.

I'm very bullish on this sector if an investor has time and patience. If you can lock up your money for years, then I believe you will be richly rewarded. It's hard to know *when* the news will come, so I'm not a fan of trying to time the gene editing stocks.  Invest, stay abreast of the news and be a witness as medical history unfolds in front of your eye.

[bwall]

This may intrigue those of you in this thread for future consideration.  Note that I am not aware of any commercial application of this YET but I do think this holds some gene editing promise for the future.  The best technology is likely still yet to come.

https://www.longevity.technology/rise-of-the-retrons-a-new-gene-editing-technique/

Wow! Great article. Thanks for sharing.

For me, this goes to show that . . . . . we still don't know what we've got and the possibilities seem endless.

"The best technology is likely still yet to come" Agreed.

I like to compare CRISPR to Columbus' discovery of the New World. This article could dovetail nicely into that; After the Treaty of Tordesillas in 1494 (replicated in the post-CRISPR litigation with the Broad Institute, filed in 2014), the Portuguese thought they'd come away with the better deal. Although as time progressed the Spanish received more wealth and power from the New World than the Portuguese did.

So it is with CRISPR; now we think that CRISPR is the best technology but the best is likely still yet to come. If my observation and timeline is correct then investing at today's prices will seem ridiculously cheap once the technology has matured.

[RunningintoFI]

I'd also suggest considering the tangentially related companies that may actually win the gene editing race.  NTLA, EDIT, CRSP are all geared towards final stage, clinical use.  Consider that these companies may have to get their Cas9 manufactured somewhere for instance.. Or they need lab equipment to store, transport, and test all of this material.  The underlying supporters are positioned to win regardless of who emerges as the victor because they can supply the entire industry - similar to how oil won the automobile race when cars took off. 

[Metalcat]

This may intrigue those of you in this thread for future consideration.  Note that I am not aware of any commercial application of this YET but I do think this holds some gene editing promise for the future.  The best technology is likely still yet to come.

https://www.longevity.technology/rise-of-the-retrons-a-new-gene-editing-technique/

Wow! Great article. Thanks for sharing.

For me, this goes to show that . . . . . we still don't know what we've got and the possibilities seem endless.

"The best technology is likely still yet to come" Agreed.

I like to compare CRISPR to Columbus' discovery of the New World. This article could dovetail nicely into that; After the Treaty of Tordesillas in 1494 (replicated in the post-CRISPR litigation with the Broad Institute, filed in 2014), the Portuguese thought they'd come away with the better deal. Although as time progressed the Spanish received more wealth and power from the New World than the Portuguese did.

So it is with CRISPR; now we think that CRISPR is the best technology but the best is likely still yet to come. If my observation and timeline is correct then investing at today's prices will seem ridiculously cheap once the technology has matured.

I don't disagree with the broad strokes of the concept of investing in gene editing tech, I'm a little puzzled as to the investing logistics of it.

I guess your position is that investing in the companies that are developing the early stages of the tech means that you will get a large piece of whatever the downline commercial product sales are in the future?

The applicability of what exists now is so narrow, and the future broad applicability has a ton of potential, but requires a lot more development, so I guess I'm just not quite seeing how this specific investment is supposed to work out to be a moonshot investment?

Do you see these companies as the final primary purveyors of gene editing products once all of the necessary research and development is done?

I feel like I'm just not seeing the same *pathway* of money and profit that you are. I hope I'm wrong though and that in a reasonable timeline you make a ton of money from your foresight.

[bwall]

I'd also suggest considering the tangentially related companies that may actually win the gene editing race.  NTLA, EDIT, CRSP are all geared towards final stage, clinical use.  Consider that these companies may have to get their Cas9 manufactured somewhere for instance.. Or they need lab equipment to store, transport, and test all of this material.  The underlying supporters are positioned to win regardless of who emerges as the victor because they can supply the entire industry - similar to how oil won the automobile race when cars took off.

I think that this is a great suggestion. I'm not sufficiently knowledgeable about the industry to have any idea which company provide these services. Can you provide a short list of suppling companies that are well respected? I'd love to be able to take a look at a few of the companies.

[bwall]

I don't disagree with the broad strokes of the concept of investing in gene editing tech, I'm a little puzzled as to the investing logistics of it.

I guess your position is that investing in the companies that are developing the early stages of the tech means that you will get a large piece of whatever the downline commercial product sales are in the future?

The applicability of what exists now is so narrow, and the future broad applicability has a ton of potential, but requires a lot more development, so I guess I'm just not quite seeing how this specific investment is supposed to work out to be a moonshot investment?

Do you see these companies as the final primary purveyors of gene editing products once all of the necessary research and development is done?

I feel like I'm just not seeing the same *pathway* of money and profit that you are. I hope I'm wrong though and that in a reasonable timeline you make a ton of money from your foresight.

Thank you for your thoughtful reply. I agree that many times it's not readily apparent how a product can be monitized. I think that setting some data points might be a helpful way to start.

I was following a company specialized in rare and orphan diseases. Stuff that had less than 10,000 people worldwide with the disease. The company, Audentes, had a market cap of $1.5b and for the life of me I couldn't see how this company could ever sell any product worth $1.5b, ever. Six months later they got a bid for $3.0b. My one (1) share doubled in value overnight. I still don't understand how that market is worth $3.0b to anyone. Read about it here:
https://www.fiercepharma.com/pharma/behind-astellas-3b-buyout-audentes-furtive-whispers-and-a-bidding-war

The above link also describes how management is ultimately the one who does or doesn't decide to sell a company to big pharma.

Here's another example; bridgebio, a company with 18 (!) therapies/drugs in it's pipeline. They number of potential patients is much higher than with Audentes, but, these are still very small target markets. Their market cap is just under $10 billion today. I think that a doctor is better qualified than I am to estimate the potential future market for these therapies. Please look at bridgbio's pipeline and tell me how common these diseases are:
https://bridgebio.com/pipeline

Now, if these are the valuations for companies working on diseases almost unknown except to those who contract them, then what should be the valuation of a company that can provide a one time treatment to cure sickle cell disease? What should such a treatment cost? If 100,000 people in the USA have that disease and the treatment sells for $10,000, then that is $1billion in revenue. If the treatment sells for $100k, that's $10b in revenue. What (P/E) multiple should be paid on that company? What if the market is larger than 100,000 because of sales in Europe and Asia? The same therapy is also being tested on Beta thelassamine, a disease I'd never heard of, which makes it a two-for-one, what's not to love?

Right now a few companies are racing to get the cure for sickle cell disease to market. I think that CRSP is in pole position. Bluebird bio is also very close, IIRC.

Incremental advances mean that future therapies and discoveries are on the way, but unknown to us today. I guess on the one hand it's a pie-in-the-sky gamble, on the other hand there's a product on the way with a large existing market that could greatly benefit from these products coming to market.

[Metalcat]

Thank you for your thoughtful reply. I agree that many times it's not readily apparent how a product can be monitized. I think that setting some data points might be a helpful way to start.

I was following a company specialized in rare and orphan diseases. Stuff that had less than 10,000 people worldwide with the disease. The company, Audentes, had a market cap of $1.5b and for the life of me I couldn't see how this company could ever sell any product worth $1.5b, ever. Six months later they got a bid for $3.0b. My one (1) share doubled in value overnight. I still don't understand how that market is worth $3.0b to anyone. Read about it here:
https://www.fiercepharma.com/pharma/behind-astellas-3b-buyout-audentes-furtive-whispers-and-a-bidding-war

The above link also describes how management is ultimately the one who does or doesn't decide to sell a company to big pharma.

Here's another example; bridgebio, a company with 18 (!) therapies/drugs in it's pipeline. They number of potential patients is much higher than with Audentes, but, these are still very small target markets. Their market cap is just under $10 billion today. I think that a doctor is better qualified than I am to estimate the potential future market for these therapies. Please look at bridgbio's pipeline and tell me how common these diseases are:
https://bridgebio.com/pipeline

Now, if these are the valuations for companies working on diseases almost unknown except to those who contract them, then what should be the valuation of a company that can provide a one time treatment to cure sickle cell disease? What should such a treatment cost? If 100,000 people in the USA have that disease and the treatment sells for $10,000, then that is $1billion in revenue. If the treatment sells for $100k, that's $10b in revenue. What (P/E) multiple should be paid on that company? What if the market is larger than 100,000 because of sales in Europe and Asia? The same therapy is also being tested on Beta thelassamine, a disease I'd never heard of, which makes it a two-for-one, what's not to love?

Right now a few companies are racing to get the cure for sickle cell disease to market. I think that CRSP is in pole position. Bluebird bio is also very close, IIRC.

Incremental advances mean that future therapies and discoveries are on the way, but unknown to us today. I guess on the one hand it's a pie-in-the-sky gamble, on the other hand there's a product on the way with a large existing market that could greatly benefit from these products coming to market.

To be clear, I never said that I didn't see how people can make money investing in pharma, I said I don't see a specific path to a moonshot investment. One that would lure me away from passive investing towards stock picking.

As for your numbers, I gave the example of the new migraine biologics drugs. Migraines are a MASSIVE market and I'm sure the companies that make these drugs are making money off of them as they are quite expensive. However, no drug company has exploded in value as a result.

I'm not failing to see profitability, I'm failing to see outsized, massive, moonshot profitability for one particular entity that I can invest in now.

I'm not convinced that the current early stage research firms are going to be the end providers of the majority of future commercials products. What I foresee is that the enormous amount of work that's going to be required for this tech to become commercially available on a larger scale is probably going to take efforts across the industry, so the commercial benefits will likely be spread around.

Now, I could just invest in the drug industry in general in anticipation of this future utility rising the entire pharma tide, but I can do that with index funds as it is.

I understand the tech, I was going to lectures on CRISPR long ago, just as I was going to lectures on the "miracle" of stem cells before that. I'm a retired medical professional, and I have extensive knowledge about treating genetic diseases because I have one.

It's not a lack of subject knowledge that's making me not see the play. It's an understanding of how research moves through the system to become treatment that's making me totally fail to see how a particular investment now could possibly become a moonshot. I just don't see how the profits don't get diluted into the industry itself.

Again, not saying there isn't money to be made, but I don't see the mechanics of a moonshot play. So yeah, I might be willing to invest some small "fun money", but not a substantial enough amount to make any real difference to my outcomes in the end either way.

[PeteD01]

Thank you for your thoughtful reply. I agree that many times it's not readily apparent how a product can be monitized. I think that setting some data points might be a helpful way to start.

I was following a company specialized in rare and orphan diseases. Stuff that had less than 10,000 people worldwide with the disease. The company, Audentes, had a market cap of $1.5b and for the life of me I couldn't see how this company could ever sell any product worth $1.5b, ever. Six months later they got a bid for $3.0b. My one (1) share doubled in value overnight. I still don't understand how that market is worth $3.0b to anyone. Read about it here:
https://www.fiercepharma.com/pharma/behind-astellas-3b-buyout-audentes-furtive-whispers-and-a-bidding-war

The above link also describes how management is ultimately the one who does or doesn't decide to sell a company to big pharma.

Here's another example; bridgebio, a company with 18 (!) therapies/drugs in it's pipeline. They number of potential patients is much higher than with Audentes, but, these are still very small target markets. Their market cap is just under $10 billion today. I think that a doctor is better qualified than I am to estimate the potential future market for these therapies. Please look at bridgbio's pipeline and tell me how common these diseases are:
https://bridgebio.com/pipeline

Now, if these are the valuations for companies working on diseases almost unknown except to those who contract them, then what should be the valuation of a company that can provide a one time treatment to cure sickle cell disease? What should such a treatment cost? If 100,000 people in the USA have that disease and the treatment sells for $10,000, then that is $1billion in revenue. If the treatment sells for $100k, that's $10b in revenue. What (P/E) multiple should be paid on that company? What if the market is larger than 100,000 because of sales in Europe and Asia? The same therapy is also being tested on Beta thelassamine, a disease I'd never heard of, which makes it a two-for-one, what's not to love?

Right now a few companies are racing to get the cure for sickle cell disease to market. I think that CRSP is in pole position. Bluebird bio is also very close, IIRC.

Incremental advances mean that future therapies and discoveries are on the way, but unknown to us today. I guess on the one hand it's a pie-in-the-sky gamble, on the other hand there's a product on the way with a large existing market that could greatly benefit from these products coming to market.

To be clear, I never said that I didn't see how people can make money investing in pharma, I said I don't see a specific path to a moonshot investment. One that would lure me away from passive investing towards stock picking.

As for your numbers, I gave the example of the new migraine biologics drugs. Migraines are a MASSIVE market and I'm sure the companies that make these drugs are making money off of them as they are quite expensive. However, no drug company has exploded in value as a result.

I'm not failing to see profitability, I'm failing to see outsized, massive, moonshot profitability for one particular entity that I can invest in now.

I'm not convinced that the current early stage research firms are going to be the end providers of the majority of future commercials products. What I foresee is that the enormous amount of work that's going to be required for this tech to become commercially available on a larger scale is probably going to take efforts across the industry, so the commercial benefits will likely be spread around.

Now, I could just invest in the drug industry in general in anticipation of this future utility rising the entire pharma tide, but I can do that with index funds as it is.

I understand the tech, I was going to lectures on CRISPR long ago, just as I was going to lectures on the "miracle" of stem cells before that. I'm a retired medical professional, and I have extensive knowledge about treating genetic diseases because I have one.

It's not a lack of subject knowledge that's making me not see the play. It's an understanding of how research moves through the system to become treatment that's making me totally fail to see how a particular investment now could possibly become a moonshot. I just don't see how the profits don't get diluted into the industry itself.

Again, not saying there isn't money to be made, but I don't see the mechanics of a moonshot play. So yeah, I might be willing to invest some small "fun money", but not a substantial enough amount to make any real difference to my outcomes in the end either way.

The new migraine medications are fully human monoclonal antibodies. Regeneron was one of the companies developing transgenic mouse monoclonal antibody development platforms. What we are seeing today, probably more MABs in clinical trials than any time before in history, is the result of pioneering work from two or three decades ago.
The clinical and commercial potential of the fully human MABs  only became obvious in the mid to late 2000s / and that was when it all was priced in and some companies were acquired. Just look at the stock price chart of Regeneron to see how a moonshot investment looks in biotech, but that was 15 yrs ago.
Don't expect spectacular impacts on stock prices by MAB tech as it is a mature technology.

And again, a moonshot investment will never have an obvious way how the money will be made - it´s a feature, and if anyone here could tell me exactly how I feel how things are going to work out I probably should sell my shares right away because it would be safe to say that it is all priced in.

To get back to therapeutic MABs, these therapeutics are produced with biotech but are still fundamentally evaluated like other (small molecule) drugs. Many MABs even target receptors like many traditional drugs do. Pharma giants are perfectly capable in integrating these so called biologics into their clinical research programs.

CRISPR tech in clinical applications is different by being more like a molecular tool resulting in a permanent alteration similar to surgery. The difference between basic research and clinical application in CRISPR tech is like the difference between setting off a large numder of fireworks and see if some land where intended and sending a probe to Mars - it is all rocketry alright, but there is a difference.
Moving CRISPR based therapies into the clinical arena is more like moving a molecular surgery platform into the arena rather than another fancy drug.
And here is where I think the early bird is going to shine.
The basic research side of gene editing has experienced a massive deflation in cost, lowering the barrier of entry, resulting in an explosion in the amount of research performed which is not matched by a similar deflation the cost of clinical research.
I believe that whoever develops platforms in which the avalanche of new tools can be brought into the clinical research arena will have a leg up in becoming a gatekeeper of sorts. That would not be unlike, for example, Microsoft, with the analogy even extending to the armies of lawyers needed to disentangle the mess of patent issues raised at every step.

   

[Metalcat]

So your position is that there's potential for significant gatekeeping of tech moving forward.

Okay, that I can actually understand. Not enough to stake significant money on it myself, but at least I get the play.

Obviously moonshots can't be predicted, but usually someone is seeing some plausible path towards it. I get the plausible path that you are seeing now.