As regular readers know, I am very excited by the investment potential of genetic sequencing and gene editing and therefore, both in the Pynk Thesis Portfolio as well as in my personal portfolio, I have been building exposure to the stocks that I believe are ideally positioned in this space. You may have also seen my write ups of two large cap stocks in the sector which I believe have attractive fundamentals and low risk to their growth plans ( ILLUMINA AND REGENERON). In fact, Regeneron is the Pynk Thesis Portfolio’s largest position and the large cap US stock I am personally most excited by.
In terms of recent news in the sector, we saw some incredibly positive news from gene therapy minnow Intellia Therapeutics which led to a more than 100% rise in their share price at the end of June 2021. Having looked at this development in detail, I feel there is significant read-through from this news for Intellia’s small cap rival Editas Medicine (which I hold personally as does the Pynk Thesis Portfolio). In simple terms, what both Intellia and Editas seek to do is ‘edit’ genes in the body (“in-vivo”) rather than removing them and editing! This is an incredible aim and step forward for the genomics space!
However, it is important to note that Editas Medicine is without doubt - like most other smaller biotech companies – high risk given its portfolio is at a very early stage and the company is loss making. Unlike most of the companies I write to you about, Editas doesn’t yet have a marketable therapy or strong defensible market position. With that proviso, today I would like to tell you about the exciting situation there is at Editas Medicine, a company where we are likely to see very important newsflow imminently!
Most people have heard of CRISPR and the ground-breaking technology capable of transforming healthcare. But most people assume (wrongly in my view) that CRISPR has this space all to themselves.
I personally love the idea that alongside making money, we can make a real difference to the World with our investments. We at Pynk may soon bring you products that reflect this impact focus and would love to hear your views on whether this would be of interest to you.
In terms of the genomics sector, imagine therapies that don’t just treat diseases, but cure them, with a single dose, by instructing the body to turn off targeted defective DNA. One study in the journal Nature said CRISPR technology could cure up to 89% of all genetic birth defects. That’s the dream, at least. The reality is that the technique is very much in its infancy, and to date, no CRISPR therapy has been approved for use by the U.S. Food and Drug Administration (FDA).
But let’s not forget the power of gene editing as a “one-time only technology” is unlike any other field of medicine, which explains e.g. the very high list price of $2.5m for Novartis’ Zolgensma, a gene therapy approved for Spinal Muscular Atrophy.
The truth is, no one really knows what a healthcare landscape flooded by safe and effective gene therapy treatments would look like - theoretically there could be far fewer patients to treat? - but at the present time, the market is only valuing gene therapy stocks on their potential to deliver breakthroughs in rare diseases or in areas where payload can be currently delivered to, such as the liver, or the eye.
As a general rule, when investing in smaller early-stage stocks like Editas, I personally take a much smaller position or diversify into a basket of them to offset their much higher risk profile while still benefiting from the asymmetric risk of some of the stocks potentially being multibaggers… To me, companies such as Editas have the real potential to transform the medical treatment landscape if the technology can be adapted to more prevalent diseases, which ought to continue to send their valuations and share prices skyward.
Editas Medicine is one of a handful of listed gene editing companies pioneering the use of CRISPR - clustered, regularly interspaced, short palindromic repeats - to create molecules that “efficiently and specifically” edit DNA. CRISPR gene-editing technology has been described as a modified protein that acts as a pair of scissors to snip parts of DNA to target parts of a specific gene, or gene mutation. To work the metaphor further, Editas Medicine is on the cutting edge of CRISPR.
Editas was founded in 2013 by many of the scientists who led the ground-breaking research into CRISPR - Feng Zhang of the Broad Institute, MIT, George Church, Keith Joung and David Liu of Harvard, and Jennifer Doudna of the University of California, Berkeley. Doudna won the Nobel Prize for her research - alongside Emmanuel Charpentier - showing how a naturally occurring genome system found in bacteria that captures snippets of DNA from invading viruses - converting them to CRISPR arrays in order to “remember” them, and then using RNA segments coupled with an enzyme, Cas9, to cut the viral DNA and disable the virus - can be co-opted for use in the cutting of human DNA.
One of Editas’ early breakthroughs was to correct a mutation in the CEP290 gene using a CAS9 protein from the Staphylococcus aureus bacteria. CEP290 causes Leber Congenital Amaurosis 10 and remains a central focus for Editas today.
Editas IPO’d in 2016, raising ~$94m, after issuing 5.9m shares at a price of $16. Initially, its share price performance was dogged by a series of patent disputes between Berkeley and Harvard’s Broad Institute, which effectively pitted Editas against CRISPR and Intellia. These were eventually resolved without any company being terminally damaged, but Editas’ progress was slow and steady, rather than spectacular, with safety concerns continuing to hamper the share price and challenge the overall CRISPR thesis.
Editas now uses two different types of enzymes - Cas9 and Cas12a - which are bound to an RNA molecule, known as guide RNA. The guide RNA is designed to recognize a specific target DNA sequence, and binds to it, while the enzyme, or nuclease, cuts and edits the DNA, targeting a mutated gene, for example. Using either Cas9 or Cas12a, Editas says that it can now create gene editing molecules for 95% of the human genome.
What may be unsettling for investors is that Editas’ management team has changed considerably since the company’s IPO though the new hires are pretty big heavy hitters. In February this year, James Mullen, who became Editas’ Chairman in 2018, was parachuted in as the company’s new CEO, after the departure of Cynthia Collins. Collins had replaced Editas’ original CEO Katrine Bosley, in 2019. Mullen was formerly CEO of Biogen, and also is a member of the Board of Directors at Thermo Fisher - his influence on the future direction and success of Editas could be vital. Lisa Michaels, formerly Head of Bayer’s Rare Diseases, Cell and Gene Therapy division, joined as Chief Medical Officer in November 2020, and Mark Shearman PhD. was appointed Chief Scientific Officer two months ago, joining from Applied Genetic Technologies Corporation. Chi Li, Ph.D. also joined as Chief Regulatory Officer in June.
The shakeup may have been related to the ending of a deal Editas had agreed with Allergan for its ocular therapies, including EDIT-101. Allergan had made a $90m payment to Editas for exclusive rights to license up to five ocular therapies utilising the biotech’s genome editing capabilities, but after AbbVie acquired Allergan in a $63bn deal last year, it decided to terminate the agreement.
EDIT-101 remains the priority at Editas at this time, which gained permission from the FDA to initiate a Phase 1 clinical trial of the therapy, which currently is in process, but the loss of a major pharma partner created inevitable disappointment at the company. Nevertheless, driven as much by Intellia’s proof-of-concept (which I will explain below) as much as by the progress of its own pipeline, Editas’ share price has risen strongly in the past three months and it now has several notable institutional owners. Ark Investment management owns a 16% stake in the company, and four other institutions - including Blackrock and Vanguard Group - own >5% stake.
I hope the rundown of the company’s history above makes clear that some of the same lauded researchers working on CRISPR technology were very closely involved with Editas. Many investors assume that CRISPR is the only company with important and ground-breaking technology in genetic sequencing and editing. But it is important to note that all these three companies are very much linked and at the forefront of this technology: Doudna left Editas in 2014, later joining Intellia Therapeutics, while Emmanuelle Charpentier became a founding scientific member of CRISPR Therapeutics. These two companies remain Editas’ two main rivals in the CRISPR gene-editing space to this day. As it may be becoming clearer, despite market perception (no doubt fueled by the Nobel prize award), CRISPR isn’t the only company in this space.
Editas’ two most promising candidates are still in early stage trials. If either is approved, it would be a huge moment, not just for Editas, but for both of its main competitors, CRISPR Therapeutics and Intellia Therapeutics (as Intellia’s results were for the others). All three companies went public in 2016 and are working to find therapies using CRISPR editing. It is anybody’s guess whether this will happen for all three companies, but I am hopeful.
Intellia’s share price rose more than 100% at the end of June 2021 on news of the company’s landmark results from a Phase 1 study of its candidate NTLA-2001 in patients with transthyretin (ATTR) amyloidosis - a liver disease caused by misfolding proteins. The data is thought to be the first ever demonstrating the safety and efficacy of in vivo CRISPR editing in humans - at the 0.3mg/kg dose, 3 patients experienced a mean 87% reduction in serum TTR.
The uptick in Intellia’s share price - and Editas’, which jumped from $42 to $57 after the data was announced - speaks to how highly the market values the promise of gene-editing companies. The major advantage of this type of treatment is that it offers the prospect of a “one time only” therapy, which can permanently cure patients, who would otherwise face a lifetime of regular treatment. Understandably it represents a truly transformative advance in healthcare and companies at the forefront of this step change in technology and treatment stand to gain enormously.
Source: company Q221 earnings presentation
The company’s lead candidate in trials is EDIT-101, which may be used to treat Leber congenital amaurosis 10, the most common cause of inherited childhood blindness. The company began a phase 1/2 trial with EDIT-101 last March, targeting mutations in the acentrosomal protein (CEP) 290 gene. The company said subjects are given a dose of EDIT-101 with a subretinal injection, with the intention of removing the CEP290 mutation, restoring normal photoreceptor function and vision.
EDIT-101 will likely generate most of the excitement around Editas over the remainder of this year. In its Q221 earnings call on Aug. 4, management told analysts that it will share initial clinical data from EDIT-101’s BRILLIANCE trial this month (September) - its first ever clinical data readout - which is an exciting near-term catalyst for investors to contemplate.
Interestingly, the data to be announced in September will be from six patients - the same figure as Intellia reported from its successful Phase 1 trial of NTLA-2001. Management was at pains to point out that the primary endpoint was safety, but mentioned reporting on efficacy endpoints including:
“Measurements of retinal responses to light as well as clinically relevant outcomes such as reproducible improvements in patient reported visual acuity, or in the ability to maneuver around objects at different levels of elimination”. Source: Lisa Michaels, Q121 earnings call.
Clinical data from EDIT-101 has been a long time coming, and it seems hard to overstate the importance of the upcoming data readout, since, as Michaels pointed out on the earnings call, validation for EDIT-101 will “also help de-risk our subsequent molecular programs.”
While Edit 101 and 102 are an opportunity to establish gene therapy leadership in the ocular market - no small achievement given its size - EDIT-301 has entered clinical studies in SCD.
EDIT-301 may be sandwiched somewhere between CRISPR and Bluebird Bio’s SCD therapies, considered front runners in the development / approval race, and Beam Therapeutics’ two earlier stage candidates, which leverage a different delivery technique, using electroporation as opposed to AAV vector technology, but ultimately it is the efficacy and safety record that counts.
Editas’ Phase 1/2 RUBY study of EDIT-301 is currently screening patients and selecting trial locations, with patient dosing expected to begin before the end of the year, and an IND expected to be submitted for EDIT-301 to treat Beta Thalassemia also before the year end.
EDIT-301 uses the Cas12A enzyme, and has a different target to rival therapies, mimicking a “naturally occurring mutation associated with hereditary persistence of foetal haemoglobin,” as opposed to targeting the BCL11A gene. This allows for greater specificity and more efficient efficacy, Editas believes.
In Sickle Cell Disease, there’s strong belief that gene therapies will succeed - which has even apparently hurt sales forecasts for two new approved therapies from Novartis for the disease - since analysts believe it’s only a matter of time before a gene-therapy is approved, with a one-time treatment regime, which will blow all other therapeutic approaches out of the water.
Recently, the FDA gave approval for Editas to begin a phase 1/2 study by dosing sickle cell disease (SCD) patients with EDIT-301, an ex vivo gene-editing cell medicine. Ex vivo refers to the process of taking cells out of a body, manipulating them, and then resubmitting them. SCD is inherited and it leads to an accumulation of haemoglobin S, abnormally shaped red blood cells that can clog blood vessels and cause tremendous pain. According to the Centres for Disease Control and Prevention (CDC), SCD affects roughly 100,000 people in the United States, and occurs in 1 of every 365 black births in the U.S. The company is also looking at EDIT-301 as a treatment for beta-thalassemia, an inherited blood disorder through which the production of haemoglobin in the blood is limited. At present, there’s only one cure for SCD – a bone marrow transplant. The problem is, bone marrow transplants are expensive and dangerous, and require bone marrow from a closely matched donor without the disease, such as a sibling. Only 2% of the U.S. population is on the bone marrow registry and many minority groups are underrepresented in the registry.
Editas’ cellular therapy division has been partnered with Juno Therapeutics - a division of Bristol Myers Squibb - since 2015. The focus is on “alpha-beta T cell experimental medicines,” and to date Editas appears to have received ~$115m of upfront and milestone payments.
Editas is in line for ~$200m in milestones and a high single-digit to low double-digit royalty share on global sales of up to two assets brought to market by Juno, but the fact that Bristol Myers’ has now brought 2 CAR-T cell therapies to market - Abecma and Breyanzi - thanks to its takeover of Celgene - might suggest that the big pharma’s focus is elsewhere.
Editas says it is working on three programs with BMY, with 1 declared development candidate, and while it would be a mistake to dismiss this collaboration based on a lack of upcoming milestones or publicity, it also would be safe to say that it’s not amongst the company’s key priorities.
Within cellular therapy, more time and resources appear to be allocated toward a proprietary gene-edited induced pluripotent stem cells (“iPSC”) platform - on which Editas is partnering with Bluerock Therapeutics.
Editas iNK cell medicine process in collaboration with BlueRock.
Source: Q221 earnings presentation.
As shown above, the technology is applied to Natural Killer (“NK)” cells, as opposed to T-cells, which present numerous advantages, being naturally allogeneic, and having the ability to recognise a larger range of tumours, recruit T-cells to attack tumours, and directly kill tumours. Editing efficiency has been measured at 70%-100% and sustained anti-tumour observed in preclinical models.
Editas is the cheapest CRISPR company to own at the present time, with potentially the most exciting near-term price catalyst in play, which is why I’m bullish on the stock. With >$600m in cash reported as of Q221, and a cash burn of $119m in the first six months of this year, Editas is in a relatively healthy place financially and importantly can ride out the next few years if fundraising markets dry up. A new management team is guiding the company through the next phase in its development, and with a market cap of $4.5bn at the time of writing, Editas is a far cheaper company to buy than Intellia, with a market cap of $11.7bn at the time of writing, Beam, market cap of $7bn, or CRISPR, market cap of $9.5bn.
Issues with how to deliver gene-editing therapies to the desired cells limits the scope of the therapeutic modality at the present time, meaning that Editas, Intellia, etc., have similar disease targets - hemoglobinopathies, notably sickle cell disease and beta thalassemia, cell therapies usually targeting haematological cancers, and central nervous system (“CNS”) and ocular diseases.
Editas can claim to be a leader in the ocular space, having advanced its candidate EDIT-101 into clinical trials for a rare eye disease known as Leber Congenital Amaurosis 10 (“LCA10”) for which there are currently no available therapies. Although the disease affects only 4,000 people in the US, and ~30k globally, Editas estimates, if the company can establish proof-of-concept with EDIT-101 - and initial data is expected before the end of the year - as Intellia has done with NTLA-2001, a significant share price bounce would be the likely outcome.
From a commercial perspective, the eye disease market is a highly lucrative space - estimated to reach ~$48bn in size by 2026, and a seemingly ideal springboard for the launch of a gene therapy. Editas already is working on a second therapy for Usher Syndrome 2a (“USH2A”), which affects ~4,500 patients in the US, and is also looking at Autosomal Dominant Retinitis Pigmentosa 4 (“RP4”) - an 18k patient market in the US and Europe.
Editas’ opportunities in Sickle Cell Disease (“SCD”) and Beta Thalassemia should not be overlooked either, nor should collaborations with Bristol Myers Squibb and Blue Rock Therapeutics in cell therapies.
Given Editas’ leadership in the ocular space, and relative lack of competition in this space from rival gene therapy developers (although Beam Therapeutics is one to watch in the space), Editas has an opportunity to carve out a lucrative niche for itself, in my view.
Theoretically, approval for LCA10 could bring a 5k patient market into play, and if we conservatively price EDIT-101 at $500k per treatment, there’s a $2.5bn market in play. Add in the USH2A treatment market attached to EDIT-102, and there’s another $2.5bn, and longer term, with retinitis pigmentosa - a potential $9bn market, we can quickly see the justification not only for Editas’ current market valuation, but also a significant amount of upside potential based on price to sales.
Therefore, if the EDIT-100 data confirms proof-of-concept, my guess would be that Editas could join the ranks of e.g. CRISPR as a double-digit billion market cap gene therapy company, offering investors a double your money bet with the odds slightly in favour of a positive result.
And even if the data does not support proof of concept, Editas has enough positive preclinical data, market goodwill, and financial clout to have a second go, and a third, etc. Granted, the share price may experience severe short-term downside, but at present I would view that as a buying opportunity. The potentially slow pace of development and the risk of emerging safety issues apply to all players including the much higher rated CRISPR.
For example, Bluebird Bio shares have fallen by 70% over the past year owing to safety concerns related to its LentiGlobin sickle cell disease (“SCD”) therapy, which has been linked with cases of acute myeloid lymphoma (“AML”) and myelodysplastic syndrome (“MDS”). Its current market cap is just over $1bn. CRISPR’s higher valuation is justified given its current pre-eminence though companies like Editas may already be taking gene therapy into the next generation of safer, more effective therapies so the potential for the valuation gap closing is there.
It’s hard to overemphasise the importance of the upcoming data readout for EDIT-101 when considering Editas as an investment opportunity. If successful, the company’s approach will be validated, it will move a small step closer to commercialising its first asset, and the delays experienced getting to the clinical study stage will be forgiven. The upside ought to be significant and sustained.
On the other hand, if the data is negative, then the time taken over EDIT-101 will look misjudged, and the rest of the company’s pipeline will likely become devalued because it will point to failures in editing efficiency, or the DNA repair process, or the AAV vector delivery process.
That will be additionally problematic due to the emergence of next-generation gene-editing companies like Beam Therapeutics. There’s always a high risk for any biotech that a better type of drug, or approach to developing drugs, is just around the corner, making its own look antiquated, and although Editas has strongly benefited from this in the past as a CRISPR pioneer, there’s a risk that the company could begin to look behind the times.
Editas new management team will be working hard to ensure that does not happen, although there may be a question mark over whether Editas’ founding team has left sufficient pipeline opportunities for the new management to capitalize upon, and whether the new management team has sufficient familiarity with the technology to develop a new pipeline.
It’s difficult to speculate about how the EDIT-101 data readout will go as Editas has never read out clinical data before. My guess however would be that, given the close relationship between Editas’ and Intellia’s technologies, Intellia’s recent success, and the time taken developing the therapy, the odds are in Editas’ favour.
We as investors may be looking at Editas’ long term potential, but it has to be said that Editas could be an attractive acquisition candidate for a bigger player looking to enter the gene editing space. For example, Moderna has a growing cash stockpile on its hands and needs to find something to do with its money. That’s where Editas Medicine just might come into the picture. Moderna certainly wants to add gene-editing therapies to its pipeline. The company’s intentions were made perfectly clear on its second-quarter conference call. CEO Stéphane Bancel stated that Moderna’s second priority (after investing internally) “is to expand our horizons by complementing our platform with external technologies or products. This means we are interested in nucleic acid technologies, gene therapy, gene editing, mRNA.”
Moderna President Stephen Hoge said that the company has “watched the [gene-editing] space quite interestingly or quite significantly in terms of ways that we could help with delivering gene-editing cargoes across a range of different tissues.” Hoge added, “And we think it’s the right time for us to start to expand in that direction.”
The company ended the second quarter with a cash position of more than $12 billion. Moderna’s cash stockpile will grow even larger with its COVID-19 vaccine expected to rake in another $14 billion or so in the second half of this year. That gives the company ample financial flexibility to go on a shopping spree.
To be sure, Moderna didn’t mention Editas Medicine nor any other gene-editing company as a potential acquisition candidate. However, there are several reasons why Editas could be a ripe target for a buyout. If Moderna prefers to acquire a clinical-stage biotech with a gene-editing focus, there aren’t many alternatives. Editas is one of only three companies with CRISPR gene-editing therapies currently in clinical testing.
CRISPR Therapeutics is joined at the hip with Vertex Pharmaceuticals, which has also teamed up with Moderna. Intellia Therapeutics is partnering with Regeneron on its lead candidate. However, Editas doesn’t have a partner for its lead program. That could put the company higher on Moderna’s list. Editas is also the least expensive by far of these three clinical-stage CRISPR-focused biotech companies. The company’s lower market cap could make it a more attractive target if Moderna doesn’t want to spend all of its cash.
While its two rivals focus only on CRISPR-Cas9 (Cas9 is a nuclease that locates and binds to targeted genes), Editas has another nuclease in its arsenal – Cas12 (also known as Cpf1). Editas believes that Cas12 could increase its opportunities to develop gene-editing therapies. Hoge said that Moderna wants to “bring new payloads, new capabilities, new enzymes into our existing technological capabilities.” Editas’ dual-option CRISPR platform could fit nicely into Moderna’s goal.
A buyout by Moderna or any other large player is pure speculation on my part. However, if Moderna shows its hand about its interest, it could spur other big drugmakers to make their own business development deals with gene-editing leaders. Even if Moderna doesn’t come calling, Editas could find others who will.
Editas is loss making and is expected to remain so although it has $600m cash in the bank so it is in a position to fund its losses for at least three years without recourse to shareholders
Editas has a new (and therefore unproven) management team
Editas has a deep and exciting pipeline of products but all of them are early stage and could therefore fail to commercialise
The upcoming readout of trial results could be disappointing causing a significant fall in the share price
The company has close rivals: Beam Therapeutics, is pioneering a new approach to gene editing known as base editing and bluebird Bio which uses its own homing endonuclease and megaTAL gene editing technology - and there can be no guarantee that these rival technologies may not progress better and faster
As with all three companies working with CRISPR, plus Beam Therapeutics, Editas shares do look expensive at $66 a share, and the company valuation is high at $4.5bn, when there are only two assets in clinical development and only one clinical trial in progress
AbbVie’s decision to terminate the ocular development partnership may represent a vote of no confidence in Editas’ flagship project
Investing in gene therapy stocks is undoubtedly risky - scientists are still scratching the surface of what may be achievable using CRISPR/Cas9, or base editing, and delivery techniques are improving with e.g. the emergence of lipid nanoparticles, but there may be limiting underlying safety concerns associated to making permanent edits to the genome and DNA, and the industry may struggle to make tangible progress, as e.g. RNAi therapeutics companies have done this over the past decade
Patent Fight: Jennifer Doudna, a biochemist at UC Berkeley, and Emmanuelle Charpentier, now with the Max Planck Institute for Infection Biology, received the Nobel Prize in Chemistry last year for their work on CRISPR gene-editing technology. The pair are currently embroiled in a patent fight over the discovery with Editas and other companies. The latest round of the battle went against the Nobel winners, with the Patent Trial and Appeal Board (PTAB) saying in September that the plaintiffs on Editas’ side had priority in its already granted patents for uses of the CRISPR system in eukaryotic cells, which is any cell that has a clearly defined nucleus. The decision isn’t final, however, and until the matter is, it could impede CRISPR innovation.
The other concern for Editas is that it isn’t in as strong a financial shape as its top competitor, CRISPR, which had more than $1 billion in cash in its last quarterly report and is further advanced, with four therapies in clinical trials
Editas is one of a trio of gene-therapy companies pioneering CRISPR/Cas9 gene-editing technology - the others being CRISPR Therapeutics and Intellia. It is probably a surprise to many investors that CRISPR is in no way ‘owner’ of the space!
Intellia’s recent success in an in-human trial of patients with transthyretin (ATTR) amyloidosis has woken investors to the near-term potential for all these companies, especially Editas
Editas has its own major trial data readout in the eye condition Leber Congenital Amaurosis 10 already this month – in the same way it was for Intellia, this could be a major upside catalyst for the share price
The company has a relatively new management team, >$600m in cash, and a deep, (albeit early stage) pipeline
At half the market cap of CRISPR and Intellia, Editas has incredible near term and long-term upside potential