Clinical trial data supporting the safety of the CRISPR-Cas9 genomic editing tool was presented on Monday by Intellia Therapeutics (NASDAQ:NTLA) for its lead product, NTLA-2001. The data was highly encouraging. However, despite NTLA-2001's positive early results as a potential treatment for the rare disease transthyretin (TTR) amyloidosis, there's still a long way to go before Intellia could bring it to market.
CRISPR appears safe
In transthyretin amyloidosis, cells in the liver produce misfolded TTR proteins, which accumulate throughout the body, causing debilitating complications that can involve the digestive system, nervous system, and heart. Once symptoms appear, they grow progressively worse, and the disease leads to death within a median of 4 to 17 years among patients with nervous system involvement, and 2 to 6 years among patients with cardiac involvement.
NTLA-2001 edits the genes in those liver cells, removing the segment that produces those lethal misfolded proteins.
Worldwide, an estimated 250,000-550,000 people suffer from some form of amyloidosis.
An interim readout from Intellia's ongoing phase 1 trial found that a single high-dose infusion of NTLA-2001 led to an 87% mean reduction in the amount of misfolded TTR in patients' bloodstreams, with a maximum reduction of 96% by day 28 in one patient. Encouragingly, no serious adverse events were observed in the six study participants. While this is a small pilot study, in previous studies of NTLA-2001 in mice, the maximum reductions in TTR persisted for 12 months after a single treatment.
All of this data provides an early indication that CRISPR gene therapies are safe and efficacious as treatments for at least some genetic diseases.
CRISPR may just be easier
There are other treatments on the market for TTR amyloidosis, but one thing that would set CRISPR apart is the relative simplicity of administering it. And that factor could lead insurers to favor CRISPR treatments for certain rare and debilitating diseases such as TTR amyloidosis and hemophilia.
For example, Alnylam's (NASDAQ:ALNY) RNA-silencing therapy Onpattro requires an infusion every three weeks at a clinician's office. Ionis Pharmaceuticals' (NASDAQ:IONS) Tegsedi requires regular injections, though they can be self-administered. Both are priced in the neighborhood of $345,000 per year, and Onpattro comes with the additional costs associated with going to a medical office and having an infusion set up. Then there is Pfizer's (NYSE:PFE) once-daily oral medication Vyndamax, which costs $225,000 annually.
As a one-time infusion, gene therapy may become a compelling option for both patients and insurers, particularly given the high prices of currently available treatments. Though TTR amyloidosis treatments are a niche market, in 2020, Onpattro generated sales of $306 million, Tegsedi just under $70 million, and Vyndamax $429 million. Assuming that Intellia charges more for NTLA-2001 -- a one-time treatment with bluebird bio's (NASDAQ:BLUE) gene therapy for beta-thalassemia, Zynteglo, costs about $1.8 million -- TTR amyloidosis treatment could easily become a multibillion-dollar addressable market for the biotech.
Notably, CRISPR therapy for TTR amyloidosis may also put less stress on the healthcare system than the lentivirus and adenovirus gene therapies that are further along in clinical trials. Consider, for instance, Zynteglo, which requires a significant amount of effort and processing prior to treatment. First, physicians must extract stem cells from the patient, which must then be transported to and treated by bluebird bio. In the meantime, the patient undergoes "myeloablative conditioning" -- essentially knocking down the patient's bone marrow in preparation for a transplant of the edited stem cells, which will contain a repaired version of the gene that (when mutated) causes beta-thalassemia. This complicated process requires treatment at a qualified transplant center.
By comparison, for TTR amyloidosis, NTLA-2001 requires pre-medication with steroids and antihistamines. That's it. No prolonged patient preparation at the hospital. No bone marrow suppression. No shipping the patient's stem cells to a lab. The relative simplicity of administering CRISPR therapies is just one reason for the degree of excitement they are generating.
It may also give them a lower total cost of treatment than current gene therapies, which could make these therapies more palatable to insurers. If NTLA-2001 pans out, we may see a new biotech boom, with Intellia leading the charge.
It's still early
Before investors get their hopes up too much, remember that these results were from a six-person, phase 1 trial, and that Intellia now holds a market cap of roughly $11 billion. In fact, its valuation rose by about $2.8 billion in a single trading session after the interim trial data was made public. That gain was more than the current $2.1 billion market cap of bluebird bio, which already has an approved gene therapy on the market as well as a CAR-T therapy, and has two more candidates in phase 3 trials.
For further context, bluebird bio announced phase 1 results for Zynteglo in December 2014. While Zynteglo was approved for use in the EU in late 2019, bluebird bio faced some backlash on pricing, and the company isn't selling it in Germany because the two sides could not agree on pricing.
Moreover, the NTLA-2001 study excluded patients who had previously received RNA-silencing therapy, and none of these patients had previously taken Vyndamax either. How previous treatments will affect the way patients respond to NTLA-2001 is not yet known. And with hundreds of millions of dollars in revenue annually on the line, it is doubtful that Alynam, Ionis, or Pfizer will surrender this market without a fight.
In sum, Intellia will still need to conduct several years of trials, leap many regulatory hurdles, and outmaneuver an array of rivals stand before it can declare the CRISPR-Cas9 platform a winner. Not only that, but -- recognizing that future studies won't be cheap -- Intellia has already proposed another public offering of $400 million worth of common stock this week, diluting its current shareholders.
So while long-term Intellia shareholders have reason to celebrate, let bluebird bio serve as a cautionary tale. That biotech was once flying high on positive trial data, hitting a market cap of around $15.5 billion in March 2018. Since then, its shares have nose-dived by more than 80%. This despite the fact that it now has two approved therapies and two more candidates in phase 3 trials.
As such, I would be concerned about investing new money in Intellia now. I suspect it will soon reach its peak for the foreseeable future. Biotech investing can be gut-wrenchingly fickle, and investors may want to consider taking a basket approach to high-risk clinical-stage biotechs, rather than investing too heavily in a single player.