A cure for genetic diseases has been little more than a whisper — until now. Thanks to the work of companies using a technique known as CRISPR gene-editing, quick and permanent cures could be on the horizon for a host of illnesses. But concerns over acceptable risk may stand in the way of these CRISPR stocks.
The world is on the cusp of seeing the first gene-editing treatment hit the market that uses CRISPR. In September, Crispr Therapeutics — which takes its name from the technology — and Vertex Pharmaceuticals said they would begin jointly submitting their application for U.S. approval of a CRISPR-based drug later this year. If approved, it would treat a pair of rare, debilitating and deadly blood diseases.
Some say CRISPR technology shouldn't stop there. For example, it could help as many as 94 million people in the U.S. with elevated cholesterol levels that put them at risk of heart disease. That's the market targeted by CRISPR stock Verve Therapeutics, which hopes to permanently lower cholesterol levels by turning off a troublesome gene.
But others believe the potential hazards associated with a new technology aren't worth it. They say the cholesterol market is already saturated with treatments from established players such as Amgen and Regeneron Pharmaceuticals. Further, they warn of unforeseen effects that often come with experimental drugs. And in the case of CRISPR drugs, which use molecular "scissors" to cut and change DNA, a mistake could become permanent and open the door to future problems.
"Maybe the gene-editing drug is able to come in and do something the regular drugs cannot and maybe there is an additional benefit," independent biotech analyst Robert Toczycki told Investor's Business Daily. "But if the only benefit is that it's a one-and-done treatment? That's fantastically ridiculous."
Trying To Solve The Problem, Not Treat It
Verve Chief Executive Sekar Kathiresan disagrees, noting there are plenty of conventional treatments for high cholesterol.
"The problem we're trying to solve is a large problem and it remains a problem," Kathiresan told IBD. "It's not like the problem is solved just because treatments are available."
Verve is a standout name among CRISPR stocks. While most companies in the space are taking on rare genetic conditions, Verve is sprinting to the starting block with a huge, potential use case.
Kathiresan says there's no reason CRISPR can't go broad.
"Just because the patient population is not 1,000, but 1 million, that doesn't preclude us from applying a new technology," he said.
One CRISPR Stock Surges
Kathiresan's company went public in mid-2021 and, after hitting a low point alongside the broader market about a year later, Verve stock has since surged. Shares have a strong Relative Strength Rating of 91, putting their 12-month performance in the top 9% of all stocks, according to IBD data.
What drives that performance? Expectations for what could be among the biggest use cases for a CRISPR gene-editing drug. The Centers for Disease Control and Prevention says roughly 11% of people in the U.S. above the age of 20 had high cholesterol from 2015-18. The incidence is slightly higher in men.
Part of the problem is high cholesterol is asymptomatic, Kathiresan says. Cholesterol tests are included in routine blood work. But a third of U.S. adults haven't had a cholesterol test within the last five years, the CDC says. That's about how often healthy adults should be tested. High cholesterol can lead to myriad cardiovascular problems, including heart attack, stroke or death.
And only about half of people who could benefit from cholesterol medicine, like statins, are taking it. Amgen and Regeneron make PCSK9 inhibitors. These block the protein responsible for raising "bad" LDL cholesterol. But Amgen and Regeneron's injections haven't gotten wide use. Verve is eyeing the gene responsible for the PCSK9 protein.
Why CRISPR Gene-Editing Drugs Might Carve A Market
Biotech companies and investors in CRISPR stocks keep hammering away at the issue of drugs being on the market that carry side effects or don't completely resolve the problem. There is still an unmet need, they say.
That's particularly true for sickle cell disease and beta thalassemia. The two diseases are popular targets for the companies behind big-name CRISPR stocks because the genetic cause is well understood. Though there are treatments on the market, insiders at gene-editing companies say they're inadequate.
Global Blood Therapeutics, which Pfizer bought for $5.4 billion, makes a sickle cell drug called Oxbryta. Oxbryta lowers hemolysis — the speed at which the body destroys red blood cells — and improves anemia. This helps stave off painful attacks in sickle cell patients known as vaso-occlusive crises. Beta thalassemia patients often depend on regular blood transfusions.
But these are not cures. They are chronic medicines that can help patients live longer with less pain. Some patients can undergo a stem cell transplant, but those come with their own complications.
"There's a misunderstanding that the entire disease is just reducing pain and, if you can do that, it's the equivalent to a cure," Graphite Bio CEO Josh Lehrer said in an interview.
Even on treatment, patients with sickle cell are at a heightened risk of stroke, brain infarction or organ damage, he added. Graphite's latest-stage effort is in sickle cell treatment. The company is also going after beta thalassemia as well as alpha-1 antitrypsin deficiency, a condition that impacts the lungs and liver.
Current Drugs Offer Stopgap Measures
The same is true for amyloidosis and hereditary angioedema, says Intellia Therapeutics CEO John Leonard. In amyloidosis, an abnormal protein builds up on the nerves or heart, causing systemic problems. Patients with hereditary angioedema experience potentially deadly swelling attacks.
There are meds on the market for both. Pfizer's Vyndaqel treats the heart component of amyloidosis while Alnylam Pharmaceuticals makes Onpattro for the nerve side. Alnylam is also testing Onpattro in patients with the heart condition.
Meanwhile, BioCryst Pharmaceuticals sells Orladeyo while partners Ionis Pharmaceuticals and Takeda Pharmaceutical make Takhzyro for angioedema treatment.
They're all stopgap measures for patients, Leonard says.
"Existing therapies fall short," he said. "There are drugs approved for (amyloidosis), but patients do progress and die. In hereditary angioedema, responses (to current treatments) are incomplete."
Still, the CRISPR stock recently toppled after one Intellia patient with the nerve component of amyloidosis, called polyneuropathy, experienced severely elevated liver enzymes. The company notes this side effect was temporary. One of the patients suffering from the heart disease cardiomyopathy also reported a serious infusion-site reaction.
CRISPR Stocks Do The Benefit-Risk Math
It's important to make sure the benefit of CRISPR gene editing outweighs the risk, Graphite's Lehrer says.
"That is not true for every disease," he said.
To understand the benefit vs. risk profile in amyloidosis and hereditary angioedema, Intellia has been as "deliberately provocative" as possible in laboratory tests, CEO Leonard says. The company has tested big concentrations of its CRISPR gene-editing drugs and loosened the chemical bindings to see where they might end up in the body. The goal is to prove there aren't "off-target" effects of the platform.
Off-target, or unintended edits, could be catastrophic down the road — theoretically. CRISPR works by employing molecular "scissors" to cut DNA's double helix at strategic points. From there, the drug can turn a gene on or off, or change it. Then, the DNA is supposed to sew itself back up.
Critics say playing around with DNA is risky and can cause potentially permanent errors. Those errors could possibly lead a patient to develop cancer in the future.
CRISPR Gene-Editing Benefits Vs. Risk
That's where the benefit-risk analysis comes in, says Toczycki, the biotech analyst. Sickle cell patients might not live decades to develop cancer. The same may not be true for high cholesterol patients who are often well treated on statins.
But the risk remains theoretical. So far, there haven't been any off-target effects among the patients who've received Crispr and Vertex's drug. The duo has conducted the most advanced testing of a CRISPR gene-editing drug. Still, the technology is relatively new, having existed for just a decade.
Leonard says DNA's response to CRISPR drugs isn't as random as people tend to believe. He also notes Intellia hasn't seen any off-target effects.
"It's a very, very predictable, precise system," he said. "We have a very good idea of where the system might go well in advance of treating a patient. These drugs have been more highly tested and qualified at the genetic level than any other class of drugs in human beings. Obviously, time will tell and I think, as we go on, our confidence will only grow as to the adequacy of all that preclinical evaluation."
CRISPR Stocks Take A Stepwise Approach To Cholesterol
Beam Therapeutics Chief Executive John Evans says the company is trying to be thoughtful in how it looks at high cholesterol with partner Verve.
The companies are taking a stepped approach. The first treatment group includes patients with a genetic form of high cholesterol who have experienced a heart attack. Then, they will move into patients who don't regularly take their cholesterol meds. Eventually, they will move into patients merely at risk of developing high cholesterol.
"Patients still die of heart attacks despite all the agents we have," he told IBD. "The one-time cure aspect of these medicines is quite important. Patients often don't take their meds, they have trouble with them, there are all sorts of reasons why you might not be active. And, in the case of heart attacks, you're taking meds to try to prevent something that's uncertain decades away."
He added: "A single intervention that will permanently lower your risk makes a lot of sense for a lot of conditions, actually."
Going After Rare Diseases
Eventually, Evans says, he imagines treating more common diseases. But first, Beam is going after sickle cell disease and beta thalassemia, followed by forms of cancer, glycogen storage disease and other rare diseases. Glycogen storage disease occurs when the body can't break down a form of sugar, impacting the liver and muscles.
"We're clearly not going after acid reflux," a very common condition, he said. "There will be places we won't go with the technology soon or yet."
Editas Chief Medical Officer Baisong Mei notes the stepped approach is common in drug development. The same was the case of RNA drugs. Companies first demonstrated the approach works in patients who have "no choice."
That's where the benefit-risk profile is clear, he told IBD. Editas first tested its tech in patients with a blindness-causing disorder. It followed that up in sickle cell and beta thalassemia.
Misconceptions Around CRISPR Gene Editing
The cholesterol treatment that CRISPR stocks Verve and Beam are testing remains in its infant stage. The duo recently dosed a patient in New Zealand. But the FDA hasn't signed off on human testing in the U.S.
Evans acknowledges it could be an uphill battle for CRISPR gene-editing approaches to gain traction. In the case of Crispr and Vertex's first-generation sickle cell and beta thalassemia drug, patients must first undergo a conditioning regimen that can render them infertile. Next-generation efforts hope to do away with that piece of the gene-editing puzzle.
Over time, the Beam CEO thinks the delivery mechanism will improve. Kathiresan, Verve's CEO, calls the CRISPR gene-editing approach "surgery without the scalpel." It's a single change in a person's DNA for what these companies hope will be a lifelong benefit. It's like a cardiac stent for a heart disease patient.
Like Intellia's Leonard, Evans says there's a benefit-risk equation. The FDA and the companies behind the biggest CRISPR stocks have made an "incredible amount of progress." He says they have a "remarkable resolution" into what happens when gene editing takes place inside a cell.
There's also a notable erroneous understanding about CRISPR gene editing. The genome, he says, isn't a static, unchanging thing. In actuality, "it changes all the time, every time your cells divide," he said.
"I think already we're at the point where, if you had an off-target profile, the type of changes you're making are way less than the natural changes of the aging body," he said. "It's relatively easy to make a case for that being acceptable."
The Eventual Market For CRISPR Drugs?
It's tough to estimate the eventual market for CRISPR gene-editing drugs.
In a recent report, RBC Capital Markets analyst Brian Abrahams estimated the first-ever drug to use the technology, Crispr and Vertex's blood diseases medicine, could top out at $550 million in annual sales. A lot will depend on how the companies price the drug. Gene therapies — which similarly hope to offer one-time approaches to inherited disorders — have recently gone for $2 million-plus a pop.
Another RBC analyst, Gregory Renza, says the argument is always that genetic drugs "will eat the lunch of any chronic drug."
But he's not seeing that. Some patients will seek curative CRISPR gene-editing drugs and some will stick with older technology, he told IBD. How that shakes out will indelibly shape the future for CRISPR stocks.
"The curative potential is certainly fantastic," he said. "But I think it's a solution that's not for everybody. When it comes to irreversibility, yeah, I think some (people) can be less comfortable. There's a place for gene manipulation, especially because we have a responsibility to patients. But we have a responsibility to vet those."
Follow Allison Gatlin on Twitter at @IBD_AGatlin.
