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'Breakthrough' CRISPR Treatment Slashes Cholesterol In First Human Clinical Trial

CRISPR-based therapies just hit another milestone.

In a small clinical trial with 10 people genetically prone to dangerously high levels of cholesterol, a single infusion of the precision gene editor slashed the artery-clogging fat by up to 55 percent. If all goes well, the one-shot treatment could last a lifetime.

The trial, led by Verve Therapeutics, is the first to explore CRISPR for a chronic disease that's usually managed with decades of daily pills. It also marks the first use of a newer class of gene editors directly in humans. Called base editing, the technology is more precise—and potentially safer—than the original set of CRISPR tools. The new treatment, VERVE-101, uses a base editor to disable a gene encoding a liver protein that regulates cholesterol.

To be clear, these results are just a sneak peek into the trial, which was designed to test for safety, rather than the treatment's efficacy. Not all participants responded well. Two people suffered severe heart issues, with one case potentially related to the treatment.

Nevertheless, "it is a breakthrough to have shown in humans that in vivo [in the body] base editing works efficiently in the liver," Dr. Gerald Schwank at the University of Zurich, who wasn't involved in the trial, told Science.

Give Your Heart a Break

CRISPR has worked wonders for previously untreatable cancers. Last week, it was also approved in the United Kingdom for the blood diseases sickle cell and beta thalassemia.

For these treatments, scientists extract immune cells or blood cells from the body, edit the cells using CRISPR to correct the genetic mistake, and reinfuse the treated cells into the patient. For edited cells to "take," patients must undergo a grueling treatment to wipe out existing diseased cells in the bone marrow and open space for the edited replacements.

Verve is taking a different approach: Instead of isolating cells for gene editing, the tools are infused into the bloodstream where they edit genes directly inside the body. It's a big gamble. Most of our cells contain the same DNA. Once injected, the tools could go on a rampage and edit the targeted gene throughout the body, causing dangerous side effects.

Verve tackled this concern head on by pairing base editing with nanoparticles.

The trial targeted PCSK9, a liver protein that keeps low-density lipoprotein (LDL), or "bad cholesterol," levels at bay. In familial hypercholesterolemia, a single mutated letter in PCSK9 alters its function, causing LDL levels to grow dangerously. People with this inherited disorder are at risk of life-threatening heart problems by the age of 50 and need to take statin drugs to keep their cholesterol in check. But the lifelong regime is tough to maintain.

A Targeted CRISPR Torpedo

Verve designed a "one-and-done" treatment to correct the PCSK9 mutation in these patients.

The therapy employs two key strategies to boost efficacy.

The first is called base editing. The original CRISPR toolset acts like scissors, cutting both strands of DNA, making the edit, and patching the ends back together. The process often leaves room for mistakes, such as the unintended rearranging of sequences that could turn on cancer genes, leading some experts to call it "genetic vandalism." Base editing, in contrast, is far more precise. Like a scalpel, base editors only nick one DNA strand, and are therefore far less likely to injure non-targeted parts of the genome.

Verve's treatment encodes the base editor in two different RNA molecules. One instructs the cells to make the components of the gene editing tool—similar to how Covid-19 vaccines work. The other strand of RNA guides the tool to PCSK9. Once edited, the treated gene produces a shortened, non-functional version of the faulty protein responsible for the condition.

The delivery method also boosts efficacy. Base editing components can be encoded into harmless viruses or wrapped inside fatty nanoparticles for delivery. Verve took the second approach because these nanoparticles are often first shuttled into the liver—exactly where the treatment should go—and are less likely to cause an immune reaction than viruses.

There's just one problem. Base editing has never been used to edit genes in the body before.

A non-human trial in 2021 showed the idea could work. In macaque monkeys, a single shot of the editor into the bloodstream reduced the gene's function in the liver, causing LDL levels to drop 60 percent. The treatment lasted at least eight months with barely any side effects.

Safety First

The new trial built on previous results to assess the treatment's safety in 10 patients with familial hypercholesterolemia. One patient dropped out before completing the trial.

The team was careful. To detect potential side effects, six patients were treated with a small dose unlikely to reverse the disorder.

Three patients received a higher dose of the base editor and saw dramatic effects. PCSK9 protein levels in their livers dropped between 47 and 84 percent. Circulating LDL fell to about half its prior levels—an effect that lasted at least six months. Follow-ups are ongoing.

The efficacy of the higher dose came at a price. At lower doses, the treatment was well tolerated overall with minimal side effects. But at higher doses, it seemed to temporarily tax the liver, bumping up markers for liver stress that gradually subsided.

More troubling were two severe events in patients with advanced heart blockage. One person receiving a low dose died from cardiac arrest about five weeks after the treatment. According to a review board, the death was likely due to underlying conditions, not the treatment.

Another patient infused with a higher dose suffered a heart attack a day after treatment, suggesting the episode could have been related. However, he had intermittent chest pains before the infusion that hadn't been disclosed to the team. His symptoms would have excluded him from the trial.

A Promising Path

Overall, an independent board monitoring data and safety determined the treatment safe. Still, there are plenty of unknowns. Like other gene editing tools, base editing poses the risk of off-target snips—something this trial did not specifically examine. Long-term safety and efficacy of the treatment are also unknown.

But the team is encouraged by these early results. "We are excited to have reached this milestone of positive first-in-human data supporting the significant potential for in vivo liver gene editing as a treatment for patients with [familial hypercholesterolemia]," said Dr. Sekar Kathiresan, CEO and cofounder of Verve.

The trial was conducted in the United Kingdom and New Zealand. Recently, US regulators approved the therapy for testing. They plan to enroll roughly 40 more patients.

Meanwhile, a new version of the therapy, VERVE-102, is already in the works. The newcomer uses a similar base editing technology and an upgraded nanoparticle carrier with potentially better targeting.

If all goes well, the team will launch a randomized, placebo-controlled trial by 2025. So far, the company hasn't released a price tag for the therapy. But the cost of existing gene therapies can run into the millions of dollars.

To Kathiresan, treatments like this one could benefit more than patients with familial hypercholesterolemia. High cholesterol is a leading health problem. A dose of the base editor in middle age could potentially nip cholesterol buildup in the bud—and in turn, lower risk of heart disease and death.

"That's the ultimate vision," he said.

Image Credit: Scientific Animations / Wikimedia Commons

Minimizing Terms For Toxicity Often Used In Multiple Myeloma Trials, Study Says

A cohort study of 65 clinical trials in multiple myeloma found that toxic effects are often described with subjective terminology that may not reflect adverse event rates reported in the studies.

A study published in JAMA Network Open found that clinical trials in multiple myeloma regularly use minimizing language to describe adverse events (AEs). The use of such terminology may not reflect actual AE rates, and investigators should instead highlight AE rates and patient-reported outcomes (PROs) instead to allow clinicians and patients to evaluate tolerability, according to the authors.

While there has been significant progress in the treatment of multiple myeloma, relapse remains common, and patients usually require ongoing, long-term treatment to manage the disease. Multiple myeloma therapies can carry substantial toxicity profiles that can negatively impact quality of life, and these toxicities become increasingly important given the long-term maintenance therapy that is often needed in this patient population.

Patient in the hospitalImage credit: Tyler Olson -stock.Adobe.Com

The authors noted that efficacy and safety are usually reported in peer-reviewed articles and at scientific meetings, but that efficacy is often assessed preliminarily in single-group, phase 2 trials. The way these trials are reported is crucial, as is the ability to accurately compare and understand the safety profiles from the patient decision-making perspective as more therapies become available. Researchers added that PROs are the best gauge of whether a therapy's AE profile is tolerable from the patient standpoint.

"Clinical trial investigators may increasingly use phrases that seek to minimize toxic effects, which we refer to as minimizing terms, when reporting clinical trial safety results. Terms such as tolerable, manageable, and safe may be used in a subjective fashion that may not reflect the actual toxic effects of these interventions," the authors wrote. "In the absence of PROs, minimizing terms also may not reflect patient perceptions of whether these side effects are indeed tolerable or manageable."

To the authors' knowledge, their analysis is the first to assess the use of minimizing terms in a cohort or randomized clinical trials (RCTs). The study included 65 RCTs published from 2015 through early 2023 and aimed to determine the prevalence of minimizing terms as well as the characteristics of the trials that used them.

A total of 56 studies in the cohort (86%) used minimizing terms, with the most common being "well-tolerated" or "tolerable," which were seen in 29 trials (45%). Further, trials often used "manageable" (28%), "acceptable" (25%), "expected" (23%), "safe" (23%), "favorable" (17%), and "convenient" (14%).

In terms of specific toxicities vs general safety profiles, 44 (78%) of the trials used at least 1 minimizing term to refer to the toxicity profile in general, 11 (20%) described both the general toxicity and a specific toxic effect with minimizing terms, and just 1 trial (2%) used minimizing language to describe a specific toxic effect alone.

The rate of serious adverse events (SAEs) among 38 trials that reported SAEs ranged from 19% to 66%, with a median of 48% (IQR, 35%-56%). In 33 of those trials, at least 1 minimizing term was used (median SAE rate, 48% [IQR, 34%-55%]). In 5 trials (13%), no minimizing terms were used (median SAE rate, 47% [IQR, 45%-63%]).

The rates of grade 3 or 4 AEs ranged from 23% to 94% in 37 trials that reported the overall frequency of grade 3 or 4 AEs. The median frequency of grade 3 or 4 AEs was 75% (IQR, 59%-82%), and 31 of these trials (84%) used at least 1 minimizing term (median grade 3 or 4 AE rate, 75% [IQR, 63%-82%]). Among the trials reporting grade 3 or 4 AEs, 6 (16%) did not use minimizing language (median grade 3 or 4 AE rate, 57% [IQR, 36%-78%]).

In a univariate analysis, there was no statistically significant association between the use of minimizing terminology and the rate of grade 3 or 4 AEs (OR, 1.35 per 10% AE rate increase; 95% CI, 0.88-2.10; P = .17). There was also no statistically significant association between the rate of grade 5, or fatal, AEs, and minimizing language use. An association was seen between the use of at least 1 minimizing term and whether a trial was industry sponsored, however (OR, 5.68; 95% CI, 1.05-41.0; P  = .03).

The study was limited in that it only analyzed RCTs, with authors noting that the use of minimizing terms may be more common in early-phase trials or conference presentations, which should also be evaluated. The statistical power of the analysis was also limited because many studies did not report SAE rates or total grade 3 or 4 AE rates.

"In this cohort study, we observed that trial investigators and sponsors regularly used minimizing terms to describe toxic effects in MM trials, especially in industry-sponsored studies, and this descriptive terminology did not reflect the actual rates of severe AEs or deaths in these trials," the authors concluded. "Instead of using these terms, trial investigators should highlight event rates and PROs to allow clinicians and patients to better evaluate the true tolerability of AEs."

Reference

Najjar M, McCarron J, Cliff ERS, et al. Adverse event reporting in randomized clinical trials for multiple myeloma. JAMA Netw Open. Published online November 10, 2023. Doi:10.1001/jamanetworkopen.2023.42195

Remote Ischemic Conditioning In Acute Stroke: A Disheartening Verdict From Rigorous Trials

In the relentless pursuit of groundbreaking stroke treatments, the medical community has explored various avenues, including remote ischemic conditioning (RIC). Initial excitement surrounded RIC with promising preclinical and clinical data suggesting its potential efficacy. However, a recent comprehensive clinical trial has challenged these optimistic expectations, dealing a significant blow to the hopes of revolutionizing acute stroke care.

RIC is a simple and noninvasive procedure involving transient cycles of limb ischemia and reperfusion on the upper extremity leading to distant organ protection in preclinical and clinical studies. The early effects exhibit enhanced collateral blood flow in the ischemic area and reduced post-stroke inflammation. Previous studies showed significantly improved functional outcomes in acute ischemic stroke. However, due to some uncertainty Danish researchers conducted a randomized, sham-controlled, multicenter clinical trial to determine whether combined prehospital and in-hospital RIC treatment improves functional outcomes in patients with acute ischemic and hemorrhagic stroke.

The trial, conducted from March 2018 to November 2022, enrolled 1,500 patients with prehospital stroke symptoms lasting less than four hours. The study aimed to assess the impact of RIC initiated in the prehospital setting and continued in the hospital. Patients were randomly divided into two groups: one receiving RIC treatment and the other a sham treatment. The primary measure of success was an improvement in functional outcomes, evaluated on the modified Rankin Scale (mRS), 90 days post-stroke.

Findings:

The results, however, were far from what researchers and medical professionals had hoped for. Among the 902 stroke-diagnosed patients, RIC failed to significantly enhance functional outcomes at the critical 90-day mark.

The mRS scores revealed no substantial difference between the group that received RIC (mRS score at 90 days was 2) and the one subjected to the sham treatment (mRS score at 90 days was 1).

Moreover, both groups experienced a similar number of serious adverse events (RIC vs Sham 169 vs 175), indicating that RIC did not provide a safer alternative.

Interestingly, upper extremity pain during treatment and skin petechia were notably higher in the RIC group, highlighting the discomfort associated with this intervention.

Thus, this study deals a significant blow to the hopes pinned on RIC as a groundbreaking stroke treatment. Despite its promise in prior studies, the meticulous scrutiny of a randomized clinical trial has shown that RIC, when initiated in the prehospital phase and sustained in the hospital, does not yield meaningful improvements in stroke patients' functional outcomes.

Further reading: Blauenfeldt RA, Hjort N, Valentin JB, et al. Remote Ischemic Conditioning for Acute Stroke: The RESIST Randomized Clinical Trial. JAMA. 2023;330(13):1236–1246. Doi:10.1001/jama.2023.16893

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