Busulfan

iStock, PhonlamaiPhoto Beam Therapeutics and Verve Therapeutics have each built their lead candidates on a technique billed as a safer alternative to conventional CRISPR. Clinical results have so far been promising. Nine years ago this month, researchers led by Harvard University’s David Liu reported on a new gene editing technique, a variation on CRISPR/Cas9 that they dubbed base editing. Today, preliminary but encouraging results are trickling out from clinical trials on the first base editing therapies. Just last month, Beam Therapeutics announced that its candidate BEAM-302 can correct the disease-causing mutation in patients with alpha-1 antitrypsin deficiency. Weeks later, Verve Therapeutics released initial results from a Phase Ib trial showing that its VERVE-102 gene therapy reduced LDL cholesterol levels by half, on average, in four participants who received the highest dose. “I think the prospects and outlook [for base editing] look very positive right now,” Sami Corwin, an analyst at William Blair, told BioSpace . “We’ve seen it de-risked in three indications so far”—AATD, familial hypercholesterolemia and sickle cell disease (SCD). Beam owns the intellectual property behind base editing and, so far, has only licensed it to Verve, Beam President Giuseppe Ciaramella told BioSpace . But that may change: “Once you show success, I’m sure there are going to be some other companies that are going to be trying to use base editing to essentially do their own product,” he said. Base Editing Basics With CRISPR/Cas9 gene editing, researchers construct a guide RNA (gRNA) complementary to a targeted stretch of DNA. The gRNA is tethered to a Cas9 enzyme that snips a double-stranded break at the target, which is then repaired by the cell’s own machinery. It’s a process that carries risks, including that off-target breaks could be created and that breaks may not be properly repaired, creating unwanted mutations. “The problem is that [with] all of the nucleases, the only thing that they could do when they landed on the spot of DNA was making a double-stranded break, and . . . basically everything else is now left to the cell to sort out,” Ciaramella said. Double-stranded breaks “need to occur only under very controlled conditions when the cells are replicating because otherwise they can lead to all sorts of unpredictable editing outcomes.” The only CRISPR/Cas9-based therapy approved so far, Vertex and CRISPR Therapeutics’ Casgevy, relies on extracting bone marrow cells from a patient with SCD and editing them outside the body to disable a gene that suppresses production of fetal hemoglobin. The cells are then expanded and transplanted back into the patient, where they produce red blood cells with fetal hemoglobin as a stand-in for the adult hemoglobin that’s mutated in the disease. Casgevy is also approved for transfusion-dependent beta thalassemia. Base editing, like the original CRISPR/Cas9, uses a gRNA. However, it leverages a modified Cas9 that, rather than creating a double-strand break in the DNA, can chemically change an adenosine (A) base to a guanine (G) or a cytosine (C) to a thymine (T). Researchers can target either the coding DNA strand or its complementary partner for these edits, Ciaramella noted, which opens up more possibilities. “Essentially, we can achieve four edits with the two base editors that we’ve got.” Base editing is “actually much more versatile than maybe even people anticipated at the beginning,” when it was viewed mainly as a way to correct point mutations, Ciaramella added. For example, by making a change in the regulatory rather than the coding region of a gene, researchers can activate that gene. Beam: Running the Gamut After his group devised base editing, Liu and CRISPR pioneer Feng Zhang co-founded Beam specifically to develop therapeutics based on the technique. The company emerged from stealth in 2018 with $87 million in series A funding. The company has not confined itself to particular kinds of disorders or means of delivery. It has both in vivo and ex vivo programs for SCD and beta thalassemia alongside in vivo programs in alpha-1 antitrypsin deficiency (AATD) and glycogen storage disease 1a (GSD1a). Beam also has collaborations with Apellis and Pfizer, about which it’s revealed little. The candidate at the center of Beam’s March 10 announcement , BEAM-302, corrects a mutation that causes the body to produce a form of the AAT protein known as Z-AAT rather than the functional form, M-AAT. Z-AAT has deleterious effects on both the lungs and liver. BEAM-302 delivers base editing machinery to the liver, where AAT is made, via lipid nanoparticles. At sites in Australia, New Zealand, the Netherlands and the U.K., the company tested single intravenous doses of 15 mg, 30 mg and 60 mg in three-patient cohorts and found dose-dependent, durable increases in total AAT and decreases in Z-AAT, along with only minor adverse events. Total circulating AAT levels were high enough in the highest-dose group that those patients can be considered to no longer have progressive disease, Ciaramella said. He added, however, that these were only interim results and that the company is testing higher doses and considering redosing some patients. The AATD data “confirmed that the sensitivity and efficacy of the base editing technology was there,” Corwin said. Since the treatment was well-tolerated even at higher doses, the readout also suggested that an inflammatory response to another base editing candidate reported earlier by Verve was due to the lipid nanoparticle vehicle rather than the base editing machinery itself, she added. Other analysts also took note. Jefferies’ Michael Yee said in a note to investors that “safety has been a major area of focus in the context of issues from other LNP products for gene editing,” but that “BEAM safety looks clean.” He added that BEAM-302 “looks to have important benefits that differentiate from RNA editing and plasma-derived AAT therapy. . . . [W]e are seeing ‘correction’ of the disease with a one-time therapy.” With another program, Beam is seeking to set itself apart in the sickle cell disease space. Both bone marrow transplants and Casgevy treatment require patients to undergo a course of the chemotherapy drug busulfan to open up space in the marrow for the new blood-making cells that will be introduced. The treatment has side effects, including the possibility of impaired fertility. Beam’s ex vivo SCD candidate, BEAM-101, edits cells so that not only is fetal hemoglobin production switched on, but a receptor is tweaked to confer resistance to an antibody Beam devised. Rather than busulfan, patients are treated with the antibody, which starves unedited bone marrow cells of a growth factor needed to proliferate. “We can confer advantages of survival to the edited cells over unedited cells simply by changing a single amino acid in this receptor,” Ciaramella said. Beam presented positive safety and efficacy data on the first seven patients treated with BEAM-101 in a U.S.-based study at the American Society of Hematology meeting in December. Verve: A Focus on the Heart Boston-based Verve’s origin story begins with a competition entry that wasn’t selected, said CEO and co-founder Sek Kathiresan. The 2016 contest, run by the American Heart Association, promised $75 million in funding for an idea to tackle coronary heart disease. Kathiresan, then a professor at Harvard Medical School and director of Massachusetts General Hospital’s Center for Genomic Medicine, said he took inspiration from natural mutations that keep cholesterol levels low and thus protect people carrying the mutations from developing heart disease. Kathiresan wanted to develop a therapy that mimicked natural protective mutations. “The proposal was really: well, we understand what causes disease, which is cholesterol. We know a key way to stop this disease, which is to get cholesterol down and keep it down for a long time,” he told BioSpace . When the application was turned down, he forged ahead anyway, gathering the investors and initial team needed to found Verve in 2018. The company tested both base editing and traditional CRISPR/Cas9 on target genes in preclinical research, and “what ultimately led us to choose base editing was the possibility of it being a fair bit safer because it did not cut DNA in both strands, but rather just tried to make the single spelling change A to G at one spot,” he said. The editing was also precise: “we’re not really seeing any off targets elsewhere in the genome.” But for another of its programs, Verve settled on a different gene editor because it found base editing wasn’t the most effective way forward. The company now has three base editors in clinical trials, although the trial of VERVE-101 was paused last April after one patient developed grade 3 drug-induced thrombocytopenia within days of dosing. Verve, like Corwin, has since attributed those abnormalities to the lipid nanoparticle vector. Verve said at the time that it would instead prioritize VERVE-102, which like VERVE-101 treats heterozygous familial hypercholesterolemia, a genetic propensity to high cholesterol. VERVE-102 uses a different lipid nanoparticle from VERVE-101 that targets the PCSK9 gene for inactivation in liver cells. Last month, Verve announced IND clearance for VERVE-102 based on initial clinical data from outside the U.S. showing the therapy was well-tolerated. In its April 14 press release , the company reported a dose-dependent response and no serious adverse events in a Phase Ib trial, with a maximum LDL cholesterol reduction of 69% in the highest-dose cohort. Verve is now testing a still-higher dose and plans to begin a Phase II trial in the second half of this year, per its announcement. Meanwhile, VERVE-201, which targets the ANGPTL3 gene in liver cells, is in trials for the homozygous version of the condition as well as for patients whose hypercholesterolemia is not responding to other therapies. The first patient was dosed with VERVE-201 in a Phase Ib trial in Canada and the U.K. in November 2024. Getting this far has required breaking new ground in a few ways, Kathiresan said, from devising the mRNA and gRNA that would go into treatments to interfacing with the FDA. “We were actually the first to go in front of the U.S. FDA and propose in vivo gene editing in humans,” he notes, as other companies in the space have so far run their early trials in other countries, just as Verve did for VERVE-102. Gene editing and other gene therapies are usually associated with rare disease, often those with no other effective treatments. High cholesterol is both common and treatable, but Kathiresan argued gene editing could nonetheless fill an important unmet need. “Theoretically, current medicines can lower LDL at a single time point [by] 40, 50, 60%. . . . But the challenge is discontinuation. A year out after starting any cardiovascular medication, a third to 50% of people have discontinued,” he said. In contrast, with base editing, “you basically lower LDL and then keep it low for your whole life. And that can really have a dramatic impact on your risk for heart attack.” Ultimately, though, Kathiresan characterized base editing not as a silver bullet but as one tool companies can consider. “I think base editing will have a place. . . . But there will be other technologies as well that I think may be even better suited for a given target,” he said. “So I think right now the focus is really on the targets and the disease indications, and then, at least for us, finding the right gene editing tool for that target.”