Thalassemia

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.”

– U.S. Regulatory Filing Under Active Review for Approval of PYRUKYND® (mitapivat) in Thalassemia, with PDUFA Goal Date of September 7, 2025 – – Phase 3 RISE UP Study of Mitapivat in Sickle Cell Disease On Track, with Topline Results Expected in Late 2025; Potential U.S. Commercial Launch in 2026 – – Tebapivat Advancing in Clinical Trials for Lower-Risk Myelodysplastic Syndromes (LR-MDS) and Sickle Cell Disease – – PYRUKYND Net Revenue of $8.7 Million in Q1; Cash, Cash Equivalents and Marketable Securities of $1.4 Billion as of March 31, 2025 – CAMBRIDGE, Mass. , May 01, 2025 (GLOBE NEWSWIRE) -- Agios Pharmaceuticals, Inc. (Nasdaq: AGIO), a leader in cellular metabolism and pyruvate kinase (PK) activation pioneering therapies for rare diseases, today reported business highlights and financial results for the first quarter ended March 31, 2025 . “We are pleased with our strong start to 2025, highlighted by the acceptance of our sNDA for thalassemia with a PDUFA goal date of September 7, 2025 . Our engagement with the FDA is progressing as expected, and we are committed to bringing PYRUKYND to thalassemia patients, irrespective of genotype or transfusion needs,” said Brian Goff , chief executive officer at Agios. “Looking ahead, our focus is also on delivering the topline results from the Phase 3 RISE UP study in sickle cell disease, which remains on track for year-end, and continuing to advance our early and mid-stage clinical programs. Supported by our strong financial position and highly experienced team, we are driving forward PYRUKYND’s multi-billion-dollar potential while building a pipeline designed for lasting impact, with the goal of creating significant value for shareholders and delivering transformative therapies for patients.” First Quarter 2025 and Recent Highlights PYRUKYND® Revenues: Generated $8.7 million in net revenue for the first quarter of 2025, compared to $8.2 million in the first quarter of 2024. A total of 234 unique patients have completed prescription enrollment forms, representing an increase of 5 percent over the fourth quarter of 2024. A total of 136 patients are on PYRUKYND therapy, inclusive of new prescriptions and continued therapy, as compared to 130 patients at the end of the fourth quarter 2024. Thalassemia: The U.S. Food and Drug Administration (FDA) accepted the company’s supplemental New Drug Application (sNDA) for PYRUKYND for the treatment of adult patients with non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia. The Prescription Drug User Fee Act (PDUFA) goal date is September 7, 2025. The FDA has communicated that at this time no advisory committee meeting is planned, and the review is ongoing. Sickle Cell Disease: The Phase 3 RISE UP study evaluating mitapivat for the treatment of sickle cell disease patients who are 16 years of age or older continued to progress as anticipated. This 52-week Phase 3 study completed enrollment in October 2024 , enrolling more than 200 patients worldwide. Advanced final preparations to initiate a Phase 2 clinical trial of tebapivat in patients with sickle cell disease in mid-2025. Pediatric Pyruvate Kinase (PK) Deficiency: Reported positive topline results from the ACTIVATE-Kids Phase 3 study of mitapivat in children aged 1 to <18 years with PK deficiency who are not regularly transfused. Safety was consistent with the profile for mitapivat previously observed in adults with PK deficiency who are not regularly transfused. ACTIVATE-Kids is the first study to demonstrate efficacy of an oral therapy for children with PK Deficiency who are not regularly transfused. Lower-risk Myelodysplastic Syndromes (LR-MDS): Progressed patient enrollment in the Phase 2b study of tebapivat in LR-MDS. Corporate: Krishnan Viswanadhan , Pharm. D, joined Agios as Chief Corporate Development and Strategy Officer, responsible for leading the company’s corporate strategy, business development, and long-term growth initiatives. Previously, he served as President and Chief Operating Officer of Be Biopharma and at various senior roles at both Bristol Myers Squibb and Celgene. The U.S. Food and Drug Administration (FDA) accepted the company’s supplemental New Drug Application (sNDA) for PYRUKYND for the treatment of adult patients with non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia. The Prescription Drug User Fee Act (PDUFA) goal date is September 7, 2025. The FDA has communicated that at this time no advisory committee meeting is planned, and the review is ongoing. The Phase 3 RISE UP study evaluating mitapivat for the treatment of sickle cell disease patients who are 16 years of age or older continued to progress as anticipated. This 52-week Phase 3 study completed enrollment in October 2024 , enrolling more than 200 patients worldwide. Advanced final preparations to initiate a Phase 2 clinical trial of tebapivat in patients with sickle cell disease in mid-2025. Reported positive topline results from the ACTIVATE-Kids Phase 3 study of mitapivat in children aged 1 to <18 years with PK deficiency who are not regularly transfused. Safety was consistent with the profile for mitapivat previously observed in adults with PK deficiency who are not regularly transfused. ACTIVATE-Kids is the first study to demonstrate efficacy of an oral therapy for children with PK Deficiency who are not regularly transfused. Progressed patient enrollment in the Phase 2b study of tebapivat in LR-MDS. Key Upcoming Milestones & Priorities Agios expects to achieve the following key milestones in 2025: Thalassemia: Receive FDA regulatory decision for PYRUKYND for the treatment of adult patients with non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia (PDUFA goal date is September 7, 2025). Continue progressing the review of regulatory applications with health authorities in the European Union , Kingdom of Saudi Arabia and United Arab Emirates . Sickle Cell Disease: Announce topline results from the Phase 3 RISE UP study of mitapivat in sickle cell disease in late 2025, with a potential U.S. commercial launch in 2026. Additionally, begin patient enrollment for the Phase 2 study of tebapivat in sickle cell disease in mid-2025. LR-MDS: Complete patient enrollment in the Phase 2b study of tebapivat for LR-MDS in late 2025. Early-Stage Pipeline: File an Investigational New Drug Application for AG-236, an siRNA targeting TMPRSS6 intended for the treatment of polycythemia vera, in mid-2025. First Quarter 2025 Financial Results Revenue: Net product revenue from sales of PYRUKYND for the first quarter of 2025 was $8.7 million , compared to $8.2 million for the first quarter of 2024. Cost of Sales: Cost of sales for the first quarter of 2025 was $1.1 million . Research and Development (R&D) Expenses: R&D expenses were $72.7 million for the first quarter of 2025, compared to $68.6 million for the first quarter of 2024. The year-over-year increase was primarily attributed to an increase in workforce-related expenses and costs associated with clinical trials of tebapivat in LR-MDS and sickle cell disease, partially offset by lower costs associated with the clinical trials of mitapivat in thalassemia and pediatric PKD. Selling, General and Administrative (SG&A) Expenses: SG&A expenses were $41.5 million for the first quarter of 2025 compared to $31.0 million for the first quarter of 2024. The year-over-year increase was primarily attributable to an increase in commercial-related activities, including headcount, as the company prepares for the potential approval of PYRUKYND in thalassemia. Net Loss: Net loss was $89.3 million for the first quarter of 2025 compared to $81.5 million for the first quarter of 2024. Cash Position and Guidance: Cash, cash equivalents and marketable securities as of March 31, 2025 , were $1.4 billion compared to $1.5 billion as of December 31, 2024 . Agios expects that its cash, cash equivalents and marketable securities, together with anticipated product revenue and interest income, will provide the financial independence to prepare for potential PYRUKYND launches in thalassemia and sickle cell disease, advance existing programs, and to opportunistically expand its pipeline through both internally and externally discovered assets. Conference Call Information Agios will host a conference call and live webcast today at 8:00 a.m. ET to discuss the company’s first quarter 2025 financial results and recent business highlights. The live webcast will be accessible on the Investors section of the company's website (www.agios.com) under the “Events & Presentations” tab. A replay of the webcast will be available on the company’s website approximately two hours after the event. About Agios Agios is the pioneering leader in PK activation and is dedicated to developing and delivering transformative therapies for patients living with rare diseases. In the U.S. , Agios markets a first-in-class pyruvate kinase (PK) activator for adults with PK deficiency, the first disease-modifying therapy for this rare, lifelong, debilitating hemolytic anemia. Building on the company's deep scientific expertise in classical hematology and leadership in the field of cellular metabolism and rare hematologic diseases, Agios is advancing a robust clinical pipeline of investigational medicines with programs in alpha- and beta-thalassemia, sickle cell disease, pediatric PK deficiency, myelodysplastic syndromes (MDS)-associated anemia and phenylketonuria (PKU). In addition to its clinical pipeline, Agios is advancing a preclinical TMPRSS6 siRNA as a potential treatment for polycythemia vera. For more information, please visit the company’s website at www.agios.com. Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding the potential benefits of PYRUKYND® (mitapivat), tebapivat, AG-236 and AG-181; Agios’ plans, strategies and expectations for its preclinical, clinical and commercial advancement of its drug development, including PYRUKYND®, tebapivat, AG-236 and AG-181; Agios’ use of proceeds from the transaction with Royalty Pharma; potential U.S. net sales of vorasidenib and potential future royalty payments; Agios’ strategic vision and goals, including its key milestones for 2025; and the potential benefits of Agios’ strategic plans and focus. The words “anticipate,” “expect,” “goal,” “hope,” “milestone,” “plan,” “potential,” “possible,” “strategy,” “will,” “vision,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from Agios’ current expectations and beliefs. For example, there can be no guarantee that any product candidate Agios is developing will successfully commence or complete necessary preclinical and clinical development phases, or that development of any of Agios’ product candidates will successfully continue. There can be no guarantee that any positive developments in Agios’ business will result in stock price appreciation. Management's expectations and, therefore, any forward-looking statements in this press release could also be affected by risks and uncertainties relating to a number of other important factors, including, without limitation: risks and uncertainties related to the impact of pandemics or other public health emergencies to Agios’ business, operations, strategy, goals and anticipated milestones, including its ongoing and planned research activities, ability to conduct ongoing and planned clinical trials, clinical supply of current or future drug candidates, commercial supply of current or future approved products, and launching, marketing and selling current or future approved products; Agios’ results of clinical trials and preclinical studies, including subsequent analysis of existing data and new data received from ongoing and future studies; the content and timing of decisions made by the U.S. FDA, the EMA or other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies; Agios’ ability to obtain and maintain requisite regulatory approvals and to enroll patients in its planned clinical trials; unplanned cash requirements and expenditures; competitive factors; Agios' ability to obtain, maintain and enforce patent and other intellectual property protection for any product candidates it is developing; Agios’ ability to establish and maintain key collaborations; uncertainty regarding any royalty payments related to the sale of its oncology business or any milestone or royalty payments related to its in-licensing of AG-236, and the uncertainty of the timing of any such payments; uncertainty of the results and effectiveness of the use of Agios’ cash and cash equivalents; and general economic and market conditions. These and other risks are described in greater detail under the caption "Risk Factors" included in Agios’ public filings with the Securities and Exchange Commission . Any forward-looking statements contained in this press release speak only as of the date hereof, and Agios expressly disclaims any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law. Contacts: Investor Contact Chris Taylor , VP, Investor Relations and Corporate Communications Agios Pharmaceuticals IR@agios.com Media Contact Eamonn Nolan , Senior Director, Corporate Communications Agios Pharmaceuticals media@agios.com Source: Agios Pharmaceuticals, Inc.

ToolGen commences legal action in UK court over Vertex's genome editing therapy, CASGEVY ® Seeks to expand licensing of its proprietary CRISPR RNP technology SEOUL, South Korea, April 21, 2025 /PRNewswire/ -- ToolGen, Inc. (KOSDAQ 199800), led by CEO Jong Sang Ryu and recognized as a global leader in genome editing technology, announced today that it has filed a patent infringement lawsuit in the United Kingdom against Vertex Pharmaceuticals and its commercial manufacturing partners, Lonza and RoslinCT, regarding Vertex's genome editing therapy CASGEVY. ToolGen has secured patents for CRISPR RNP (Ribonucleoprotein complex) worldwide including in Europe. CRISPR RNP represents a groundbreaking method that delivers the Cas9 protein directly into cells in its protein form. This approach avoids the cellular toxicity often associated with DNA- and mRNA-based systems and eliminates the risk of foreign DNA integration into the genome. With its significantly lower off-target effects providing superior safety profiles, the technology is now widely adopted in therapeutic development as well as in plant and animal genome editing. CASGEVY became the world's first genome editing therapy to receive marketing authorization, beginning with the United Kingdom in November 2023, followed by the European Commission (EC) in February 2024. It provides a novel treatment for patients with sickle cell disease and beta-thalassemia. The one-time treatment is reportedly priced at approximately £1.7 million (approx. $2.2 million USD), with sales projections indicating blockbuster potential. In December 2023, Vertex entered into a licensing agreement with Editas Medicine for CRISPR genome editing technology. ToolGen's CEO Jong Sang Ryu commented, "Vertex's CASGEVY was born from ToolGen's proprietary CRISPR RNP technology. As the company behind the world's first CRISPR Cas9-based gene therapy, we believe Vertex should fairly recognize ToolGen's contribution through appropriate licensing for the use of our CRISPR Cas9 and CRISPR RNP technologies in developing this innovative treatment." He continued, "This lawsuit is not aimed at restricting patient access to CASGEVY in the United Kingdom. Rather, it seeks to ensure ToolGen is properly acknowledged and rewarded through a fair licensing agreement." Logo - WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED