Granulomatous Disease, Chronic

BOSTON--( BUSINESS WIRE )--Ensoma, a genomic medicines company advancing the future of medicine through one-time, in vivo treatments capable of precisely and durably engineering the hematopoietic system, today announced the U.S. Food and Drug Administration (FDA) has granted both rare pediatric disease and orphan drug designations to the company’s lead program, EN-374, for the treatment of X-linked chronic granulomatous disease (X-CGD). Ensoma anticipates it will submit an investigational new drug application (IND) for EN-374 in the first half of 2025. Chronic granulomatous disease (CGD) is a rare and severe genetic disorder, which significantly impairs the immune system. It leaves patients vulnerable to recurrent and severe bacterial and fungal infections, often leading to chronic and life-threatening dysregulated inflammation and serious complications. CGD affects approximately 1 in 100,000-200,000 live births, and the median life expectancy for individuals with the condition is around 45 years. X-CGD is the most common form of the condition, affecting 60-70% of CGD patients, and is caused by mutations in the CYBB gene that prevent white blood cells called neutrophils from fighting infection. EN-374 is designed to treat X-CGD through the delivery of a functional CYBB gene directly to hematopoietic stem cell (HSCs) in vivo . It uses a promoter for selective expression in neutrophils, the primary cell type affected by X-CGD. Successful expression will restore patients’ ability to fight infection. “These designations from the FDA highlight the significant medical need in chronic granulomatous disease,” said Drew Dietz, M.D., MSCR, vice president of clinical development at Ensoma. “Current treatments, including antibiotics, antifungals, interferon gamma and allogeneic stem cell transplantation, offer limited benefit and/or come with significant burdens. EN-374 represents the first in vivo HSC-directed therapy for X-CGD, building on a mechanism that has been validated ex vivo . Designed to function for any CYBB mutation, this approach offers the potential to improve upon transformative benefits of ex vivo gene therapies in a way that’s simpler, potentially safer and more accessible for patients. Our team is incredibly proud to be at the forefront of advancing this groundbreaking therapy. We remain on track to submit an IND in the first half of this year.” Rare pediatric disease designation is granted by the FDA to incentivize development of treatments for serious or life-threatening rare diseases that primarily affect children aged 18 years or younger and impact fewer than 200,000 people in the U.S. If a Biologics License Application for EN-374 is approved in the U.S., Ensoma may be eligible to receive a Priority Review Voucher from the FDA. Orphan drug designation is granted by the FDA to products that prevent, diagnose or treat a rare disease or condition affecting fewer than 200,000 people in the U.S. The designation affords Ensoma the potential for certain benefits, including up to seven years market exclusivity after approval, tax credits for qualified clinical trials and exemption from certain FDA fees. About Ensoma Ensoma is developing curative medicines through precision in vivo cellular engineering. Our platform combines class-leading proprietary base editing and high-efficiency gene integration systems with high-capacity virus-like particles (VLPs) to provide one-time and durable genetic medicines in an outpatient procedure. We are focused on in vivo engineering of hematopoietic stem cells (HSCs) to address genetic diseases, immune disorders and cancer. Ensoma is supported by top-tier investors and a passionate team committed to a bold, global vision for genomic medicines. Ensoma is based in Boston. For more information, visit ensoma.com .

SAN DIEGO — New and experimental gene therapies made with blood stem cells rely on the same grueling, decades-old methods for a process called conditioning that’s used for bone marrow transplants. It’s a regimen typically consisting of intense chemotherapy that helps clear space in the bone marrow but can come with serious side effects like sores, infertility and an all-around terrible experience for patients. A handful of companies are trying to lessen that burden using gene editing. In new preclinical research at the American Society of Hematology annual meeting this weekend, Beam Therapeutics and Prime Medicines — both founded by the Broad Institute’s David Liu — posited they can add a new edit to their ex vivo gene therapies and combine it with an antibody to remove chemotherapy from the conditioning regimen entirely. For Beam, whose base-editing (“CRISPR 2.0”) programs are farther along, the idea is closest to fruition in treating sickle cell disease — though likely still several years away from reaching patients. For Prime, which uses prime editing (“CRISPR 3.0”), the future is even murkier as the company is focusing on getting its earlier programs into the clinic first. But the appeal is enticing for both patients and biopharma companies. In Beam’s clinical trial of a gene-edited sickle cell treatment, a patient died from respiratory failure likely related to conditioning with the chemotherapy busulfan, underscoring the need for new approaches. Beam CEO John Evans told Endpoints News the potential could not only make such gene therapies more safe and tolerable for patients, but also significantly expand the number of sickle cell patients that are able to be treated. The current therapies are approved only for severe sickle cell patients where the benefits of undergoing treatment outweigh the risks, many of which are tied to conditioning. “We conservatively estimate quadrupling the number of patients to about 40,000,” Evans said. “In reality, there may not be an upper limit.”’ The central theory involves CD117, also known as c-kit, which is expressed in most blood stem cells. An antibody directed at CD117 would act as the conditioning agent in place of busulfan, and the hope is that it would be gentler and safer for patients. Beam and Prime are then adding an additional gene edit to their therapies so the antibody doesn’t bind to the therapeutic cells, in hopes that it will effectively hide them from the conditioning antibody. Beam alongside the NIH has tested this approach in three non-human primates thus far, first giving the conditioning antibody and then the experimental sickle cell therapy, followed by additional rounds of the antibody. The company said that the researchers did not see any of the severe side effects of busulfan conditioning and saw “only minor decline in neutrophil counts and platelet levels.” Early results also showed hemoglobin levels increased by 50% through at least six months — reaching the milestone needed to have confidence the therapeutic cells will stick long-term, Evans said. Harvard stem cell researcher David Scadden, who co-founded a company called Magenta Therapeutics that tried to develop a gentler conditioning agent targeting CD117 in an antibody-drug conjugate, noted there hasn’t been an approved c-kit antibody before. It could potentially complicate the development process, and Magenta had to stop its study following a patient death and merged with another company in 2023. But so far, everything Beam is doing seems to look safe and effective. “It looks like they’ve been able to demonstrate proof-of-principle for this working. And so it’s encouraging as a way to try to reduce the complexity for the patient of having to get conditioning for a gene modified ex vivo cell therapy,” Scadden said. Scadden added that using just an antibody without an additional warhead may be less potent, and pointed out that Beam had to use multiple rounds of their antibody for the cells to be engrafted at high efficiency. And like Magenta, CRISPR Therapeutics, which alongside Vertex Pharmaceuticals developed one of the first approved sickle cell gene therapies Casgevy, is also researching a CD117-targeted antibody-drug conjugate in preclinical studies. Prime is still in mice testing, chief scientific officer Jeremy Duffield told Endpoints, and presented new results at ASH testing the antibody with its lead program for a rare genetic condition called p47phox chronic granulomatous disease. Eventually, Duffield envisions a future where the antibody could be given multiple times if the transplant starts to lose engraftment, or even give patients the gene therapy before an antibody conditioning regimen. “You don’t need to do this sequentially. You can imagine this is a big advantage,” Duffield said. “Of course, you don’t need to wipe out the bone marrow and then put cells back. You can actually put cells back and then add the antibody.” While there are some differences between the two companies’ approaches — Beam will use base editing and Prime will use prime editing, plus the designs of the antibodies are different — the central theory remains similar. And both agree that accomplishing something of this magnitude is not something that will happen overnight. Gene editing companies are also trying to develop in vivo gene editing treatments that could do away with the need for conditioning altogether, but those approaches may be even further down the line. At ASH, Tessera Therapeutics reported that it saw 24% hemoglobin editing in non-human primates. “It’s easy to say you want to change conditioning, but it’s a different thing to actually do it. And there’s been some great companies that have been focused on this for some time,” Evans said. “So it’s not like a new insight that we want to get rid of chemotherapy in transplants, the question is, how would you do it?”

-- Presented initial in vivo data for universal liver-targeted LNP and Wilson’s Disease program at ESGCT; initiated IND-enabling activities for Wilson’s Disease program in 4Q 2024 and remains on track to file IND and/or CTA in 1H 2026 -- -- Announced strategic research collaboration and license agreement with Bristol Myers Squibb; received $110 million upfront, with potential for more than $3.5 billion in milestone payments -- -- On track to report initial data from Phase 1/2 clinical trial of PM359 for p47phox CGD in 2025 -- -- Unveiled strategically focused pipeline, prioritizing set of high value programs, each with a clearly defined path to value creation and the potential to accelerate development of follow-on programs -- -- Pro-forma cash, cash equivalents and investments as of September 30, 2024, expected to be sufficient to fund planned operations into 1H 2026 -- CAMBRIDGE, Mass., Nov. 12, 2024 (GLOBE NEWSWIRE) -- Prime Medicine, Inc. (Nasdaq: PRME), a biotechnology company committed to delivering a new class of differentiated one-time curative genetic therapies, today reported financial results for the third quarter ended September 30, 2024 and provided a business update. “In October, we presented the first in vivo preclinical data from our Wilson’s Disease program, demonstrating that Prime Editors can efficiently correct pathogenic mutations, without introducing safety concerns or detectable off-target edits,” said Keith Gottesdiener, M.D., President and Chief Executive Officer of Prime Medicine. “These data are meaningful both for our efforts in Wilson’s Disease – a devasting condition that is believed to affect more than 20,000 people in the United States and Europe, and for which there are currently no approved disease-modifying therapies – and for our efforts in liver disease programs more broadly. Our Wilson’s Disease program leverages our proprietary, universal LNP platform, and these interim results suggest that our LNP may successfully deliver increased potency, as well as an improved safety profile and biodistribution, compared to other commonly used LNPs in development. We look forward to advancing our Wilson’s Disease program toward an IND and/or CTA filing in the first half of 2026.” Dr. Gottesdiener continued, “Also in recent months, we announced our decision to strategically prioritize a set of high value programs, each with a clear path to value inflection and the potential to unlock multiple follow-on opportunities. This includes our wholly owned efforts in CGD and Wilson’s Disease, as well as our efforts in cell therapy and cystic fibrosis, which we are advancing with support from Bristol Myers Squibb and the Cystic Fibrosis Foundation, respectively. We believe partnerships like these will continue to play a critical role as we build Prime Medicine, allowing us access to best-in-class expertise and non-dilutive capital and enabling us to more rapidly realize the full potential of Prime Editing.” Recent Business Updates Pipeline Updates In September 2024, Prime Medicine unveiled its strategically focused pipeline and plans to prioritize a set of high value programs, each targeting a disease with well-understood biology and a clearly defined clinical development and regulatory path. Each prioritized program is also intended to serve as a beachhead, in that the modularity of the Prime Editing platform is expected to allow Prime Medicine to generate follow-on candidates rapidly and efficiently. The prioritized programs sit across Prime Medicine’s core areas of focus (hematology, immunology and oncology, liver, and lung), and include ex vivo hematopoietic stem cell (HSC) programs for the treatment of p47phox chronic granulomatous disease (CGD) and X-linked CGD; ex vivo T-cell therapies; a lipid nanoparticle (LNP) Prime Editor for the treatment of Wilson’s Disease; and LNP or adeno-associated virus (AAV) Prime Editors for the treatment of cystic fibrosis (CF). In order to pursue these prioritized high value programs as rapidly as possible, the Company is identifying partnership opportunities to advance its other programs, including those for neurological diseases, cell therapy, ocular diseases and hearing loss. Hematology, Immunology and Oncology: In the third quarter of 2024, Prime Medicine initiated its global Phase 1/2 clinical trial of PM359 in the United States. The Phase 1/2 clinical trial is a multinational, first-in-human trial designed to assess the safety, biological activity and preliminary clinical activity of PM359 in adult and pediatric study participants. Prime Medicine expects to report initial clinical data from the Phase 1/2 trial in 2025. Liver: At the European Society for Gene and Cell Therapy (ESGCT) 31st Annual Congress (October 22-25, 2024), Prime Medicine presented data from multiple studies showcasing the potential of its proprietary, universal LNP platform to precisely deliver Prime Editors to correct disease-causing mutations in the liver, including in Wilson’s Disease. Prime Medicine’s universal LNP contains a GalNAc-targeting ligand (GalNAc-LNP), a validated mechanism for liver-specific delivery of gene editors. Highlights included: Preclinical data demonstrated that the delivery of Prime Editors using a GalNAc-LNP (GalNAc-LNP Prime Editor) resulted in increased potency, as well as improved safety profile and biodistribution, compared to traditional LNPs that have gone into the clinic.In vivo proof-of-concept data from Prime Medicine’s GalNAc-LNP Prime Editor for the treatment of Wilson’s Disease, demonstrated up to 80% precise correction of the H1069Q mutation and restoration of ATP7B mRNA to wild-type levels in a humanized mouse model, as well as precise editing of liver cells in non-human primates (NHPs), with up to 51% precise editing with a surrogate H1069Q Prime Editor. In preclinical studies to-date, Prime Medicine observed significant reductions of copper accumulation in the livers of humanized mice. In both mouse and NHP studies, no detectable off-target edits or unintended edits at the target site were observed. Prime Medicine is completing the final stages of lead optimization and recently initiated investigational new drug (IND)-enabling activities for its Wilson’s Disease program, with an IND and/or clinical trial application (CTA) filing expected in the first half of 2026. Prime Medicine will present on its Wilson’s Disease program at the American Association for the Study of Liver Diseases (AASLD), to be held on November 15-19, 2024. Longer term, the Company expects to use its universal LNP across all liver disease programs, allowing more rapid and cost-efficient expansion into follow-on rare and non-rare liver indications. Corporate Updates In September 2024, Prime Medicine entered into a strategic research collaboration and license agreement with Bristol Myers Squibb to develop and commercialize multiple Prime Edited ex vivo T-cell therapies. Under the terms of the agreement, Prime Medicine received a $55 million upfront payment and a $55 million equity investment from Bristol Myers Squibb. Prime Medicine is also eligible to receive more than $3.5 billion in milestones, including up to $1.4 billion in development milestones and more than $2.1 billion in commercialization milestones, along with royalties on net sales. Third Quarter 2024 Financial Results Research and Development (R&D) Expenses: R&D expenses were $40.3 million for the three months ended September 30, 2024, as compared to $41.0 million for the three months ended September 30, 2023.General and Administrative (G&A) Expenses: G&A expenses were $14.1 million for the three months ended September 30, 2024, as compared to $10.5 million for the three months ended September 30, 2023. The increase in G&A expenses was driven by personnel expenses, primarily related to an increase in non-cash stock-based compensation expense.Net Loss: Net loss was $52.5 million for the three months ended September 30, 2024, as compared to $50.7 million for the three months ended September 30, 2023.Cash Position: As of September 30, 2024, pro-forma cash, cash equivalents, investments and restricted cash were $244.6 million, which includes the $55 million equity investment from Bristol Myers Squibb received in September 2024 and the $55 million up-front consideration received in October 2024. Cash, cash equivalents, investments, and restricted cash were $189.6 million, as compared to $135.2 million as of December 31, 2023. Financial GuidanceBased on its current operating plans, Prime Medicine expects that its pro-forma cash, cash equivalents and investments as of September 30, 2024 will be sufficient to fund its operating expenses and capital expenditure requirements into the first half of 2026. About Prime MedicinePrime Medicine is a leading biotechnology company dedicated to creating and delivering the next generation of gene editing therapies to patients. The Company is deploying its proprietary Prime Editing platform, a versatile, precise and efficient gene editing technology, to develop a new class of differentiated one-time curative genetic therapies. Designed to make only the right edit at the right position within a gene while minimizing unwanted DNA modifications, Prime Editors have the potential to repair almost all types of genetic mutations and work in many different tissues, organs and cell types. Taken together, Prime Editing’s versatile gene editing capabilities could unlock opportunities across thousands of potential indications. Prime Medicine is currently progressing a diversified portfolio of investigational therapeutic programs organized around our core areas of focus: hematology, immunology and oncology, liver and lung. Across each core area, Prime Medicine is focused initially on a set of high value programs, each targeting a disease with well-understood biology and a clearly defined clinical development and regulatory path, and each expected to provide the foundation for expansion into additional opportunities. Over time, the Company intends to maximize Prime Editing’s broad and versatile therapeutic potential, as well as the modularity of the Prime Editing platform, to rapidly and efficiently expand beyond the diseases in its current pipeline, potentially including additional genetic diseases, immunological diseases, cancers, infectious diseases, and targeting genetic risk factors in common diseases, which collectively impact millions of people. For more information, please visit www.primemedicine.com. © 2024 Prime Medicine, Inc. All rights reserved. PRIME MEDICINE, the Prime Medicine logos, and PASSIGE are trademarks of Prime Medicine, Inc. All other trademarks referred to herein are the property of their respective owners. Forward Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements about Prime Medicine’s beliefs and expectations regarding: the timing, progress, and results of its Wilson’s Disease program, including the timing of the release of updated data and filing of an IND and/or CTA application in the first half of 2026; the potential for its modular universal LNP platform to precisely deliver Prime Editors, correct disease-causing mutations in the liver, and deliver transformative treatments for Wilson’s Disease, GSD1b, and other rare and non-rare liver indications; the modular universal LNP platform’s ability to be used repeatedly to generate candidates that offer an improved safety profile and biodistribution compared to other LNPs in development; the anticipated maturation into a clinical-stage company by bringing PM359 into clinical development in 2024 with initial clinical data from the ongoing Phase 1/2 clinical trial of PM359 expected in 2025; the collaboration with Bristol Myers Squibb and the intended and potential benefits thereof, including the receipt of potential milestone and royalty payments from commercial product sales, if any; the safety profile, tolerability, and durability of its universal LNP; the initiation, timing, progress, and results of its research and development programs, preclinical studies and future clinical trials; the modularity of the Prime Editing platform and the benefits thereof; the potential for Prime Editors to more precisely and effectively achieve genetic modification; the potential for Prime Editors to repair genetic mutations and offer curative genetic therapies for a wide spectrum of diseases; its continued development and optimization of various non-viral and viral delivery systems; its ability to demonstrate superior off-target profiles for Prime Editing programs; the expansion of Prime Editing’s therapeutic potential and the creation of value through strategic business development to extend the reach and impact of Prime Editing to areas beyond Prime Medicine’s current core areas of focus; exploring business development opportunities that could accelerate existing work and the benefits thereof; its expectations regarding the breadth of Prime Editing technology and the implementation of its strategic plans for its business, programs, and technology; and the potential of Prime Editing to unlock opportunities across thousands of potential indications. The words “may,” “might,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “expect,” “estimate,” “seek,” “predict,” “future,” “project,” “potential,” “continue,” “target” and similar words or expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, risks associated with: uncertainties related to Prime Medicine’s product candidates entering clinical trials; the authorization, initiation, and conduct of preclinical and IND-enabling studies and other development requirements for potential product candidates, including uncertainties related to opening INDs and obtaining regulatory approvals; risks related to the development and optimization of new technologies, the results of preclinical studies, or clinical studies not being predictive of future results in connection with future studies; the scope of protection Prime Medicine is able to establish and maintain for intellectual property rights covering its Prime Editing technology; Prime Medicine’s ability to identify and enter into future license agreements and collaborations; and general economic, industry and market conditions. These and other risks and uncertainties are described in greater detail in the section entitled “Risk Factors” in Prime Medicine’s most recent Annual Report on Form 10-K, as well as any subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent Prime Medicine’s views only as of today and should not be relied upon as representing its views as of any subsequent date. Prime Medicine explicitly disclaims any obligation to update any forward-looking statements subject to any obligations under applicable law. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements. Investor ContactGregory DearbornPrime Medicine713-503-3364gdearborn@primemedicine.com Hannah DeresiewiczPrecision AQ212-362-1200hannah.deresiewicz@precisionaq.com Media ContactDan Budwick, 1ABdan@1ABmedia.com Condensed Consolidated Balance Sheet Data(unaudited) (in thousands) September 30,2024 December 31,2023Cash, cash equivalents, and investments 175,527 121,665Total assets 332,784 193,851Total liabilities 143,280 60,780Total stockholders’ equity 189,504 133,071 Condensed Consolidated Statement of Operations(unaudited) Three Months EndedSeptember 30,(in thousands, except share and per share amounts) 2024 2023 Collaboration revenue $209 $— Operating expenses: Research and development $40,340 $40,967 General and administrative 14,101 10,492 Total operating expenses 54,441 51,459 Loss from operations (54,232) (51,459)Other income: Accretion (amortization) of investments 885 1,769 Interest income 697 410 Change in fair value of short-term investment — related party 215 (1,579)Other income, net (83) 43 Total other income, net 1,714 643 Net loss before income taxes (52,518) (50,816)Benefit from income taxes — 108 Net loss attributable to common stockholders $(52,518) $(50,708)Net loss per share attributable to common stockholders, basic and diluted $(0.44) $(0.55)Weighted-average common shares outstanding, basic and diluted 119,764,270 91,846,835