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18 July, 2022 |
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Automation Strategies to Enable Scale-up of CAR-T Therapies
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CAR-T therapies continue to show tremendous clinical potential; however, manufacturing remains challenging due to the lack of control and automation, as well as process and product characterization during development and manufacturing stages. In this article, Dr. Qasim Rafiq of UCL discusses the importance of establishing standardized, scalable manufacturing and shares insights from his development of an automated CAR-T expansion process. |
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Happy Monday and thanks for starting off your week with Endpoints. With the third quarter well underway, we’re prepping our coverage for all the big earnings reports due out soon. Be sure to subscribe to Endpoints Pharma to get the latest on that — you can sign up here.
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Max Gelman |
Senior Editor, Endpoints News
@MaxGelman
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Are we closer than we think to personalized genetic medicine?
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by Metagenomi
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When gene editing exploded onto the scene over three decades ago, it brought previously inconceivable disease treatment and potentially curative therapies into view. Today, gene editing remains one of the most gripping topics in biopharma — and a recent wave of partnerships may move the industry even closer to broad, curative treatment for genetic disease. Discoveries across the natural environment deriving in vivo and ex vivo biotechnologies have ushered a floodgate of development possibilities. With giants like Bayer, Moderna, Vertex and others signaling that gene editing will be a key driver of their future pipelines, how will the industry leverage this new frontier of genomic technology? A panel sponsored by Metagenomi and moderated by Endpoints News at the 2022 BIO International Convention convened an integrated group of thought leaders, leading scientists and investors to discuss the best practices to develop safe, efficacious gene therapies for the. Here we capture insights from each perspective and panelist. | Expanding the gene editing toolbox through metagenomics | Most genetic modification trials today employ the revolutionary CRISPR-Cas9 method of DNA cutting, whose creators were awarded the Nobel Prize in chemistry just two years ago. While CRISPR-Cas9 techniques may provide a chance to treat some gene-related diseases, more innovation is needed to unlock the full potential of gene editing. With that goal in mind, Metagenomi is leading a new wave of startups looking to create powerful next-generation gene editing systems that can enable and accelerate the discovery and development of customized gene editing therapies across a wider range of genetic diseases and tissues. Backed by $300 million, Metagenomi is combing the world’s natural microbial environment to discover breakthrough gene editing systems capable of editing DNA more precisely than current technology can. The science behind the company is metagenomics, which examines the genealogical composition of microbes from rich, natural environments such as hot springs, wetlands and salt flats. It’s a science that was pioneered by Metagenomi’s CEO and founder, Brian C. Thomas, who spent two decades dedicated to scientific research at UC Berkeley. “Using metagenomics, we’re tapping into four billion years of microbial evolution, and the answers are there,” said Thomas. “We haven’t had to spend significant amounts of time in the lab engineering these enzymes in order to attain the high levels of activity that they’re able to hit, because they’ve been optimized naturally.” The company is rapidly building the world’s largest, most diverse toolbox of both CRISPR and non-CRISPR-based gene editing systems through its proprietary discovery and analysis engine. This approach recovers DNA from natural samples and uses advanced AI-based cloud computing to reveal novel cellular machinery from previously unstudied organisms that can be optimized for therapeutic applications. Having a wider selection of modular tools enables scientists and healthcare providers to target aggressive cancers, rare diseases and other complexities as they seek to make a difference for patients. | Solving genetic editing challenges | So far Metagenomi has identified thousands of novel enzymes, many of which are ultra-small and display unique characteristics for enhanced gene editing applications. Compared to current editing systems, which are based on a few, large enzymes with targeting and delivery issues, Metagenomi systems offer flexibility. This broad enzyme diversity and smaller size enables greater efficiency, specificity and genome targetability, resulting in enhanced patient safety. “ we started our survey in the natural environment of these unique nucleases, we tried to find characteristics that would really be beneficial with current delivery capabilities,” said Thomas. He noted that the company is still exploring the biochemical properties of its unique nucleases, including greater stability and resilience due to their origins in extreme environments, where pH and temperature, for example, are wildly atypical. The company’s toolbox is currently weighted toward CRISPR-based systems but is expanding to include targeted integration of large DNA fragments, base editing and other types of gene editing tools. | Propelling in vivo and ex vivo therapies through partnerships | Metagenomi’s pipeline focuses on deploying its wholly-owned diverse toolbox in both in vivo and ex vivo applications. “As we started to develop these tools from the natural environment, we realized they had characteristics and properties that could make them unique in either of those settings,” noted Thomas. “From a business point of view, we’ve really focused on a partnership strategy around leveraging both of these technology applications.” In addition to enabling partners, Metagenomi also has a wholly-owned pipeline of next-generation therapies developed using the company’s novel technologies. Moderna realized a partnership with Metagenomi — which was announced last year — could help differentiate it as an in vivo market leader in the future, including through genetic system reprogramming. The research collaboration will combine Metagenomi’s gene editing systems with Moderna’s mRNA technologies to develop innovative in vivo gene editing therapeutics targeting various genetic diseases. “When working with partners like Metagenomi, we can actually create the next generation of functional genomic factors that combine mRNA technology and the powers of chain manufacturing,” explained Eric Huang, Moderna Genomics’ chief scientific officer. “That’s our blue-sky ambition and goal … combining that knowhow, the future technology generation, as well as Moderna’s manufacturing prowess, to really make personalized genetic medicine into reality” in years to come. The Metagenomi team is also “excited about the fact that in the ex vivo cell therapy space, where the gene editing component is a tool to create a more impactful and powerful cell product, there’s a lot of room for development,” shared Thomas. In fact, the company just announced a partnership with startup Affini-T Therapeutics to advance next-generation ex vivo T-cell receptor therapies — or TCR — for patients with solid tumors. The work will target core oncogenic drivers using Metagenomi’s proprietary gene editing systems to promote sustained clinical outcomes for cancer patients. “Solid tumors are really the next frontier in oncology,” noted Aude Chapuis, co-founder of Affini-T, associate professor at the Fred Hutchinson Cancer Center and a scientific advisor to Metagenomi. “We’re interested in TCR technology because it is able to target intracellular antigens … we can really broaden the number of proteins that we’re targeting,” she said. “Ultimately, the non-viral gene editing is going to be extremely valuable for the TCR field in particular.” |
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Jay Hagan, Regulus Therapeutics CEO |
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by Max Gelman
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Sanofi is scrapping a drug from a longtime partner. The Big Pharma tells Endpoints News it has halted development of lademirsen, discovered by Regulus Therapeutics, after the program failed a Phase II interim analysis. Sanofi added that the move was not due to safety concerns. Lademirsen is designed to slow kidney function decline in patients with Alport syndrome. “While this trial did not provide the results we had anticipated, our research has added value to the scientific understanding of Alport Syndrome, and we remain committed to advancing new therapies for rare kidney diseases,” a Sanofi spokesperson told Endpoints. Regulus investors did not take the news well, with the biotech’s stock RGLS falling roughly 20% in early Monday trading, but rebounding to settle around a 10% drop. Endpoints has reached out to Regulus for comment and will update accordingly. The companies first teamed up back in 2010, signing a deal worth $25 million upfront and up to $750 million in milestones. Their agreement centered around microRNA and at the time was billed as the largest microRNA pact ever agreed upon. Sanofi and Regulus set their sights on fibrosis with four microRNA targets. Lademirsen, then known as RG-012, was their lead partnership program, and the pair soon expanded on the deal in 2012 to include oncology. In 2014, Sanofi announced it had obtained the option to in-license any of the drugs on which the companies collaborated, and things were looking up for the biotech. |
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by Jared Whitlock
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It’s rare for a company to highlight its burgeoning competition. But Illumina did just that in a court filing last month. The San Diego-based company — which makes DNA sequencers that power everything from consumer genetic tests to precision drug development — commands about 80 percent of the market. The Federal Trade Commission in 2021 cited Illumina’s market share in challenging the company’s acquisition of Grail, a cancer testing company. But in response to the FTC, Illumina in the legal brief contended it’s not a monopolist by pointing to rivals, including companies that recently released DNA sequencers and a Chinese behemoth that will soon enter the US market. The FTC has argued that sequencing remains a tough market to crack and potential competition will take time to scale. Illumina has simultaneously played up rivals in hopes of fending off antitrust regulators while spending heavily on internal programs aimed at competitors. Researchers and clinicians suddenly have more sequencer options, with more due to arrive soon, for purposes like finding the genetic basis of life-threatening diseases. “It’s funny to have a company coming out and saying something to the effect of, ‘No, we’re not actually that great,’” said Keith Robison, a computational biologist who blogs about the genomics industry. Observers say Illumina’s novel strategy of touting sequencing competitors serves to not only secure Grail, but tap a cancer testing market that could be worth as much as $50 billion by 2035. Illumina declined an interview request. |
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Baisong Mei, incoming Editas VP and CMO |
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by Aayushi Pratap
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Cambridge-based genome editing company Editas Medicine has appointed Baisong Mei as its new VP and chief medical officer, the company announced Monday. The new hire comes five months after Editas fired its former CMO Lisa Michaels just 15 months after her joining. It is unclear why she was let go. In April, the company got its new CEO, Gilmore O’Neill, its third CEO in the last three years. The new hires are part of a rebuilding of the C-suite. “I am very excited to join Editas,” Mei told Endpoints News. “Editas has great technology and science in gene editing and therapy and have a great potential to treat patients with unmet needs.” Mei has over 20 years of experience in the biotech and pharmaceutical industry. He previously served as the senior global project head for rare diseases and rare blood disorders at Sanofi for nearly six years where he led the clinical development pipeline in several rare diseases in hematology, neurology and nephrology. Prior to that, he was at Biogen for almost seven years where he worked on hemophilia and hemoglobinopathy. Some of his major achievements include bringing novel medicines through clinical development and global regulatory approval, including Alprolix and Eloctate, medicines for hemophilia B. “First thing I need to do is learn more about what is going on at Editas,” Mei added. Editas, founded in 2013, was born out of the science of CRISPR and gene editing leaders Feng Zhang, George Church, J. Keith Joung and David Liu. The company uses gene editing tools such as CRISPR/Cas9 and CRISPR/Cas12a to build a pipeline of treatments for diseases. While Editas was the first to test gene-editing therapy in humans, Intellia Therapeutics, its competitor, became the first biotech to announce results of genome editing in humans. |
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Thomas Cannell, Sesen Bio CEO |
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by Lei Lei Wu
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Following an FDA rejection last year, Sesen Bio announced this morning that it will be pausing development on its lead bladder cancer drug. With the pause, Sesen can save money while it looks for alternatives, the Cambridge, MA-based biotech said in a press release. It noted that it would be looking for a partner for its bladder cancer drug Vicineum. In August, the FDA rejected Vicineum — which the biotech ascribed to manufacturing issues and the FDA asking for more data. The biotech said its decision for pausing development came after assessing costs for an additional Phase III trial for the drug in bladder cancer. In a statement, Sesen Bio CEO and president Thomas Cannell noted that the biotech has had four meetings with the FDA since the rejection. He added: |
We have also recently observed an evolution of the current treatment paradigm in NMIBC, with substantial uptake of intravesical chemotherapy (monotherapy and combination therapy) during the ongoing BCG shortage. In assessing the impact of the regulatory and commercial landscape, we have made the decision to pause the clinical development of Vicineum. |
| In a separate SEC filing, the biotech also said that it is selling its line of IL-6 antibodies to Roche, which it originally out-licensed to the Swiss pharma in 2016, when it was still known as Eleven Bio. In the original deal, the biotech had licensed the antibodies, including one known as EBI-031 for which the FDA had cleared for clinical trials, for an upfront fee of $7.5 million. |
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Bahija Jallal, Immunocore CEO |
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by Paul Schloesser
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Looking to secure a fresh raise to invigorate R&D, Immunocore is putting together a PIPE. The former Medigene spinout, six months after the FDA approved its TCR drug tebentafusp, put out word Monday that it's selling just over 3.7 million shares of company stock at $37.50 each. This is going to certain investors as a PIPE financing for a total of $140 million. Shares of IMCR stayed consistent in premarket trading, only sliding down half of 1% after closing at $43.25 a share Friday afternoon. Different investors that jumped in on the round included RTW Investments, LP, Rock Springs Capital, and General Atlantic. The financing is slated to close sometime Wednesday, Immunocore said in a statement. The news comes amidst a growing trend of biotechs seeking private placements as bears continue to close the market's window for follow-on rounds. Earlier this month, a triumvirate of companies — Annexon, Provention Bio and Nurix Therapeutics — put together private placements in the span of 24 hours, and Faseem Hasnain's Gossamer Bio channeled its efforts into a placement of its own last week. CEO Bahija Jallal tells Endpoints News that accelerating the company's pipeline is something that is "always on our radar," and that the focus will be on developing candidates for more indications in cancer, including in solid tumors and in infectious diseases. So far, the biotech has two candidates in infectious disease: one for HIV and one for HBV. "We're very happy with where we are," the CEO said. |
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Chris Schelling, Acer Therapeutics CEO |
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by Amber Tong
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Less than a month after the FDA rejected Acer Therapeutics’ treatment for urea cycle disorders because its contract packaging manufacturer wasn’t ready for an inspection, the biotech said it’s sorted things out. The biotech has refiled an NDA for ACER-001, it announced Monday morning, and believes the resubmission addresses all the concerns raised in the complete response letter. In a statement, founder and CEO Chris Schelling praised his team’s “outstanding job” resubmitting the NDA one month after the CRL. “Our third-party contract manufacturing partner has been incredibly responsive and has confirmed that it is ready for inspection,” he added. “Our manufacturing partner is regarded as a global leader in clinical supply chain and commercial packaging services with more than 70 years of experience.” Regulators now have 14 days to decide whether to accept the refiled NDA. Shares ACER climbed around 6% in the wake of the news to $1.62 but were far from recuperating the loss from the rejection. When it disclosed the rejection, Acer noted that while the FDA requested “additional existing nonclinical information to be provided in the resubmission of the NDA, it was “not an approvability issue.” Developed in partnership with Relief Therapeutics, ACER-001 is an oral formulation of sodium phenylbutyrate designed to minimize the unpleasant taste that Acer said has led to compliance problems with existing drugs containing the compound and approved to treat urea cycle disorders. It is also being developed for maple syrup urine disease. |
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Bob Azelby, Eliem Therapeutics CEO |
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by Kyle LaHucik
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In the drug R&D world, plans are not set in stone, as Eliem Therapeutics exhibited Monday with shifts to its depression strategy. The Seattle-UK biotech originally wanted to start two mid-stage depression trials this year but will have to delay one — in major depressive disorder — until next year and indefinitely postpone the other in perimenopausal depression. Back in April, Eliem delayed the launches of both Phase IIa trials because the biotech was curious as to why the exposure was lower than expected in a Phase Ib study, which tried to prove out the concepts of ETX-155 in photosensitive epilepsy. Now, with results from an initial review, the biotech thinks certain parts of the CMC are “most likely” to blame for the reduced exposure levels. The company thinks there might have been differences between the batches of drug used in Phase I trials and the Phase Ib PSE study. With that info in hand, Eliem will take the GABAa positive allosteric modulator through another Phase I pharmacokinetic trial using the drug batches that were used in the PSE study. The biotech plans to find out which dose will provide a similar exposure to the 60 mg dose used in the 14-day repeat dose healthy volunteer study previously conducted. Results from that trial are slated for the fourth quarter, and then a randomized, placebo-controlled Phase IIa in MDD patients will kick off the first quarter of the new year. The mid-stage trial will test the drug as a four-week treatment, with topline data to come through in mid-2024. |
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Emma Walmsley, GSK CEO (GSK Investor Day 5) |
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What a difference one really good Phase III readout and a couple of late-stage buyouts can make. GSK CEO Emma Walmsley has been trying, hard, to build some excitement around the pipeline. And with the recent positive outcome for their RSV vaccine, she’s finally earning some market respect on that score. And with the big consumer split today, with the birth of Haleon, you can expect plenty of buzz about the need for another M&A deal to position the company. Reuters helped set the stage for that with some numbers crunching around New GSK, which will stake its future on drug R&D. Haleon sailed away with a heavy load of debt, reports the wire service, New GSK will be left “with borrowing of less than 1 times 2023 EBITDA, according to Breakingviews calculations.” They’ll also have a solid HIV business at ViiV and a blockbuster shingles vaccine Shingrix that has enormous potential, driving expectations of sales growth. And if the R&D team under Tony Wood — with Hal Barron’s departure from the top post in research — can’t add some more excitement about blockbusters-to-be, then the BD team will need to step in again. Reuters helpfully even posts a suggested natural target for New GSK: their partner SpringWorks, which has been roughed up this year on Wall Street. Shares are off more than 50% since the start of the year, leaving a $1.5 billion target well within Walmsley’s reach. And that is after a positive Phase III trial for their partnered drug nirogacestat in soft tissue tumors. |
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by Amber Tong
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For the past seven years, biotech spinouts from the University of Oxford have often tapped into a reliable source of investments from Oxford Science Enterprises, the company tasked with founding, funding and building startups based on “exceptional science” flowing out of Oxford. And the pool has gotten $300 million (£250 million) deeper as Oxford Science Enterprises bags a new raise that puts its tally over $1 billion (£850 million). Life sciences isn’t the only focus of Oxford Science Enterprises — there’s also health tech and deep tech vying for attention — but drug developers may take particular delight in its plans to deploy “increasingly large amounts of capital in later-stage funding rounds.” With portfolio companies maturing and getting closer to promised breakthroughs in cancer, heart failure and infectious diseases alongside climate change, food security and quantum computing, such “scale-up capital” will be increasingly crucial, said CEO Alexis Dormandy. "This fundraise comes at an exciting and pivotal time for OSE,” he said in a statement. “Over the next few years, we expect these companies will continue to make important progress; with our ongoing efforts, and the support of our shareholders, we look forward to helping them deliver impact and returns.” Oxford Science Enterprises likes to tout its founding investor role in Vaccitech, the vaccine developer that played a considerable role in AstraZeneca’s Covid-19 shot. |
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by Aayushi Pratap
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French company Enterome, which works with the microbiome, has scored $40 million in a wide-ranging deal with its long-time Swiss investor Nestlé Health Science to co-develop an oral pill for food allergies that's on the cusp of entering the clinic. “Today, we believe that we have reached a level where we understand what the bacteria living in the human gut are able to produce,” said Pierre Belichard, CEO of Enterome. Studying human gut bacteria, Enterome has discovered a protein that mimics a naturally produced human hormone called Interleukin- 10 (IL-10), known to fight food allergies and conditions such as inflammatory bowel disease. “IL-10 has been seen for a long time as a magic bullet able to decrease inflammation in a lot of different organs in the body,” Belichard added. Reduced inflammation reduces the impact of food allergies, he said. The two companies will work on a compound dubbed EB1010, which contains the newly discovered protein. Nestlé is also betting that there's more where that came from. Leveraging what Enterome calls EndoMimics, the two partners will keep looking for compounds that act like human hormones or cytokines. Down the road, they also hope to create a new class called AllerMimics: antigens produced by microbiome that mimic allergens such as peanuts. To kick off this alliance, Enterome will receive a cash upfront as well as equity from Nestlé. The biotech will be responsible for leading drug discovery activities and bear related costs up to the investigational new drug application. In the future, Nestlé, which hold around 17% stakes in Enterome, could shell out additional clinical and sales payments for each licensed therapeutic candidate plus royalties on net sales. |
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by Paul Schloesser
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Applications are now open for Merck KGaA's newest collaboration program focused on startups located in Asia. The German pharma announced Thursday, sparing a few details, that it was launching a new program in Asia called Uptune, which "aims to generate collaboration opportunities with early-stage innovative companies." The plan, according to Merck KGaA, will support and give some financing to certain companies in the healthcare and life science space, plus electronics and smart manufacturing. It did emphasize it will look for companies with a focus on digital health and "innovative technologies/materials for semiconductor and display." On top of those emphases, Merck KGaA noted it was also looking at companies working in manufacturing, utilizing cellular, molecular- and immuno-assays or cell and gene therapy tools, engaging in manufacturing specialties such as supply chain innovation, data management, simulation and analytics; and finally, "chemistry and materials for life science." As part of the application process, Merck KGaA said it is looking to partner with up to five companies and grant up to €100,000 in financial assistance, plus mentoring and coaching. The goal for these startups is to develop proof-of-concepts and possibly test what they come up with — and if they do well, it could end up in a partnership with Merck KGaA. The Merck Uptune startup collaboration program is taking applicants through Sept. 4, starting the program officially sometime in mid-November. The company did not respond to a request for comment from Endpoints News. |
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by Kyle LaHucik, Tyler Patchen |
The FDA approved an oral liquid formulation of the drug zonisamide, originally made by Eton Pharmaceuticals and currently owned by Azurity Pharmaceuticals. The nod gives Azurity the ability to market Zonisade as an adjunctive therapy for treating partial seizures in adults and kids 16 years and older who have epilepsy. The green light comes after three double-blind and placebo-controlled clinical studies of the drug, which is administered once or twice a day. Zonisamide was originally approved in the early 2000s as a capsule for treating partial epileptic seizures and has been marketed by a variety of companies, including the former Irish biotech Elan Pharmaceuticals, Japanese drugmaker Eisai and Sumitomo Dainippon. In 2010, Elan and Eisai agreed to pay $214.5 million to resolve allegations of off-label marketing of Zonegran. Eton sold the oral liquid formulation of the drug to Azurity as part of a February 2021 deal, worth up to $45 million in payments, including $5 million when the drug is launched. "This is now the eighth product approval that our team has contributed to, and we are excited for Azurity to bring the product to patients. The proceeds from the launch milestone will be used to further grow our rare disease portfolio,” Eton CEO Sean Brynjelsen said in a statement. For Azurity, the nod adds to a long list of FDA-approved products across cardiovascular, CNS, endocrinology and orphan diseases. — Kyle LaHucik |
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Worldwide made. Thanks for reading.
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