Flagship Biotech International Pvt Ltd.

Researchers a Ring also found that their new viral vector was on par with an adeno-associated viral vector at delivering gene therapy to the brain in mice. Ring Therapeutics’ hunt for new human viruses that can deliver gene therapies multiple times in a single patient appears to have landed on a viable candidate, new mouse data have suggested.  In a preprint (PDF) posted March 30 to bioRxiv, a distribution service for research articles that have not yet been published, Ring scientists reported that a viral vector developed using the company's Anellogy platform, which is based on the human anellovirus, successfully delivered a gene to the retinas of mice. The company’s viral vectors, called Anellovectors, were expressed at stable levels for up to nine months without any signs of toxicity.  “We set out to develop an entirely new vector system based on human commensal viruses to address the many hurdles facing current genetic medicine delivery—and we’ve achieved that at remarkable speed,” Ring CEO Tuyen Ong, M.D., said in a press release. “This new publication shows we can successfully harness the unique characteristics of anelloviruses to generate the Anellovector—the first novel viral vector in decades.”  Preprint articles have not yet completed peer review, a process where scientists unaffiliated with the study take a critical eye to its methods and results before it’s officially accepted to an academic journal. While Fierce Biotech Research typically does not report on preprint studies, the announcement of a possible new candidate viral vector for gene therapy was significant enough to warrant coverage even at this stage.  Nearly all the gene therapies approved by the FDA for treating genetic disorders arising from a single gene mutation—known as monogenetic disease—involve the use of adeno-associated virus vectors (AAVs). While reasonably safe and effective, as many as 70% of patients already have antibodies to AAVs, and those who don’t will likely develop antibodies to them after the initial dose. This means that AAV-based gene therapies can only be used once and must be administered in sufficiently high doses that the gene will be delivered to a sufficient number of cells to treat the condition. That can raise the risk of side effects.  To get around those challenges, Ring is looking for new viruses that don’t raise the immune system’s alarm bells and could thus lay the groundwork for gene therapies that are dosed repeatedly. The company’s search is centered on anelloviruses, a family of viruses that aren't yet associated with any human disease and don’t appear to stimulate an immune response. In this case, the company tested a vector based on a virus from the Betatorquevirus genus.  In the new study, Ring tested its Anellovector’s ability to deliver a gene expressing a fluorescent green protein to retinal cells. After seeing that it could do so in cell cultures, they tested it in live mice. The Anellovector delivered the gene to cells in the retina, where the researchers measured its expression at three, six and nine months. They found that while copies of the delivered DNA declined over time, the gene was expressed at stable levels from months three to nine.  To see how its product stacked up against AAV vectors and whether they worked in tissue beyond the eye, the researchers injected either a dose of AAV9 vectors—one of the most commonly used AAV vectors—or its anellovirus vectors into the left and right ventricles of the brains of two separate groups of mice, where it expressed the same green fluorescent protein they had used to study their delivery efficacy in the retina. At 21 days post-injection, anellovirus vectors were at about the same levels as AAV9 vectors. Brain sections showed that expression levels were roughly the same between the two groups as well.  “Taken together, these data demonstrate the Anellovector has tropism for cells in the CNS and suggests it can express its transgene to similar levels as an AAV9-based vector,” the researchers wrote in their study.  Ring has also developed a production system for its Anellovectors. Called the Self-Amplifying Trans-complementation of a Universal Recombinant aNellovector (SATURN for short) system, it uses a self-replicating plasmid to package one anellovirus’ vector genome into the capsid of another. Experiments in the new study demonstrated that the SATURN system can do this between several different types of anellovirus species, which will potentially allow the company to make use of many different ones.  Ring got its start at Flagship Pioneering, a Boston-based biotech incubator where Ong is also CEO-partner. The company has raised nearly $254 million so far, including a $117 million series B from in 2021 that attracted backing from the likes of Invus, Altitude Life Science Ventures and UPMC Enterprises in addition to Flagship. The biotech's most recent raise was a $86.5 million series C in March 2023.  With the new preclinical results in hand, Ring is preparing to launch investigational new drug-enabling studies, Ong said in the release. The company's work hasn't been limited to mice, either. At the 2023 Annual Congress of the European Society of Gene & Cell Therapy last October, Ring shared that it had successfully used an Anellovector to deliver a gene to the retina in a pilot study involving nonhuman primates. 

Work on the vaccine dates back to at least 2016, when Moderna announced that BARDA was providing $8 million to finance a phase 1 toxicology study. Moderna does not plan to advance a midstage Zika vaccine without additional outside cash, despite receiving U.S. funding thus far, according to a regulatory disclosure.  The news, tucked into Moderna’s annual report released Friday, throws cold water on the most mature vaccine in Moderna’s public health pipeline. The company is also working on vaccines for mpox and Niphah under the public health umbrella, both of which are in phase 1 studies. The Flagship biotech’s Zika vaccine, mRNA-1893, is currently in a phase 2 study that’s fully enrolled some 800 patients in the mainland U.S. and Puerto Rico. The primary completion date is late July 2024, according the study’s clinical trial record.  Work on the vaccine dates back to at least 2016 when Moderna announced that the U.S. Biomedical Advanced Research and Development Authority (BARDA) was providing $8 million to finance a phase 1 toxicology study. BARDA also offered $117 million for future phase 2 and phase 3 studies, plus large-scale manufacturing.  When Moderna finalized plans for an mRNA manufacturing site in Kenya last year, CEO Stéphane Bancel specifically mentioned the potential to develop vaccines for "persistent infectious diseases like HIV and outbreak threats such as Zika and Ebola," according to a release.  Moderna's Hamilton Bennett, who serves as senior director of Vaccine Access and Partnership, mentioned the vaccine as being a key part of the company's global health portfolio in a December 2023 ESG Day. At that time, she noted that partnerships would be key to the global health portfolio.  "The value in mRNA access is that the exploratory research that our academic collaborators are conducting is taking place on a platform and a platform that is built an early development engine, an engine that can accelerate products not only into the clinic but to licensure," Bennett said. "It's this kind of collaborative model for innovative research and the type of bold approach that Moderna is willing to take in our mission to advance the greatest impact on public health." Spokespeople for BARDA and Moderna did not immediately respond to requests for comment on the decision and on how much money had been awarded thus far.  This is the latest example of Moderna reallocating resources as it tries to stave off evaporating COVID vaccine sales with near-term launches. The company recently confirmed that some employees would be laid off after reducing its COVID manufacturing investments. Executives described 2023 as a pivot year after the commercial COVID market shaped up and demand dwindled.  Now, Moderna is looking elsewhere to resuscitate revenue and investor excitement. First and foremost is the company’s respiratory syncytial virus vaccine, slated for a decision by the FDA in May. If approved, it would join the likes of GSK and Pfizer in the older adult population. Moderna also expects interim phase 3 data on its cytomegalovirus vaccine this year. A phase 3 trial is underway testing Moderna’s individualized neoantigen therapy plus Keytruda in patients with high-risk melanoma.

The bulk of the metabolic dysfunction-associated steatohepatitis companies have traded steadily along the same lines over the past month. Madrigal Pharmaceuticals’ FDA approval could change that. Madrigal Pharmaceuticals’ metabolic dysfunction-associated steatohepatitis (MASH) drug has been approved, to be sold as Rezdiffra. For the other companies with up-and-coming treatments trailing in the clinic, the question is: What now? Terns Pharmaceuticals already signaled a retreat from the space in January, shelving the oral thyroid hormone receptor-beta (THR-β) agonist TERN-501 in MASH, previously known as nonalcoholic steatohepatitis (NASH). But the therapy was expected to go on, potentially finding a foothold in another competitive indication: obesity. In an earnings release that coincidentally was released the same day as Madrigal’s triumph, the company indicated that the hunt for a future indication is still ongoing for TERN-501. While the journey may be over for Terns, analysts at William Blair and Global Data saw a brighter side to the Rezdiffra label. The FDA will not require a liver biopsy before treatment, which means patient selection should be easier and access more streamlined. Could there still be hope for the companies to come after Madrigal? “The absence of liver biopsy requirement in Rezdiffra’s label should buoy biotech stocks with exposure to MASH,” William Blair wrote in a Friday morning note. “Accordingly, we expect biotech companies with MASH exposure to broadly rally today, given that one of the commercial overhangs has been removed.” That’s exactly what happened Friday morning when the markets opened—at least for Madrigal, which jumped more than 16% to $283.55. Other companies in the space had more modest bumps, such as 89bio, which climbed 4.5% to $13.18; Aligos Therapeutics saw barely a blip, with a 1% gain to 88 cents; Terns stepped up just over 6% to $7.15. The closer trailing competitors fell: Viking Therapeutics went down 2% to $63.47, while Akero Therapeutics fell just under 5% to $26.07.  https://public.flourish.studio/visualisation/17172049/ While the bulk of the MASH companies have traded steadily along the same lines over the past month, Viking is an outlier, thanks to data published Feb. 26 linking the company’s obesity drug VK2735 to weight loss of up to 14.7% after 13 weeks of treatment. The dual agonist of GLP-1 and GIP has emerged as the star of Viking’s pipeline, but VK2809 has put up strong data in MASH. The therapy was linked to mean relative changes in liver fat of up to 51.7% without causing widespread gastrointestinal side effects in a phase 2b study that read out in May 2023. Viking used the weight loss data to raise $550 million in an underwritten public offering after the obesity data, with the proceeds going toward both VK2809 and VK2735 as well as VK0214 for the rare genetic disorder X-linked adrenoleukodystrophy. William Blair believes VK2809 could “outshine” Madrigal’s clinical profile. Rezdiffra was specifically approved for the treatment of MASH with moderate or severe liver scarring, or fibrosis, consistent with stage F2 and F3 disease. The therapy met both goals of MASH resolution and fibrosis improvement in a phase 3 trial. The FDA nod was based on an analysis of about 900 patients with biopsy-confirmed MASH and liver fibrosis who enrolled in the MAESTRO-NASH trial. In the study, Rezdiffra, given at either 80 mg or 100 mg once daily, cleared MASH with no worsening of fibrosis in 25.9% and 29.9% of patients, respectively, versus 9.7% for those who received placebo, according to data published in The New England Journal of Medicine. In addition, 24.2% and 25.9% of patients on the two Rezdiffra doses showed fibrosis improvement of at least one stage, with no worsening on a fatty liver disease activity score. The rates were significantly more than the 14.2% seen in the placebo group. These data will now be the bar that companies like Viking will have to clear, Global Data Senior Pharma Analyst Sravani Meka said in a Friday morning note. “In an indication where there were previously no approved therapies and multiple development failures, the approval of Rezdiffra will now set the standard for all other treatments in development,” Meka said. “Future therapies will now have to meet or outperform efficacy and safety data generated from resmetirom’s Phase III MAESTRO studies.” GlobalData estimates that the total MASH market is expected to reach $25.7 billion in 2032 across the U.S., France, Germany, Italy, Spain, the U.K. and Japan. Competitors such as Viking and the GLP-1 heavyweights Novo Nordisk and Eli Lilly should arrive in 2024 through 2032. Madrigal has a major head start, but the GLP-1 challengers like Novo’s Wegovy and Lilly’s Zepbound pose a huge challenge to the small biotech’s potential market share. Novo has also looked outside its GLP-1 stable to lock in future prospects in the market. The company signed a deal with venture creation firm Flagship Pioneering in January to gain access to two cardiometabolic disease partnerships, each worth up to $532 million. Flagship biotech Cellarity is working on a small molecule to treat MASH.  Elsewhere, Boehringer Ingelheim recently announced that a Zealand Pharma-partnered candidate called survodutide improved disease activity and liver scarring in a phase 2 trial. Up to 83% of adults treated with survodutide achieved a statistically significant improvement of MASH, with the trial also meeting all secondary endpoints, including a statistically significant improvement in liver fibrosis. Boehringer was not specific on the phase 3 plans in MASH but did say the therapy has already moved into late-stage studies across subpopulations of people living overweight and with obesity, including cardiovascular and chronic kidney disease patients. Meanwhile, small biotechs in the race will need to differentiate. 89bio just this week initiated a phase 3 program for pegozafermin with hopes of securing an accelerated approval for non-cirrhotic MASH, or fibrosis stages F2-F3—the same as Madrigal. That could be a tough climb, as patients in that category now have a treatment option with Rezdiffra. The biotech will likely have to show MASH improvements way outside of what Madrigal has achieved to convince the FDA that an accelerated nod is warranted.  89bio CEO Rohan Palekar acknowledged the huge achievement that the approval of Rezdiffra is for patients, in a statement provided to Fierce Biotech Friday afternoon. But his company is charging ahead with its plans.  "This is just the beginning and we at 89bio look forward to building further on this success as we progress development of pegozafermin," Palekar said. "Because of the large and growing patient population in MASH, many therapeutic options will be both needed and successful." He specifically cited patients with advanced fibrosis and suggested the community needs options that improve tolerability and dosing convenience to ensure compliance.  Palekar is confident the FDA will be open to an accelerated approval.  "We worked closely with the FDA prior to the initiation and aligned on key elements of our MASH development strategy. Based on these discussions, if our phase 3 trials are successful, we do expect the FDA will grant pegozafermin accelerated approval for both F2-F3 and cirrhotic MASH using histology endpoints," the CEO said.  Over at Aligos, CEO Lawrence Blatt, Ph.D., similarly made the case for his own drug, issuing a statement suggesting there’s room for more. “Despite this approval, there still remains a large patient population that may need additional or different therapy than what resmetirom can offer,” Blatt said in a statement. “Aligos is not only supportive of the progress this approval represents but happy to see this class validated as we begin the phase 2a trial of our own highly potent and selective THR-β agonist, ALG-055009.” Editor's note: This story was updated at 5 p.m. ET on Friday, March 15, to add comment from 89bio.