Garadacimab

In the OASISplus study, an open-label extension and switch trial, attack rates continued to improve over time, with 93% and 92% improvements from baseline in the four-week and eight-week groups. We can now envision the oasis that Ionis Pharmaceuticals saw with its hereditary angioedema data. Earlier this year, the company announced that donidalorsen had met the primary endpoint of a phase 3 study, but now we know it’s because the treatment spurred an 81% lower monthly rate of swelling attacks in patients who received the drug every four weeks. Data from the OASIS-HAE and OASISplus studies also showed that 84% of patients who switched from previous prophylactic treatment preferred Ionis’ offering. Patients can administer the treatment themselves via auto-injector. The therapy had a favorable safety profile, according to Ionis’ Friday announcement. The data will be presented at the 2024 European Academy of Allergy and Clinical Immunology Annual Congress in Valencia, Spain. Ionis is taking the data to regulators to support an approval in HAE, a life-threatening condition that causes random swelling attacks to parts of the body. Donidalorsen is an RNA-targeting prophylactic therapy that reduces the production of prekallikrein, thereby interrupting the pathway that leads to HAE attacks. “These data underscore the potential of donidalorsen to continually improve HAE attack rates and quality of life over time, positioning donidalorsen as an attractive potential treatment option,” said Ionis CEO Brett Monia, Ph.D. “In our prospective switch cohort, patients switched to donidalorsen from another prophylactic without increased breakthrough attacks and achieved greater disease control. In fact, a majority of patients who switched reported a preference for donidalorsen.” Ionis previously reported in January that the OASIS-HAE study met its primary endpoint, with the rate of angioedema attacks at both the four-week and eight-week regimens of donidalorsen lower than the placebo cohorts. The study featured patients receiving 80 mg of donidalorsen every four weeks or every eight weeks or placebo, with a total of 90 people across the cohorts. In the four-week cohort, which featured 45 patients, donidalorsen significantly reduced monthly attacks by 87% compared to placebo, which was a key secondary endpoint. The drug also reduced severe to moderate attacks per month by 89% in the same time frame and reduced attacks that required acute therapy by 92%. At week 25, 91% of patients taking the drug in this group had well-controlled disease. While Ionis did not provide detailed data on the eight-week group, the company said patients had a similar benefit. In the OASISplus study, an open-label extension and switch trial, attack rates continued to improve over time, with 93% and 92% improvements from baseline in the four-week and eight-week groups, respectively. Patients also had improved quality of life. In a group of patients who previously switched over to donidalorsen, there was a 62% improvement in monthly attacks compared to baseline. Patients also managed the transition without breakthrough attacks. William Blair analysts said donidalorsen has showcased a “highly competitive” profile with the latest cut of data. An approval in 2025 is expected as Ionis is planning to submit a new drug application soon. “Ultimately, we see donidalorsen’s profile as generally superior to current prophylactic options, with less frequent dosing and at-home autoinjector dosing potential being further differentiators,” William Blair’s analysts wrote Friday morning. The profile is comparable to CSL Behring’s garadacimab, which is under review for the indication with a decision expected by year end. However, garadacimab requires a loading dose administered in-office followed by monthly injections, whereas patients can self-administer donidalorsen, with the possibility of dosing every eight weeks. Ionis is behind CSL Behring, but William Blair believes the market can handle multiple options. If Ionis captures a conservative 15% of the market, revenue could reach $450 million in the U.S. in 2030. “We view today’s updates as positive for Ionis, with the current donidalorsen clinical profile appearing as good or better overall than available and other late-stage options, which is reinforced in data from the switch study showing a strong patient preference,” the analysts said.

New research has revealed a previously unknown biological process through which breast tumor cells develop resistance to standard treatment, which could open the door for cancer scientists around the world to further target this vulnerability in hopes of creating more effective therapies for disease. Additionally, the research team tested a promising drug in combination with an existing therapy that achieved total remission in one breast cancer model that was resistant to the standard of care, and reduced cancer growth by nearly 70% in other models of advanced disease. New research out of VCU Massey Comprehensive Cancer Center -- recently published in Drug Resistance Updates -- revealed a previously unknown biological process through which breast tumor cells develop resistance to standard treatment, which could open the door for cancer scientists around the world to further target this vulnerability in hopes of creating more effective therapies for disease. Additionally, the research team tested a promising drug in combination with an existing therapy that achieved total remission in one breast cancer model that was resistant to the standard of care, and reduced cancer growth by nearly 70% in other models of advanced disease. "Overcoming drug resistance is very important; we're talking about developing new drugs that will provide hope to cancer patients who have exhausted all options available to them," said study author Yuesheng Zhang, M.D., Ph.D., the Harrigan, Haw and Luck Families Chair in Cancer Research and a member of the Developmental Therapeutics research program at Massey. HER2-positive breast cancers represent nearly one-fifth of all breast tumors and often grow and spread much faster than tumors that are HER2-negative, according to the American Cancer Society. In the clinic, there are three classes of drugs approved to treat this type of cancer: 1) monoclonal antibodies (trastuzumab, sold under the brand name Herceptin, is the most commonly used drug to treat HER2-positive breast cancer), 2) tyrosine kinase inhibitors and 3) antibody small molecule conjugates. These drugs are all designed to target the HER2 protein receptor, but Zhang's team found that none of them are actually strong enough to completely eliminate it, offering the tumor cells more freedom to partner with other proteins within the cells to initiate cancer signaling, continue to multiply and spread. "It's actually quite striking. It turns out the efficacy of the standard of care is very limited, and not only do a small percentage of patients respond to treatment, even the ones who are responding will very quickly develop resistance," said Zhang, who is also a professor in the Department of Pharmacology and Toxicology at the VCU School of Medicine. This paper shines a light on the clinical need to more completely rid the cancer cells of HER2, but it also points a finger at the EGFR gene family being just as important in these tumors, suggesting that truly effective drugs need to target both the HER2 and EGFR receptors to eradicate disease. "This study shows that an agent that targets the degradation of both HER2 and EGFR is highly effective in overcoming drug resistance in this disease," Zhang said. "The findings provide new insights and innovations for advancing treatment of drug-resistant HER2-positive breast cancer that remains an unmet problem." In addition to unveiling a key flaw hindering current treatment options for breast cancer, Zhang and his research team also tested a novel agent that showed promising results against these tumors. In one model, the drug achieved complete remission in combination with garadacimab, another type of monoclonal antibody. In other models where the tumors had spread to the brain, the researchers found their drug inhibited tumor growth by up to 68%. "This means that this drug can actually cross the blood-brain barrier to attack the tumor in the brain," Zhang said. Zhang added they are currently in talks with the National Cancer Institute for them to manufacture the drug in an effort to gain FDA approval and move it into clinical trials. While the team observed encouraging results with the drug they tested in the study, Zhang said the most important impact of this research is to inform other investigators about the underlying mechanism that can be targeted in HER2-positive breast cancer to improve patient outcomes. "This paper will move the field forward because cancer scientists can develop other drugs to target this vulnerability; our agent is only one of those," Zhang said. Collaborators on this study include Lu Yang, Ph.D., Arup Bhattacharya, Ph.D., Yun Li, M.S., and Valentina Robila, M.D., Ph.D., of the VCU School of Medicine; Darrell Peterson, Ph.D., of the VCU School of Pharmacy; Xiaozhuo Liu, Ph.D., of Roswell Park Comprehensive Cancer Center; and Elisabetta Marangoni, Ph.D., of the Institute of Curie in France.