NKX3-1

Astellas’ headquarters for the Americas iStock, JHVEPhoto One patient developed elevated liver blood tests after receiving Astellas Pharma’s non-hormonal small molecule blocker, leading the regulator to add a warning to the drug’s label. The FDA on Thursday added a warning to the label of Astellas Pharma ’s hot flash therapy Veozah (fezolinetant), alerting patients and prescribers to a newly documented risk of “rare but serious” liver injury. The new warning was prompted by a postmarketing review of a patient who was taking Veozah and subsequently saw spikes in liver blood test values. The patient also showed signs of liver injury after being treated for around 40 days, according to the regulator. Per Veozah’s updated label , prescribers should test their patients’ blood liver markers more frequently, including monthly screens for the first two months after initiating Veozah, followed by additional tests after three, six and nine months. Doctors and prescribers should also conduct hepatic testing before starting patients on Veozah. In case of signs that could indicate liver problems, patients should stop taking Veozah “immediately” and contact their healthcare professional, according to the FDA. Common symptoms of liver harm include fatigue, jaundice, nausea and vomiting, as well as unusual itching and light-colored stools. Despite being a hit to Veozah’s safety profile, Thursday’s label seems unlikely to substantially hurt Astellas. Jeffries analysts in a note to investors said that the new warning “strengthened Veozah’s label” and that while the additional testing requirements will put more burden on patients, they “may not have much impact on demand overall.” Administered orally, Veozah is a non-hormonal small molecule blocker of the NK3 receptor which plays a part in the signaling cascade that results in the release of specific hormones involved in the menstrual cycle. Veozah specifically acts on neurons in the brain’s thermoregulatory centers, allowing it to reduce the frequency and intensity of hot flashes and night sweats. The FDA approved Veozah in May 2023 for women in menopause. In December 2023, Astellas unveiled more Phase IIIb data for Veozah, touting statistically significant improvements in moderate to severe vasomotor symptoms in patients at 24 weeks compared with placebo. Veozah also reduced sleep disturbance in these patients. At the time, the pharma noted that these findings will help it with reimbursement negotiations in Europe. Bayer is also advancing a non-hormonal competitor to Veozah. Elinzanetant is a small molecule dual inhibitor of the NK1 and NK3 receptors, which the pharma is also positioning as a treatment for moderate to severe vasomotor symptoms in menopause. Bayer won rights to elinzanetant when it bought KaNDy Therapeutics in August 2020 for $425 million upfront . In May 2024, Bayer reported data from its pivotal Phase III OASIS 1 and OASIS 2 studies, demonstrating that elinzanetant significantly lowered the frequency of hot flashes, reduced sleep disturbances and improved menopause-related quality of life.

Bayer has unveiled detailed data from two pivotal trials of its investigational menopause drug elinzanetant, setting the stage for a heated commercial battle with Astellas' already approved Veozah (fezolinetant) in the long-neglected vasomotor symptoms (VMS) market.At the American College of Obstetricians and Gynecologists (ACOG) annual meeting, Bayer presented detailed results from the OASIS 1 and 2 studies, demonstrating that the dual neurokinin-1,3 (NK-1,3) receptor antagonist significantly reduced the frequency and severity of moderate-to-severe hot flashes associated with menopause. A total of about 800 post-menopausal women were enrolled across the two studies.Stacking up to VeozahIn OASIS 1, elinzanetant showed significant mean reductions versus placebo in hot flash frequency of 3.29 at week 4 and 3.22 at week 12. For severity, the reductions were 0.33 and 0.40 at those timepoints, respectively.OASIS 2 yielded similar results, with elinzanetant demonstrating significant mean reductions in frequency of 3.04 at week 4 and 3.24 at week 12, and in severity of 0.22 and 0.29, respectively.The data could position elinzanetant as a strong competitor to Veozah, an NK-3 receptor antagonist approved last year for the treatment of VMS. It is also cleared in Europe under the name Veoza. In the SKYLIGHT 1 and SKYLIGHT 2 trials, Astellas' drug reduced hot flash frequency by 2.07 and 2.55 at week 4 and by 2.53 and 2.55 at week 12. Hot flash severity reductions were about 0.20 and 0.29 across the two SKYLIGHT studies, respectively.While efficacy data suggest a closely matched rivalry, other factors could tilt the scales. Bayer said elinzanetant also met key secondary endpoints in OASIS 1 and 2, significantly improving sleep compared to placebo. Mean change from baseline to week 12 on the PROMIS sleep disturbance measure was 5.58 in OASIS 1 and 4.32 in OSAIS 2 in favour of elinzanetant over placebo.No liver injuryStudy drop-outs due to adverse events were higher in the elinzanetant arms than placebo in both studies (8.5% vs 6.7% in OASIS 1; 6.5% vs 2% in OASIS 2).Liver safety has also been a point of concern for Veozah, which requires liver function testing due to possible increases in hepatic serum transaminase levels. However, researchers said there were "no cases of drug-induced liver injury causally related to elinzanetant" or any incidences of endometrial hyperplasia or malignant neoplasm in either of the OASIS studies, according to the ACOG presentations.In a recent interview with FirstWord, Waljit Dhillo, professor of endocrinology and metabolism at Imperial College London, said "it would definitely be a big difference" if elinzanetant avoids such liver monitoring requirements. "If you can just give a tablet and then go away, that would be attractive."Hitting the NK1 receptor could theoretically provide elinzanetant with better liver safety and less sleep disturbance compared to Veozah, which only targets NK3. However, when asked how optimistic he was about whether elinzanetant could necessitate less liver monitoring, Dhillo noted that since there are no NK3 receptors in the liver, any differentiation in liver safety may come down to differences in the specific molecules rather than their receptor targets.FirstWord recently caught up with Astellas leadership to discuss Veozah, including the concerns regarding liver safety. For more on that interview, see – ViewPoints: Having broken ground in untapped menopause market, Astellas outlines strategy for Veozah as competition heats up.First-mover advantage?"The robust efficacy and favourable safety profile of elinzanetant reinforces its potential as a non-hormonal treatment for women experiencing menopause," said Bayer's R&D head Christian Rommel in a company release. Bayer plans to submit elinzanetant's data to regulatory authorities for marketing approval this year, setting up a commercial clash with Astellas' first-mover advantage. "Our preparations to obtain first-market authorisations are running at full steam," Bayer CEO Bill Anderson stated at the company's earning call this week.Bayer would not disclose elinzanetant's price until the FDA clears it, although some analysts suggest it could cost as much as or more than Veozah, which can cost at least $550 for a month's supply.Commenting on the OASIS readouts, Morgan Stanley analysts said that "although elinzanetant appears slightly more effective than Veozah in reducing symptom frequency over 12 weeks, we do not think this will make a big difference in terms of business. Bayer is due to launch the drug in 2025, giving Veozah a two-year advantage."

Studies exploring metformin's power to prevent prostate cancer progression have been inconclusive. Research now shows that the drug has promise, but only for specific patients. In the years since a 2005 study found that diabetes patients taking metformin had lower rates of cancer, oncologists have been excited by the prospect of using the inexpensive, safe, and widely used diabetes drug to prevent or slow the development of many cancers. But in studies of prostate cancer, metformin performance has been mixed, with some studies reporting a lower incidence of prostate cancer among men using metformin and others finding no relationship. Now a new study from Columbia researchers suggests that metformin is indeed a promising drug that could prevent the progression of prostate cancer, but only for tumors with low levels of NKX3.1, which are more likely to develop into aggressive cancers. The researchers found that metformin restores cancer-fighting mitochondrial activity that is lost when NKX3.1 levels are low, prevents prostate cancer progression in mice, and is associated with better survival in patients with low-NKX3.1 tumors but not high-NKX3.1 tumors. "Where we see metformin having the biggest impact is in patients who've just been diagnosed with prostate cancer," says Alex Papachristodoulou, Ph.D., associate research scientist, who conducted the research in the lab of Cory Abate-Shen, Ph.D., chair of the Department of Molecular Pharmacology & Therapeutics. Most patients with new diagnoses of prostate cancer have low-grade tumors that are not treated and are instead monitored by active surveillance. But some of these tumors will become more aggressive and potentially life-threatening. "Metformin could be given to patients under surveillance with high-risk tumors when there's still time to prevent progression to advanced disease," Abate-Shen says. "Until this study no one understood this essential aspect of metformin and which patients could benefit," says Columbia oncologist Mark Stein, M.D., who is helping design a clinical trial to test the idea in newly diagnosed patients but was not involved in the new study. "The new work reinvigorates the idea of using this safe and inexpensive drug in a way that could benefit prostate cancer patients, potentially sparing them from additional treatment, and allows us to test the drug in a more focused way." The mitochondria connection The idea to test metformin and its interaction with NKX3.1 developed from Papachristodoulou and Abate-Shen's previous study, which revealed how low levels of the protein promote prostate cancer. Low levels of NKX3.1 have been linked with aggressive disease for years, but it was unclear why the deficiency drove cancer development. Papachristodoulou and Abate-Shen found that when prostate cells are under oxidative stress (as happens during prostate cancer development), NKX3.1 moves into the cells' mitochrondria to reduce the stress and protect the cells. If NKX3.1 levels are low, less protection is available, and prostate cells are more likely to turn malignant. "That's when we realized how metformin might be able help, since metformin is known to act on the mitochondria," Papachristodoulou says. In mice and men, metformin slows prostate cancer To test metformin's effect on low-NKX3.1 prostate cancers, the researchers gave metformin to low-NKX3.1 mice that tend to develop prostate cancer. "These mice mimic the progression from lower- to higher-grade prostate cancer, similar to the cancers found in men who are put on active surveillance," Papachristodoulou says, "but with metformin, we were able to stop further progression of the cancer." The researchers then looked at human prostate cancer cells and tissues, confirming that metformin works on the same mitochondrial processes in people and prevents further cancerous changes. "The work was very elegant," says Stein. "The models they have developed to understand the disease were key to answering the question. And to find a whole new mechanism of action for a drug that's so ubiquitous is very unusual." Finally, with the help of long-standing clinical collaborators James McKiernan, Renu Virk, and Mitchell Benson at Columbia, Max Loda at Cornell, and others in Europe, the researchers retrospectively examined the effect of metformin in two groups of men who had been treated for prostate cancer. (Many men in both groups took metformin for their diabetes.) After measuring NKX3.1 levels in tissue samples from the patients, researchers found that metformin only benefitted patients with low NKX3.1 levels and mitochondrial impairment. Remarkably, among men with low NKX3.1 cancers under active surveillance, those taking metformin (three out of three) had their cancers downgraded during the surveillance period, while three out of four patients who did not take metformin had their cancers upgraded. Potential to help reduce prostate cancer disparities Papachristodoulou and Abate-Shen are now working with Stein, McKiernan, Loda, and others to set up a clinical trial to test if metformin can prevent the progression of prostate cancer in men with newly diagnosed, low-NKX3.1 tumors who are under active surveillance. NKX3.1 levels are not typically measured in men newly diagnosed with prostate cancer, but based on the two cohorts examined, about 50% to 60% of patients may have low expressing NKX3.1 tumors. Metformin could be particularly helpful for Black men, Papachristodoulou says, because they are more likely than white men to develop aggressive prostate cancer. "Though some of the health disparities are due to socioeconomic and health care inequities, we think there are biological factors like differences in NKX3.1 levels and mitochondria that also contribute," Papachristodoulou says. Along with studies to find additional biomarkers that identify patients with the greatest risk of developing aggressive prostate cancer, Papachristodoulou will continue to pursue disparities research in the Abate-Shen lab and his future independent career, with the help of a new K99/R00 grant he received last month. Mitochondria, he thinks, may provide some answers. "The search for biomarkers that can predict prostate cancer development and progression has largely focused on the nuclear genome, overlooking the mitochondrial genome," he says, "but we know that alterations in mitochondrial genes are associated with lethal prostate cancer, particularly in Black men. I'm hoping that with the new grant, I'll be able to identify more mitochondrial-related biomarkers like NKX3.1 and we can ultimately improve survival."