SMAD2

Human papillomavirus (HPV) is the second most common cancer-causing virus, accounting for 690,000 cervical and other cancers each year worldwide. While the immune system usually clears HPV infections, those that persist can lead to cancer, and a new finding suggests that certain women may have a genetic susceptibility for persistent or frequent HPV infections. These genetic variants could raise a woman's risk of getting cervical cancer from a high-risk HPV infection. Human papillomavirus (HPV) is the second most common cancer-causing virus, accounting for 690,000 cervical and other cancers each year worldwide. While the immune system usually clears HPV infections, those that persist can lead to cancer, and a new finding suggests that certain women may have a genetic susceptibility for persistent or frequent HPV infections. These genetic variants, identified in a study led by University of Maryland School of Medicine researchers, could raise a woman's risk of getting cervical cancer from a high-risk HPV infection. Findings were recently published in The European Journal of Human Genetics. The research team conducted a genome-wide association study of high-risk HPV infections in a cohort of over 10,000 women, whose data were collected as part of the African Collaborative Center for Microbiome and Genomics Research (ACCME) cohort study. A total of 903 of the participants had high-risk HPV infections when the study began, with 224 participants having HPV infections that resolved, and 679 having persistent HPV infections. More than 9,800 HPV-negative women from the ACCME study served as controls. "We found certain genetic variants were associated with having high-risk HPV infections, while other variants and human leukocyte antigen (HLA) genes were associated with persistent infections, which increase the risk of developing cervical cancer," said study leader Sally N. Adebamowo, MBBS, MSc, ScD, Associate Professor of Epidemiology & Public Health at UMSOM. "This is a critical finding that suggests genetic underpinnings for cervical cancer risk. It is the first sufficiently powered genome-wide association study of cervical high-risk HPV infections. Our polygenic risk score models should be evaluated in other populations." Specifically, she and her colleagues found that the top variant associated with prevalent high-risk HPV infection was rs116471799, on the fourth chromosome near the LDB2 gene, which encodes for proteins. They found persistent HPV was associated with variants clustered around the TPTE2, a protein encoding gene associated with gallbladder cancer. The genes SMAD2 and CDH12 were also associated with persistent high risk HPV infections, and significant polygenic risk scores. Together the findings enabled the research team to develop polygenic risk scores to determine the likelihood that a certain genetic pro increase the risk of having prevalent or persistent HPV infections. "Our findings can be used for risk stratification of persistent high-risk HPV infections for precision or personalized cervical cancer prevention. We hope to conduct long-term studies on the integration of PRS and genomic risk factors into the continuum of cervical cancer prevention," said study corresponding author Clement A. Adebamowo, BM, ChB, ScD, Professor of Epidemiology & Public Health at UMSOM. A recent report from the American Cancer Society found that cervical cancer among women ages 30 to 44 rose almost 2 percent a year from 2012 to 2019. This is after a big decline in cervical cancer rates over the past half-century due to early detection from Pap smears and HPV screening tests. In addition, rates of cervical cancer, have steadily declined among younger women who were among the first to benefit from HPV vaccines, which were approved for use in 2006. In the U.S., more than half of women diagnosed with cervical cancer have never been screened or were not screened in the last five years, according to the Centers for Disease Control and Prevention. In Nigeria, only a small percentage of women have access to the HPV vaccine, so those included in the study were largely unvaccinated. "The results provide insight into the role of antigen processing and presentation, and HLA-DRB1 alleles in immune surveillance and persistence of high-risk HPV infections," said Mark T. Gladwin, MD, who is the John Z. and Akiko K. Bowers Distinguished Professor and Dean, UMSOM, and Vice President for Medical Affairs, University of Maryland, Baltimore. "Confirmatory studies are crucial to validate these important findings in other populations, with the goal of reducing the burden of high-risk HPV related diseases on global health." Study co-authors included those from: the National Human Genome Research Institute in Bethesda, MD; Asokoro District Hospital in Abuja, Nigeria; Federal Medical Center in Keffi, Nigeria; Wuse General Hospital in Abuja, Nigeria; University College Hospital, University of Ibadan, Ibadan, Nigeria; Institute of Human Virology Nigeria, Abuja, Nigeria; Garki Hospital Abuja, Abuja, Nigeria; University of Abuja Teaching Hospital, Gwagwalada, Abuja, Nigeria; National Hospital Abuja, Abuja, Nigeria; Kubwa General Hospital, Abuja, Nigeria. This work was supported by the African Collaborative Center for Microbiome and Genomics Research Grant (NIH/NHGRI 1U54HG006947), UM-Capacity Development for Research in AIDS Associated Malignancy Grant (NIH/NCI 1D43CA153792-01), and Polygenic Risk Score (PRS) Methods and Analysis for Populations of Diverse Ancestry -- Study Sites (NIH/NHGRI 1U01HG011717).

Pictured: Bristol Myers Squibb in NJ/iStock, arlutz73 Bristol Myers Squibb is advancing towards its $4 billion-plus sales aspirations for Reblozyl with another indication added to its label. Monday, BMS announced that the FDA bumped up the therapy to a first-line treatment option for anemia in adults with low- to intermediate-risk myelodysplastic syndromes who may require regular blood transfusions. Reblozyl, a recombinant fusion protein designed to suppress the Smad2/3 signaling pathway to increase red blood cell counts, was first authorized in 2019 for anemia in beta-thalassemia. The therapy, co-marketed with Merck, was approved for myelodysplastic syndromes (MDS)-related anemia in 2020 but only in patients who had failed to respond to an erythropoiesis-stimulating agent (ESA), the historically front-line treatment. The label expansion was backed by data from the Phase III COMMANDS study, which put BMS’ therapy head-to-head with the ESA standard of care treatment. Over 58% of patients treated with Reblozyl achieved transfusion independence compared to 31% of patients receiving epoetin alfa, the ESA drug manufactured by Amgen and Johnson & Johnson marketed as Epogen and Procrit, respectively. The trial also proved the drug was effective in patients with and without ring sideroblasts—blood cells with iron deposits circling the nucleus. Previous approval had limited the drug’s use to MDS patients exhibiting this common symptom. “Reblozyl is the first and only therapy to demonstrate superiority compared to an erythropoiesis stimulating agent (ESA) in MDS-related anemia,” according to the company’s press release. BMS has high hopes for the therapy. Second-quarter 2023 sales came in at $234 million. As the company works to add more indications to the drug’s label, BMS is projecting sales of over $4 billion by 2030. Reblozyl is also in a Phase III trial for myelofibrosis patients with myeloproliferative neoplasm slated for a readout in 2025. However, competition may be heating up in the MDS market as Geron Corporation submitted its NDA earlier this month for a first-in-class telomerase inhibitor to treat transfusion-dependent anemia with lower risk MDS. Tested in a Phase III trial against a placebo, imetelstat showed significantly higher results in the eight-week transfusion independence endpoint. “The majority of patients with MDS experience chronic anemia and require RBC transfusions,” Tracey Iraca, executive director of the MDS Foundation, said in the BMS press release. “The approval of Reblozyl in the first-line treatment of anemia for patients with lower-risk MDS represents a crucial step in making transfusion independence possible for more patients.” Kate Goodwin is a freelance life science writer based in Des Moines, Iowa. She can be reached at kate.goodwin@biospace.com and on LinkedIn.

Pictured: FDA sign in front of building/iStock, JHVEPhoto The FDA is facing down three upcoming target action dates in the next two weeks, including one in myelodysplastic syndrome and another in wet age-related macular degeneration (AMD). Read below for more. BMS Pushes to Expand Reblozyl’s Label By Aug. 28, the FDA will release its verdict on Bristol Myers Squibb’s supplemental BLA, proposing Reblozyl (luspatercept-aamt) as a treatment option for anemia in adult patients with low- to immediate-risk myelodysplastic syndromes (MDS) without prior use of erythropoiesis-stimulating agents (ESA). Reblozyl is a recombinant fusion protein that works by binding several ligands under the TGF-β superfamily. In turn, this suppresses the Smad2/3 signaling pathway, which leads to an increase in the number and quality of mature red blood cells. The treatment was first authorized in November 2019 for anemia in beta-thalassemia. In April 2020, Reblozyl also won approval as a treatment for anemia in lower-risk MDS, but only patients who had failed a prior round of ESA treatment were eligible to receive it. In BMS’s sBLA, which the FDA accepted and granted priority review in May 2023, the company proposed making Reblozyl accessible even for ESA-naive patients. BMS backed its bid for label expansion with data from the Phase III COMMANDS study, an open-label and randomized trial that compared Reblozyl with the ESA epoetin alfa in the front-line setting for MDS. Results from the study, which were presented at the 2023 ASCO Annual Meeting last May, demonstrated that 58.5% of Reblozyl-treated patients achieved transfusion independence, compared with 31.2% of those who received epoetin alfa. There were slightly more safety signals in the Reblozyl arm, including eight patients who dropped out due to toxicities, as opposed to four withdrawals in the epoetin alfa group, but death and progression to acute myeloid leukemia were similar between treatment arms. BMS acquired Reblozyl when it bought Celgene in 2019 and is developing and commercializing the therapy in collaboration with Merck, which acquired Acceleron, Celgene’s partner in Reblozyl’s development, in September 2021. Outlook Awaits Verdict in Wet AMD A day after its BMS decision is on the calendar, the FDA is scheduled to release its verdict on Outlook Therapeutics’ BLA for ONS-5010 in the treatment of wet AMD. If approved, Outlook expects ONS-5010, an investigational ophthalmic formulation of bevacizumab, to have 12 years of regulatory exclusivity in the U.S. and could eliminate the need to use off-label and unapproved intravitreal bevacizumab from compounding pharmacies, according to the company. Bevacizumab, sold by Genentech under the brand name Avastin for the treatment of several cancers, is a VEGF inhibitor that works by blocking the interaction of the protein with its cell surface receptors. This prevents the growth of blood vessels, thereby cutting off a tumor’s supply of nutrients and oxygen. In eye diseases, however, bevacizumab is often used on an off-label basis, meaning that it is being administered without the FDA’s specific approval. “We estimate that approximately 50% of the millions of anti-VEGF injections in ophthalmology are off-label compounded bevacizumab that is administered with no FDA-approved labeling,” Outlook president and CEO Russell Trenary said in the company’s press release announcing the FDA’s acceptance of its BLA. Outlook’s bevacizumab formulation meets the regulator’s criteria for intravitreal biologics, the company said. Its BLA is supported by data from the NORSE clinical program, which includes three trials looking at the safety and efficacy of the investigational formulation as compared with Genentech’s Lucentis (ranibizumab), an approved wet AMD treatment. Overall, the studies showed that Outlook’s formulation was safe and could elicit significant vision improvements, according to the company, which is also seeking approval for its bevacizumab formulation in Europe. BioLineRx Proposes Aphexda for Stem Cell Mobilization Next week, on or before Sept. 9, the FDA will decide on BioLineRx’s NDA proposing Aphexda (motixafortide) as a stem cell mobilization agent for patients with multiple myeloma scheduled for autologous stem cell transplantation (ASCT). In multiple myeloma, as in many other blood cancers, ASCT is part of the standard treatment regimen, often used alongside high-dose chemotherapy. To eliminate the cancer cells from the body, patients with multiple myeloma are exposed to systemic aggressive treatments, including chemotherapy and whole-body radiation therapy. However, these also often end up damaging healthy stem cells. ASCT replenishes these cells and helps the body make healthy blood cells. Before stem cells can be harvested from the body, they must first be mobilized, a process by which the stem cells are drawn into the bloodstream from the bone marrow. This is usually achieved through chemotherapy itself or with the use of colony stimulating factors (CSF). In its NDA, BioLineRx presented data from the Phase III GENESIS trial, which assessed the effect of adding Aphexda to granulocyte-CSF on stem cell mobilization. Just one round of add-on Aphexda in a single apheresis session mobilized the optimal number of stem cells in around 90% of patients, who were then able to proceed directly to transplantation. In comparison, only 10% of patients who received granulocyte-CSF with placebo reached a similar level of stem cell mobilization. These data suggest that Aphexda has the potential to “become the standard of care in the multiple myeloma transplant setting,” BioLineRx CEO Philip Serlin said in a statement announcing the NDA’s acceptance. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.