SMAD2

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.

LEXINGTON, Mass., May 22, 2023 (GLOBE NEWSWIRE) -- Keros Therapeutics, Inc. (“Keros”) (Nasdaq: KROS), a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of novel treatments for patients suffering from hematological, pulmonary and cardiovascular disorders with high unmet medical need, today announced that it presented additional biomarker data from its completed Phase 1 clinical trial of KER-012 in healthy post-menopausal women at the American Thoracic Society (“ATS”) 2023 International Conference, held from May 19 through May 24, 2023. In addition, Keros presented preclinical data showing the potential of a research form of KER-012 (“RKER-012”) to improve left ventricular function in a mouse model of left ventricular pressure overload, as well as preclinical data evaluating transforming growth factor-beta (“TGF-β”) signaling in two major cell types involved in the dysregulated vascular remodeling in pulmonary arterial hypertension (“PAH”), and KER-012’s effect on this ligand-induced signaling. “We are pleased to present clinical and preclinical data from our KER-012 program at the ATS conference this year. The preclinical presentations demonstrate observed ligand selectivity of KER-012 and changes in inflammation and fibrosis in models of PAH and cardiovascular diseases. From our completed Phase 1 clinical trial of KER-012 in healthy post-menopausal women, we presented new data with observed sustained changes in serum biomarkers of cardiac dysfunction, inflammation and fibrosis,” said Jasbir S. Seehra, Ph.D., President and Chief Executive Officer of Keros. “We believe these data support the potential of KER-012 to treat fibrosis and inflammation in patients with PAH and in patients with cardiovascular disease.” Clinical Presentation Administration of KER-012, a Modified Activin Receptor IIB Ligand Trap, Led to Changes in Biomarkers of Cardiovascular Health in a Ph1 Study Conducted in Healthy Post-Menopausal Women This Phase 1 clinical trial was a randomized, double-blind, placebo-controlled, two-part trial to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of KER-012. Keros reported preliminary topline data from the Part 1 single ascending dose portion of the trial in May 2022, and additional preliminary clinical data from the Part 2 multiple ascending dose portion of the trial in September 2022. The following data from the subjects enrolled in the highest dose cohort (4.5 mg/kg) from Part 2 of this trial were presented at ATS 2023: Serum proteins associated with inflammation and structural remodeling pathways were altered following one dose of 4.5 mg/kg of KER-012 versus placebo, which Keros believes is consistent with the predicted mechanism of action of KER-012: Decreases in markers of fibrosis, as indicated by changes in matrix metalloproteinases (MMP-7 and 10) and collagen fragments, were observed;Reductions in pro-inflammatory cytokines (IL-6 and IL-11) were observed; andIncreases in anti-inflammatory cytokines (IL-4 and IL-35) and markers of macrophage polarization (MARCO and sCD163) were also observed. Sustained reductions in a biomarker of cardiac dysfunction (serum N-terminal pro-brain natriuretic peptide) were observed in subjects administered 4.5 mg/kg of KER-012 versus placebo. Preclinical Presentations RKER-012, a Novel Modified ActRII Ligand Trap, Attenuated Cardiac Remodeling and Fibrosis in a Transverse Aortic Constriction Model of Heart Failure Keros used a transverse aortic constriction (“TAC”) model of left ventricle overload to evaluate whether RKER-012 could prevent or treat cardiac remodeling and fibrosis in mice. Mice either underwent sham or TAC surgery. Following these procedures, sham mice received vehicle and TAC mice received either vehicle (“TAC-vehicle”) or 10 mg/kg of RKER-012 (“TAC-RKER-012”) twice weekly, starting from the first day (“TAC-RKER-012 Group 1”) or fourteenth day (“TAC-RKER-012 Group 2”) after surgery. Eight weeks post-surgery, mice were assessed for associated cardiac pathologies. Relative to sham mice, TAC-vehicle mice had increased heart weight, left ventricular posterior wall thickness, interventricular septal end diastole, left ventricular fibrosis and elevated tissue remodeling markers, indicating that the TAC surgery worked as intended. TAC-RKER-012 Group 1 mice had significantly reduced heart weight, left ventricular posterior wall thickness, interventricular septal end diastole and left ventricular fibrosis compared to TAC-vehicle mice. TAC-RKER-012 Group 2 mice had significantly reduced left ventricular posterior wall thickness and interventricular septal end diastole compared to TAC-vehicle mice, while heart weight and left ventricular fibrosis trended towards a decrease. These data demonstrate that RKER-012 lessened the severity of cardiac fibrosis and remodeling, leading to an improvement in left ventricular function, which Keros believes supports the potential of KER-012 to benefit heart failure patients as a preventative or treatment option. RKER-012, a Novel Activin Receptor Type IIB (ActRIIB) Ligand Trap, Inhibited Mediators of Dysregulated Vascular Remodeling in Pulmonary Endothelial and Smooth Muscle Cells This preclinical study evaluated TGF-β ligand signaling in human pulmonary arterial endothelial cells (“HPAECs”) and smooth muscle cells (“HPASMCs”), which are two major cell types involved in the dysregulated vascular remodeling in PAH, and KER-012’s effect on this ligand-induced signaling. HPAECs and HPASMCs were treated with activin A, GDF11, or bone morphogenetic protein 9 (“BMP9”) in the presence of KER-012. KER-012 treatment reduced activin A and GDF11-induced SMAD 2/3 signaling in the HPAECs and HPASMCs, but did not inhibit BMP9-induced pSMAD1 signaling. Separately, pulmonary arterial cells cultured in normoxia or hypoxia for 48 hours to mimic conditions in PAH were evaluated with RKER-012. Keros observed increases in activin A induced by hypoxia in HPAECs, but not in HPASMCs, which is consistent with the role of endothelial dysfunction in PAH and suggests that activin A may be released from endothelial cells during vascular remodeling. RKER-012 was able to reduce SMAD2 activation in hypoxic endothelial cells back to normoxic levels by binding endogenously upregulated activin A in an in vitro model replicating hypoxia in PAH. These data from this in vitro model suggest that KER-012 can potentially correct imbalanced SMAD signaling in PAH, partially by inhibiting activin A, a key pathogenic driver of PAH. About the Completed Phase 1 Clinical Trial of KER-012 in Healthy Volunteers In September 2022, Keros completed a randomized, double-blind, placebo-controlled, two-part Phase 1 clinical trial to evaluate single and multiple ascending doses of KER-012 in healthy post-menopausal women. The primary objectives of this trial were to evaluate the safety and tolerability of escalating doses of KER-012 administered as single and multiple subcutaneous doses in healthy post-menopausal women. In Part 1 of this trial, 32 subjects received either a single 0.75, 1.5, 3 or 5 mg/kg dose of KER-012 and eight subjects received a single dose of placebo, each administered subcutaneously with an eight-week safety follow-up. The subjects were enrolled in sequential single-ascending dose escalation cohorts of ten subjects each. In Part 2 of the trial, subjects received three subcutaneous doses of either 0.75, 1.5 or 4.5 mg/kg of KER-012 or placebo administered 28 days apart with a 16-week safety follow-up. A total of 26 subjects were enrolled in three sequential multiple-ascending dose escalation cohorts, with eight subjects in the 0.75 mg/kg cohort and six subjects in each of the 1.5 mg/kg and 4.5 mg/kg cohorts receiving KER-012. Six subjects enrolled in Part 2 of this trial received placebo doses. About KER-012 KER-012 is designed to bind to and inhibit the signaling of TGF-β ligands that suppress bone growth, including activin A and activin B. Keros believes that KER-012 has the potential to increase the signaling of bone morphogenic protein (“BMP”) pathways through this inhibition of activin A and activin B signaling, and consequently treat diseases such as PAH that are associated with reduced BMP signaling due to inactivating mutations in the BMP receptors. KER-012 is being developed for the treatment of PAH and for the treatment of cardiovascular disorders. About Keros Therapeutics, Inc. Keros is a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of novel treatments for patients suffering from hematological, pulmonary and cardiovascular disorders with high unmet medical need. Keros is a leader in understanding the role of the TGF-β family of proteins, which are master regulators of red blood cell and platelet production as well as of the growth, repair and maintenance of a number of tissues, including blood vessels and heart tissue. Keros’ lead protein therapeutic product candidate, KER-050, is being developed for the treatment of low blood cell counts, or cytopenias, including anemia and thrombocytopenia, in patients with myelodysplastic syndromes and in patients with myelofibrosis. Keros’ lead small molecule product candidate, KER-047, is being developed for the treatment of functional iron deficiency. Keros’ third product candidate, KER-012, is being developed for the treatment of PAH and for the treatment of cardiovascular disorders. Cautionary Note Regarding Forward-Looking Statements Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. Words such as "believes," "intends," “potential” and "suggest" or similar expressions are intended to identify forward-looking statements. Examples of these forward-looking statements include statements concerning: Keros’ expectations regarding its growth, strategy, progress and the design, objectives and timing of its clinical trials for KER-012; the potential of KER-012 to treat fibrosis and inflammation in patients with PAH and in patients with cardiovascular disease; the potential of KER-012 to benefit heart failure patients as a preventative or treatment option; and the potential of KER-012 to correct imbalanced SMAD signaling in PAH. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. These risks and uncertainties include, among others: Keros’ limited operating history and historical losses; Keros’ ability to raise additional funding to complete the development and any commercialization of its product candidates; Keros’ dependence on the success of its product candidates, KER-050, KER-047 and KER-012; that Keros may be delayed in initiating, enrolling or completing any clinical trials; competition from third parties that are developing products for similar uses; Keros’ ability to obtain, maintain and protect its intellectual property; and Keros’ dependence on third parties in connection with manufacturing, clinical trials and preclinical studies. These and other risks are described more fully in Keros’ filings with the Securities and Exchange Commission (“SEC”), including the “Risk Factors” section of the Company’s Quarterly Report on Form 10-Q, filed with the SEC on May 4, 2023, and its other documents subsequently filed with or furnished to the SEC. All forward-looking statements contained in this press release speak only as of the date on which they were made. Except to the extent required by law, Keros undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made. Investor Contact: Justin Frantzjfrantz@soleburytrout.com617-221-9100