DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for anemia (phenotype) — screening already-approved drugs against its 66-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleAnemia (phenotype) maps to a 66-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Structures already discussed alongside anemia (phenotype) in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
ABO, alpha 1-3-N-acetylgalactosaminyltransferase and alpha 1-3-galactosyltransferase (ABO) — ABO is one of the genes in this disease's Open Targets module — part of the target space DeCure's repurposing candidates point at. The protein backbone is drawn as a cartoon. The structure has octyl 2-o-(6-deoxy-alpha-l-galactopyranosyl)-beta-d-galactopyranoside bound in it, shown as sticks.
Loading structure…
helix sheet 6-deoxy-alpha-l-galactopyranosyldrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4Y63 · 1.3 Å · ligand octyl 2-O-(6-deoxy-alpha-L-galactopyranosyl)-beta-D-galactopyranoside (BHE). Experimental structure, not a prediction.
What the evidence adds up to
In a double-blind, placebo-controlled phase III trial, 320 lung cancer patients receiving chemotherapy (haemoglobin ≤11.0 g/dL) were randomly assigned to weekly darbepoetin alfa or placebo for 12 weeks. Among the 297 patients who completed at least 28 days, those receiving darbepoetin alfa required fewer transfusions (27% versus 52%; mean difference 25%, 95% CI 14% to 36%, P<.001), needed fewer units of blood (0.67 versus 1.92; mean difference 1.25, 95% CI 0.65 to 1.84, P<.001), and had more hematopoietic responses (66% versus 24%; mean difference 42%, 95% CI 31% to 53%, P<.001). Improvement in FACT-Fatigue scores of at least 25% was seen in 32% of the darbepoetin alfa group versus 19% of the placebo group (mean difference 13%, 95% CI 2% to 23%, P=.019). Adverse events were similar, and no antibodies to the drug were detected. The authors state that no conclusions about survival can be drawn from this study.
In a separate analysis of 1872 patients with chronic kidney disease and type 2 diabetes not on dialysis, a poor initial haemoglobin response to darbepoetin alfa (less than 2% increase after two weight-based doses) occurred in 471 patients. These poor responders had lower average haemoglobin at 12 weeks and during follow-up despite receiving higher doses (median 232 μg versus 167 μg, P<0.001). They also had higher rates of the composite cardiovascular endpoint (adjusted hazard ratio 1.31, 95% CI 1.09 to 1.59) and death (adjusted hazard ratio 1.41, 95% CI 1.12 to 1.78). The authors raise concern about target-based strategies for treating anaemia in chronic kidney disease.
Epoetin alfa (recombinant human erythropoietin) has been used for more than a decade, originally for anaemia in chronic kidney disease. In a 1990 review of 333 patients with end-stage renal disease, epoetin alfa corrected anaemia in 97% (haematocrit increase of at least 6 percentage points or reaching 35%), and 127 patients who previously required transfusions became transfusion-independent. The major side effect was increased diastolic blood pressure, controlled with additional antihypertensives. No antibody formation was reported. Later reviews note that epoetin alfa has been evaluated for anaemia associated with HIV infection, congestive heart failure, hepatitis C treatment, and critical illness, and that preclinical studies suggest neuroprotective and antiapoptotic properties.
Methoxy polyethylene glycol-epoetin beta (MPG-EPO, also called continuous erythropoietin receptor activator) is a pegylated derivative with a half-life of approximately 130 to 137 hours, allowing dosing intervals up to 4 weeks. Subcutaneous or intravenous administration once every two weeks or monthly achieved a high haemoglobin response rate in chronic kidney disease patients, regardless of dialysis status. The most commonly reported adverse effects are hypertension, nasopharyngitis, and diarrhoea. Subcutaneous injection of MPG-EPO is reported as significantly less painful than subcutaneous darbepoetin. A rapid assay based on polyethylene glycol precipitation and a commercial immunoassay can detect MPG-EPO in serum for several weeks after intravenous administration, and has been proposed as a screening tool for doping control.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
JNCI Journal of the National Cancer Institute · 2002 · 479 citations · open access
Double-Blind, Placebo-Controlled, Randomized Phase III Trial of Darbepoetin Alfa in Lung Cancer Patients Receiving Chemotherapy
AbstractBACKGROUND: Patients receiving chemotherapy often develop anemia. Darbepoetin alfa (Aranesp(TM)) is an erythropoiesis-stimulating glycoprotein that has been shown, in dose-finding studies, to be safe and clinically active when administered to patients with cancer every 1, 2, or 3 weeks. This phase III study compared the safety and efficacy of darbepoetin alfa with placebo in patients with lung cancer receiving chemotherapy. METHODS: In this multicenter, double-blind, placebo-controlled study, 320 anemic patients (hemoglobin <or=11.0 g/dL) were randomly assigned to receive darbepoetin alfa or placebo injections weekly for 12 weeks. The 297 patients who completed at least the first 28 days of study were assessed for red blood cell transfusions, the primary endpoint. Patients were also assessed for hemoglobin concentration (i.e., hematopoietic response), adverse events, antibody formation to darbepoetin alfa, hospitalizations, Functional Assessment of Cancer Therapy (FACT)-Fatigue score, and disease outcome. Efficacy endpoints were assessed using Kaplan-Meier analyses, Cox proportional hazards analyses, and chi-square tests where appropriate. All statistical tests were two-sided. RESULTS: Patients receiving darbepoetin alfa required fewer transfusions (27% versus 52%; mean difference = 25%; 95% confidence interval [CI] = 14% to 36%; P<.001), required fewer units of blood (0.67 versus 1.92; mean difference = 1.25, 95% CI = 0.65 to 1.84; P<.001), had more hematopoietic responses (66% versus 24%; mean difference = 42%; 95% CI = 31% to 53%; P<.001), and had better improvement in FACT-Fatigue scores (56% versus 44% overall improvement; 32% versus 19% with >or=25% improvement; mean difference = 13%; 95% CI = 2% to 23%, P =.019) than patients receiving placebo. Patients receiving darbepoetin alfa did not appear to have any untoward effect in disease outcome and did not develop antibodies to the drug. Adverse events were similar between the groups. CONCLUSIONS: Patients with chemotherapy-associated anemia can safely and effectively be treated with weekly darbepoetin alfa therapy. Darbepoetin alfa decreased blood transfusion requirements, increased hemoglobin concentration, and decreased fatigue. Although no conclusions can be drawn about survival from this study, the potential salutary effect on disease outcome warrants further investigation in a prospectively designed study.
New England Journal of Medicine · 2010 · 470 citations · open access
Erythropoietic Response and Outcomes in Kidney Disease and Type 2 Diabetes
AbstractBACKGROUND: Non–placebo-controlled trials of erythropoiesis-stimulating agents (ESAs) comparing lower and higher hemoglobin targets in patients with chronic kidney disease indicate that targeting of a lower hemoglobin range may avoid ESA-associated risks. However, target-based strategies are confounded by each patient's individual hematopoietic response. METHODS: We assessed the relationship among the initial hemoglobin response to darbepoetin alfa after two weight-based doses, the hemoglobin level achieved after 4 weeks, the subsequent darbepoetin alfa dose, and outcomes in 1872 patients with chronic kidney disease and type 2 diabetes mellitus who were not receiving dialysis. We defined a poor initial response to darbepoetin alfa (which occurred in 471 patients) as the lowest quartile of percent change in hemoglobin level (<2%) after the first two standardized doses of the drug. RESULTS: Patients who had a poor initial response to darbepoetin alfa had a lower average hemoglobin level at 12 weeks and during follow-up than did patients with a better hemoglobin response (a change in hemoglobin level ranging from 2 to 15% or more) (P<0.001 for both comparisons), despite receiving higher doses of darbepoetin alfa (median dose, 232 μg vs. 167 μg; P<0.001). Patients with a poor response, as compared with those with a better response, had higher rates of the composite cardiovascular end point (adjusted hazard ratio, 1.31; 95% confidence interval [CI], 1.09 to 1.59) or death (adjusted hazard ratio, 1.41; 95% CI, 1.12 to 1.78). CONCLUSIONS: A poor initial hematopoietic response to darbepoetin alfa was associated with an increased subsequent risk of death or cardiovascular events as doses were escalated to meet target hemoglobin levels. Although the mechanism of this differential effect is not known, these findings raise concern about current target-based strategies for treating anemia in patients with chronic kidney disease. (Funded by Amgen; ClinicalTrials.gov number, NCT00093015.)
Archives of Internal Medicine · 2004 · 92 citations
Epoetin Alfa
AbstractRecombinant human erythropoietin (epoetin alfa) has been used in clinical settings for more than a decade. Its indications have expanded considerably from its original use as hormone therapy in the treatment of anemia in adults with chronic kidney disease. Since the introduction of epoetin alfa, a greater understanding of anemia pathophysiology and the interactions of erythropoietin, iron, and erythropoiesis has been elucidated. Anemia is now independently associated with increased mortality and disease progression. Potential survival benefits associated with correction of anemia in various patient populations are leading to consideration of earlier, more aggressive treatment of mild to moderate anemia with epoetin alfa. Moreover, this agent's therapeutic use may extend beyond currently accepted roles. Epoetin alfa is undergoing evaluation with promising results in a variety of new clinical settings, including anemia associated with congestive heart failure, ribavirin-interferon alfa treatment of hepatitis C virus infection, and critical illness. Preclinical studies also have established erythropoietin and its recombinant equivalent to be a pleiotropic cytokine with antiapoptotic activity and neuroprotective actions in the central nervous system. The therapeutic potential of epoetin alfa appears yet to be fully realized.
International Journal of Nephrology and Renovascular Disease · 2012 · 17 citations · open access
Methoxy polyethylene glycol-epoetin beta for anemia with chronic kidney disease
AbstractChronic kidney disease (CKD) is a risk factor for end-stage renal failure and cardiovascular events. In patients with CKD, anemia is often caused by decreased erythropoietin production relative to hemoglobin levels. As correction of anemia is associated with improved cardiac and renal function and quality of life, erythropoiesis-stimulating agents (ESAs) are standard therapy for anemia in CKD patients. However, traditional ESAs such as epoetin or darbepoetin have short half-lives and require frequent administration, dose changes, and close monitoring of hemoglobin concentration to maintain target hemoglobin levels. Methoxy polyethylene glycol-epoetin beta (MPG-EPO) is the only ESA that is generated by chemical modification of glycosylated erythropoietin through the integration of one specific, long, linear chain of polyethylene glycol. This ESA induces continuous erythropoietin receptor activation and has a long half-life (approximately 130 hours). Subcutaneous or intravenous administration of MPG-EPO once every 2 weeks or monthly achieved a high hemoglobin response rate in patients with anemia associated with CKD, regardless of whether the patient was undergoing dialysis. According to data from an observational time and motion study, MPG-EPO maintains hemoglobin levels when the same dose is administered, however infrequently. This suggests that compared with the use of traditional ESAs, administration of MPG-EPO reduces the overall time and cost associated with the management of anemia in CKD patients undergoing dialysis. MPG-EPO is generally well tolerated and most adverse events are of mild to moderate severity. The most commonly reported adverse effects are hypertension, nasopharyngitis, and diarrhea. Subcutaneous injection of MPG-EPO is significantly less painful than subcutaneous injection of darbepoetin. In conclusion, MPG-EPO is as effective and safe as traditional ESAs in managing renal anemia, irrespective of whether the patient is undergoing dialysis.
Epoetin Alfa for Treatment of Anemia in HIV-Infected Patients
AbstractDespite the availability of highly active antiretroviral therapy and the resulting reduction in severe anemia associated with HIV infection, epoetin alfa has continued to play an important role in the management of HIV-infected patients. Mild-to-moderate anemia remains common, and its correction with epoetin alfa has resulted in significant improvements in quality of life, physical functioning, and possibly prolongation of survival. New research has demonstrated that epoetin alfa may have therapeutic potential beyond its ability to stimulate erythropoiesis due to its neuroprotective and antiapoptotic properties. Current and future research will further clarify the role of epoetin alfa in the clinical management of the HIV-infected population.
Journal of Applied Physiology · 2010 · 8 citations · open access
A rapid and simple assay to determine pegylated erythropoietin in human serum
AbstractStimulation of erythropoiesis by the third-generation erythropoietin drug, continuous erythropoietin receptor activator (CERA), a pegylated derivative of epoetin-beta, has provided valuable therapeutic benefits to patients suffering from renal anemia, but has also rapidly found application as an illicit performance-enhancing strategy in endurance sports. We present here a novel method for selective determination of CERA in serum, based on polyethylene glycol precipitation, followed by a commercial homogeneous immunoassay. The developed method was highly discriminating between serum samples from CERA-treated patients and control subjects, as the covalently linked polyethylene glycol chain in CERA strongly enhanced the solubility of the protein in a polyethylene glycol-containing medium. Intravenous administration of CERA could be detected for several weeks in the majority of subjects tested. This assay outperforms the currently available CERA detection methods in terms of simplicity, convenience, cost, and throughput, making it ideal as a screening tool for doping control.
Methoxy polyethylene glycol-epoetin beta for the treatment of anemia associated with chronic renal failure
AbstractSince more than two decades erythropoiesis-stimulating agents are the main pillar for treatment of anemia associated with chronic kidney disease. Methoxy polyethylene glycol-epoetin beta (MPG-EPO), also called continuous erythropoietin receptor activator, is the longest acting erythropoiesis-stimulating agent currently available. MPG-EPO is characterized by an elimination half-life of approximately 137 h and offers extended dosing intervals up to 4 weeks. Numerous phase I/II studies and a comprehensive clinical phase III program demonstrated the feasibility of MPG-EPO therapy for anemia correction and maintenance of stable hemoglobin levels in adult chronic kidney disease patients. Due to patent disputes MPG-EPO was only available outside the US market so far. In view of a prevailing US market introduction, this review focuses on efficacy and safety data from pivotal trials, summarizes recent clinical research and finally tries to substantiate potential benefits associated with the use of this anti-anemic drug.
Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · 1990 · 6 citations
Review of Patients' Responses to Epoetin Alfa Therapy
AbstractThe efficacy of epoetin alfa (recombinant human erythropoietin) has been tested for treating the anemia associated with end-stage renal disease. This anemia is caused by severely decreased levels of erythropoietin, 90% of which is ordinarily produced by healthy kidneys. Treatment with epoetin alfa successfully corrected the anemia of 97% of 333 patients, as evidenced by hematocrit levels that increased by at least 6 percentage points or reached a study target level of 35%, 2 points above current guidelines. The 127 patients who previously required red cell transfusions to maintain an adequate hematocrit became completely transfusion independent after receiving epoetin alfa. Furthermore, treatment with this growth factor alleviated many of the symptoms of uremia, such as loss of energy and appetite. The major side effect observed with epoetin alfa treatment was increased diastolic blood pressure; however, this was well controlled by additional antihypertension medication. There have been no reports of antibody formation in response to this drug. Thus, epoetin alfa is a safe and effective means of treating the anemia caused by chronic renal insufficiency.
Disease module: DeepOracle (Open Targets). Approved indication: ChEMBL drug_indication (max_phase=4). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works, resolved on OpenAlex.
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