Omontys (peginesatide) / Affymax - LARVOL DELTA

30 years of classical hematology drugs in the US: Approvals, costs, and sales (ASH 2025) - "Six drugs have been discontinued (year approved/year discontinued/reason): betrixaban(2017/2020/business), daprodustat (2023/2024/business), fidanacogene elaparvovec(2024/2025/business), oprelvekin (1997/2011/business), peginesatide (2012/2013/safety), and voxelotor(2019/2024/safety).There are limitations to our study. Some drugs have non-classical hematology indications (anticoagulantsin atrial fibrillation; luspatercept in myelodysplastic neoplasm) and/or may also be prescribed by non-classical hematologists (erythropoiesis stimulating agents by nephrologists and medical oncologists)...Classical hematology drugs contribute substantially to US prescription drug spending, with over $70billion in annual sales and medications for thromboembolism accounting for over half of the costs.Approvals have accelerated over the past three decades, doubling each decade. Biologics and biosimilarsnow represent two-thirds of approvals. Continuous-duration treatments, particularly for..."

Anemia • Atrial Fibrillation • Beta-Thalassemia • Cardiovascular • Chemotherapy-Induced Neutropenia • Chronic Kidney Disease • Complement-mediated Rare Disorders • Gene Therapies • Genetic Disorders • Hematological Malignancies • Hemophagocytic lymphohistiocytosis • Hemophilia • Immune Thrombocytopenic Purpura • Immunology • Myelodysplastic Syndrome • Nephrology • Neutropenia • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Renal Disease • Sickle Cell Disease • Thrombocytopenia • Thrombocytopenic Purpura

Erythropoietin-Mimetic Peptide Pegmolesatide Therapy for Pure Red Cell Aplasia in a Patient with Nondialysis-Dependent Type 1 Diabetic Nephropathy: A Case Report (KIDNEY WEEK 2025) - "Enarodustat and roxadustat were administered successively after discontinuation of EPO, but anemia did not improve, and the patient was maintained with weekly blood transfusions...Discussion The new EPO-mimetic peptide pegmolesatide, which consists of 44 amino acids and has a completely different peptide chain structure from peginesatide and EPO (Fig 4), was independently developed in China...Thus, there is no cross-immune response between pegmolesatide and EPO. In addition, pegmolesatide rarely produces drug antibodies, attributed to the low immunogenicity.Based on these findings, we speculate that pegmolesatide can provide a safe, effective, and convenient therapeutic strategy for PRCA in Chinese patients with chronic kidney disease."

Case report • Clinical • Anemia • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Hematological Disorders • Nephrology • Renal Disease • Type 1 Diabetes Mellitus

Acute Kidney Injury after Cardiac Surgery Is Associated with Increased Iron Deficiency Anemia Risk (ASH 2024) - "Exclusion criteria included diagnoses of acute kidney failure (ICD-10-CM N17), chronic kidney disease (N18), end stage renal disease (N18.6), renal dialysis (Z99.2), and hemoglobin ≤8 g/dL within 1-month preoperatively.A propensity-matched cohort analysis was used to examine the relationship between 7-day postoperative AKI and 3-month, 6-month, and 12-month postoperative mortality, all cause anemia, iron deficiency anemia (D50), repeat cardiac surgery, RBC transfusion, acute myocardial infarction (MI) (I21), atrial fibrillation and flutter (I48), and recent hemoglobin (Hb) and hematocrit (Hct) levels within the outcome period.Propensity score matching was performed for age, ethnicity, race, sex, preoperative diabetes mellitus (E08-E13), neoplasms (C00-D49), alcohol related disorders (F10), liver diseases (K70-K77), sepsis (A40-41), MI, cerebral infarction (I63), essential hypertension (I10), renal tubulo-interstitial diseases (N10-N16), acute and subacute endocarditis..."

Surgery • Acute Kidney Injury • Anemia • Atrial Fibrillation • Cardiovascular • Chronic Kidney Disease • CNS Disorders • Diabetes • Diabetic Nephropathy • Hematological Disorders • Hepatology • Hypertension • Infectious Disease • Metabolic Disorders • Myocardial Infarction • Nephrology • Renal Disease • Septic Shock

Serious Adverse Drug Reactions (sADRs) Involving Hematology and Resulting in Black Box Warnings or FDA Non-Approval: Results from the First Quarter Century of RADAR/Sonar (ASH 2024) - "Results : sADRs were frequently identified based on very small case series, including ticlopidine-and clopidogrel associated thrombotic thrombocytopenic purpura (22 and 10 patients, respectively), thalidomide- and lenalidomide-associated venous thromboembolism (9 and 5 patients, respectively), rituximab-associated progressive multi-focal leukoencephalopathy (22 patients), peginesatide-associated fatal anaphylaxis (5 patients), and COVID-19 vaccine associated immune thrombocytopenia (1 patient)...Time from FDA approval to sADR discovery was a median of 5 years (range, 0 months (thalidomide-associated venous thromboembolism) to 34 years (ciprofloxacin-associated neuropsychiatric toxicity)...Discussion : RADAR/SONAR has proven to be a very important adjunct to FDA and pharmaceutical manufacturer-led safety investigations for hematology, paralleling the success in medical oncology and in cardiology. Going forward, independent centers of excellence for safety-focused..."

Adverse drug reaction • Cardiovascular • CNS Disorders • Hematological Disorders • Immune Thrombocytopenic Purpura • Infectious Disease • Psychiatry • Thrombocytopenia • Thrombocytopenic Purpura • Venous Thromboembolism

The Pharmaceutical Industry in 2024: An Analysis of the FDA Drug Approvals from the Perspective of Molecules. (PubMed, Molecules) - "This year saw the authorization of two more PEGylated drugs-both peptides-highlighting a renewed interest in this strategy for extending drug half-life, despite the setback caused by the withdrawal of peginesatide from the market in 2014 due to adverse side effects...Herein, the 50 new drugs authorized by the FDA in 2024 are analyzed exclusively on the basis of their chemical structure. They are classified as the following: biologics (antibodies, proteins), TIDES (oligonucleotides and peptides), combined drugs, natural products, F-containing molecules, nitrogen aromatic heterocycles, aromatic compounds, and other small molecules."

FDA event • Journal • Review

A non inferiority randomized controlled clinical study on the prevention of delayed platelet reconstruction after allogeneic hematopoietic stem cell transplantation using Hematide and rhTPO. (ChiCTR) - P4 | N=134 | Recruiting | Sponsor: Guangdong Provincial Hosipital of Chinese Medicine; Guangdong Provincial Hosipital of Chinese Medicine

New P4 trial • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Oncology • Transplantation

The Pharmaceutical Industry in 2023: An Analysis of FDA Drug Approvals from the Perspective of Molecules. (PubMed, Molecules) - "Three drugs in this year's harvest are pegylated, which may indicate the return of pegylation as a method to increase the half-lives of drugs after the withdrawal of peginesatide from the market in 2013...Herein, the 55 new drugs approved by the FDA in 2023 are analyzed exclusively on the basis of their chemical structure. They are classified as the following: biologics (antibodies, proteins/enzymes); TIDES (peptide and oligonucleotides); combined drugs; pegylated drugs; natural products; nitrogen aromatic heterocycles; fluorine-containing molecules; and other small molecules."

FDA event • Journal • Review • Infectious Disease • Novel Coronavirus Disease

A singlicate immunogenicity method to detect anti-polyethylene glycol antibodies: pre- and post-dose of PEGylated therapies. (PubMed, Bioanalysis) - "Omontys and Krystexxa withdrawal and SARS-CoV-2 RNA vaccine anaphylaxis have all been linked to APAs. Materials & The repetitive, linear PEG structure prevented the use of a bridging homogenous format, hence the requirement to use a solid phase extraction and acid dissociation assay coupled with the Meso Scale Discovery platform. Results & Using singlicate analysis, the method was validated to successfully detect APA pre- and postdose, with a crucial aspect of the method being the preparation of an appropriate negative control."

Journal • Review • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

ROS-scavenging ‘stealth’ polymer, poly(thioglycidyl glycerol)(PTGG), outperforms PEG in protein conjugates and nanocarriers, and enhances protein stability to environmental and biological stressors (ACS-Sp 2023) - "Poly(ethylene glycol)(PEG) is commonly used for extending plasma half-lives of biologics but has significant drawbacks; for example, immunogenicity has led to market withdrawal of peginesatide (Omontys), pegloticase (Krystexxa) and the cessation of pegnivacogin (Revolixys) trials, while dozens of other PEG formulations present antiPEG antibodies, accelerated blood clearance (ABC), infusion reactions and reduced efficacy overtime. B. Unlike with PEG, no anti-polymer antibodies were formed in PTGG/OVA treated mice."

LYZ

Commentary: Multiplex dPCR and SV-AUC are Promising Assays to Robustly Monitor the Critical Quality Attribute of AAV Drug Product Integrity. (PubMed, J Pharm Sci) - "In this commentary, the proper approach to managing uncertainty (described by Rosenberg et al., 2012) when determining critical quality attributes is stated and applied retrospectively to Peginesatide and prospectively to AAV drug product integrity...The proper management of uncertainty requires a robust quantitative measurement of AAV drug product integrity to ensure control of efficacy and safety. Multiplex dPCR and SV-AUC are promising technologies that together have the potential to enable the development of assays fit for the purpose of measuring AAV drug product integrity more precisely."

Journal • Gene Therapies

Pharmacokinetics of 40 kDa Polyethylene glycol (PEG) in mice, rats, cynomolgus monkeys and predicted pharmacokinetics in humans. (PubMed, Eur J Pharm Sci) - "PEG40 or 40 kDa PEG is a double-branched PEG, routinely employed to improve the pharmacokinetics (PK) of therapeutics, including successful marketed products such as Pegasys® and Omontys®...Finally, in human, intrinsic CL and V of PEG40 were projected to be 0.02 mL/min/kg (0.084 L/h) and 0.22 L/kg, respectively. This comprehensive report of PK of PEG40 in non-clinical species and its subsequent prediction in humans is expected to be useful to drug discovery and development scientists for efficient decision-making and optimal resource utilization."

Journal • PK/PD data • Preclinical

Q4 Omontys sales disappoint, Affymax headed lower (Seekingalpha.com) - "Sales for the nine-month period ending Dec. 31 came in at $34.6 million, which implies Q4 2012 sales of $19.6 million, significantly below Wall Street's Q4 sales expectations for $25 million. While analysts are defending the stock, noting that reported sales are more reflective of ordering patterns rather than demand, we expect the stock to take a tumble on the news."

Sales • Renal Disease

Absorption, distribution, metabolism and excretion of peginesatide, a novel erythropoiesis-stimulating agent, in rats (Xenobiotica) - Plasma clearance was slow & elimination was biphasic with unchanged peginesatide representing greater than 90% of the total radioactivity of the total radioactive exposure; Slow uptake of the radiolabeled compound from the vascular compartment into the tissues was observed; Biodistribution to bone marrow & extramedullary hematopoietic sites, & to highly vascularized lymphatic & excretory tissues occurred; Renal excretion was the primary mechanism of elimination, with parent molecule the major moiety excreted

Preclinical-animal • Renal Disease

Intravenous (IV) iron use in US hemodialysis (HD) Patients (Pts) receiving peginesatide for anemia due to chronic kidney disease (KIDNEY WEEK 2012) - Presentation time: Thursday, November 1, 2012 4:30 PM - 6:30 PM; P3, N=1,289; EMERALD 1 & 2; Peginesatide pts received less IV iron, had higher TSAT, & had similar ferritin levels over 60 weeks, while maintaining similar Hb levels, vs epoetin pts

P3 data • Renal Disease

Dose-finding study of peginesatide for anemia correction in chronic kidney disease patients (Clin J Am Soc Nephrol) - P=NA, N=139; Across all cohorts, 96% of pts achieved a hemoglobin response; A dose-response relationship was evident for hemoglobin increase; Rapid rates of hemoglobin rise and hemoglobin excursions >13g/dl tended to occur more frequently with every-2-weeks dosing than they did with every-4-weeks dosing

Clinical data • Renal Disease

Peginesatide for maintenance treatment of anemia in hemodialysis and nondialysis patients previously treated with darbepoetin alfa (Clin J Am Soc Nephrol) - P2, N=101; NCT00752609; PMID: 23243269; "Once-monthly peginesatide resulted in a slight decrease in mean hemoglobin levels in individuals on hemodialysis and a small increase in individuals with CKD who were not on dialysis."

P2 data • Renal Disease

Omontys (peginesatide) injection now available for adult chronic kidney disease (CKD) patients on dialysis in the United States (Takeda) - Affymax & Takeda Pharmaceutical announced that Omontys (peginesatide) injection is now available only for use in treating anemia due to CKD in adult pts on dialysis; Takeda’s consolidated financial statements for the 2011 fiscal year will be announced on May 11, 2012; The fiscal 2012 outlook & mid-range plan 2012-14 will also be presented, will include this product launch

Anticipated financial results • Product launch • Renal Disease

Peginesatide and erythropoietin stimulate similar EPOR-mediated signal transduction and gene induction events (Exp Hematol) - Peginesatide & rHuEPO were found to regulate the tyrosine phosphorylation of an essentially equivalent set of protein substrates, & modulate the expression of a similar set of target genes; Consistent with their roles in stimulating erythropoiesis, peginesatide & rHuEPO regulate similar cellular pathways

Gene expression study • Renal Disease

Robert W. Baird Health Care Conference (Affymax) - Hematide / Affymax; NDA planned for H1 ’11; initially proposing dialysis only indications which are subjected to FDA feedback; filling will be most extensive for ESA in US market; FDA discussion planned by Q4 ’10; data to be presented at ASN in Nov ’10; milestone payment to be received from Takeda

Pipeline update

Long-term results from a study of peginesatide in patients with antibody-mediated pure red cell aplasia (AB+PRCA) (ERA-EDTA 2012) - Presentation date: Friday, May 25, 2012; P2, N=18; Peginesatide dosing remained constant for the duration of the study; Anti-EPO antibody levels were decreased; Median serum ferritin & TSAT gradually decreased over time, reaching >50% reduction from baseline by 1 & 3 years, respectively, after initiation of peginesatide; Mean peginesatide doses were similar between dialysis & non-dialysis PRCA pts; Peginesatide treatment within this population continued to show no new safety concerns

P2 data • Renal Disease

Affymax announces FDA advisory committee to review Peginesatide (Affymax) - Affymax announced that the US FDA Oncologic Drugs Advisory Committee (ODAC) will review the NDA for peginesatide proposed for the treatment of anemia associated with CKD in adult pts on dialysis on December 7, 2011, during the afternoon session; The FDA has established an action date of March 27, 2012, under the PDUFA; The company intends to begin a self-imposed quiet period on November 16, 2011, in anticipation of receipt of FDA briefing documents, & this quiet period will continue until after the Advisory Committee meeting is completed

Anticipated FDA review • Renal Disease

An open-label, sequential, dose-finding study of peginesatide for the maintenance treatment of anemia in chronic hemodialysis patients (BMC Nephrol) - P2, N=164; NCT00228449; Overall, proportion of pts with hemoglobin levels within ±1.0g/dL of baseline increased over the course of study from 39% (Wks 2-13) to 54% (Wks 18-25); Peginesatide safety profile was consistent with those of marketed erythropoiesis-stimulating agents; Once-monthly peginesatide is feasible in hemodialysis pts; Results of this study were used to guide the dosing regimens used subsequently in P3 studies

P2 data • Renal Disease

Developing in vitro and in vivo Models to Predict Drug-Induced Acute Allergic Adverse Reactions (AAAAI 2019) - "These in vitro and in vivo models will not only help the agency to quickly identify and respond to potential causes of drug-induced acute allergic AEs, but also better determine the likelihood and potentially mitigate the risk of acute reactions for regulated products."

Preclinical