Necheles TF, Finkel HE, Sheehan RG, Allen DM. S1 in the Supplementary Appendix). A digital journal for innovative original research and fresh, bold ideas in clinical trial design and clinical decision-making. The mean (SD) residual level of pyruvate kinase protein in red cells at baseline was 5933% among the patients who had a hemoglobin response and 1421% among those without a hemoglobin response. FOIA Selective reticulocyte destruction in erythrocyte pyruvate kinase deficiency. Zanella A, Bianchi P. Red cell pyruvate kinase deficiency: from genetics to clinical manifestations. 2022 Jul 5;82(13):2403-2416. doi: 10.1158/0008-5472.CAN-21-2352. The efficacy and safety of mitapivat continue to be studied in the extension phase as well as in two ongoing phase 3 studies (ClinicalTrials.gov numbers, NCT03559699 and NCT03548220). ); Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, Milan (W.B. Measurements of erythrocyte glucose consumption, potassium flux and adenosine triphosphate stability. The hemoglobin response was sustained during nearly 3 years of follow-up in the extension phase (Fig. The actual dose received by 80% of the patients with a hemoglobin response was 50 mg or less twice daily, whereas 15% of the patients with a hemoglobin response received an actual dose of 300 mg twice daily, which shows that a hemoglobin response can be achieved with a low dose of mitapivat (Table S4 in the Supplementary Appendix). Blood 2017;130:1347-1356. Structure and function of human erythrocyte pyruvate kinase: molecular basis of nonspherocytic hemolytic anemia. Peer-reviewed journal featuring in-depth articles to accelerate the transformation of health care delivery. Methods: Before Hematologic Measures in Patients with and Those without a Hemoglobin Response. Adverse effects were mainly low-grade and transient. J Lab Clin Med 1968;71:41-47. 12. van Wijk R, van Solinge WW. Stay connected to what's important in medical research and clinical practice, Subscribe to the most trusted and influential source ofmedical knowledge. Manco L, Vagace JM, Relvas L, Rebelo U, Bento C, Villegas A, Letcia Ribeiro M. Eur J Haematol. 3.
Haematologica 2018;103(2):e82-e86. The median hemoglobin level at baseline was 8.9 g per deciliter (range, 6.5 to 12.3); 48% of the patients had a history of treatment with iron chelation despite the absence of regular red-cell transfusions. After a screening period of no more than 6 weeks, patients were randomly assigned in a 1:1 ratio to receive open-label mitapivat at a dose of 50 mg or 300 mg twice daily for a 24-week core period. Subsequently, after a protocol amendment, patients who did not have an increase from baseline of at least 1.0 g per deciliter in the hemoglobin level as evaluated in at least three of the last four measurements were withdrawn from the extension phase of the study. Shojania AM, Israels LG, Zipursky A. Valentini G, Chiarelli LR, Fortin R, et al. Events did not correspond to changes in hormone levels or correlate with age or sex. Treatment with mitapivat was associated with a rapid, clinically significant increase in the hemoglobin level in approximately half the treated patients. Of the 13 patients who were excluded during screening, 1 patient withdrew consent; 1 withdrew consent and had a concurrent medical condition; 3 had a concurrent medical condition, although 1 of these patients was successfully rescreened and enrolled; 1 was undergoing transfusion; 6 had a hemoglobin level that exceeded the entry criterion; and 1 did not complete screening assessments in the allotted time, although this patient was successfully rescreened and enrolled. Lakomek M, Winkler H, Pekrun A, et al. Quintana-Bustamante O, Faanas-Baquero S, Dessy-Rodriguez M, Ojeda-Prez I, Segovia JC. Details regarding the hemoglobin response and the baseline characteristics of the patients who had a response are provided in Tables S4 and S5 in the Supplementary Appendix. Adults (18 years of age) were eligible for participation if they had received a diagnosis of pyruvate kinase deficiency, as documented by lower activity of pyruvate kinase than that of other age-dependent enzymes in red cells and by the presence of at least two mutations in PKLR on genotyping. The content of this site is intended for health care professionals. Aydin Kker S, Oymak Y, Bianchi P, Gzmen S, Karapinar TH, Fermo E, Vergin RC. For the primary evaluation of the safety and side-effect profile of mitapivat, we determined that the enrollment of 25 patients in each of the two dose groups would provide a probability of 72% of observing a rate of adverse events of 5% in either group and a 93% probability of observing a rate of 10%. This finding is consistent with previous ex vivo observations and provides further evidence that mitapivat is working by means of its proposed mechanism of action. MeSH ), and Unit des Maladies Gntiques du Globule Rouge, Centre Hospitalier Universitaire Henri Mondor, Crteil (F.G.) both in France; Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (D.M.L. One of these patients returned to a dose of 300 mg to sustain the hemoglobin response after a dose taper in the extension phase (see Table S1 in the Supplementary Appendix). However, since there were exceptions to this observation, the baseline level of pyruvate kinase protein is not a consistent predictor of hemoglobin response. Insomnia typically occurred within 14 days after the initiation of mitapivat, was self-resolving (generally in <7 days), and was not unexpected on the basis of off-target antagonistic or inverse agonist activity against the histamine H3 receptor.23. The administration of mitapivat was associated with a rapid increase in the hemoglobin level in 50% of adults with pyruvate kinase deficiency, with a sustained response during a median follow-up of 29 months during the extension phase. Bethesda, MD 20894, Web Policies All the patients who had an increase from baseline of more than 1.0 g per deciliter had at least one missense mutation; none of the 10 patients who had two non-missense mutations and none of the 5 patients who were homozygous for R479H mutations (most common in the Amish population) had this level of hemoglobin response. Percentages may not total 100 because of rounding. S5 in the Supplementary Appendix). The type of splenectomy was not reported for 2 patients; all the others underwent a complete splenectomy. 4. In Panel B, the values for the reticulocyte count per cubic millimeter are presented at 0.001 of the actual value. The indirect bilirubin levels decreased in all the patients. The primary objective of this study was to assess the safety and side-effect profile of mitapivat administration in patients with pyruvate kinase deficiency. government site. 11. Of the 52 patients who received mitapivat, 20 (38%) all of whom had at least one missense mutation had a mean increase of more than 1.0 g per deciliter in the hemoglobin level (indicated by a thick gray line); 19 patients had a mean increase of at least 1.5 g per deciliter (thin gray line) (Table S6 in the Supplementary Appendix). After abrupt withdrawal of mitapivat, one patient had two serious adverse events, which were reported sequentially as hemolysis followed by hemolytic anemia. The safety analysis included all the enrolled patients who had received at least one dose of mitapivat. Extreme hemolysis and red-cell distortion in erythrocyte pyruvate kinase deficiency. An official website of the United States government. One patient had persistent bleeding after tonsillectomy. Life-span and organ sequestration of the red cells in pyruvate kinase deficiency. 2019 Jan;41(1):e1-e2. 2022 Apr 14;386(15):1432-1442. doi: 10.1056/NEJMoa2116634. Epub 2022 Jan 24. Prevalence and management of iron overload in pyruvate kinase deficiency: report from the Pyruvate Kinase Deficiency Natural History Study. Forsyth S, Schroeder P, Geib J, Vrishabhendra L, Konstantinidis DG, LaSalvia K, Ribadeneira MD, Wu E, Kelly P, Kalfa TA. Erythrocyte pyruvate kinase deficiency: 2015 status report. 18. Davidson SM, Schmidt DR, Heyman JE, O'Brien JP, Liu AC, Israelsen WJ, Dayton TL, Sehgal R, Bronson RT, Freinkman E, Mak HH, Fanelli GN, Malstrom S, Bellinger G, Carracedo A, Pandolfi PP, Courtney KD, Jha A, DePinho RA, Horner JW, Thomas CJ, Cantley LC, Loda M, Vander Heiden MG. Cancer Res. A data and safety monitoring board consisting of the treating investigators and representatives of the sponsor reviewed the data on an ongoing basis. Zanella A, Fermo E, Bianchi P, Chiarelli LR, Valentini G. Pyruvate kinase deficiency: the genotype-phenotype association. ); University of Utah, Salt Lake City (H.Y. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. The patients were randomly assigned to receive either 50 mg or 300 mg of mitapivat twice daily for a 24-week core period; eligible patients could continue treatment in an ongoing extension phase. Mitapivat increases pyruvate kinase activity ex vivo in red cells obtained from patients with pyruvate kinase deficiency.21 In a dose-escalation study involving healthy volunteers,22 investigators reported an acceptable safety profile and changes in glycolytic intermediates that were consistent with glycolytic pathway activation, findings that supported further investigation of mitapivat as a potential targeted treatment for pyruvate kinase deficiency. (Details are provided in the Supplementary Appendix, available at NEJM.org.) The most common serious adverse events, hemolytic anemia and pharyngitis, each occurred in 2 patients (4%). As of the data cutoff on August 31, 2018, the median treatment duration since randomization for the 19 patients who continued in the open-label extension phase was 28.9 months (range, 21.6 to 34.8). 2022 Mar 1;97(3):E120-E125. Blood 2005;106:4034-4042. After the removal of the 10 patients who had two non-missense mutations, a hemoglobin response occurred in 20 of 42 patients (48%; 95% CI, 32 to 64); with further removal of the 5 patients who were homozygous for R479H mutations, a hemoglobin response occurred in 20 of 37 patients (54%). Shown are the mean levels of hemoglobin (Panel A), the absolute reticulocyte count (Panel B), indirect bilirubin (Panel C), and haptoglobin (Panel D) during the 24-week core period, according to whether the patients had a hemoglobin response or no hemoglobin response. Safety and Efficacy of Mitapivat in Pyruvate Kinase Deficiency. Baillieres Best Pract Res Clin Haematol 2000;13:57-81. Grade 3 or greater adverse effects that were considered by the investigator to be related to mitapivat were seen in 17% of patients who were treated daily for up to 35 months. 2022 Jun 6;6(6):e739. Clinical spectrum of pyruvate kinase deficiency: data from the Pyruvate Kinase Deficiency Natural History Study. Clipboard, Search History, and several other advanced features are temporarily unavailable. 7. Dose decreases were allowed for adverse events thought to be related to mitapivat or if the hemoglobin level exceeded the midpoint of the normal range (>15.0 g per deciliter in men and >13.5 g per deciliter in women). 19. The hemoglobin level was 12.0 g per deciliter or less in men and 11.0 g per deciliter or less in women. 2022 Jun 30;386(26):2539. doi: 10.1056/NEJMc2206275. II. The site is secure. The Use of Next-generation Sequencing in the Diagnosis of Rare Inherited Anaemias: A Joint BSH/EHA Good Practice Paper. In addition to finding that 88% of the patients could continue to receive mitapivat without unacceptable adverse events, we showed that the subsequent pyruvate kinase activation resulted in clinically significant hemoglobin increases and improvement in hemolytic markers in approximately half the patients with pyruvate kinase deficiency, particularly those with a PKLR genotype that included at least one missense mutation. The adverse events that led to treatment discontinuation were an increase in the alanine aminotransferase level plus nonalcoholic steatohepatitis, hemolytic anemia, nausea plus pharyngitis, hypertriglyceridemia, left renal-cell carcinoma, and pleural effusion (in one patient each). Blood Cells Mol Dis 2016;57:100-109. 6. N Engl J Med. ); Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands (E.J.B. 2022 Mar 28;13:848261. doi: 10.3389/fphys.2022.848261. Mitapivat is an oral, small-molecule allosteric activator of pyruvate kinase in red cells. DOI: 10.1056/NEJMoa1902678, Tap into groundbreaking research and clinically relevant insights. 13. These events resolved within 7 days after the initiation of treatment in 60 of 65 episodes (92%) of headache, in 16 of 34 episodes (47%) of insomnia, and in 25 of 32 episodes (78%) of nausea. N Engl J Med 1968;278:73-81. Results: A total of 26 patients (50%) had an increase of more than 1.0 g per deciliter in the hemoglobin level. The authors vouch for the accuracy and completeness of the data and for the fidelity of the study to the protocol. The most common adverse events occurred in at least 15% of the patients in the overall population. A total of 26 patients (50%) had an increase of more than 1.0 g per deciliter in the hemoglobin level. Background: ALT denotes alanine aminotransferase, and NASH nonalcoholic steatohepatitis.
The relative prevalence of PKLR mutation types was consistent with the literature, with 81% of the patients having at least one missense mutation. Of these patients, 9 (17%) had 11 events that were deemed by the investigator to be possibly or probably related to mitapivat, including hypertriglyceridemia (in 4 patients [6%]), hemolytic anemia (in 2 [4%]), and hemolysis, dizziness, headache, renal-cell carcinoma in the left kidney, and insomnia (in 1 each [2%]).23 The patient with renal-cell carcinoma had a kidney lesion that had been present at the time of enrollment and was identified retrospectively. Changes in sex hormone levels stayed mainly within normal ranges and did not correlate with adverse events or changes in bone mineral density. 17. To convert the values for bilirubin to micromoles per liter, multiply by 17.1. Monkeypox Virus Infection in Humans across 16 Countries AprilJune 2022, Protection Associated with Previous SARS-CoV-2 Infection in Nicaragua, Nirmatrelvir for Nonhospitalized Adults with Covid-19, Efficacy of Antibodies and Antiviral Drugs against Omicron BA.2.12.1, BA.4, and BA.5 Subvariants, Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults, Case 23-2022: A 49-Year-Old Man with Hypoglycemia, Trial of Anti-BDCA2 Antibody Litifilimab for Cutaneous Lupus Erythematosus, Overall Survival with Brentuximab Vedotin in Stage III or IV Hodgkins Lymphoma, NEJM Catalyst Innovations in Care Delivery. 16. **Hot flush events were transient and generally reported within the first 7 days after treatment initiation and resolved without treatment within 3 days. For some patients with a hemoglobin response, the magnitude of the change in the hemoglobin level varied according to the dose. Am J Hematol. J Clin Invest 1968;47:1929-1946. Schwartz JD, Barcellini W, Grace RF, Bianchi P, Zanella A, Lpez Lorenzo JL, Sevilla J, Shah AJ, Glader B, Nicoletti E, Navarro Ordoez S, Segovia JC. The protocol (available with the full text of this article at NEJM.org) was approved by the institutional review board or ethics committee at each study center. Mitapivat (AG-348) is an oral, small-molecule allosteric activator of red-cell pyruvate kinase.21 In vitro experiments have shown that mitapivat activates wild-type and a variety of mutant red-cell pyruvate kinase enzymes. Roy NBA, Da Costa L, Russo R, Bianchi P, Del Mar Ma-Pereira M, Fermo E, Andolfo I, Clark B, Proven M, Sanchez M, van Wijk R, van der Zwaag B, Layton M, Rees D, Iolascon A. Hemasphere. The most effective and engaging way for clinicians to learn, improve their practice, and prepare for board exams. With the exception of nasopharyngitis, the cumulative safety profile (during the core phase plus the extension phase) remained similar to that observed in the core period, which indicated no change in the safety profile to date with extended treatment. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02476916. Patients who were homozygous for the R479H mutation are indicated by asterisks. Concise summaries and expert physician commentary that busy clinicians need to enhance patient care. The selection of the two doses was based on the results of a dose-escalation study involving healthy volunteers.22 Randomization was stratified according to the PKLR mutation (R510Q vs. R486W vs. R479H vs. all other mutations) to maintain balance for the most frequently expected mutations. 24. In this uncontrolled, phase 2 study, we evaluated the safety and efficacy of mitapivat in 52 adults with pyruvate kinase deficiency who were not receiving red-cell transfusions. Worldwide study of hematopoietic allogeneic stem cell transplantation in pyruvate kinase deficiency. official website and that any information you provide is encrypted Baseline levels of pyruvate kinase protein in red cells were measured as described previously.21. N Engl J Med. Of the 65 patients who had undergone screening, 52 were eligible for participation and were randomly assigned to receive mitapivat twice daily at a dose of 50 mg (27 patients) or 300 mg (25 patients) (Figure 1, and Fig. The bars indicate 95% confidence intervals. One patient had an existing renal lesion before enrollment in the study. A mean increase of more than 1.0 g per deciliter in the hemoglobin level did not occur in any of the 5 patients who were homozygous for the R479H mutation (as indicated by an asterisk) or in any of the 10 patients who were homozygous for non-missense mutations (as indicated by a red bar). In 1 patient, the baseline level of red-cell pyruvate kinase protein was not available, so the day 15 sample was used. Therefore, mitapivat may have the potential to increase hemoglobin levels in the majority of patients with this disease.5 This prediction requires prospective testing in patients across a broader range of genotypes and disease severity patients who are being included in ongoing clinical trials. Haematologica 2019;104(2):e51-e53. Hemoglobin responses were observed only in patients who had at least one missense PKLR mutation and were associated with the red-cell pyruvate kinase protein level at baseline. The authorized source of trusted medical research and education for the Chinese-language medical community. However, the lactate dehydrogenase levels (Table S8 in the Supplementary Appendix) and reticulocyte counts changed only in the patients with a hemoglobin response. Phase 1 single- and multiple-ascending-dose randomized studies of the safety, pharmacokinetics, and pharmacodynamics of AG-348, a first-in-class allosteric activator of pyruvate kinase R, in healthy volunteers. Patient-reported quality of life was not assessed in this phase 2 safety study, although such outcome measures are being evaluated in the ongoing phase 3 trials. The hemoglobin response was sustained for up to 35 months with ongoing mitapivat administration and was associated with improvement in laboratory markers of hemolysis. We summarized adverse events and other categorical safety measurements according to frequency distributions for the overall population and randomly assigned starting dose. Among these patients, the mean maximum increase in the hemoglobin level was 3.4 g per deciliter (range, 1.1 to 5.8). sharing sensitive information, make sure youre on a federal We thank all the patients, research nurses, study coordinators, and subinvestigators for their contributions to this study; David Nathan and Donna Neuberg of the DanaFarber Cancer Institute and Karen Anderson of Agios Pharmaceuticals for their discussions; Susanne Vidot of Excel Medical Affairs for providing writing assistance; and all the Clinical and Translational Research Centers for their services during the study. Thus, there may be an independent effect of mitapivat on bilirubin metabolism. De Gruchy GC, Santamaria JN, Parsons IC, Crawford H. Nonspherocytic congenital hemolytic anemia. Thakkar MM. 22. We conducted the study at eight sites in North America and six sites in Europe. A professional medical writer paid by the sponsor assisted the authors in the preparation of the manuscript. Zanella A, Berzuini A, Colombo MB, et al. 9. Yang H, Merica E, Chen Y, et al. Accessibility All 52 of the patients who were included in the safety analysis had at least one adverse event, the majority of which were grade 1 or 2 in severity (Table 2). J Pediatr Hematol Oncol. Panel B shows the patients who had a hemoglobin response (defined as an increase from baseline of >1.0 g per deciliter in the hemoglobin level at >50% of the assessments during the core period) and those who did not have a response, according to the baseline level of pyruvate kinase protein in red cells, a value that has been normalized to the hemoglobin level (an approximation of the total red-cell protein level) and to the pyruvate kinase protein level measured in a sample obtained from a healthy control (to allow for interassay comparisons). Preclinical data have shown that mitapivat activates pyruvate kinase activity in vitro across a broad spectrum of PKLR mutations, a finding that was consistent with the known binding site for mitapivat, which is distinct from the areas of the most common PKLR mutations.21 In this study, mitapivat administration resulted in a robust and sustained hemoglobin response in patients with diverse PKLR genotypes, all of whom had at least one PKLR missense mutation. The 3 patients who selected other race were from North and West Africa. Among these patients, the mean maximum increase was 3.4 g per deciliter (range, 1.1 to 5.8), and the median time until the first increase of more than 1.0 g per deciliter was 10 days (range, 7 to 187); 20 patients (77%) had an increase of more than 1.0 g per deciliter in the hemoglobin level at more than 50% of visits during the core study period, with improvement in markers of hemolysis. Of the 52 patients, 19 (37%) had adverse events of grade 3 or higher, as reported by the investigator. Headache was transient and generally resolved within several days. Nathan DG, Oski FA, Sidel VW, Diamond LK. The majority of patients had undergone splenectomy (83%) and cholecystectomy (73%). Clin Pharmacol Drug Dev 2019;8:246-259. The study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. Reply. Epub 2022 Jan 12. According to the protocol, dose adjustments were allowed for reasons of safety, side-effect profile, and hemoglobin response. Blood 1962;19:267-295. In this study, there were no significant trends regarding whole-blood ATP or 2,3-diphosphoglycerate metabolite levels in patients with a hemoglobin response, a finding that contrasted with the results in healthy volunteers (Fig. The study was designed and analyzed by the sponsor (Agios Pharmaceuticals) in collaboration with the authors. Most patients with pyruvate kinase deficiency have compound heterozygous PKLR alterations with at least one missense mutation. Mitapivat is a small-molecule, allosteric activator of pyruvate kinase in red cells with a side-effect profile that allowed continued administration in 46 of 52 patients (88%) with pyruvate kinase deficiency in this phase 2 study. The median time until the first observed increase of more than 1.0 g per deciliter in the hemoglobin level was 10 days (range, 7 to 187). Changes in dose were permitted during the core period on the basis of safety, side-effect profile, and hemoglobin response. Canu G, De Bonis M, Minucci A, Capoluongo E. Red blood cell PK deficiency: an update of PK-LR gene mutation database. Analyses of hemoglobin response included the number and proportion of patients who had an increase of more than 1.0 g per deciliter in the postbaseline hemoglobin level in more than 50% of assessments during the core period. Mojzikova R, Koralkova P, Holub D, Zidova Z, Pospisilova D, Cermak J, Striezencova Laluhova Z, Indrak K, Sukova M, Partschova M, Kucerova J, Horvathova M, Divoky V. Br J Haematol. : Toward an expanded definition of severe PKD. The relationship of adenosine triphosphate concentration to erythrocyte aging. 23. The safety profile that was shown in this study provides equipoise for studies of mitapivat as a disease-altering therapy for patients with pyruvate kinase deficiency, who are likely to undergo therapy for years. The hemoglobin response was maintained in the 19 patients who were continuing to be treated in the extension phase, all of whom had at least 21.6 months of treatment (Fig. This result suggests that patients with at least one missense PKLR mutation are more likely than patients with two non-missense mutations to have a hemoglobin response to mitapivat. A total of 18 serious adverse events were reported in 15 patients, all as single events with the exception of pharyngitis and hemolytic anemia (in 2 patients each [4%]). Valuable tools for building a rewarding career in health care. S1). Of the 52 patients, 26 (50%) had an increase from baseline of more than 1.0 g per deciliter in the hemoglobin level (Table S3 and Fig. In 4 patients who did not have a hemoglobin response, the twice-daily dose was increased from 50 mg to 300 mg; however, none of these patients met the definition of having had a hemoglobin response at the higher dose. The administration of mitapivat was associated with a rapid increase in the hemoglobin level in 50% of adults with pyruvate kinase deficiency, with a sustained response during a median follow-up of 29 months during the extension phase. The response was sustained in all 19 patients remaining in the extension phase, with a median follow-up of 29 months (range, 22 to 35). One patient had a progressive worsening of hemolysis and no hemoglobin response despite an increase in the dose of mitapivat to 300 mg twice daily and blood transfusions. Tanaka KR, Valentine WN, Miwa S. Pyruvate kinase (PK) deficiency hereditary nonspherocytic hemolytic anemia. A relationship was observed between the level of pyruvate kinase protein in red cells at baseline and the hemoglobin response (Figure 2B). doi: 10.1097/HS9.0000000000000739. Changes in the average age of red cells associated with a reduction in the number of reticulocytes and reduced hemolysis could contribute to this observation, since reticulocytes have higher ATP levels than older blood cells.25.
Sitemap 28