), and Agios Pharmaceuticals, Cambridge (A.J.B., S.B., L.H., C.K., P.H., M.-H.J., C.B.) 13. J Clin Invest 1971;50:688-699. DOI: 10.1056/NEJMoa1902678, Tap into groundbreaking research and clinically relevant insights. The doses of mitapivat that were administered and the rate of treatment adherence are summarized in Table S1 in the Supplementary Appendix. Necheles TF, Finkel HE, Sheehan RG, Allen DM. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. S4 in the Supplementary Appendix). Serum levels of sex hormones (testosterone, estradiol, and estrone) and DXA scans were monitored because of reversible, mild, off-target aromatase inhibition that had been observed in preclinical studies (authors unpublished data) and in healthy volunteers.22 We also evaluated adverse events, treatment-related adverse events, serious adverse events, and specific events of interest (acute hemolysis after abrupt mitapivat discontinuation, osteoporosis, elevations in liver enzymes, hypertriglyceridemia, and insomnia). Prevalence and management of iron overload in pyruvate kinase deficiency: report from the Pyruvate Kinase Deficiency Natural History Study. Safety and Efficacy of Mitapivat in Pyruvate Kinase Deficiency. 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). 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. doi: 10.1002/ajh.26458. 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. J Clin Invest 1968;47:1929-1946. Hematologic Measures in Patients with and Those without a Hemoglobin Response. Zanella A, Bianchi P. Red cell pyruvate kinase deficiency: from genetics to clinical manifestations. 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. 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. Changes from baseline in sex hormone levels, the result of off-target aromatase inhibition, were observed in male patients, with most levels of testosterone and estradiol remaining within the normal range (Fig. The type of splenectomy was not reported for 2 patients; all the others underwent a complete splenectomy. Measurements of erythrocyte glucose consumption, potassium flux and adenosine triphosphate stability. 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. all in Massachusetts; Hpital Saint Vincent de Paul, Lille (C.R. Extreme hemolysis and red-cell distortion in erythrocyte pyruvate kinase deficiency. Valentini G, Chiarelli LR, Fortin R, et al. A digital journal for innovative original research and fresh, bold ideas in clinical trial design and clinical decision-making. Iron status in red cell pyruvate kinase deficiency: study of Italian cases. In 9 patients, the dose of mitapivat was reduced owing to a rapid hemoglobin response. September 5, 2019N Engl J Med 2019; 381:933-944 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. Panel A shows the mean change from baseline in the hemoglobin level during the 24 weeks of the core period, according to the patients PKLR genotype category. 14. An inherited molecular lesion of erythrocyte pyruvate kinase: identification of a kinetically aberrant isozyme associated with premature hemolysis. Nathan DG, Oski FA, Sidel VW, Diamond LK. 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. Methods: 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. Would you like email updates of new search results? 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%. Background: sharing sensitive information, make sure youre on a federal Manco L, Vagace JM, Relvas L, Rebelo U, Bento C, Villegas A, Letcia Ribeiro M. Eur J Haematol. 2022 Jun 30;386(26):2539. doi: 10.1056/NEJMc2206275. 7. 23. Demographic and Clinical Characteristics of the Patients at Baseline. 18. II. ); Weill Cornell Medical College, New York (S.S.); Bruce A. 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. The most commonly reported adverse events occurred soon after drug initiation and were transient. Am J Hematol 2011;86:827-834. Zanella A, Berzuini A, Colombo MB, et al. Events did not correspond to changes in hormone levels or correlate with age or sex. Among these patients, the mean maximum increase in the hemoglobin level was 3.4 g per deciliter (range, 1.1 to 5.8). 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. N Engl J Med 1965;272:118-123. 11. Yang H, Merica E, Chen Y, et al. Am J Hematol 2001;67:197-199. Quintana-Bustamante O, Faanas-Baquero S, Dessy-Rodriguez M, Ojeda-Prez I, Segovia JC. These genetic alterations lead to a deficit of pyruvate kinase activity in red cells and to hemolytic anemia of variable severity.1-8 In addition to anemia, pyruvate kinase deficiency is associated with serious complications that include gallstones, pulmonary hypertension, extramedullary hematopoiesis, and iron overload and its sequelae, which occur regardless of the degree of anemia or transfusion burden.9,10 Patients most commonly have compound heterozygous mutations in the gene encoding the L and R isozymes of pyruvate kinase (PKLR), with more than 300 mutations described; most patients have at least one missense mutation.9,11 Red-cell pyruvate kinase deficiency results in impaired glucose utilization and reduced ATP generation in red cells, which leads to compromised red-cell membrane homeostasis and hemolysis.1,12-14. Am J Hematol 2015;90:825-830. N Engl J Med. A professional medical writer paid by the sponsor assisted the authors in the preparation of the manuscript. ); Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands (E.J.B. (Details are provided in the Supplementary Appendix, available at NEJM.org.) The primary objective of this study was to assess the safety and side-effect profile of mitapivat administration in patients with pyruvate kinase deficiency. 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. Percentages may not total 100 because of rounding. NEW! 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). 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. 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. A relationship between genotype and hemoglobin response was observed (Figure 2A; and Tables S5, S6, and S7 in the Supplementary Appendix). However, the lactate dehydrogenase levels (Table S8 in the Supplementary Appendix) and reticulocyte counts changed only in the patients with a hemoglobin response. 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). 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. We conducted the study at eight sites in North America and six sites in Europe. S3 in the Supplementary Appendix). One patient had persistent bleeding after tonsillectomy. 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. 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). Of the 26 patients, 20 (77%) had an increase from baseline of more than 1.0 g per deciliter at more than 50% of the assessments in the core period, which met the definition of a hemoglobin response. To convert the values for bilirubin to micromoles per liter, multiply by 17.1. ); Wayne State University School of Medicine, Childrens Hospital of Michigan, Detroit (Y.R. Red cell pyruvate kinase deficiency: the effect of splenectomy. ); and Stanford University School of Medicine, Palo Alto, CA (B.G.). The safety analysis included all the enrolled patients who had received at least one dose of mitapivat. doi: 10.1097/HS9.0000000000000739. 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, 26 (50%) had an increase from baseline of more than 1.0 g per deciliter in the hemoglobin level (Table S3 and Fig. doi: 10.1097/MPH.0000000000001254. The .gov means its official. The authorized source of trusted medical research and education for the Chinese-language medical community. In a post hoc analysis, these patients were defined as having had a hemoglobin response. : Toward an expanded definition of severe PKD. 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. Lakomek M, Winkler H, Pekrun A, et al. 19. Clinical spectrum of pyruvate kinase deficiency: data from the Pyruvate Kinase Deficiency Natural History Study. A data and safety monitoring board consisting of the treating investigators and representatives of the sponsor reviewed the data on an ongoing basis. The most effective and engaging way for clinicians to learn, improve their practice, and prepare for board exams. A New Variant of PKLR Gene Associated With Mild Hemolysis may be Responsible for the Misdiagnosis in Pyruvate Kinase Deficiency. Mitapivat is an oral, small-molecule allosteric activator of pyruvate kinase in red cells. The https:// ensures that you are connecting to the 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. Life-span and organ sequestration of the red cells in pyruvate kinase deficiency. 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. Prepare to become a physician, build your knowledge, lead a health care organization, and advance your career with NEJM Group information and services. An additional seven patients for whom dose reduction was necessary because of a robust hemoglobin response underwent dose tapering, according to a protocol amendment, without acute hemolysis. Nathan DG, Oski FA, Miller DR, Gardner FH. 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%). The renal-cell carcinoma did not grow at an abnormally rapid rate during the study, according to expert review. Most patients with pyruvate kinase deficiency have compound heterozygous PKLR alterations with at least one missense mutation. 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. In 49 patients who were evaluated, there was no worsening of bone mineral density as determined with the use of DXA scans of the total hip, total lumbar spine, and femoral neck, which were obtained and interpreted locally during screening and during treatment over a median of 17 months (range, 4 to 30) (Table S2 in the Supplementary Appendix). Please enable it to take advantage of the complete set of features! The most common serious adverse events, hemolytic anemia and pharyngitis, each occurred in 2 patients (4%). This site needs JavaScript to work properly. MeSH Adverse effects were mainly low-grade and transient. 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. The hemoglobin response was sustained for up to 35 months with ongoing mitapivat administration and was associated with improvement in laboratory markers of hemolysis. 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. Chou R, DeLoughery TG. However, during the extension phase, 14 patients who were receiving twice-daily doses of more than 25 mg of mitapivat underwent a dose taper; the hemoglobin levels in 11 of these patients were maintained at the lower doses. This study establishes proof of concept for a molecular therapy targeting the underlying enzymatic defect of a hereditary enzymopathy. Tanaka KR, Valentine WN, Miwa S. Pyruvate kinase (PK) deficiency hereditary nonspherocytic hemolytic anemia. Grace RF, Bianchi P, van Beers EJ, et al. 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). Baillieres Best Pract Res Clin Haematol 2000;13:57-81. Pyruvate kinase deficiency is caused by mutations in PKLR and leads to congenital hemolytic anemia. J Lab Clin Med 1968;71:41-47. Information and tools for librarians about site license offerings. 2014 May;165(4):556-63. doi: 10.1111/bjh.12779. Grace RF, Zanella A, Neufeld EJ, et al. 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. Information, resources, and support needed to approach rotations - and life as a resident. 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. Shown are the numbers of patients who received the listed doses of mitapivat for the longest duration during the core period of the study, which was defined as the actual dose. Enzyme Protein 1994;48(3):149-163. Shojania AM, Israels LG, Zipursky A. 6. Since mitapivat directly binds and activates residual mutant red-cell pyruvate kinase enzyme, it is hypothesized that a minimal level of full-length red-cell pyruvate kinase protein may be required for pyruvate kinase activation by mitapivat. Van Straaten S, Bierings M, Bianchi P, et al. 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. Al-Samkari H, Galactros F, Glenthj A, Rothman JA, Andres O, Grace RF, Morado-Arias M, Layton DM, Onodera K, Verhovsek M, Barcellini W, Chonat S, Judge MP, Zagadailov E, Xu R, Hawkins P, Beynon V, Gheuens S, van Beers EJ; ACTIVATE Investigators. S1 in the Supplementary Appendix). Stay connected to what's important in medical research and clinical practice, Subscribe to the most trusted and influential source ofmedical knowledge. For some patients with a hemoglobin response, the magnitude of the change in the hemoglobin level varied according to the dose. 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. Grade 4 adverse events were hypertriglyceridemia, influenza, and mesenteric-vein thrombosis (in one patient each). (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02476916. Bethesda, MD 20894, Web Policies 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. The most common serious adverse events, hemolytic anemia and pharyngitis, each occurred in 2 patients (4%). Epub 2014 Feb 18. 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. Doses of mitapivat that were significantly lower than the initial doses were associated with hemoglobin responses. 2022 May;11(5):654-665. doi: 10.1002/cpdd.1058. Changes in sex hormone levels stayed mainly within normal ranges and did not correlate with adverse events or changes in bone mineral density. Mitapivat versus Placebo for Pyruvate Kinase Deficiency. The data bars in Panels A and B are not aligned for each patient, so a 1:1 comparison of the individual data bars in the two panels is not possible. HHS Vulnerability Disclosure, Help The efficacy analysis included all the patients who had received mitapivat for at least 3 weeks. Pyruvate kinase deficiency is caused by mutations in PKLR and leads to congenital hemolytic anemia. Clin Pharmacol Drug Dev. Enrollment during Core Period and Extension Phase, According to Actual Dose of Mitapivat. and transmitted securely. 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 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. J Biol Chem 2002;277:23807-23814. ), 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. Histamine in the regulation of wakefulness. 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). The bars indicate 95% confidence intervals. Patients who were homozygous for the R479H mutation are indicated by asterisks. In this phase 2, multicenter study, we evaluated the safety and efficacy of mitapivat in adults with pyruvate kinase deficiency who were not receiving regular red-cell transfusions. ), and Childrens Hospital of Philadelphia and Perelman School of Medicine of the University of Pennsylvania, Philadelphia (J.L.K. Address reprint requests to Dr. Grace at Boston Childrens Hospital, 450 Brookline Ave., Dana 3-106, Boston, MA 02215, or at [emailprotected]. Erythrocyte pyruvate kinase deficiency: the influence of physiologically important metabolites on the function of normal and defective enzymes. Blood 2017;130:1347-1356. The most trusted, influential source of new medical knowledge and clinical best practices in the world. 2022 Jul 5;82(13):2403-2416. doi: 10.1158/0008-5472.CAN-21-2352. 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. All the patients provided written informed consent before screening. 4. I. Morphology, erythrokinetics and family enzyme studies. Increases in dose were allowed if the hemoglobin level remained below the lower limit of the normal range (<13.0 g per deciliter in men and <11.6 g per deciliter in women) after at least 12 weeks of treatment.