Brand Name
Pyrukynd
Generic Name
Mitapivat
View Brand Information FDA approval date: February 18, 2022
Classification: Pyruvate Kinase Activator
Form: Tablet, Kit
What is Pyrukynd (Mitapivat)?
PYRUKYND is indicated for the treatment of hemolytic anemia in adults with pyruvate kinase deficiency. PYRUKYND is a pyruvate kinase activator indicated for the treatment of hemolytic anemia in adults with pyruvate kinase deficiency.
Approved To Treat
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Brand Information
PYRUKYND (mitapivat)
1INDICATIONS AND USAGE
PYRUKYND is indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency.
2DOSAGE AND ADMINISTRATION
PYRUKYND is taken orally with or without food. The tablets should be swallowed whole. Do not split, crush, chew, or dissolve the tablets.
2.1Recommended Dose
PYRUKYND is taken with or without food and swallowed whole. Do not split, crush, chew, or dissolve the tablets.
The starting dosage for PYRUKYND is 5 mg orally twice daily. To gradually increase hemoglobin (Hb), titrate PYRUKYND from 5 mg twice daily to 20 mg twice daily, and then to the maximum recommended dose of 50 mg twice daily, with these dose increases occurring every 4 weeks (see Table 1). Assess Hb and transfusion requirement before increasing to the next dose level, as some patients may reach and maintain normal Hb at 5 mg twice daily or 20 mg twice daily.
Discontinue PYRUKYND if no benefit has been observed by 24 weeks, based on the hemoglobin and hemolysis laboratory results and transfusion requirements.
2.2Missed Dose
If a dose of PYRUKYND is missed by 4 hours or less, administer the dose as soon as possible. If a dose of PYRUKYND is missed by more than 4 hours, do not administer a replacement dose, and wait until the next scheduled dose. Subsequently, return to the normal dosing schedule.
2.3Interruption or Discontinuation
To reduce the risk of acute hemolysis, avoid abrupt interruption or abrupt discontinuation of PYRUKYND when possible
2.4Recommended Dosage for Hepatic Impairment
Avoid use of PYRUKYND in patients with moderate or severe hepatic impairment
2.5Recommended Dosage for Drug Interactions
Strong CYP3A Inhibitors
Avoid co-administration of strong CYP3A inhibitors with PYRUKYND
Moderate CYP3A Inhibitors
Monitor Hb and for increased risks of adverse reactions from PYRUKYND. When used with a moderate CYP3A inhibitor, do not titrate PYRUKYND beyond 20 mg twice daily
Strong CYP3A Inducers
Avoid co-administration of strong CYP3A inducers with PYRUKYND
Moderate CYP3A Inducers
Consider alternative therapies that are not moderate CYP3A inducers during treatment with PYRUKYND. If there are no alternative therapies, monitor Hb and titrate beyond the 50 mg twice daily dose, if necessary, but do not exceed a maximum recommended dose of 100 mg twice daily
2.6Dose Modifications for Adverse Reactions and Hemoglobin Levels Above Normal
If a dose reduction is required because of an adverse reaction or tolerability, or for Hb above normal, the dose may be reduced to the next lower dose level, 20 mg twice daily or 5 mg twice daily.
If a patient needs to discontinue PYRUKYND, the dose taper schedule (Table 2) should be followed. In situations where the risk to the patient due to the adverse reaction or Hb above normal is greater than the risk of acute hemolysis due to sudden withdrawal of the drug, treatment may be stopped without taper and patients should be monitored for signs of acute hemolysis.
3DOSAGE FORMS AND STRENGTHS
- 5 mg tablets: round, blue, film-coated tablets with "M5" printed on one side.
- 20 mg tablets: round, blue, film-coated tablets with "M20" printed on one side.
- 50 mg tablets: oblong, blue, film-coated tablets with "M50" printed on one side.
4CONTRAINDICATIONS
None
5ADVERSE REACTIONS
The following clinically significant adverse reaction is described elsewhere in labeling:
- Acute Hemolysis with Abrupt Treatment Discontinuation
- Hepatocellular Injury in Another Condition
5.1Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
A total of 155 patients received PYRUKYND, 79% of whom were exposed for longer than 24 weeks. PYRUKYND was administered up to 50 mg orally twice daily in 67 patients with PK deficiency in the ACTIVATE trial (N=40) and the ACTIVATE-T trial (N=27)
ACTIVATE Trial
In the ACTIVATE trial patients with PK deficiency who were not regularly transfused received PYRUKYND in incremental doses up to 50 mg twice daily (N=40) or placebo (N=39).
Serious adverse reactions occurred in 10% of patients receiving PYRUKYND in the ACTIVATE Trial, including atrial fibrillation, gastroenteritis, rib fracture, and musculoskeletal pain, which each occurred in 1 patient.
In the ACTIVATE trial, the most common adverse reactions including laboratory abnormalities (≥10%) in patients with PK deficiency were estrone decreased (males), increased urate, back pain, estradiol decreased (males), and arthralgia.
Table 3 summarizes the adverse reactions in the ACTIVATE trial.
Laboratory abnormalities of PYRUKYND included increased urate (15%).
Variations in Reproductive Hormones
In ACTIVATE, increases in serum testosterone and decreases in serum estrone and estradiol were observed in men receiving PYRUKYND (Table 4). These changes in hormones persisted throughout the study period. In patients who discontinued PYRUKYND and had follow-up hormone measurements, the hormone changes returned close to the baseline levels 28 days after discontinuing PYRUKYND. In female patients, sex hormone analysis was limited due to physiologic variations in hormones during the menstrual cycle and the use of hormonal contraceptives.
ACTIVATE-T Trial
The adverse reactions reported in the population of patients who were regularly transfused (ACTIVATE-T) were consistent with that seen in ACTIVATE.
6DESCRIPTION
The active ingredient of PYRUKYND is mitapivat, a pyruvate kinase activator, present as mitapivat sulfate. The chemical name of mitapivat sulfate is 8-quinolinesulfonamide, N-[4-[[4- (cyclopropylmethyl)-1-piperazinyl]carbonyl]phenyl]-, sulfate, hydrate (2:1:3). The chemical structure of mitapivat sulfate is:
The molecular formula is (C
PYRUKYND is available as 5 mg, 20 mg, and 50 mg tablets for oral administration. Each tablet contains 5 mg, 20 mg, or 50 mg mitapivat free base, provided as 5.85 mg, 23.4 mg, or 58.5 mg, respectively, of the sulfate hydrate salt, and the following inactive ingredients: croscarmellose sodium, mannitol, microcrystalline cellulose, and sodium stearyl fumarate. The tablet film coating contains the inactive ingredients FD&C Blue No. 2, hypromellose, lactose monohydrate, titanium dioxide, and triacetin. The tablets are imprinted with black ink containing the inactive ingredients ammonium hydroxide, ferrosoferric oxide, isopropyl alcohol, n-butyl alcohol, propylene glycol, and shellac glaze.
7CLINICAL STUDIES
Patients with PK Deficiency
Patients Not Regularly Transfused
The efficacy of PYRUKYND was evaluated in ACTIVATE, a multinational, randomized, double-blind, placebo-controlled clinical study (NCT03548220) of 80 adults with PK deficiency who were not regularly transfused, defined as having had no more than 4 transfusions in the 52- week period prior to treatment and no transfusions in the 3-month period prior to treatment.
Patients were included if they had documented presence of at least 2 variant alleles in the pyruvate kinase liver and red blood cell (PKLR) gene, of which at least 1 was a missense variant, and Hb less than or equal to 10 g/dL. Patients who were homozygous for the c.1436G>A (p.R479H) variant or had 2 non-missense variants (without the presence of another missense variant) in the PKLR gene were excluded because these patients did not achieve Hb response (change from baseline in Hb ≥1.5 g/dL at >50% assessments) in the dose-ranging study.
Randomization was stratified by average screening Hb (<8.5 vs ≥8.5 g/dL) and PKLR gene variant category (missense/missense vs. missense/non-missense).
Among the 80 patients with PK deficiency, 40 patients were randomized to PYRUKYND. Following a period of dose titration up to 50 mg twice daily, patients continued a fixed dose of PYRUKYND for 12 weeks. Eighty-eight percent of patients were maintained on 50 mg twice daily.
The median duration of treatment with PYRUKYND was 24.1 weeks (range 23.6 to 27.4 weeks). Overall, 30 (75%) patients were exposed to PYRUKYND for >24 weeks and <28 weeks. Among the 80 randomized patients, the median age was 33 years (range 18 to 78) and 40% were male; race was reported in 88% of patients: 75% were White, 10% Asian, 1.3% Native Hawaiian/Other Pacific Islander and 1.3% were other races. The median baseline hemoglobin was 8.5 g/dL (range: 6.4 to 10.2 g/dL). There were 55 patients (69%) with the missense/missense PKLR gene variant category, and 25 patients (31%) with the missense/non-missense PKLR gene variant category. There were 58 patients (73%) who had a history of splenectomy. Complications and comorbidities associated with PK deficiency included iron overload with a median baseline ferritin of 479 ng/mL (range: 21 to 5890 ng/mL), chelation therapy use in the year before the first dose of study treatment in 15 patients (19%), decreased bone mineral density in 64 patients (80%) who had a baseline femoral neck T-score or lumbar spine T-score <-1.0, and history of cholecystectomy in 58 patients (73%).
Efficacy was based upon Hb response, defined as a ≥1.5 g/dL increase in Hb from baseline sustained at 2 or more scheduled assessments (Weeks 16, 20, and 24) during the fixed dose period without transfusions. The efficacy results, including changes in markers of hemolysis are shown in Table 6.
In ACTIVATE, the LS Mean change from baseline with PYRUKYND compared to placebo was -0.4 (standard error [SE] 0.1) for jaundice (scale: 0-4), -1.1 (SE 0.4) for tiredness (scale: 0-10), and -0.3 (SE 0.3) for shortness of breath (scale: 0-10), assessed with the daily Pyruvate Kinase Deficiency Diary (PKDD) where lower scores represent less sign/symptom severity.
In ACTIVATE, the majority of PYRUKYND-treated patients experienced an increase in Hb, while the majority of patients in the placebo arm experienced a decrease in Hb as measured by average change from baseline at weeks 16, 20, and 24 (Figure 1).
a Approximately 99% of all randomized patients completed 24 weeks of treatment.
CI: confidence interval, Hb: hemoglobin, LS: least square
Fifteen of the 16 patients with a Hb response in ACTIVATE continued in a long-term extension study and were evaluable for maintenance of response. Thirteen maintained increases in Hb concentration from baseline above the response threshold of ≥1.5 g/dL at the last available Hb assessment without requiring any transfusions. The median duration of response for the 16 patients with Hb response was 6.9 months (range: 3.3, 18.4+).
Patients Who Were Regularly Transfused
The efficacy of PYRUKYND in patients with PK deficiency who were regularly transfused was evaluated in ACTIVATE-T, a multinational single-arm clinical trial (NCT03559699) of 27 adults with PK deficiency who had a minimum of 6 transfusion episodes in the 52-week period prior to informed consent. Patients were included if they had documented presence of at least 2 variant alleles in the PKLR gene, of which at least 1 was a missense variant. Patients who were homozygous for the c.1436G>A (p.R479H) variant or had 2 non-missense variants (without the presence of another missense variant) in the PKLR gene were excluded. Following a period of dose titration up to 50 mg twice daily, patients continued on a fixed dose of PYRUKYND for 24 weeks.
The median duration of treatment with PYRUKYND was 40.3 weeks (range 16.3 to 46.3 weeks). Overall, 20 (74%) patients were exposed to PYRUKYND for >40 weeks and <47 weeks. The median age was 36 years (range 18 to 68) and 26% were male; race was reported in 85% of patients: 74% were White and 11% Asian. The median baseline hemoglobin was 9.1 g/dL (range: 7.4 to 10.9 g/dL). Patients had a median of 9 transfusion episodes (range: 6 to 17 episodes) in the 52 weeks before the first dose of study treatment and a median of 7 red blood cell units transfused (range: 3 to 20 units) standardized to 24 weeks. There were 20 patients (74%) with the missense/missense PKLR gene variant category, and 7 patients (26%) with the missense/non-missense PKLR gene variant category. There were 21 patients (78%) who had a history of splenectomy. Patients had evidence of complications and comorbidities associated with PK deficiency including iron overload (median baseline ferritin was 1324 ug/L; range: 163 to 5357 ng/mL), chelation therapy use in the year before the first dose of study treatment in 24 patients (89%), decreased bone mineral density in 20 patients (74%) who had a baseline femoral neck T-score or lumbar spine T-score <-1.0, and history of cholecystectomy in 23 patients (85%).
Efficacy was based on transfusion reduction response and was defined as ≥33% reduction in the number of red blood cell (RBC) units transfused during the fixed dose period compared with the patient’s historical transfusion burden.
Efficacy results for patients with PK deficiency who were regularly transfused are presented in Table 7.
All 6 (22%) patients who were transfusion free in ACTIVATE-T remained transfusion free in a long-term extension study. The median duration of response for the 6 patients was 17 months (range: 11.5+, 21.8+).
8HOW SUPPLIED/STORAE AND HANDLING
How Supplied
Storage
Store at 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Store the blister wallets in the original carton until use.
9PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Acute Hemolysis with Abrupt Treatment Interruption
Inform patients of the risk of developing acute hemolysis and subsequent anemia following abrupt interruption or discontinuation of PYRUKYND. Inform patients to follow their healthcare provider’s instructions for discontinuing PYRUKYND. Upon discontinuing PYRUKYND, tell patients to immediately report any symptoms suggestive of acute hemolysis including jaundice, scleral icterus, dark urine, dizziness, confusion, fatigue, or shortness of breath to their healthcare provider for further evaluation
Hepatocellular Injury in Another Condition
Inform patients of the risk of hepatocellular injury observed in patients with another condition during the first 6 months of treatment with PYRUKYND at a higher dose than that recommended for patients with PK deficiency. Tell patients to immediately report any symptoms suggestive of liver injury including jaundice, dark urine, right upper quadrant pain, nausea, vomiting, or loss of appetite to their healthcare provider for further evaluation
Drug Interactions
Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications, vitamins, and herbal products
Dosing and Storage Instructions
- Instruct patients to swallow the tablets whole with or without food and not to split, crush, chew, or dissolve the tablets.
- Advise patients if a dose of PYRUKYND is missed by 4 hours or less, to take the scheduled dose as soon as possible. If a dose of PYRUKYND is missed by more than 4 hours, advise the patient to not take a replacement dose and wait until the next scheduled dose.
PYRUKYND
© 2022 Agios Pharmaceuticals, Inc.
Manufactured for and Distributed by:
Agios Pharmaceuticals, Inc.
Cambridge, MA 02139
AG-PI-002
10PRINCIPAL DISPLAY PANEL - 5 mg Tablet Blister Pack Carton
NDC 71334-205-05
Rx Only
pyrukynd ®
56 tablets
Contains 4-week supply of PYRUKYND ®
11PRINCIPAL DISPLAY PANEL - 20 mg Tablet Blister Pack Carton
NDC 71334-210-20
Rx Only
pyrukynd ®
56 tablets
Contains 4-week supply of PYRUKYND ®
12PRINCIPAL DISPLAY PANEL - 50 mg Tablet Blister Pack Carton
NDC 71334-215-50
Rx Only
pyrukynd ®
56 tablets
Contains 4-week supply of PYRUKYND ®
13PRINCIPAL DISPLAY PANEL - 5 mg Tablet Blister Pack Carton - 220-11
NDC 71334-220-11
Rx Only
pyrukynd ®
Week 1
5 mg TAPER PACK
7 tablets
Swallow tablets whole.
14PRINCIPAL DISPLAY PANEL - 20 mg/5 mg Tablet Blister Pack Carton - 225-12
NDC 71334-225-12
Rx Only
pyrukynd ®
Week 1
Week 2
20 mg and 5 mg TAPER PACK
14 tablets
Contains two 7-day blister wallets with 7 tablets per wallet:
Swallow tablets whole.
15PRINCIPAL DISPLAY PANEL - 50 mg/20 mg Tablet Blister Pack Carton - 230-13
NDC 71334-230-13
Rx Only
pyrukynd ®
Week 1
Week 2
50 mg and 20 mg TAPER PACK
14 tablets
Contains two 7-day blister wallets with 7 tablets per wallet:
Swallow tablets whole.
