For patients weighing at least 40 kg, administer NIKTIMVO 0.3 mg/kg, up to a maximum dose of 35 mg, as an intravenous infusion over 30 minutes every 2 weeks until progression or unacceptable toxicity.

Monitor aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), creatine phosphokinase (CPK), amylase, and lipase prior to the start of NIKTIMVO therapy, every 2 weeks for the first month, and every 1 to 2 months thereafter until abnormalities are resolved.

For recommended NIKTIMVO dosage modifications due to adverse reactions, see Table 1.

Table 1: Recommended NIKTIMVO Dosage Modifications for Adverse Reactions

AST = aspartate aminotransferase; ALT = alanine aminotransferase; ULN = upper limit of normal; ALP = alkaline phosphatase; CPK = creatine phosphokinase.
Adverse Reaction	SeverityGraded per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.	Dosage Modification
Infusion-related reactions [see Warnings and Precautions (5.1)]	Grade 1 or 2	Temporarily interrupt the infusion until resolution or decrease infusion rate by 50%. Initiate symptomatic treatment (e.g., antihistamines and antipyretics). For subsequent infusions, premedicate and resume the infusion at 50% of the prior infusion rate.
	Grade 3 or 4	Permanently discontinue NIKTIMVO.
Elevation of AST or ALT (on the day of dosing) [see Adverse Reactions (6.1)]	Grade 3 with total bilirubin ≤ Grade 1	Withhold NIKTIMVO until recovery to Grade 2, then resume NIKTIMVO at 0.2 mg/kg (maximum 23 mg) every 2 weeks.
Elevation of AST or ALT (regardless of the time of the reaction) [see Adverse Reactions (6.1)]	ALT or AST ≥ 3 times ULN with total bilirubin ≥ 2 times ULN and ALP < 2 times ULN	Withhold NIKTIMVO and investigate for drug-induced liver injury. If confirmed, permanently discontinue NIKTIMVO.
	Grade 4	Permanently discontinue NIKTIMVO.
Elevation of CPK, amylase, or lipase [see Adverse Reactions (6.1)]	≥ Grade 3	If diagnostic evaluation results show no evidence of end-organ damage, continue NIKTIMVO without dose reduction. If diagnostic evaluation results show evidence of end-organ damage, permanently discontinue NIKTIMVO.
	Symptomatic ≥ Grade 3	Permanently discontinue NIKTIMVO.
Other Nonhematologic Adverse Reactions [see Adverse Reactions (6.1)]	Grade 3	Withhold NIKTIMVO until recovery to Grade 2: If delayed by ≤ 4 weeks from the planned infusion, resume NIKTIMVO at 0.2 mg/kg (maximum 23 mg) every 2 weeks. If delayed by > 4 weeks from the planned infusion, permanently discontinue NIKTIMVO.
	Grade 4	Permanently discontinue NIKTIMVO.

Preparation

• Use aseptic technique to prepare NIKTIMVO.
• Visually inspect the vial for particulate matter and discoloration prior to dilution. NIKTIMVO is a slightly opalescent, pale brownish yellow solution. Discard the vial if the solution is cloudy, discolored, or contains visible particles.
• Do not shake the vial.
• Determine the dose [see Dosage and Administration (2.1)] and total volume of NIKTIMVO solution needed. Each 1 mL vial of NIKTIMVO contains 50 mg of axatilimab-csfr.

Dilution

• Withdraw the calculated volume of NIKTIMVO solution from the vial and add it into an intravenous infusion bag made of polyvinyl chloride (PVC), polyolefin, polyolefin with polyamide, or ethylene vinyl acetate (EVA) containing 0.9% Sodium Chloride Injection to achieve a final concentration between the range of 0.24 mg/mL and 0.75 mg/mL.
• Discard vial with any unused portion.
• Mix diluted solution by gentle inversion. Do not shake.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The diluted solution is a clear to slightly opalescent, colorless solution that may contain trace amounts of translucent to white particles. Discard if the solution is cloudy, discolored, or contains extraneous particulate matter other than trace amounts of translucent to white particles.

Storage of diluted NIKTIMVO solution

• Immediately use diluted NIKTIMVO solution. If not used immediately, the diluted solution can be stored:
  
  - At room temperature [up to 25°C (77°F)] for no more than 4 hours from the time of preparation to the end of the infusion.
  
  OR
  
  - Refrigerated at 2°C to 8°C (36°F to 46°F) for no more than 24 hours. If refrigerated, allow the diluted solution to come to room temperature prior to administration. The diluted solution must be administered within 4 hours (including infusion time) once it is removed from the refrigerator.

• Do not freeze or shake the diluted solution.

Administration

• Administer diluted NIKTIMVO solution by intravenous infusion over 30 minutes through a dedicated infusion line that includes a sterile, low-protein binding 0.2-micron in-line or add-on polyethersulfone (PES) filter.
• Do not co‑administer other drugs through the same infusion line.
• After administration, flush the infusion line with 0.9% Sodium Chloride Injection.

NIKTIMVO can cause infusion-related reactions. Infusion-related reactions, including hypersensitivity reactions, occurred in 18% of patients who received NIKTIMVO in the clinical trial (AGAVE-201), with Grade 3 or 4 reactions in 1.3% [see Adverse Reactions (6.1)].

Premedicate with an antihistamine and an antipyretic for patients who have previously experienced an infusion-related reaction to NIKTIMVO [see Dosage and Administration (2.2)]. Monitor patients for signs and symptoms of infusion-related reactions, including fever, chills, rash, flushing, dyspnea, and hypertension. Interrupt or slow the rate of infusion or permanently discontinue NIKTIMVO based on severity of the reaction [see Dosage and Administration (2.2)].

Based on its mechanism of action, NIKTIMVO may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with NIKTIMVO and for 30 days after the last dose [see Use in Specific Populations (8.1, 8.3)].

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.

Chronic Graft-Versus-Host Disease

The safety of NIKTIMVO was evaluated in 79 adult and pediatric patients with cGVHD treated with NIKTIMVO 0.3 mg/kg intravenously every 2 weeks in the AGAVE‑201 trial [see Clinical Studies ( 14 )]. The median duration of treatment was 10.3 months (range: 0.5 to 28.6 months), and 73.4% were treated for more than 6 months.

Serious adverse reactions occurred in 44% of patients who received NIKTIMVO. Serious adverse reactions in more than 2 patients included infection (pathogen unspecified), viral infection, and respiratory failure. Permanent discontinuation of NIKTIMVO due to an adverse reaction occurred in 10% of patients and dose reduction due to adverse reaction occurred in 8% of patients. Dose interruptions due to an adverse reaction occurred in 44% of patients. The adverse reactions leading to dose interruption in more than 2 patients were viral infection, infection (pathogen unspecified), bacterial infection, musculoskeletal pain, and pyrexia.

The most common (≥ 15%) adverse reactions, including laboratory abnormalities, were increased AST, infection (pathogen unspecified), increased ALT, decreased phosphate, decreased hemoglobin, viral infection, increased gamma glutamyl transferase (GGT), musculoskeletal pain, increased lipase, fatigue, increased amylase, increased calcium, increased CPK, increased ALP, nausea, headache, diarrhea, cough, bacterial infection, pyrexia, and dyspnea.

Table 2 summarizes the nonlaboratory adverse reactions in AGAVE-201.

Table 2: Adverse Reactions in ≥ 10% of Patients With cGVHD Who Received NIKTIMVO in AGAVE-201

Graded according to NCI CTCAE v5.0.
Adverse Reaction	NIKTIMVO 0.3 mg/kg intravenously every 2 weeks (N = 79)
	All Grades (%)	Grades 3-4 (%)
Infections and infestations
Infection (pathogen unspecified)Includes abscess jaw, atypical pneumonia, bacteremia, bronchitis, conjunctivitis, cystitis, device-related infection, enterocolitis infectious, gastroenteritis, gastrointestinal infection, groin abscess, hordeolum, liver abscess, nasopharyngitis, otitis media, otitis media acute, pneumonia, respiratory tract infection, rhinitis, sepsis, sinusitis, tooth infection, upper respiratory tract infection, urinary tract infection, and wound infection.	57	14
Viral infectionIncludes adenoviral upper respiratory infection, BK virus infection, COVID-19, coronavirus infection, enterovirus infection, gastroenteritis astroviral, gastroenteritis viral, herpes simplex, herpes zoster, influenza, metapneumovirus bronchiolitis, metapneumovirus infection, norovirus infection, oral viral infection, parainfluenza viral bronchitis, parainfluenza virus infection, respiratory syncytial virus infection, rhinovirus infection, viral infection, and viral upper respiratory tract infection.	43	15
Bacterial infectionIncludes bacterial diarrhea, bacterial vaginosis, campylobacter gastroenteritis, campylobacter infection, cellulitis, clostridium difficile colitis, clostridium difficile infection, enterococcal infection, erysipelas, hemophilus infection, lower respiratory tract infection bacterial, pseudomonal skin infection, staphylococcal bacteremia, staphylococcal infection, stenotrophomonas infection, streptococcal infection, and urinary tract infection enterococcal.	15	8
Musculoskeletal and connective tissue disorders
Musculoskeletal painIncludes arthralgia, back pain, flank pain, musculoskeletal pain, myalgia, pain in extremity.	35	3
General disorders and administration site conditions
FatigueIncludes asthenia, fatigue, and malaise.	32	4
Pyrexia	15	1
EdemaIncludes localized edema and peripheral edema.	13	1
Gastrointestinal disorders
NauseaIncludes nausea and vomiting.	23	3
DiarrheaIncludes colitis and diarrhea.	18	5
Nervous system disorders
HeadacheIncludes headache and migraine.	20	1
DizzinessIncludes dizziness and dizziness postural.	11	0
Respiratory, thoracic and mediastinal disorders
CoughIncludes cough and productive cough.	18	0
DyspneaIncludes dyspnea and dyspnea exertional.	15	3
Immune system disorders
Drug hypersensitivityIncludes bronchospasm, flushing, hot flush, hypersensitivity, infusion-related hypersensitivity reaction, infusion-related reaction, and urticaria.	13	3
Metabolism and nutrition disorders
Decreased appetite	11	4
Vascular disorders
HemorrhageIncludes contusion, epistaxis, hematochezia, hematoma, and vaginal hemorrhage.	11	1
Skin and subcutaneous tissue disorders
RashIncludes dermatitis bullous, dermatitis exfoliative generalized, rash, and rash maculo-papular.	10	0

Clinically relevant adverse reactions in < 10% of patients who received NIKTIMVO included:

• Eye disorders: periorbital edema
• Skin and subcutaneous skin disorders: pruritus
• Vascular disorders: hypertension

Table 3 summarizes the laboratory abnormalities in AGAVE-201.

Table 3: Selected Laboratory Abnormalities in Patients with cGVHD Who Received NIKTIMVO in AGAVE-201

NA = not applicable.
Laboratory Abnormality	NIKTIMVO 0.3 mg/kg intravenously every 2 weeks (N=79)
	All GradesThe denominator used to calculate the rate varied from 78 to 79 based on the number of patients with at least 1 post-treatment value. (%)	Grade 3 or 4 (%)
Hematology
Decreased hemoglobin	48	4
Chemistry
Increased aspartate aminotransferase	61	5
Increased alanine aminotransferase	51	3
Decreased phosphate	51	NA
Increased gamma glutamyl transferase	39	4
Increased lipase	34	3
Increased amylase	32	0
Increased calcium	31	1
Increased alkaline phosphatase	28	0
Increased creatine phosphokinase	25	0

  Immunogenicity: Anti-Drug Antibody–Associated Adverse Reactions

 In 276 patients with cGVHD who received NIKTIMVO in clinical trials, among the patients who developed anti-drug antibodies (ADAs), hypersensitivity reactions occurred in 26% (13/50) of patients with neutralizing antibodies (NAb) and in 4% (2/45) of those without NAb [see Clinical Pharmacology (12.6)].

Risk Summary

Based on its mechanism of action, NIKTIMVO may cause fetal harm when administered to pregnant women [see Clinical Pharmacology (12.1)]. There are no available data on the use of NIKTIMVO in pregnant women to evaluate for a drug-associated risk. No animal reproductive and developmental toxicity studies have been conducted with axatilimab-csfr.

Targeted mutation of CSF-1R or CSF-1 in rodent models results in prenatal and perinatal death, deficits in growth, and pleiotropic impact on multiple organ systems, including skeletal and reproductive. Regulation by CSF-1R on non-mononuclear phagocytic cells and macrophages plays a role in the innate immune protection of the fetus and in pregnancy maintenance and embryo-fetal development. Human immunoglobulin G (IgG) is known to cross the placenta; therefore, NIKTIMVO has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to the fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Risk Summary

There are no data on the presence of axatilimab-csfr in human milk or the effects on the breastfed child or milk production. Maternal IgG is known to be present in human milk. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment and for 30 days after the last dose of NIKTIMVO.

NIKTIMVO may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating NIKTIMVO [see Use in Specific Populations (8.1)].

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with NIKTIMVO and for 30 days after the last dose of NIKTIMVO.

The safety and effectiveness of NIKTIMVO for the treatment of cGVHD after failure of at least two prior lines of systemic therapy have been established in pediatric patients weighing at least 40 kg. Use of NIKTIMVO in pediatric patients weighing at least 40 kg is supported by evidence from clinical trials that included 3 children (ages 6 to less than 12 years old) and 5 adolescents (ages 12 to less than 17 years old) [see Clinical Studies (14)]. The safety and effectiveness of NIKTIMVO have not been established in pediatric patients weighing less than 40 kg.

Compared to adult and pediatric patients weighing 40 kg and above, patients weighing less than 40 kg had lower maximum concentration, trough concentration, and average concentration at the same weight-based dosage.

Based on findings of thickening of the growth plate and metaphysis and/or degeneration of the growth plate in the femur in animals, monitor bone growth and development in pediatric patients [see Nonclinical Toxicology (13.2)].

Of the 79 patients with cGVHD treated with NIKTIMVO, 21 (26.6%) were 65 years and older, and 2 (2.5%) were 75 years and older [see Clinical Studies (14)]. No overall differences in the safety or effectiveness of NIKTIMVO have been observed between patients 65 years of age and older and younger patients.

Axatilimab-csfr is a monoclonal antibody that binds to colony stimulating factor-1 receptors (CSF-1R) expressed on monocytes and macrophages. Blocking CSF-1R with axatilimab-csfr reduces the levels of these circulating proinflammatory and profibrotic monocytes and monocyte-derived macrophages, as demonstrated by a reduction of nonclassical monocyte counts in nonclinical studies with axatilimab-csfr, and inhibits the activity of pathogenic macrophages in tissues.

CSF-1 and Interleukin (IL)-34

Axatilimab-csfr caused a dose-dependent increase from 0.15 mg/kg to 6 mg/kg (0.5 to 20 times the approved recommended dosage) in CSF-1 and interleukin (IL)-34 concentrations and a dose-dependent reduction in the levels of nonclassical monocytes in peripheral blood.

Axatilimab-csfr pharmacokinetics are presented as geometric mean (coefficient of variation [%CV]) in adult patients with cGVHD following axatilimab-csfr 0.3 mg/kg (maximum 35 mg) every 2 weeks, unless otherwise specified. Axatilimab-csfr AUC increased in a greater than dose-proportional manner following single-dose administration of axatilimab-csfr over a dose range of 0.15 mg/kg to 3 mg/kg (0.5 to 10 times the approved recommended dosage) in healthy subjects.

There was no axatilimab-csfr systemic accumulation following the approved recommended dosage.

Distribution

Axatilimab-csfr volume of distribution is 6.06 L (16.3% CV).

Elimination

Axatilimab-csfr total clearance is 0.07 L/h (38.8% CV). The median (5th to 95th percentile) time to 97% reduction from C_max after the end of infusion is 4.0 (2.3 to 7.2) days following axatilimab-csfr 0.3 mg/kg (maximum 35 mg).

The total clearance of axatilimab-csfr is composed of linear and non-linear components such that axatilimab-csfr clearance decreased from 2.32 mL/h/kg to 0.21 mL/h/kg and mean terminal half-life increased from 10.7 hours to 108 hours following single-dose administrations of axatilimab-csfr over a dose range of 0.15 mg/kg to 3 mg/kg (0.5 to 10 times the approved recommended dosage).

Metabolism

Axatilimab-csfr is expected to be metabolized into small peptides by catabolic pathways.

Specific Populations

No clinically meaningful differences in the exposure of axatilimab-csfr were observed in adult and pediatric patients based on age (12 to 81 years), sex, body weight (40 to 151 kg), race (White, Black, or Asian), mild to moderate renal impairment (estimated creatinine clearance 30-89 mL/min by the Cockcroft-Gault equation), or mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin 1 to ≤ 1.5 times ULN and any AST) following the approved recommended dosage of 0.3 mg/kg (maximum 35 mg) every 2 weeks.

The effect of severe renal impairment (estimated creatinine clearance 15-29 mL/min, Cockcroft-Gault equation) and moderate to severe hepatic impairment (total bilirubin > 1.5 times ULN and any AST) on axatilimab-csfr pharmacokinetics is unknown.

Pediatric Patients

Axatilimab-csfr exposures in pediatric patients weighing 40 kg and above are comparable to those in adults following the approved recommended dosage of 0.3 mg/kg (maximum 35 mg) every 2 weeks.

The observed incidence of ADAs is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADAs in the studies described below with the incidence of ADAs in other studies, including those of NIKTIMVO or of other axatilimab products.

ADAs were assessed in 276 patients with cGVHD who received NIKTIMVO. The incidence of axatilimab-csfr treatment-emergent ADAs was 33.7% (93/276) following a median exposure time of 7.8 months. NAb were detected in 47 of 93 cGVHD patients with treatment-emergent ADAs. There was no clinically meaningful effect of anti–axatilimab-csfr antibodies or NAb on the pharmacokinetics, pharmacodynamics, or effectiveness of NIKTIMVO. The presence of NAb correlated with the occurrence of hypersensitivity reactions [see Adverse Reactions (6.1)].

No studies have been performed to assess the potential of axatilimab-csfr for carcinogenicity or genotoxicity.

Dedicated fertility studies have not been conducted with axatilimab-csfr. Administration of axatilimab-csfr to sexually mature cynomolgus monkeys in a 3-month toxicology study had no effect on menstrual cyclicity in females, sperm parameters (morphology, motility, or number) in males, and produced no histopathologic findings in female and male reproductive organs, indicating that axatilimab-csfr did not adversely affect reproductive function. Targeted deletion of CSF-1R or CSF-1 in rodent models resulted in impairment of fertility.

In a 6-month chronic toxicity study in sexually immature cynomolgus monkeys, axatilimab-csfr was administered once weekly at doses of 10, 30, or 100 mg/kg/week via intravenous injection. The primary findings included periorbital swelling, widespread accumulation of basophilic material, and effects on bone at doses ≥ 10 mg/kg/week. Alterations in bone included decreases in bone markers, thickening of the growth plate and metaphysis and/or degeneration of the growth plate in the femur. In a 3-month toxicity study in sexually mature monkeys, intravenous administration of axatilimab-csfr at doses of 10, 30, or 100 mg/kg/week resulted in decreases in bone biomarkers at doses ≥ 30 mg/kg/week.