Get your patient on Tryngolza - Olezarsen Sodium injection, Solution (Olezarsen Sodium)

In adults with FCS:

• The recommended dosage of TRYNGOLZA is 80 mg injected subcutaneously once monthly [see Dosage and Administration (2.2) ] .

In adults with sHTG:

• The recommended dosage of TRYNGOLZA is 50 mg injected subcutaneously once monthly [see Dosage and Administration (2.2) ].
• Assess TG when clinically appropriate. The TG-lowering effect of TRYNGOLZA may be measured within 3 months after initiation.
• For patients who tolerate the 50 mg dosage and additional TG reduction is clinically indicated, the dosage may be increased to 80 mg injected subcutaneously once monthly.

• Prior to initiation, train patients and/or caregivers on proper preparation and administration of TRYNGOLZA [see Instructions for Use ] .
• Advise patients to maintain a low-fat diet in conjunction with TRYNGOLZA. Instruct patients with FCS to consume 20 g or less of fat per day.
• Remove the single-dose autoinjector from the refrigerator and let the autoinjector come to room temperature 30 minutes prior to the injection. Do not use other warming methods.
• Inspect TRYNGOLZA visually for particulate matter prior to administration. The solution should be a clear and colorless to yellow liquid. Do not use if cloudiness, particulate matter, or discoloration is observed prior to administration.
• Inject TRYNGOLZA subcutaneously into the abdomen or front of the thigh. The back of the upper arm can also be used as an injection site if a healthcare provider or caregiver administers the injection.
• Administer TRYNGOLZA as soon as possible after a missed dose. Resume dosing at monthly intervals from the date of the most recently administered dose.

The safety and effectiveness of TRYNGOLZA in pediatric patients have not been established.

No dose adjustment is recommended in patients aged 65 years and older [see Clinical Pharmacology (12.3) ] . In clinical trials, 243 patients treated with TRYNGOLZA were ≥65 years of age. No overall differences in safety or effectiveness of TRYNGOLZA have been observed between patients 65 years of age and older and younger adult patients.

No dose adjustment is necessary in patients with mild to moderate renal impairment [estimated glomerular filtration rate (eGFR) ≥30 to <90 mL/min] [see Clinical Pharmacology (12.3) ] . TRYNGOLZA has not been studied in patients with severe renal impairment or end-stage renal disease.

No dose adjustment is recommended in patients with mild or moderate hepatic impairment [see Clinical Pharmacology (12.3) ] . TRYNGOLZA has not been studied in patients with severe hepatic impairment.

Hypersensitivity reactions (including symptoms of bronchospasm, diffuse erythema, facial swelling, urticaria, chills, and myalgias) have been reported in patients treated with TRYNGOLZA [see Adverse Reactions (6.1) ] . Advise patients on the signs and symptoms of hypersensitivity reactions and instruct patients to promptly seek medical attention and discontinue use of TRYNGOLZA if hypersensitivity reactions occur. TRYNGOLZA is contraindicated in patients with a history of serious hypersensitivity to olezarsen or any of the excipients in TRYNGOLZA.

TRYNGOLZA can cause increases in liver enzymes and hepatic fat in adults [see Adverse Reactions (6.1) ] .

Increases in liver enzymes were more frequently reported with the 80 mg dose as compared to the 50 mg dose. In patients with sHTG, increases in liver enzymes greater than or equal to three times the upper limit of normal were reported more frequently with TRYNGOLZA 80 mg (7%) compared to TRYNGOLZA 50 mg (3%) and placebo (3%).

Consider liver enzyme testing before TRYNGOLZA initiation or an increase in dosage and when clinically indicated thereafter. If persistent elevations in liver enzymes occur (such as three times the upper limit of normal or greater), consider dose interruption and/or dose reduction. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue TRYNGOLZA.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of TRYNGOLZA cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trial in Patients with FCS

The safety of TRYNGOLZA was evaluated in 66 patients with FCS enrolled in Trial 1 (NCT #04568434) [see Clinical Studies (14.1) ] . In this trial, 43 patients received at least one dose of TRYNGOLZA, 50 mg (N=21) or 80 mg (N=22) and 23 patients received placebo. TRYNGOLZA 50 mg is not an approved dosing regimen for FCS [see Dosage and Administration (2.1) ]. Across treatment groups, the mean age was 45 years and 42% of patients were male. Eighty-five percent (85%) of patients were White, 9% were Asian and 6% were reported as other races; 11% identified as Hispanic or Latino ethnicity. Forty-three (43) patients were exposed to TRYNGOLZA for a median of 52 weeks; 22 patients were treated with TRYNGOLZA 80 mg every 4 weeks for a median of 52 weeks.

Adverse reactions led to discontinuation of treatment in 7% of TRYNGOLZA-treated patients and 0% of placebo-treated patients. The most common reason for TRYNGOLZA treatment discontinuation was hypersensitivity reactions. Adverse reactions (>5% of patients treated with TRYNGOLZA and at >3% higher frequency than placebo) are presented in Table 1.

Table 1. Adverse Reactions That Occurred in >5% of Patients with FCS Treated with TRYNGOLZA and at >3% Higher Frequency than with Placebo (Trial 1)

Clinical Trials in Patients with sHTG
The safety of TRYNGOLZA was evaluated in two randomized, double-blind, placebo-controlled trials [Trial 2 (NCT #05079919) and Trial 3 (NCT #05552326)] that included a total of 1,061 adult patients with sHTG [see Clinical Studies (14.2) ] . In these trials, 705 patients received at least one dose of TRYNGOLZA, 50 mg (N=354) or 80 mg (N=351), and 356 patients received placebo. Across treatment groups, the mean age was 54 years and 76% of patients were male. Eighty-eight percent (88%) of patients were White, 5% Asian, 2% Black or African American, 2% American Indian or Alaskan Native, less than 1% Native Hawaiian or Pacific Islander, and 2% other or multiple races; 12% identified as Hispanic or Latino ethnicity. The median exposure to TRYNGOLZA was 364 days (N=705).

Adverse reactions led to discontinuation of treatment in 5% of TRYNGOLZA-treated patients and 2% of placebo-treated patients. The most common adverse reaction for TRYNGOLZA treatment discontinuation was injection site reactions.

Adverse reactions (in patients treated with TRYNGOLZA at ≥2% higher frequency than placebo) are presented in Table 2.

Table 2. Adverse Reactions Occurring in ≥2% of Patients with sHTG Treated with TRYNGOLZA than with Placebo (Trial 2 and Trial 3)

Olezarsen is an ASO-GalNAc ₃ conjugate that binds to apoC-III mRNA leading to mRNA degradation and resulting in a reduction of serum apoC-III protein. Reduction of apoC-III protein leads to increased clearance of plasma TG and very low-density lipoprotein (VLDL).

Fasting apoC-III
Olezarsen decreased fasting apoC-III following administration of TRYNGOLZA 80 mg dosage every 4 weeks to patients with FCS [see Clinical Studies (14.1) ] . The placebo-corrected percent change in fasting apoC-III from baseline was -57% at 1 month, -69% at 3 months, -72% at 6 months, and -80% at 12 months. Olezarsen also decreased fasting apoC-III following administration of TRYNGOLZA 50 mg and 80 mg every 4 weeks in patients with sHTG [see Clinical Studies (14.2) ] . The placebo-corrected percent change in fasting apoC-III from baseline in Trial 2 was -68% at Month 6 and -67% at Month 12 in patients treated with TRYNGOLZA 50 mg, and -77% at Month 6 and -72% at Month 12 in patients treated with TRYNGOLZA 80 mg. In Trial 3, the placebo-corrected percent change in fasting apoC-III from baseline was -57% at Month 6 and -53% at Month 12 in patients treated with TRYNGOLZA 50 mg, and -63% at Month 6 and -58% at Month 12 in patients treated with TRYNGOLZA 80 mg.

Olezarsen steady-state geometric mean (geometric % coefficient of variation [geometric %CV]) maximum concentrations (C _max ) is 659 (88.5%) ng/mL and area under the curve (AUC _τ ) is 8,030 (83.7%) ng•h/mL at the approved recommended dosage in patients with FCS (80 mg per month); 157 (90%) ng/mL and 3,470 (104%) ng•h/mL, respectively, at 50 mg once monthly in patients with sHTG, and 251 (90%) ng/mL and 5,550 (104%) ng•h/mL, respectively, at 80 mg once monthly in patients with sHTG. Olezarsen C _max and AUC increase dose-proportionally following single subcutaneous doses ranging from 10 to 120 mg (i.e., 0.13- to 1.5-times the approved recommended dose) in healthy volunteers. No olezarsen accumulation occurs with repeat dosing.

The observed incidence of anti-drug antibodies (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 study described below with the incidence of anti-drug antibodies in other studies, including those of olezarsen.

In Trial 1, among patients with FCS treated with TRYNGOLZA, 18 of 43 patients (42%) developed treatment-emergent anti-drug antibodies (ADAs) through 53 weeks of treatment. In Trials 2 and 3, among patients with severe hypertriglyceridemia (sHTG) treated with TRYNGOLZA, 218 of 409 patients (53%) and 147 of 296 patients (50%), respectively, developed treatment-emergent ADAs through 53 weeks of treatment. The presence of ADAs did not affect olezarsen plasma C _max , but increased C _trough . These ADA-associated pharmacokinetic changes were not identified to be clinically significant. There was no identified clinically significant effect of ADAs on pharmacodynamics, safety, or efficacy of TRYNGOLZA in patients with FCS or sHTG.

The efficacy of TRYNGOLZA was demonstrated in a randomized, placebo-controlled, double-blind clinical trial in adult patients with genetically identified FCS and fasting TG levels ≥880 mg/dL (Trial 1; NCT04568434 ). After a ≥4-week run-in period where patients continued to follow a low-fat diet with ≤20 grams fat per day, patients were randomly assigned to receive doses every 4 weeks of TRYNGOLZA 80 mg (n=22) or matching volume of placebo (n=23) via subcutaneous injection over a 53-week treatment period.

Patient demographic and baseline characteristics were generally similar across the treatment groups [see Adverse Reactions (6.1) ] . The proportion of patients with diabetes at enrollment was 32% in the TRYNGOLZA 80 mg group compared with 26% in the placebo group. Patients in the TRYNGOLZA 80 mg and placebo groups were treated with statins (27%), omega-3 fatty acids (42%), fibrates (49%), or other lipid-lowering therapies (13%) at study entry. Seventy-one percent (71%) of patients in the TRYNGOLZA 80 mg and placebo groups combined had a history of documented acute pancreatitis in the prior 10 years. Mean (SD) and median fasting TG levels at baseline were 2,604 (1,364) mg/dL and 2,303 mg/dL, respectively (range of 334 to 6,898 mg/dL).

The primary endpoint was percent change in fasting TG from baseline to Month 6 (average of Weeks 23, 25, and 27) compared to placebo. The difference between TRYNGOLZA 80 mg group and the placebo group in percent change in fasting TG from baseline to Month 6 was -43% (95% CI: -74%, -11%; p=0.0084). For additional results see Table 3.

Table 3. Mean Baseline (BL) and Mean Percent (%) Changes from Baseline in Lipid/ Lipoprotein Parameters in Patients with FCS at Month 6 in Patients with FCS (Trial 1)

Median percent change from baseline (Figure 1) and median absolute TG values (Figure 2) over time demonstrated a consistent lowering effect during the 12-month treatment period.

Figure 1. Percent Change in Fasting TG (mg/dL) Over Time in Patients with FCS (Trial 1)

Figure 2. Fasting TG (mg/dL) Over Time in Patients with FCS (Trial 1)

Over the 12-month treatment period, the numerical incidence of acute pancreatitis in patients treated with TRYNGOLZA 80 mg was lower compared with placebo [1 (5%) patient in the TRYNGOLZA 80 mg group compared with 7 (30%) patients in the placebo group]; all of these patients had a prior history of pancreatitis within 10 years prior to screening.

The efficacy of TRYNGOLZA was demonstrated in two randomized, double-blind, placebo-controlled trials (Trial 2, NCT05079919 and Trial 3, NCT05552326 ). These trials enrolled adult patients with sHTG. Patients had fasting TG ≥500 mg/dL and were on optimized, stable background lipid-lowering therapy prior to enrollment and throughout the trial. After an approximately 4- to 8-week screening and qualification period that included at least 2 weeks of diet and lifestyle stabilization, patients were randomly assigned to receive subcutaneous injections once every 4 weeks of TRYNGOLZA 50 mg (n=354) or 80 mg (n=351), or placebo (n=356) for a 53-week treatment period.

Patient demographic and baseline characteristics across pooled Trial 2 and Trial 3 were generally similar across treatment groups [see Adverse Reactions (6.1) ] . At enrollment, 23% of patients had atherosclerotic cardiovascular disease, 63% of patients had type 2 diabetes mellitus (59% Trial 2; 68% Trial 3); 99% of patients were on background lipid-lowering therapies, (42% high-intensity statin, 27% moderate-intensity statin, 63% fibrates, 32% omega-3 fatty acids), and 15% of patients had a history of pancreatitis within the prior 10 years. (19% Trial 2; 10% Trial 3). Mean (SD) and median fasting TG at baseline were 1,116 (990) mg/dL and 793 mg/dL, respectively (range 379 to 13,545 mg/dL).

The primary endpoint in Trial 2 and Trial 3 was the percent change in fasting TG from baseline to Month 6 (average of Weeks 25 and 27) compared with placebo. Table 4 summarizes the mean percent change from baseline in TG at Month 6 and other key lipid parameters (non-HDL-C, LDL-C, total ApoB, and ApoB-48) for TRYNGOLZA 50 mg and 80 mg compared with placebo in Trial 2 and Trial 3. In both Trial 2 and Trial 3, TRYNGOLZA demonstrated statistically significant decreases in fasting TG at Month 6 and Month 12. In Trial 2, the placebo-corrected difference in percent change in fasting TG from baseline to Month 6 was -63% (95% CI: -72%, -54%; p <0.0001) for TRYNGOLZA 50 mg and -72% (95% CI: -81%, -63%; p <0.0001) for TRYNGOLZA 80 mg. In Trial 3, the placebo-corrected difference in percent change in fasting TG from baseline to Month 6 was -49% (95% CI: -60%, -39%; p <0.0001) for TRYNGOLZA 50 mg and -55% (95% CI: -65%, -44%; p <0.0001) for TRYNGOLZA 80 mg.

Table 4. Mean Baseline (BL) and Mean Percent (%) Change from Baseline in Lipid/Lipoprotein Parameters at Month 6 in Patients with sHTG – Trial 2 and Trial 3

In Trial 2 (Figure 3) and Trial 3 (Figure 4), TRYNGOLZA demonstrated a consistent TG-lowering effect during the 12-month treatment period, as shown by reductions in mean percent change from baseline over time.

Figure 3. Percent Change in Fasting TG (mg/dL) Over Time in Patients with sHTG (Trial 2)

Figure 4 . Percent Change in Fasting TG (mg/dL) Over Time in Patients with sHTG (Trial 3)

Pancreatitis events were assessed as a secondary endpoint in an integrated analysis of Trials 2 and 3. Events were adjudicated by a blinded, independent committee according to the Revised Atlanta Diagnostic Criteria, and event rates were compared between TRYNGOLZA groups and pooled placebo over 53 weeks. In the integrated analysis, TRYNGOLZA 50 mg and 80 mg reduced the adjudicated acute pancreatitis event rate by 91% (Rate Ratio: 0.09; 95% CI: 0.02, 0.42) and 76% (RR: 0.24; 95% CI: 0.08, 0.69) relative to placebo, respectively, with the pooled TRYNGOLZA group demonstrating an 85% reduction (RR: 0.15; 95% CI: 0.05, 0.40).

The overall treatment effect was predominantly observed in the prespecified high-risk subgroup of subjects with baseline fasting TG ≥880 mg/dL and a prior history of pancreatitis, which accounted for 25 of 29 total adjudicated acute pancreatitis events (86%). In this subgroup (N=141), TRYNGOLZA 50 mg and 80 mg reduced the acute pancreatitis event rate by 89% (RR: 0.11; 95% CI: 0.02, 0.51) and 75% (RR: 0.25; 95% CI: 0.08, 0.82) relative to placebo, respectively, with the pooled TRYNGOLZA group demonstrating an 83% reduction (RR: 0.17; 95% CI: 0.06, 0.47). For additional results, see Table 5.

Table 5. Adjudicated Acute Pancreatitis Event Rate from Week 1 to Week 53 in Patients with sHTG from Trials 2 and 3

In the integrated analysis of Trials 2 and 3, the pooled TRYNGOLZA group had a statistically significantly longer time to first adjudicated acute pancreatitis event compared with placebo (p<0.0001), with consistent separation between treatment groups throughout the follow-up period (see Figure 5).

Figure 5. Kaplan−Meier Estimate of Time to First Acute Pancreatitis in Patients with sHTG from Trials 2 and 3

a. The time was censored at Week 53, or at the post-treatment follow-up termination date, whichever occurred first.

b. The time to the first adjudicated pancreatitis event was compared between the pooled TRYNGOLZA treatment group and the placebo group using a log-rank test, stratified by study identifier (Trial 2 or Trial 3).

TRYNGOLZA injection is a sterile, preservative-free, clear, colorless to yellow solution supplied in a single-dose autoinjector. Each autoinjector of TRYNGOLZA is filled to deliver 0.8 mL of solution containing 50 mg or 80 mg of olezarsen.

TRYNGOLZA is supplied as:

• Carton containing one 50 mg single-dose autoinjector: (NDC 71860-102-01).
• Carton containing one 80 mg single-dose autoinjector: (NDC 71860-101-01).

Store the TRYNGOLZA autoinjector in the refrigerator between 2°C and 8°C (36°F and 46°F) in the original carton.

Once taken out of the refrigerator, the TRYNGOLZA autoinjector can be stored at room temperature between 15°C and 30°C (59°F and 86°F) in the original carton for up to 6 weeks. If not used within the 6 weeks stored at room temperature, discard TRYNGOLZA.

Do not expose to heat. Protect from light.