2.1 Dose

The recommended dose of ADSTILADRIN is 75 mL at a concentration of 3 x 1011 viral particles (vp)/mL instilled once every three (3) months into the bladder via a urinary catheter [see Dosage and Administration (2.2)].

Premedication with an anticholinergic is recommended before each instillation of ADSTILADRIN.

2.2 Preparation and Handling

ADSTILADRIN is a non-replicating adenoviral vector-based gene therapy. Follow universal biosafety precautions for handling.

Individuals who are immunosuppressed or immune-deficient, should not prepare, administer, or come into contact with ADSTILADRIN [see Warnings and Precautions (5)].

ADSTILADRIN is provided as a sterile frozen suspension.

All four vials of ADSTILADRIN must be thawed and brought to room temperature (20°C to 25°C [68°F to 77°F]) prior to use.

WHEN THAWING AT ROOM TEMPERATURE

Frozen ADSTILADRIN vials will thaw in approximately 3 to 5 hours outside the cardboard nest when placed at room temperature (up to 25°C [77ºF]) (8 to 10 hours inside the nest).

WHEN THAWING IN REFRIGERATOR

Frozen ADSTILADRIN vials will thaw in approximately 4 to 5 hours outside the cardboard nest when placed in the refrigerator (up to 8°C [46ºF]) (11 to 13 hours inside the nest). Subsequent time for bringing thawed ADSTILADRIN to room temperature is approximately 2 hours 30 minutes outside of the cardboard nest (6 hours inside the nest).

Do not expose the vials to higher temperatures. Protect from light. DO NOT refreeze.

The vials may be moved between refrigerator and room temperature if the total storage time at each condition is not exceeded (24 hours at room temperature and 7 days refrigerated including thawing time).

2.3 Bladder instillation of ADSTILADRIN

1. Premedication with an anticholinergic before each instillation of ADSTILADRIN is recommended.
2. ADSTILADRIN must be brought to room temperature before administration [see Dosage and Administration (2.2)].
3. Before administering ADSTILADRIN to the patient, insert one straight, or intermittent, urinary catheter with a proximal funnel opening that will accommodate the Luer lock adapter.
4. Use only catheters made of vinyl/PVC (uncoated or coated with hydrogel), red rubber latex or silicone to instill ADSTILADRIN. Do not use catheters coated or embedded with silver or antibiotics.
5. Use the catheter to completely empty the patient's bladder before instillation of ADSTILADRIN. Do not remove the catheter.
6. Attach the Luer lock end of the same catheter adaptor to the syringe containing ADSTILADRIN and insert the tapered end of the catheter adaptor into the funnel opening of the catheter.
7. Slowly instill 75 mL of ADSTILADRIN into the bladder through the catheter, ensuring that the complete volume is administered.
8. After the instillation, ADSTILADRIN should be retained in the bladder for 1 hour. During the 1 hour dwell time, the patient should reposition approximately every 15 minutes from left to right, back and abdomen to maximize bladder surface exposure. If, during the dwell time, the patient exhibits bladder cramping or premature voiding, repositioning of the patient may be adjusted or discontinued.
9. Evacuate ADSTILADRIN from the bladder as part of routine emptying of the bladder, or the patient may void and completely empty the bladder after 1 hour has elapsed.
10. Voided urine should be disinfected for 15 minutes with an equal volume of virucidal agent before flushing of the toilet. [see Patient Counseling Information (17)].

5.1 Risk of Muscle Invasive or Metastatic Bladder Cancer with Delayed Cystectomy

Delaying cystectomy in patients with BCG-unresponsive CIS could lead to development of muscle invasive or metastatic bladder cancer, which can be lethal. The risk of developing muscle-invasive or metastatic bladder cancer increases the longer cystectomy is delayed in the presence of persisting CIS.

Of the patients with CIS treated with ADSTILADRIN on Study CS-003 who underwent subsequent radical cystectomy and for whom pathologic data were available, 14% (n = 6) had muscle-invasive (T2 or greater) disease at cystectomy.  Median time from persistence or recurrence of CIS to cystectomy in these patients was 235 days (range 38 to 582 days).  Two additional patients who did not undergo cystectomy experienced progression to muscle-invasive disease during the treatment period.

If patients with CIS do not have a complete response to treatment after 3 months or if CIS recurs, consider cystectomy.

5.2 Risk of Disseminated Adenovirus Infection

Immunocompromised persons, including those receiving immunosuppressant therapy, may be at risk for disseminated adenovirus infection because of the possible presence of low levels of replication-competent adenovirus in ADSTILADRIN. Individuals who are immunosuppressed or immune-deficient should not come into contact with ADSTILADRIN.

6.1 Clinical Trials 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.

The safety of ADSTILADRIN was evaluated in Study CS-003, a multicenter, single-arm, open-label study in 157 U.S. patients [see Clinical Studies (14)] with high-risk BCG‑unresponsive NMIBC, 107 of whom had BCG-unresponsive carcinoma in situ (CIS) with or without papillary tumors.

Patients received 75 mL (3 x 1011 vp/mL) ADSTILADRIN administered intravesically once every 3 months for up to 12 months [see Clinical Studies (14)]. All patients with an absence of high-risk recurrence or progression were offered continued treatment every 3 months beyond 12 months. The median number of instillations of ADSTILADRIN was 2 (range 1 to 5).

Serious adverse reactions occurred in 11% of patients who received ADSTILADRIN. Serious adverse reactions occurring in >1% of patients included coronary artery disease and hematuria (blood in urine).

Permanent discontinuation of ADSTILADRIN due to an adverse reaction occurred in 3 (1.9%) patients. Adverse reactions that resulted in permanent discontinuation of ADSTILADRIN included bladder spasm instillation site discharge, and benign neoplasm of the bladder.

Dosage interruptions of ADSTILADRIN due to an adverse reaction occurred in 54 (34%) patients.  Adverse reactions in >10% of patients that required dosage interruption included instillation site discharge, bladder spasm, and micturition urgency.

The most common (>10%) adverse reactions, including laboratory abnormalities (>15%), were glucose increased, instillation site discharge, triglycerides increased, fatigue, bladder spasm, micturition (urination) urgency, creatinine increased, hematuria (blood in urine), phosphate decreased, chills, dysuria, and pyrexia (fever).

Tables 1 and 2 summarize adverse reactions and laboratory abnormalities, respectively, in patients on ADSTILADRIN in CS-003.

Clinically relevant adverse reaction in <10% of patients who received ADSTILADRIN include syncope (fainting) (1.3%).

Clinically relevant adverse reactions in <10% of patients who received ADSTILADRIN included coronary artery disease (1.3%), acute coronary syndrome (1.3%), atrial fibrillation (1.3%), dehydration (1.3%), hypoglycemia (low blood sugar) (1.3%), syncope (fainting) (1.3%), heart failure (0.6%), pericarditis, (0.6%), brain edema (swelling) (0.6%), bile duct stone (0.6%), and sepsis (0.6%).

Table 2 summarizes the laboratory abnormalities in CS-003.

8.1 Pregnancy

Risk Summary

Adequate and well-controlled studies with ADSTILADRIN have not been conducted in pregnant women. Animal reproductive and developmental toxicity studies have not been conducted with ADSTILADRIN. Advise pregnant women of the potential risk to a 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.

8.2 Lactation

Risk Summary

There is no information regarding the presence of ADSTILADRIN in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ADSTILADRIN and any potential adverse effects on the breastfed infant from ADSTILADRIN or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

No nonclinical or clinical studies were performed to evaluate the effect of ADSTILADRIN on fertility.

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating ADSTILADRIN.

Contraception

Females
Advise females of reproductive potential to use effective contraception during treatment with ADSTILADRIN and for 6 months following the last dose.

Males
Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ADSTILADRIN and for 3 months following the last dose.

8.4 Pediatric Use

Safety and effectiveness of ADSTILADRIN in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of ADSTILADRIN in BCG-unresponsive high-risk NMIBC with CIS did not include sufficient numbers of patients younger than 65 years of age to determine whether safety and effectiveness differ from older patients.

8.6 Gender-specific Use

In clinical studies with ADSTILADRIN, no overall differences in safety or efficacy were observed between females and males.

12.1 Mechanism of Action

ADSTILADRIN is a non-replicating adenoviral vector-based gene therapy designed to deliver a copy of a gene encoding a human interferon-alfa 2b (IFNα2b) to the bladder urothelium. Intravesical instillation of ADSTILADRIN results in cell transduction and transient local expression of the IFNα2b protein that is anticipated to have anti-tumor effects.

12.2 Pharmacodynamics

A Phase 1 first-in-human study was performed to determine the safety, tolerability, and maximum tolerated dose (MTD) of ADSTILADRIN in 17 patients with BCG-unresponsive NMIBC. Five dose levels (3 x 109 vp/mL, 1 x 1010 vp/mL, 3 x 1010 vp/mL, 1 x 1011 vp/mL, and 3 x 1011 vp/mL; all in a dose volume of 75 mL) of ADSTILADRIN were tested and quantifiable concentrations of the pharmacodynamic marker IFNα2b protein were detected in the urine of all patients, with the exception of two patients at the lowest dose level. Measurable concentrations of urine IFNα2b protein up to Day 10 post-dose suggested expression of IFNα2b in the bladder.  In a Phase 2 study, all patients had quantifiable concentrations of IFNα2b protein in the urine at Day 2 after dosing with ADSTILADRIN at two different dose levels (1 x 1011 vp/mL and 3 x 1011 vp/mL). Measurable concentrations of urine IFNα2b protein was detected up to Day 12 post-dose. This was more common in patients at the high dose level.

Generally, higher IFNα2b concentrations and exposure were observed with increasing doses of ADSTILADRIN.

12.3 Pharmacokinetics

Nonclinical data

Human IFN protein in urine, and vector-specific DNA in blood and tissue samples, were detectable following ADSTILADRIN dosing in monkeys, with higher levels at higher doses.  All monkeys had vector-specific DNA in the bladder tissue at necropsy on Days 8 and 98 (i.e., seven days after the first and second dose, respectively). Vector-specific DNA was also detected in a limited number of monkeys in the liver, kidney and gonad.  At Day 148, only one animal showed vector-specific DNA in one tissue (kidney).

Clinical data

ADSTILADRIN biodistribution and shedding were investigated in two clinical studies. Only a single patient receiving a second dose in one study (Phase 2 study) at dose level of 3 x 1011 vp/mL (2.25 x 1013 vp) had measurable vector DNA in blood; no other patients in either study had measurable vector DNA at one hour post-dosing in blood. In urine, measurable vector DNA was detected in both studies. Generally, a higher frequency of detection of urine samples positive for vector-derived DNA, and persistence of vector-derived DNA, correlated with increasing dose level.

At the dose level of 3 x 1011 vp/mL (2.25 x 1013 vp), one patient (out of 4 enrolled) had detectable levels of vector DNA at Day 14 in the Phase 1 study and 16 subjects (out of 19 at visit) had detectable levels of vector DNA at Day 12 in the Phase 2 study.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies have been conducted to evaluate the effects of ADSTILADRIN on carcinogenesis, mutagenesis, or impairment of fertility.

13.2 Animal Toxicology and/or Pharmacology

In cynomolgus monkeys, two repeat intravesical administrations of ADSTILADRIN of either 2.5 x 1011 or 1.25 x 1013 viral particles (1 x 1011 or 5x1011 viral particles/mL, 90 days apart) were associated with inflammation, urothelial hyperplasia, cytoplasmic vacuolation, and focal/multifocal ulceration in the urinary bladder and irritation in the ureter and urethra at necropsy 7 days after the first and second doses. Near complete resolution of these findings was observed following the 57-day recovery period after the second administration, with minimal fibrosis in the lamina propria of the bladder in a limited number of monkeys. Both dose level groups developed antibodies to the adenovirus and human interferon protein.