Nogapendekin Alfa Inbakicept

Nogapendekin alfa inbakicept is a complex of two nogapendekin alfa molecules bound to inbakicept, produced in Chinese hamster ovary (CHO-K1) cells by recombinant technology. It mimics interleukin-15 (IL-15), a cytokine that regulates natural killer (NK) cell and memory T-cell function.

Mechanism of Action

• IL-15 receptor agonist: IL-15 signals through a heterotrimeric receptor made of the common gamma chain, the beta chain and an IL-15-specific alpha subunit (IL-15 receptor alpha). IL-15 is trans-presented by the alpha subunit to the shared IL-2/IL-15 receptor (beta and gamma chains) on CD4+ and CD8+ T cells and NK cells.
• Immune activation: binding of the complex causes proliferation and activation of NK cells, CD4+ and CD8+ T cells and memory T cells, without proliferation of immunosuppressive regulatory T (Treg) cells.
• Engineered variant: nogapendekin alfa is an IL-15 variant with an asparagine-to-aspartate change at position 72 (N72D), which raises biological activity and lengthens serum half-life compared with free IL-15 (DrugBank).
• Preclinical activity: in a carcinogen-induced bladder cancer model in immunocompetent rats, intravesical administration alone or with BCG showed anti-tumour activity; with BCG it reduced tumour burden and increased infiltration of the bladder by stimulated CD8+ T cells and NK cells (DrugBank).
• Immunogenicity: treatment-emergent anti-drug antibodies occurred in 5% of subjects in the phase 2b study (QUILT-2.005) and 3% in QUILT-3.032. No effect on pharmacokinetics, efficacy or safety was seen, but data are limited.

Pharmacokinetics

• Systemic exposure: after intravesical dosing at the recommended dose, systemic exposure was below 100 pg/mL, which was below the lower limit of quantitation in all patients. Absorption into the body is therefore negligible.
• Distribution, metabolism and elimination: the SmPC reports no further pharmacokinetic data.
• Special populations: no dose adjustment is needed in elderly patients or in hepatic or renal impairment.

• BCG-unresponsive NMIBC: in combination with Bacillus Calmette-Guérin (BCG), for the treatment of adult patients with BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS), with or without papillary tumours.

In the pivotal single-arm study (QUILT-3.032, 100 adults), BCG-unresponsive disease was defined as persistent or recurrent CIS, alone or with Ta/T1 disease, within 12 months of completing adequate BCG therapy.

• Hypersensitivity to the active substance or to any of the excipients.

In the clinical study (180 patients aged 46 to 93 given Anktiva with BCG) the most common reactions were dysuria (35%), haematuria (35%), pollakiuria (32%), urinary tract infection (24%), micturition urgency (22%), fatigue (20%), chills (13%), musculoskeletal pain (11%) and pyrexia (10%). These frequencies may not be fully attributable to Anktiva, because they can include contributions from the underlying disease or from BCG. Grade 3 or higher reactions seen in more than one patient were urinary tract infection (2%), bacteraemia (1%), sepsis (1%), haematuria (3%), musculoskeletal pain (1%) and myalgia (1%). Serious reactions seen in more than one patient were urinary tract infection (2%), bacteraemia (1%) and haematuria (3%).

Very common (≥1/10): urinary tract infection, musculoskeletal pain (including back and flank pain), haematuria (including haemorrhagic cystitis), dysuria, pollakiuria, micturition urgency, fatigue, chills, pyrexia.

Common (≥1/100 to <1/10): cystitis, bacteriuria, bacteraemia, sepsis, anaemia, leukocytosis, lymphadenopathy, decreased appetite, dehydration, dizziness, headache, dyspnoea, diarrhoea, nausea, abdominal pain, constipation, vomiting, night sweats, pruritus, rash, myalgia, arthralgia, muscular weakness, bladder spasm, non-infective cystitis, nocturia, urinary incontinence, urinary tract pain, urinary retention, bladder pain, urge incontinence, lower urinary tract symptoms, urinary hesitation, decreased urine flow, leukocyturia, genital pain, prostatitis, benign prostatic hyperplasia, influenza-like illness, chest pain, increased blood creatinine, cancer cells present in urine.

Uncommon (≥1/1,000 to <1/100): arthritis, abnormal urine, polyuria, decreased glomerular filtration rate, increased blood urea, penile discharge, pain at the instillation site.

Because of its immune-activating mechanism, immune-related toxicity cannot be excluded, although systemic exposure after intravesical use is below the limit of quantitation. The serious reactions of note are urinary tract infection, bacteraemia and haematuria.

No interaction studies have been performed.

• BCG: Anktiva is used only as a mixture with BCG, so the SmPC of the BCG product applies to that component (including the possibility of severe systemic BCG infection, bladder retention and patient positioning).
• Mixture compatibility: Anktiva has been studied only with OncoTICE and BCG-medac (see Shelf Life).

Anktiva is given only into the bladder (intravesically), as a mixture with BCG, through a urinary catheter. It must not be given by subcutaneous, intravenous or intramuscular injection. The vial must not be shaken, and dilution before intravesical use is described in section 6.6 of the SmPC.

Recommended Dose

• Induction: 400 micrograms intravesically, as a mixture with BCG in a volume of 50 mL, once a week for 6 weeks.
• Re-induction: a second induction course may be given if CIS, with or without high-grade Ta, remains at the first assessment after induction (week 12). The SmPC asks that cystectomy be reconsidered before re-induction in eligible patients (see Special Instructions).
• Maintenance: for patients with no disease or with low-grade Ta, 400 micrograms with BCG once a week for 3 consecutive weeks at months 4, 7, 10, 13 and 19 (15 doses in all). Low-grade Ta needs a transurethral resection of the bladder tumour (TURBT) before instillation; treatment may be delayed by up to 28 days after TURBT if required.
• Extended maintenance: patients with an ongoing complete response at month 25 or later (negative cystoscopy, with TURBT or biopsies as applicable, and negative urine cytology) may receive three weekly instillations at months 25, 31 and 37, up to 9 additional instillations.
• Assessment and duration: tumour status is assessed every 3 months for up to 24 months, and after that according to local standards. Treatment continues until disease persists after the last induction course, disease recurs or progresses (new CIS and/or any T1 disease or higher), toxicity is unacceptable, or a maximum of 37 months is reached.

Method of Administration

• The 50 mL mixture of Anktiva and BCG is drawn up, either by connecting a catheter to the container or through a 50 mL syringe, and instilled into the bladder through a urinary catheter. The catheter is removed after instillation.
• The mixture is retained in the bladder for 2 hours and then voided. Patients who cannot retain it for 2 hours may void sooner if necessary; the dose is not repeated if the patient voids before 2 hours.
• The SmPC of the BCG product gives information on retention in the bladder and patient positioning.

Special Populations

• Elderly: no dose adjustment.
• Hepatic or renal impairment: no dose adjustment.
• Children and adolescents: there is no relevant use in children aged 0 to under 18 years in this indication.

Traceability and Route

To improve traceability of this biological medicinal product, the name and batch number of the product given must be clearly recorded. Anktiva is for intravesical use only.

Severe Systemic BCG Infections

The possibility of severe systemic BCG infection, needing anti-tuberculosis therapy, should be considered before BCG therapy starts. The SmPC of the specific BCG product used gives the details.

Delaying Cystectomy

Delaying cystectomy in patients with BCG-unresponsive NMIBC with CIS, with or without papillary tumours, treated with Anktiva and BCG could lead to muscle-invasive or metastatic bladder cancer. Of 100 evaluable patients in QUILT-3.032, 10% progressed to muscle-invasive disease (T2 or higher), and 5% of all participants developed metastatic disease by 24 months (none at 12 months). If a patient with CIS who is medically eligible for cystectomy has not reached a complete response (no disease, or low-grade Ta) at the 12-week assessment after induction, cystectomy should be reconsidered as an alternative to re-induction. The risk of muscle-invasive or metastatic disease rises the longer cystectomy is delayed while CIS persists.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential must use effective contraception during treatment and for 1 week after the last dose.
• Pregnancy: there are no data in pregnant women and no animal reproduction studies. In mouse pregnancy models the IL-15 pathway increases uterine NK cells and interferon-gamma, which disrupts maternal tolerance of the foetus and raises embryo-foetal loss. Treatment is not recommended in pregnancy or in women of childbearing potential who are not using effective contraception.
• Breastfeeding: systemic exposure of the breastfeeding woman is negligible (below the limit of quantitation), so no effect on the infant is expected, and the SmPC states that treatment can be used during breastfeeding. There are no data on milk transfer. The statements above concern Anktiva alone; the SmPC of the BCG product sets its own advice.
• Fertility: no clinical data. No effect on fertility is expected, because systemic exposure is below the limit of quantitation.

Excipients

Each dose contains less than 1 mmol (39 mg) of potassium and less than 1 mmol (23 mg) of sodium, that is, it is essentially potassium-free and sodium-free.

Effect on Driving

Anktiva has no or negligible influence on the ability to drive and use machines.

Store in a refrigerator at 2–8 °C. Do not freeze. Keep the vial in the outer carton to protect it from light. As a refrigerated product it travels in the cold chain from supply to the clinic or hospital.

• Unopened vial: 3 years.
• Mixture with BCG: chemical and physical in-use stability has been shown for up to 2 hours at 2–8 °C, protected from light, with OncoTICE, and for up to 24 hours under the same conditions with BCG-medac. Anktiva has been studied only with these two BCG products.
• Microbiological point of view: unless the method of opening, reconstitution or dilution rules out the risk of contamination, the product should be used immediately; otherwise in-use storage times and conditions are the responsibility of the user.

Prescription only (Rx). Anktiva is mixed with BCG and instilled into the bladder through a urinary catheter by healthcare professionals, so it is supplied to the clinic or hospital that administers it. Cold-chain delivery at 2–8 °C is required.