Marlene Wang, MS

is an interleukin-23 (IL-23) antagonist. The 

FDA approved the treatment in 2018 for adults with moderate-to-severe plaque psoriasis

 who are candidates for systemic therapy or phototherapy based on the data from 2 randomized phase 3 trials (reSURFACE 1 and reSURFACE 2).

In these 2 trials, 926 enrolled patients received either 100 mg tildrakizumab-asmn (n=616) or placebo (n=310) with the co-primary endpoints of proportion of patients achieving Psoriasis Area Sensitivity Index 75% (PASI 75) and Physician's Global Assessment (PGA) response of clear or minimal with at least a 2-grade reduction from baseline at week 12 after 2 doses. Both studies met the primary efficacy endpoints by showing the significant clinical improvement of 100 mg tildrakizumab-asmn compared to the placebo group on the above measurements. The results are shown below in 

Table 1. Primary efficacy endpoint from 2 phase 3 trials at week 12

After the FDA approval, the researchers continued the extension studies from those 2 trials to evaluate the 5-year efficacy and safety of tildrakizumab-asmn in patients with moderate-to-severe psoriasis. The pooled analysis from the phase 3 trials showed nearly 9 of 10 patients treated with tildrakizumab-asmn 100 mg maintained their responses through year 5 and that this dosage level was well-tolerated during the trials.

Tildrakizumab-asmn is a humanized IgG1/k monoclonal anti-IL-23 antibody. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses. Tildrakizumab-asmn selectively binds to the p19 subunit of IL-23 to inhibit its interaction with the IL-23 receptor and downstream signaling to block the release of pro-inflammatory cytokines and chemokines.

The recommended dose is 100 mg at weeks 0, 4, and every 12 weeks thereafter. Each pre-filled syringe contains 1 mL of 100 mg/mL tildrakizumab-asmn. If patients miss a dose, clinicians should administer the dose as soon as possible and then resume dosing at the regularly scheduled interval.

Clinicians should administer tildrakizumab-asmn subcutaneously in areas with clear skin and easy access such as the abdomen, thighs, or upper arms. They should avoid the areas 2 inches around the navel or where the skin is tender, bruised, erythematous, indurated, or affected by psoriasis. They must avoid injecting into scars, stretch marks, or blood vessels.

Tildrakizumab-asmn is a clear to slightly opalescent, colorless to slightly yellow solution. The clinician who administers the dose should inspect visually for precipitation and discoloration prior to administration. If the liquid contains visible particles or the syringe is damaged, clinicians should discard the dose. Air bubbles may be present and need to be removed.

The most common (≥1%) adverse reactions are upper respiratory infections, injection site reactions, and diarrhea.

Hypersensitivity cases, such as angioedema and urticaria, occurred during clinical trials in patients administered tildrakizumab-asmn. If patients experience serious hypersensitivity reactions, the prescriber should stop the medication and initiate the appropriate treatment immediately.

Tildrakizumab-asmn may increase the risk of infection. Patients with any clinically important active infection should not take tildrakizumab-asmn until the infection resolves or is appropriately treated.

Health care providers (HCPs) should consider the risks and benefits before initiating the treatment on patients with a chronic infection or a history of recurrent infection. Instruct patients to consult with an HCP when experiencing signs or symptoms of clinically important chronic or acute infection.

Clinicians should monitor patients closely and discontinue treatment if necessary until the infection resolves. In clinical trials, 23% of patients treated with tildrakizumab-asmn developed infections; however, the different frequency of infections was <1% compared to the placebo group during the placebo-controlled period.

In addition, the tildrakizumab-asmn group had more upper respiratory infections than placebo. The rates of serious infections for the tildrakizumab-asmn group and the placebo group were ≤0.3%.

Tuberculosis (TB) evaluation and treatment for latent TB should be done prior to initiating the tildrakizumab-asmn regime. Prescribers should consider anti-TB therapy before starting tildrakizumab-asmn treatment for patients with past history of latent or active TB but without confirmation of an adequate treatment.

HCPs should monitor the signs or symptoms of active TB during and after tildrakizumab-asmn treatment. Do not administer tildrakizumab-asmn to patients with active TB. During clinical trials, 55 patients were under preventive treatment for TB while receiving tildrakizumab-asmn, but none of them developed active TB during the mean follow-up of 56.5 weeks. The only individuals in the trials who developed active TB were not from this group of 55 patients.

Consider completing all age-appropriate vaccinations before initiating tildrakizumab-asmn treatment. Patients undergoing treatment with tildrakizumab-asmn should avoid live vaccines, although there were no data available on the response to live or inactive vaccines.

Researchers have insufficient human data on the use of tildrakizumab-asmn during pregnancy and on the presence of tildrakizumab-asmn in human milk, the effects on the breastfed infant, or the effects on milk production to make a recommendation.

Marlene Wang, MS, is a research scientist in the pharmaceutical industry.

Sun Pharma Announces U.S. FDA Approval of ILUMYA™ (tildrakizumab-asmn) for the Treatment of Moderate-to-Severe Plaque Psoriasis. Sun Pharmaceutical Industries Ltd. Accessed May 26, 2022. 

https://sunpharma.com/wp-content/uploads/2020/12/Sun-Pharma-Announces-U.S.-FDA-Approval-of-ILUMYA.pdf

Thaci D, Piaserico S, Warren RB, et al. Five-year efficacy and safety of tildrakizumab in patients with moderate-to-severe psoriasis who respond at week 28: pooled analyses of two randomized phase III clinical trials (reSURFACE 1 and reSURFACE 2). 

 2021;185(2):323-334. doi:10.1111/bjd.19866

Sun Pharma’s PrILUMYA™ (tildrakizumab injection) now available to help Canadians living with moderate-tosevere plaque psoriasis.Sun Pharmaceutical Industries Ltd. Accessed May 26, 2022. 

https://sunpharma.com/wp-content/uploads/2021/10/Press-Release-ILUMYA-availability-in-Canada.pdf

ILUMYA [product information]. Cranbury NJ: Sun Pharmaceutical Industries Ltd; September 2019. Accessed May 26, 2022.

Articles

Tildrakizumab-asmn is a humanized IgG1/k monoclonal anti-IL-23 antibody indicated for the treatment of adults with moderate-to-severe plaque psoriasis. 

Clinical Overview: Tildrakizumab-asmn (Ilumya) for Plaque Psoriasis

Imlunestrant is an orally selective estrogen receptor degrader (SERD) currently under investigation as monotherapy or in combination with other anticancer therapies for patients with estrogen receptor-positive (ER+) locally advanced or metastatic 

 and endometrial cancer. Researchers launched imlunestrant’s phase 1a/b dose escalation study in December 2019 and published its first interim data at the 2021 

As of April 7, 2021, the study enrolled 65 patients, including 58 with ER+ advanced breast cancer and 7 with ER+ endometrial endometrioid cancer (EEC). The advanced breast cancer patients had received a median of 2 prior lines of therapy, including fulvestrant (60% of patients), a CDK4/6 inhibitor (83%), and chemotherapy (26%). 

Among the 54 patients with ctDNA (circulating tumor DNA) data available, 37% had ESR1 mutations. Enrolled patients received imlunestrant at doses from 200 mg once daily (QD) to 1200 mg QD.

Based on the study design, patients were considered efficacy-evaluable for objective response rate (ORR) if they had measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST v 1.1) at baseline and at least 1 post-baseline tumor assessment or discontinued treatment prior to their first post-baseline assessment.

At the data cutoff, 35 patients with ER+ advanced breast cancer were efficacy evaluable. Two of 35 had partial response after 24 weeks at the 400 mg daily dose.

One had prior fulvestrant treatment, CDK4/6, and chemotherapy-refractory disease. The other patient had 3 lines of prior endocrine therapy, including an mTOR inhibitor.

The clinical benefit rate (CBR) was 48% (13/27) from all dose levels. In EEC patients, the researchers observed no objective responses in 6 efficacy-measurable patients and CBR was 50% (2/4).

Plasma ctDNA analysis indicated 86% (18/21) had early declines (cycle 2 day 1) in overall ctDNA, including patients with mutant ESR1. The magnitude of decrease was greater in patients who experienced clinical benefit than those who did not. At data cutoff, 35 patients remained on treatment, including both patients with confirmed partial responses, and 79% (31/39) of those with stable disease or partial responses.

The pharmacokinetic analysis demonstrated dose-proportional increases across all evaluated doses. The steady state of imlunestrant in patient plasma exceeded the EC80 range associated with efficacy in preclinical studies in all evaluated doses. The concentration was higher than the steady state of fulvestrant peak serum concentration.

In October 2021, the sponsor initiated a randomized, open-label, phase 3 study in patients with ER+, human epidermal growth factor receptor 2-negative  locally advanced or metastatic breast cancer previously treated with endocrine therapy. Patients are being randomized to receive monotherapy with imlunestrant, investigator's choice of endocrine monotherapy (fulvestrant or exemestane), or a combination of imlunestrant and abemaciclib. The trial is expected to complete its primary endpoint in June 2023 and fully complete in 2026.

From the published phase 1 data, no dose-limiting toxicities were observed and no maximum tolerated dose was established. Treatment-emergent adverse events (TEAEs) were mostly grade 1-2, including nausea (19 [29%]), diarrhea (11 [17%]), and fatigue (8 [12%]).

Grade 3 TEAEs occurred in 6 (9%) patients, including 2 (3%) patients with TEAEs: diarrhea (n=1) and decreased neutrophil count (n=1). Three patients (5%) experienced serious AEs, only 1 of which (grade 3 diarrhea) was treatment-related.

No cardiac safety signals occurred. The researchers executed dose reductions for 2 patients (3%) due to AEs, including the 1 with treatment-related grade 3 diarrhea. No patients discontinued due to an AE.

, is a research scientist in the pharmaceutical industry.

Lilly Announces New Clinical Data from Verzenio and Oral SERD Programs at the American Society of Clinical Oncology Annual Meeting. Eli Lilly and Company. 

https://investor.lilly.com/news-releases/news-release-details/lilly-announces-new-clinical-data-verzenio-and-oral-serd

A Study of Imlunestrant, Investigator's Choice of Endocrine Therapy, and Imlunestrant Plus Abemaciclib in Participants With ER+, HER2- Advanced Breast Cancer (EMBER-3).

https://clinicaltrials.gov/ct2/show/study/NCT04975308

A Phase 3, Randomized, Open-Label Study of Imlunestrant, Investigator's Choice of Endocrine Therapy, and Imlunestrant Plus Abemaciclib in Patients With Estrogen-Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer Previously Treated With Endocrine Therapy. Eli Lilly and Company. https://www.lillyloxooncologypipeline.com/molecule/selective-er-degrader/clinical-trial/NCT04975308. Accessed May 10. 2022.

Imlunestrant is currently under investigation as monotherapy or in combination with other anticancer therapies for patients with estrogen receptor-positive,  locally advanced or metastatic breast cancer and endometrial cancer.

Oncology Overview: Investigational Imlunestrant for Breast Cancer, Endometrial Cancer

Cabenuva, the combination of cabotegravir, a 

 integrase strand transfer inhibitor (INSTI), and rilpivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), works by decreasing HIV concentrations in the blood.

 (cabotegravir 200 mg/mL and rilpivirine 300 mg/mL) as a once-monthly treatment for HIV-1 infected adults who are virologically suppressed (HIV-1 RNA ≤ 50 copies/mL [c/mL]) on a stable antiretroviral regimen.

Eligible patients must have no history of treatment failure and no known or suspected resistance to cabotegravir or rilpivirine.

 In the phase 2 and 3 randomized trials, researchers showed the monthly injectable combination had comparable results with current daily oral antiretroviral regimens.

The FDA recently approved the extended label to be administrated every 2 months based on non-inferiority trial data.

 In the phase 3b study, researchers randomized 1045 participants to receive either cabotegravir 600 mg/rilpivirine 900 mg every 8 weeks or cabotegravir 400 mg/rilpivirine 600 mg every 4 weeks.

The primary endpoint was the proportion of patients with HIV RNA ≥ 50 c/mL at week 48 between 2 groups with a non-inferiority margin of 4%.

 Dosing every 8 weeks and dosing every 4 weeks resulted in similar efficacy.

The researchers identified an RNA ≥ 50 c/mL in 2% of the every 8-weeks group and 1% in the every 4-weeks group. The every 8-weeks group experienced 2% confirmed virological failures (CVF; 2 sequential measures ≥200 c/mL), whereas that figure was 1% in the every 4-weeks group.

Cabotegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration, which is essential for the HIV replication cycle. Rilpivirine is a diarylpyrimidine NNRTI of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase.

Before initiating treatment, health care providers (HCP) should address the importance of adherence and carefully select patients who agree to the dosing schedule. Prior to injection, prescribers should initiate patients on daily oral lead-in with 30 mg cabotegravir and 25 mg rilpivirine with a meal for 1 month to assess the tolerability.

Clinicians should administer cabotegravir/rilpivirine (which are co-packaged) as a gluteal intramuscular injection at separate injection sites (on opposite side or 2 cm apart).

On the last day of oral lead-in, clinicians should administer 600 mg (3 mL) of cabotegravir and 900 mg (3 mL) of rilpivirine. The following monthly injections are lower doses of 400 mg (2 mL) of cabotegravir and 600 mg (2 mL) of rilpivirine.

On the last day of oral lead-in, clinicians should administer 600 mg (3 mL) of cabotegravir and 900 mg (3 mL) of rilpivirine 1 month apart for 2 consecutive months. Then, continue the following injections every 2 months with same dosage.

From monthly to every 2-month: Clinicians should administer an injection 1 month after the last monthly injection and then every 2 months injections thereafter.

From every 2-month to monthly: Clinicians should administer an injection 2 months after the last every 2-month injections and then monthly thereafter.

Planned missing dose by more than 7 days: After 1 month (monthly injection schedule) or 2 months (2-months injection schedule) from the last injection, start daily oral cabotegravir 30 mg and rilpivirine 25 mg with a meal for up to 2 months.

The most common adverse reactions are injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash.

Hypersensitivity reactions with rilpivirine-containing regimens have been reported. Serious post-injection reactions with rilpivirine were reported.

If patients experience dyspnea, bronchospasm, agitation, abdominal cramping, rash/urticaria, dizziness, flushing, sweating, oral numbness, changes in blood pressure, and pain (e.g., back and chest), the prescriber should stop the medication. Hepatotoxicity has been reported in patients receiving cabotegravir or rilpivirine with or without known pre-existing hepatic disease or identifiable risk factors. The approved product labeling recommends monitoring liver chemistries.

Disorders include depressed mood, depression, major depression, mood altered, mood swings, dysphoria, negative thoughts, and suicidal ideation or attempt have been reported with this combination product and the individual drug products. The approved product labeling recommends prompt evaluation for depressive symptoms.

Residual cabotegravir and rilpivirine may remain in patients’ systemic circulation for 12 months or longer after discontinuation. Initiate an alternative antiretroviral regimen no later than 1 month after the final injections of Cabenuva when dosed monthly and no later than 2 months after the final injections when dosed every 2 months to avoid waning virologic response and resistance development. Use an alternative regimen if virologic failure is suspected.

Researchers have insufficient human data on the use of cabotegravir/rilpivirine during pregnancy and long-lasting residual cabotegravir/rilpivirine in patients’ systemic circulation to make a recommendation.

The Centers for Disease Control and Prevention doesn’t recommend breastfeeding for patients with HIV.

, is a research scientist in the pharmaceutical industry

CABENUVA [product information]. Research Triangle Park, NC: ViiV healthcare; February 2022. Accessed March 7, 2022.

ONCE-MONTHLY CABENUVA CLINICAL TRIAL. Viiv healthcare. 

https://cabenuvahcp.com/efficacy/atlas-flair/

ViiV HEALTHCARE ANNOUNCES US FDA APPROVAL OF 

 (CABOTEGRAVIR, RILPIVIRINE) FOR USE EVERY TWO MONTHS, EXPANDING THE LABEL OF THE FIRST AND ONLY COMPLETE LONG-ACTING HIV TREATMENT. Viiv healthcare. 

https://viivhealthcare.com/en-us/media-center/news/press-releases/2022/january/viiv-healthcare-announces-us-fda-approval-of-cabenuva/

Overton ET, Richmond G, Rizzardini G, et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study. 

. 2021;396(10267):1994-2005. doi:10.1016/S0140-6736(20)32666-0

Cabotegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration.

Clinical Overview: Cabenuva for HIV

Cabenuva, the combination of cabotegravir, an 

 integrase strand transfer inhibitor, and rilpivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), works by decreasing HIV concentrations in the blood. The 

 (cabotegravir 200 mg/mL and rilpivirine 300 mg/mL) as a once-monthly treatment for adults with HIV-1 who are virologically suppressed (HIV-1 RNA ≤ 50 copies/mL [c/mL]) on a stable antiretroviral regimen.

 In the phase 2 and 3 randomized trials, researchers showed the monthly injectable combination had comparable results with current daily oral antiretroviral regime.

 In the phase 3b study, researchers randomized 1045 participants to receive either cabotegravir 600 mg/rilpivirine 900 mg every 8 weeks or cabotegravir 400 mg/rilpivirine 600 mg every 4 weeks. 

Dosing every 8 weeks and dosing every 4 weeks resulted in similar efficacy. 

Clinicians should administer cabotegravir/rilpivirine, which are co-packaged, as a gluteal intramuscular injection at separate injection sites, on opposite side or 2 cm apart.

On the last day of oral lead-in, clinicians should administer 600 mg (3mL) of cabotegravir and 900 mg (3 mL) of rilpivirine 1 month apart for 2 consecutive months. Then, continue the following injections every 2 months with same dosage.

: Clinicians should administer an injection 1 month after the last monthly injection and then every 2 months injections thereafter.

: Clinicians should administer an injection 2 months after the last every 2-month injections and then monthly thereafter.

The most common AEs are injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash.

Hypersensitivity reactions with rilpivirine-containing regimens have been reported, as have serious post-injection reactions with rilpivirine. If patients experience dyspnea, bronchospasm, agitation, abdominal cramping, rash/urticaria, dizziness, flushing, sweating, oral numbness, changes in blood pressure, and pain (e.g., back and chest), the prescriber should stop the medication.

Hepatotoxicity has been reported in patients receiving cabotegravir or rilpivirine with or without known pre-existing hepatic disease or identifiable risk factors. The approved product labeling recommends monitoring liver chemistries.

Disorders include depressed mood, depression, major depression, altered mood, mood swings, dysphoria, and negative thoughts. Suicidal ideation or attempts been reported with this combination product and the individual drug products. The approved product labeling recommends prompt evaluation for depressive symptoms.

Researchers have insufficient human data on the use of cabotegravir/rilpivirine during pregnancy and long-lasting residual cabotegravir/rilpivirine in patients’ systemic circulation to make a recommendation. The Centers for Disease Control and Prevention doesn’t recommend breastfeeding for patients with HIV.

Marlene Wang, MS, is a research scientist in the pharmaceutical industry

ONCE-MONTHLY CABENUVA CLINICAL TRIAL.Viiv healthcare. 

The FDA recently approved cabotegravir 200 mg/mL and rilpivirine 300 mg/mL as a once-monthly treatment for adults with HIV-1 who are virologically suppressed on a stable antiretroviral regimen.