Weeks Of Dosing Research Articles

Patient-Reported Hair Loss and Its Impacts as Measured by the Alopecia Areata Patient Priority Outcomes Instrument in Patients Treated with Ritlecitinib: The ALLEGRO Phase 2b/3 Randomized Clinical Trial.

The ALLEGRO phase 2b/3 study investigated the efficacy and safety of ritlecitinib in patients with alopecia areata (AA). To describe the impact of ritlecitinib on patient-reported hair loss using the Alopecia Areata Patient Priority Outcomes (AAPPO) instrument and evaluate the relationship between clinically meaningful hair regrowth and improvements in patient-reported impacts. In ALLEGRO-2b/3, patients aged ≥ 12 years with AA and ≥ 50% scalp hair loss received once-daily ritlecitinib 50 or 30 mg (± 4-week 200-mg daily loading dose), 10 mg, or placebo for 24 weeks andthen continued ritlecitinib or switched from placebo to ritlecitinib 200/50 or 50 mg for 24 weeks. The AAPPO instrument evaluated improvement in hair loss, emotional symptoms (ES), and activity limitations (AL) from weeks 4 to 48 (secondary endpoint). Mean changes in ES and AL domain scores and individual items at weeks 24 and 48 were calculated for Severity of Alopecia Tool (SALT) score ≤ 20 responders and nonresponders (exploratory endpoint). Overall, 718 patients were randomized. At week 24, 5-36% of patients receiving ritlecitinib 10-200/50 mg reported improvement in scalp hair loss versus 9% receiving placebo. The results for eyebrow, eyelash, and body hair loss were similar. Mean change from baseline in ES and AL scores at weeks 24 and 48 was small and similar between groups. Mean change was larger for individual hair loss and ES items at weeks 24 and 48 in SALT score ≤ 20 responders versus nonresponders. The AAPPO instrument demonstrated the beneficial impact of ritlecitinib on patient-reported hair growth, which was consistent with improvements in clinician-reported outcomes. NCT03732807. INFOGRAPHIC.

Sustained hair regrowth with continued ritlecitinib treatment through Week 48 in patients with alopecia areata with or without early target responses: post hoc analysis of the ALLEGRO phase 2b/3 trial

Few treatments for alopecia areata (AA) have demonstrated sustained efficacy. Evaluate the efficacy and safety of continued ritlecitinib treatment to Week 48 in patients with AA with or without target efficacy responses at Week 24. Patients aged ≥12 years received daily ritlecitinib (± 4-week loading dose): 200/50 mg, 200/30 mg, 50 mg, or 30 mg. Patients with clinical response at Week 24, based on a Severity of Alopecia Tool (SALT) score ≤20 and ≤10 were evaluated for sustained response through Week 48. Nonresponders at Week 24 were assessed for response through Week 48. Among ritlecitinib-treated patients with SALT score ≤20 and ≤10 responses at Week 24, ≥85% and ≥68%, respectively, sustained these responses through Week 48. Of those with SALT score >20 at Week 24, 22%-34% achieved SALT score ≤20 at Week 48. Of those with a SALT score >10 at Week 24, 20%-26% achieved SALT score ≤10 at Week 48. Safety was similar across subgroups. Small sample size. Hair regrowth was sustained through Week 48 in patients with response at Week 24. Up to one-third of patients who did not meet target efficacy at Week 24 achieved response with continued ritlecitinib treatment.

A phase III, open-label clinical trial evaluating pegunigalsidase alfa administered every 4 weeks in adults with Fabry disease previously treated with other enzyme replacement therapies.

Pegunigalsidase alfa, a PEGylated α-galactosidase A enzyme replacement therapy (ERT) for Fabry disease, has a longer plasma half-life than other ERTs administered intravenously every 2 weeks (E2W). BRIGHT (NCT03180840) was a phase III, open-label study in adults with Fabry disease, previously treated with agalsidase alfa or beta E2W for ≥3 years, who switched to 2 mg/kg pegunigalsidase alfa every 4 weeks (E4W) for 52 weeks. Primary objective assessed safety, including number of treatment-emergent adverse events (TEAEs). Thirty patients were enrolled (24 males); 23 previously received agalsidase beta. Pegunigalsidase alfa plasma concentrations remained above the lower limit of quantification throughout the 4-week dosing interval. Thirty-three of 182 TEAEs (in 9 patients) were considered treatment-related; all were mild/moderate. No patients developed de novo anti-drug antibodies (ADAs). In the efficacy analysis (n = 29), median (inter-quartile range) eGFR change from baseline over 52 weeks was -1.9 (-5.9; 1.8) mL/min/1.73 m2 (n = 28; males [n = 22]: -2.4 [-5.2; 3.2]; females [n = 6]: -0.7 [-9.2; 2.0]). Overall, median eGFR slope was -1.9 (-8.3; 1.9) mL/min/1.73 m2/year (ADA-negative [n = 20]: -1.2 [-6.4; 2.6]; ADA-positive [n = 9]: -8.4 [-11.6; -1.0]). Lyso-Gb3 concentrations were low and stable in females, with a slight increase in males (9/24 ADA-positive). The BRIGHT study results suggest that 2 mg/kg pegunigalsidase alfa E4W is tolerated well in stable adult patients with Fabry disease. Due to the low number of patients in this study, more research is needed to demonstrate the effects of pegunigalsidase alfa given E4W. Further evidence, outside of this clinical trial, should be factored in for physicians to prolong the biweekly ERT intervals to E4W. TAKE-HOME MESSAGE: Treatment with 2 mg/kg pegunigalsidase alfa every 4 weeks could offer a new treatment option for patients with Fabry disease.

A loading dose of clofazimine to rapidly achieve steady-state-like concentrations in patients with nontuberculous mycobacterial disease.

Clofazimine is a promising drug for the treatment of nontuberculous mycobacterial (NTM) diseases. Accumulation of clofazimine to reach steady-state plasma concentrations takes months. A loading dose may reduce the time to steady-state-like concentrations. We evaluated the pharmacokinetics (PK), safety and tolerability of a loading dose regimen in patients with NTM disease. Adult participants received a 4-week loading dose regimen of 300 mg clofazimine once daily, followed by a maintenance dose of 100 mg once daily (combined with other antimycobacterial drugs). Blood samples for PK analysis were collected on three occasions. A population PK model for clofazimine was developed and simulations were performed to assess the time to reach steady-state-like (target) concentrations for different dosing regimens. Twelve participants were included. The geometric mean peak and trough clofazimine concentrations after the 4-week loading phase were 0.87 and 0.50 mg/L, respectively. Adverse events were common, but mostly mild and none led to discontinuation of clofazimine. Our loading dose regimen reduced the predicted median time to target concentrations by 1.5 months compared to no loading dose (3.8 versus 5.3 months). Further time benefit was predicted with a 6-week loading dose regimen (1.4 versus 5.3 months). A 4-week loading dose regimen of 300 mg once daily reduced the time to target clofazimine concentrations and was safe and well-tolerated. Extending the loading phase to 6 weeks could further decrease the time to target concentrations. Using a loading dose of clofazimine is a feasible strategy to optimize treatment of NTM disease. NCT05294146.

Abstract PR-10: Phase 1b study of maintenance soluble beta-glucan (Odetiglucan) in combination with a CD40 agonistic monoclonal antibody (CDX-1140) in patients with metastatic pancreatic adenocarcinoma that had not progressed on first-line chemotherapy

Abstract Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) has a dismal 5-year overall survival (OS) rate of 3%. Current standard of care provides only modest anti-cancer impact. Preclinical models show that combinations of myeloid agonists can induce strong anti-tumor activity in PDAC tumors resistant to immunotherapy, including immune checkpoint blockade (anti-CTLA4, anti-PD1). This study combines odetiglucan, a beta glucan pathogen-associated molecular pattern (PAMP), with CDX-1140, a fully human Ig2K agonistic monoclonal CD40 antibody, in the maintenance setting after cytotoxic chemotherapy induction. Preliminary findings are presented as the study was closed early for financial reasons. Methods: Patients with mPDAC who had not progressed after 4-8 months of 1L chemotherapy were enrolled and received weekly odetiglucan (4 mg/kg) plus every 3-week dosing of CDX-1140 (1.5 mg/kg). The primary endpoints were safety, MTD and RP2D, with secondary endpoints including DOR, PFS, ORR, and OS. Tissue and blood samples were collected at baseline and during treatment to evaluate immune pharmacodynamic responses. Results: A total of 5 patients received treatment on study including 4 patients who were efficacy evaluable and 1 patient who withdrew due to adverse event (arthralgia) after beginning treatment. Treatment-related emergent adverse events were seen in all patients with most common AEs including grade 1-2 arthralgia, chills, and fatigue. Grade 3 AEs included arthralgia (n=1), fatigue (n=1), and leukopenia (n=2). The ORR included 1 PR, 1 SD, and 2 PD. Two patients remained on treatment for >100 days. The pharmacodynamic profile was consistent with the mode of action of odetiglucan and CDX-1140, including a reduction in peripheral Dectin-1 expressing monocytes and transient decreases in peripheral B cells. Patients with disease control (PR or SD, n=2) compared to patients with progression (PD, n=2) showed expansion of peripheral Ki67+ CD8+ T cells following treatment. Analysis of a paired tumor biopsy from 1 patient with PD confirmed penetration of odetiglucan into a liver metastasis with expansion of CD11b+ macrophages and a reduction of cytokeratin+ tumor content, but without significant changes in T cell infiltration. Conclusions: The combination of odetiglucan and CDX-1140 was feasible and safe when administered as maintenance therapy in patients with mPDAC whose disease had not progressed on 1L chemotherapy. Treatment produced encouraging activity with changes in immunological correlates associated with disease control. These early results support further investigation combining odetiglucan with a CD40 agonist in mPDAC. Citation Format: Mark H O'Hara, Max Wattenberg, Ignacio Garrido-Laguna, Eileen M O'Reilly, Michael Yellin, Tibor Keler, Michele Gargano, Nick Niles, Jeremy Drees, Nandita Bose, Gregory L Beatty. Phase 1b study of maintenance soluble beta-glucan (Odetiglucan) in combination with a CD40 agonistic monoclonal antibody (CDX-1140) in patients with metastatic pancreatic adenocarcinoma that had not progressed on first-line chemotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr PR-10.

Abstract B061: Phase 1b study of maintenance soluble beta-glucan (Odetiglucan) in combination with a CD40 agonistic monoclonal antibody (CDX-1140) in patients with metastatic pancreatic adenocarcinoma that had not progressed on first-line chemotherapy

Abstract Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) has a dismal 5-year overall survival (OS) rate of 3%. Current standard of care provides only modest anti-cancer impact. Preclinical models show that combinations of myeloid agonists can induce strong anti- tumor activity in PDAC tumors resistant to immunotherapy, including immune checkpoint blockade (anti-CTLA4, anti-PD1). This study combines odetiglucan, a beta glucan pathogen- associated molecular pattern (PAMP), with CDX-1140, a fully human Ig2K agonistic monoclonal CD40 antibody, in the maintenance setting after cytotoxic chemotherapy induction. Preliminary findings are presented as the study was closed early for financial reasons. Methods: Patients with mPDAC who had not progressed after 4-8 months of 1L chemotherapy were enrolled and received weekly odetiglucan (4 mg/kg) plus every 3-week dosing of CDX-1140 (1.5 mg/kg). The primary endpoints were safety, MTD and RP2D, with secondary endpoints including DOR, PFS, ORR, and OS. Tissue and blood samples were collected at baseline and during treatment to evaluate immune pharmacodynamic responses. Results: A total of 5 patients received treatment on study including 4 patients who were efficacy evaluable and 1 patient who withdrew due to adverse event (arthralgia) after beginning treatment. Treatment-related emergent adverse events were seen in all patients with most common AEs including grade 1-2 arthralgia, chills, and fatigue. Grade 3 AEs included arthralgia (n=1), fatigue (n=1), and leukopenia (n=2). The ORR included 1 PR, 1 SD, and 2 PD. Two patients remained on treatment for >100 days. The pharmacodynamic profile was consistent with the mode of action of odetiglucan and CDX-1140, including a reduction in peripheral Dectin-1 expressing monocytes and transient decreases in peripheral B cells. Patients with disease control (PR or SD, n=2) compared to patients with progression (PD, n=2) showed expansion of peripheral Ki67+ CD8+ T cells following treatment. Analysis of a paired tumor biopsy from 1 patient with PD confirmed penetration of odetiglucan into a liver metastasis with expansion of CD11b+ macrophages and a reduction of cytokeratin+ tumor content, but without significant changes in T cell infiltration. Conclusions: The combination of odetiglucan and CDX-1140 was feasible and safe when administered as maintenance therapy in patients with mPDAC whose disease had not progressed on 1L chemotherapy. Treatment produced encouraging activity with changes in immunological correlates associated with disease control. These early results support further investigation combining odetiglucan with a CD40 agonist in mPDAC. Citation Format: Mark H O'Hara, Max Wattenberg, Ignacio Garrido-Laguna, Eileen M O'Reilly, Michael Yellin, Tibor Keler, Michele Gargano, Nick Niles, Jeremy Drees, Nandita Bose, Gregory L Beatty. Phase 1b study of maintenance soluble beta-glucan (Odetiglucan) in combination with a CD40 agonistic monoclonal antibody (CDX-1140) in patients with metastatic pancreatic adenocarcinoma that had not progressed on first-line chemotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B061.

Impact of Previous Alopecia Areata Treatment on Efficacy Responses up to Week 48 Following Ritlecitinib Treatment: A Post Hoc Analysis.

Patients with alopecia areata (AA) may have received several therapies for management of AA during their lives. In the ALLEGRO phase 2b/3 (NCT03732807) study, the oral JAK3/TEC family kinase inhibitor ritlecitinib demonstrated efficacy and an acceptable safety profile in patients aged ≥ 12years with AA and ≥ 50% scalp hair loss. This post hoc analysis investigated associations between prior use of AA therapies and Severity of Alopecia Tool (SALT) responses in patients receiving ritlecitinib for AA. Patients receiving ritlecitinib 30mg or 50mg once daily with or without an initial 4-week 200-mg daily loading dose were grouped by previous exposure to AA treatments, including topicals, intralesional corticosteroids (ILCS), topical immunotherapy, and systemic immunosuppressants or any prior AA treatment. Multivariable logistic regression analyses evaluated the association between response based on a SALT score of ≤ 20 and any prior treatment for AA at weeks 24 and 48. Of 522 patients, 360 (69.0%) had previous exposure to any AA treatment. At Week 24, SALT ≤ 20 response was positively associated with prior use of ILCS (odds ratio [OR], 2.12; 95% confidence interval [CI], 1.23-3.65; P < 0.05) and negatively associated with prior use of systemic immunosuppressants (OR 0.50; 95% CI 0.28-0.88; P < 0.05). Prior use of topicals or topical immunotherapy was not associated with SALT ≤ 20 response at Week 24. By Week 48, no association was identified between SALT ≤ 20 response and prior use of topicals, ILCS, topical immunosuppressants, or systemic immunosuppressants (all P > 0.05). Previous exposure to any AA therapy was not associated with SALT ≤ 20 response at weeks 24 or 48 (all P > 0.05). Prior AA treatment history had no effect on longer-term treatment response to ritlecitinib. NCT03732807.

Efficacy and safety of ritlecitinib in vitiligo patients across Fitzpatrick skin types with biomarker analyses.

Efficacy and safety of ritlecitinib (an oral JAK3/TEC family kinase inhibitor) were evaluated in patients with nonsegmental vitiligo (NSV) across Fitzpatrick skin types (FSTs). Patients with FST I-III ('light skin'; n = 247) and FST IV-VI ('dark skin'; n = 117) received once-daily ritlecitinib 50 mg (with/without 4-week loading dose), low-dose ritlecitinib or placebo for 24 weeks. At baseline, patients with light skin displayed higher CLM-1 and NCR1 serum levels than patients with dark skin (p < 0.05). At 24 weeks, ritlecitinib 50 mg improved the extent of depigmentation measured by percent change from baseline in facial-vitiligo area scoring index (placebo-adjusted mean difference [90% CI]) in patients with light (-15.2 [-24.7, -5.8]; p = 0.004) and dark (-37.4 [-50.3, -24.4]; p < 0.0001) skin, with continuous re-pigmentation through week 48. Treatment-emergent adverse events were similar across FSTs. At weeks 4 and 24, ritlecitinib 50 mg reduced CXCL11 serum levels (p < 0.001) in patients with light skin, whereas patients with dark skin had increased levels at week 4 (p = 0.05) and no significant change at week 24. Ritlecitinib 50 mg decreased IL-9 and IL-22 expression levels in dark skin compared with light skin (qPCR; p < 0.05). These differences in immune dysregulations may explain why NSV patients with dark skin respond to therapy earlier than patients with light skin.

Preclinical toxicological assessment of amido-bridged nucleic acid-modified antisense oligonucleotides targeting synaptotagmin XIII for intra-abdominal treatment of peritoneal metastasis of gastric cancer.

Peritoneal metastasis of gastric cancer is closely associated with dismal prognosis. In previous preclinical proof-of-concept studies, an amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotide (ASO), designated ASO-4733 that targets the gene encoding synaptotagmin XIII (SYT13), inhibited cellular functions required for the formation of peritoneal metastasis of gastric cancer cells. ASO-4733 achieved therapeutic effects when intra-abdominally administered to mouse xenograft models. Here, we conducted an analysis of Syt13-deficient mice to determine the pharmacokinetics and toxicity of intra-abdominal administration of ASO-4733. The effects of Syt13-deficiency in mice were determined. Good Laboratory Practice toxicity tests and the toxicokinetics of intra-abdominal administration of ASO-4733 were conducted in cynomolgus monkeys and rats. The pharmacokinetics of ASO-4733 administered intravenously or intra-abdominally to rats were investigated. Syt13-deficient mice exhibited normal reproduction, organ functions, and motor functions. Weekly intra-abdominal administration of ASO-4733 (125mg/kg), corresponding to a 50-fold increase of the estimated clinical dose for 4weeks, was well tolerated by cynomolgus monkeys. In rats, off-target toxicity (not attributable to hybridization) was observed after weekly intra-abdominal administration of ASO-4733. Blood concentrations of ASO-4733 were lower and rose more slowly after intra-abdominal administration compared with intravenous administration. The preclinical profile of intra-abdominal administration of ASO-4733 demonstrated its suitability for entry into clinical trials of patients with peritoneal metastasis of gastric cancer.

A phase 2a study investigating the effects of ritlecitinib on brainstem auditory evoked potentials and intraepidermal nerve fiber histology in adults with alopecia areata.

Reversible axonal swelling and brainstem auditory evoked potential (BAEP) changes were observed in standard chronic (9-month) toxicology studies in dogs treated with ritlecitinib, an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma family kinase inhibitor, at exposures higher than the approved 50-mg human dose. To evaluate the clinical relevance of the dog toxicity finding, this phase 2a, double-blind study assessed BAEP changes and intraepidermal nerve fiber (IENF) histology in adults with alopecia areata treated with ritlecitinib. Patients were randomized to receive oral ritlecitinib 50 mg once daily (QD) with a 4-week loading dose of 200 mg QD or placebo for 9 months (placebo-controlled phase); they then entered the active-therapy extension and received ritlecitinib 50 mg QD (with a 4-week loading dose of 200 mg in patients switching from placebo). Among the 71 patients, no notable mean differences in change from baseline (CFB) in Waves I-V interwave latency (primary outcome) or Wave V amplitude on BAEP at a stimulus intensity of 80 dB nHL were observed in the ritlecitinib or placebo group at Month 9, with no notable differences in interwave latency or Wave V amplitude between groups. The CFB in mean or median IENF density and in percentage of IENFs with axonal swellings was minimal and similar between groups at Month 9. Ritlecitinib treatment was also not associated with an imbalanced incidence of neurological and audiological adverse events. These results provide evidence that the BAEP and axonal swelling finding in dogs are not clinically relevant in humans.

Safety of topical sildenafil cream, 3.6% in a randomized, placebo-controlled trial for the treatment of female sexual arousal disorder.

There are currently no Food and Drug Administration-approved treatments for female sexual arousal disorder (FSAD), which is physiologically analogous to male erectile dysfunction. The study sought to test the systemic and local genital safety of topical sildenafil cream, 3.6% (sildenafil cream) among healthy premenopausal women with FSAD and their sexual partners over a 12-week treatment period. This was a phase 2b, exploratory, randomized, placebo-controlled, double-blind study of sildenafil cream among healthy premenopausal women with FSAD. Safety was assessed by the frequency and incidence of treatment-emergent adverse events (TEAEs) among participants and their sexual partners. Participants recorded the incidence of TEAEs in a daily eDiary (electronic diary). Sexual partners were contacted within 72hours of each sexual event in which investigational product was used. All participants used placebo cream for 1 month, during a single-blind run-in period, and then if eligible, were randomized 1:1 to sildenafil cream or placebo cream. Participants used their assigned investigational product over a 12-week double-blind dosing period. They attended monthly follow-up visits, in which their eDiary TEAE data were reviewed by the study staff and graded for severity and relationship to study product. The frequency and incidence of TEAEs among participants and their sexual partners. During the 12-week double-blind dosing period, there were 78 TEAEs reported by 29 of 99 sildenafil-assigned participants and 65 TEAEs reported by 28 of 94 placebo-assigned participants (P= .76). All TEAEs were mild or moderate in severity. The most common treatment-related TEAE among active and placebo-assigned participants was application site discomfort. There were no differences in the number of treatment-related TEAEs among sildenafil cream vs placebo cream users (P> .99). Four sildenafil cream participants and 3 placebo cream participants discontinued the study due to TEAEs involving application site discomfort (P> .99). There were 9 TEAEs reported by 7 of 91 sexual partners exposed to sildenafil cream vs 4 TEAEs reported by 4 of 84 sexual partners exposed to placebo cream (P= .54). These data support further clinical development of topical sildenafil cream for the treatment of FSAD. Safety was assessed among participants and their sexual partners after 1357 and 1160 sexual experiences in which sildenafil cream or placebo cream were used, respectively. The phase 2b study was powered for the primary objectives of efficacy, rather than safety. These data demonstrate that topically applied sildenafil cream was safe and well tolerated by exposed users and their sexual partners.

An Evidence-Based Rationale for Dose De-escalation of Subcutaneous Atezolizumab.

Atezolizumab is a programmed death-ligand 1 (PD-L1) checkpoint inhibitor for the treatment of different forms of cancer. The subcutaneous formulation of atezolizumab has recently received approval. However, treatment with atezolizumab continues to be expensive, and the number of patients needing treatment with this drug continues to increase. We propose two alternative dosing regimens for subcutaneous atezolizumab to reduce drug expenses while ensuring effective exposure; one may be directly implemented in the clinic. We developed two alternative dose interval prolongation strategies based on pharmacokinetic modeling and simulation. The first dosing regimen was based on patients' weight while maintaining equivalent systemic drug exposure by adhering to Food and Drug Administration (FDA) guidelines for in silico dose adjustments. The second dosing regimen aimed to have a minimum atezolizumab concentration above the 6 µg/mL threshold, associated with 95% intratumoral PD-L1 receptor saturation for at least 95% of all patients. We found that, for the weight-based dosing regimen, the approved 3-week dosing interval could be extended to 5 weeks for patients < 50 kg and 4 weeks for patients weighing 50-65 kg. Besides improving patient convenience, these alternative dosing intervals led to a predicted 7% and 12% cost reduction for either the USA or European population. For the second dosing regimen, we predicted that a 6-week dosing interval would result in 95% of the patients above the 6 µg/mL threshold while reducing costs by 50%. We have developed and evaluated two alternative dosing regimens that resulted in a cost reduction. Our weight-based dosing regimen can be directly implemented and complies with FDA guidelines for alternative dosing regimens of PD-L1 inhibitors. For the more progressive alternative dosing regimen aimed at the intratumoral PD-L1 receptor threshold, further evidence on efficacy and safety is needed before implementation.

Ritlecitinib, a JAK3/TEC family kinase inhibitor, stabilizes active lesions and repigments stable lesions in vitiligo

The efficacy of ritlecitinib, an oral JAK3/TEC family kinase inhibitor, on active and stable lesions was evaluated in patients with active non-segmental vitiligo in a phase 2b trial (NCT03715829). Patients were randomized to placebo or daily ritlecitinib 50 mg (with or without 4-week 100-mg or 200-mg loading dose), 30 mg, or 10 mg for 24 weeks. Active lesions showed greater baseline expression of inflammatory/immune markers IFNG and CCL5, levels of CD103, and T-cell infiltrates than stable lesions. Patients with more active than stable vitiligo lesions showed higher baseline serum levels of CXCL9 and PD-L1, while patients with more stable than active lesions showed higher baseline serum levels of HO-1. At Week 24, ritlecitinib 50 mg significantly stabilized mean percent change from baseline in depigmentation extent in both active lesions and stable lesions vs. placebo-response, with stable lesions showing greater repigmentation. After 24 weeks of treatment, ritlecitinib 50 mg increased expression of melanocyte markers in stable lesions, while Th1/Th2-related and co-stimulatory molecules decreased significantly in both stable and active lesions. Serum from patients with more active than stable lesions showed decreased levels of ICOS and NK cell activation markers. These data, confirmed at transcription/protein levels, indicate that stable lesion repigmentation occurs early with ritlecitinib, while active lesions require stabilization of inflammation first. ClinicalTrials.gov: NCT03715829.

Immunogenicity and safety of beta variant COVID-19 vaccine AZD2816 and AZD1222 (ChAdOx1 nCoV-19) as primary-series vaccination for previously unvaccinated adults in Brazil, South Africa, Poland, and the UK: a randomised, partly double-blinded, phase 2/3 non-inferiority immunobridging study

AZD2816 is a variant-adapted COVID-19 vaccine that expresses the full-length SARS-CoV-2 beta variant spike protein but is otherwise similar to AZD1222 (ChAdOx1 nCoV-19). This study aimed to evaluate the safety and immunogenicity of AZD1222 or AZD2816 (or both) primary-series vaccination in a cohort of adult participants who were previously unvaccinated. In this phase 2/3, randomised, multinational, active-controlled, non-inferiority, immunobridging study, adult participants previously unvaccinated for COVID-19 were enrolled at 16 study sites in Brazil, South Africa, Poland, and the UK. Participants were stratified by age, sex, and comorbidity and randomly assigned 5:5:5:2 to receive a primary series of AZD1222 (AZD1222 group), AZD2816 (AZD2816 [4-week] group), or AZD1222-AZD2816 (AZD1222-AZD2816 group) at 4-week dosing intervals, or AZD2816 at a 12-week interval (AZD2816 [12-week] group) and evaluated for safety and immunogenicity through 180 days after dose 2. Primary outcomes were safety (rates of solicited adverse events occurring during 7 days and unsolicited adverse events occurring during 28 days after each dose) and immunogenicity (non-inferiority of pseudovirus neutralising antibody geometric mean titre [GMT], GMT ratio margin of 0·67, and seroresponse rate, rate difference margin of -10%, recorded 28 days after dose 2 with AZD2816 [4-week interval] against beta vs AZD1222 against ancestral SARS-CoV-2) in participants who were seronegative at baseline. This trial is registered with ClinicalTrials.gov, NCT04973449, and is completed. Between July 7 and Nov 12, 2021, 1449 participants were assigned to the AZD1222 group (n=413), the AZD2816 (4-week) group (n=415), the AZD1222-AZD2816 group (n=412), and the AZD2816 (12-week) group (n=209). Ten (2·6%) of 378 participants who were seronegative at baseline in the AZD1222 group, nine (2·4%) of 379 in the AZD2816 (4-week) group, eight (2·1%) of 380 in the AZD1222-AZD2816 group, and 11 (5·8%) of 191 in the AZD2816 (12-week) group had vaccine-related unsolicited adverse events. Serious adverse events were recorded in one (0·3%) participant in the AZD1222 group, one (0·3%) in the AZD2816 (4-week) group, two (0·5%) in the AZD1222-AZD2816 group, and none in the AZD2816 (12-week) group. Co-primary immunogenicity endpoints were met: neutralising antibody GMT (ratio 1·19 [95% CI 1·08-1·32]; lower bound greater than 0·67) and seroresponse rate (difference 1·7% [-3·1 to 6·5]; lower bound greater than -10%) at 28days after dose 2 were non-inferior in the AZD2816 (4-week) group against beta versus in the AZD1222 group against ancestral SARS-CoV-2. Seroresponse rates were highest with AZD2816 against beta (12-week interval 94·3% [95% CI 89·4-97·3]; 4-week interval 85·7% [81·5-89·2]) and with AZD1222 (84·6% [80·3-88·2]) against ancestral SARS-CoV-2. Primary series of AZD1222 and AZD2816 were well tolerated, with no emergent safety concerns. Both vaccines elicited robust immunogenicity against beta and ancestral SARS-CoV-2 with greater responses demonstrated when testing against SARS-CoV-2 strains that matched those targeted by the respective vaccine. These findings demonstrate the continued importance of ancestral COVID-19 vaccines in protecting against severe COVID-19 and highlight the feasibility of using the ChAdOx1 platform to develop COVID-19 vaccines against future SARS-CoV-2 variants. AstraZeneca.

Safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of KT-253, a targeted protein degrader of MDM2, in patients with relapsed/refractory (R/R) solid tumors, lymphoma, high grade myeloid malignancies and acute lymphoblastic leukemia (ALL).

3084 Background: The tumor suppressor p53 is mutated in approximately 50% of cancers. In those cancers with wild-type p53, its activity is controlled by mouse double minute 2 (MDM2), an E3 ligase that tags p53 for degradation. KT-253 is a novel, highly potent heterobifunctional MDM2 degrader that upregulates p53 activity and overcomes the p53-MDM2 feedback loop, resulting in &gt;200-fold higher potency compared to MDM2 inhibitors. In preclinical PDX models of sensitive p53WT solid tumors, AML and ALL, KT-253 robustly activates p53, induces apoptosis, and results in tumor regressions with every 3-week dosing. The ability to rapidly induce an acute apoptotic response and dose intermittently may result in a therapeutic index that has eluded previous MDM2 targeting agents. Methods: The ongoing open-label Phase 1 study evaluates safety, PK, PD and preliminary efficacy of IV KT-253 administered on Day 1 of 21-day cycles. Patients (pts) with advanced (≥2 prior therapies) solid tumors (ST)/lymphomas (Arm A) and relapsed/refractory (R/R) high grade myeloid malignancies (AML, high/very-high risk myelodysplastic syndrome (MDS), MDS/myeloproliferative neoplasms) and ALL (Arm B) are eligible. Blood samples are collected for KT-253 PK/PD analyses. Results: As of 26 January 2024, 18 pts have been treated, 13 in Arm A dose levels (A: DL) 1-4 and 5 in Arm B dose levels (B: DL) 1-2, with mean number of 3 and 2 doses, respectively. The most common solid tumor types were Merkel cell carcinoma ((MCC) n=3), adenoid cystic carcinoma ((ACC) n=2) and uveal melanoma (n=2). Arm B included 5 pts with R/R AML. The median age was 61 years (yrs) (range 42, 81) in Arm A and 66 yrs (range 57, 70) in Arm B. The most common adverse events (AEs) in &gt; 20% of pts included nausea, fatigue, headache, and vomiting. There was 1 DLT of AEs leading to discontinuation that included Grade (G) 2 nausea and fatigue in A: DL4. There were no neutropenia or thrombocytopenia AEs in either arm. KT-253 related SAEs included G3 hypotension in a pt with decreased oral intake (A: DL1). Overall best response: 1 CR (B: DL2, AML); 2 PRs (A: DL1, MCC; B: DL1, AML); 3 SD (A: DL1, fibromyxoid sarcoma; DL2, ACC; DL3, renal cell cancer). PD data from A: DL1-4 and B: DL1-2 demonstrated rapid upregulation of plasma GDF-15 protein and upregulation of CDKN1A and PHLDA3 mRNA levels in blood. KT-253 demonstrated dose-dependent increase in plasma exposure with levels approximating efficacious doses. Conclusions: KT-253 results in potent upregulation of p53-dependent biomarkers and has demonstrated early signs of anti-tumor activity including objective responses in MCC and AML at doses that are well tolerated. Dose escalation is ongoing at DL4 in Arm A and at DL2 in Arm B and analyses from additional pts will be presented at the meeting. Clinical trial information: NCT05775406 .

Patient-reported experience with an immunotherapy telehealth platform.

1637 Background: The Making Telehealth Delivery of Cancer Care at Home Effective and Safe for Immunotherapy (MATCHES-IO) intervention seeks to improve the efficiency and patient experience for those treated with single agent pembrolizumab. Because pembrolizumab is administered as an outpatient infusion every 3-weeks, patients require up to 18 clinic visits per year to receive treatment, which is arduous. During the COVID-19 pandemic, the FDA granted accelerated approval for an extended interval dosing administered every 6 weeks, but despite this approval every 3-week dosing remains the standard (65% of prescriptions) as clinicians perceive this schedule enables them to identify and manage toxicity early. Telehealth may be the impetus to change the standard to the more convenient 6-week in person schedule, but evidence is needed. Methods: We conducted a single arm pragmatic trial to evaluate the efficiency and patient experience of a telehealth immunotherapy platform (MATCHES-IO) in patients with non-small cell lung, genitourinary, or melanoma cancers receiving single agent pembrolizumab. MATCHES-IO evaluates whether in-person visits for pembrolizumab therapy q6wk (rather than q3wk), with interim telehealth toxicity checks between in-person treatments, is more efficient and enhances patient experience relative to the standard q3wk infusion visits. The components of the platform include clinician-patient virtual visits, labs at home, biometric devices at home for vital sign monitoring, and electronic patient-reported outcomes to monitor for common IO-related toxicities. Patient experience was assessed after each MATCHES-IO televisit for up to two televisits. We measured experience with a patient experience survey that included the net promoter score, of how likely are they to recommend this intervention to similar patients (scale 0-10, higher score is desirable). A score of 9 or greater is considered excellent. Results: Between July 2023 and February 2024, 27 patients were enrolled, median age 68 (range 45–85), 74% white, 11% black, 11% Asian, and 41% female. Cancer types included thoracic (59% of patients), genitourinary (33%), and melanoma (7%). 19 patients (70.4%) have completed a MATCHES-IO televisit and completed the patient experience survey. The median net promoter score was 9 (range 2-10). 94% patients perceived a benefit to the MATCH-IO televisit including saved time (83% of respondents), patient convenience (83%), convenience for caregiver/family (44%), saved money (44%), and better monitoring of cancer and treatment (39%). 78% of patients found the at home visit less stressful than the in-person visit. Conclusions: Patients endorsed an enhanced experience with an immunotherapy telehealth platform for extended dosing of pembrolizumab. Further follow-up is needed to confirm these experience findings and determine whether this platform improved efficiency through fewer in-person visits.

Abstract PO3-19-01: A Randomized Controlled Trial of Metastasis-directed Therapy for Oligometastases in Breast Cancer (OLIGAMI trial; JCOG2110)

Abstract Background: Oligometastases were initially described as a concept bridging localized disease with widespread distant metastases, but a consensus on its definition has yet to be reached. Recently, the term "metastasis-directed therapy" (MDT) was coined to encompass local therapy for distant metastases, including surgery and radiation therapy (RT), especially stereotactic body radiation therapy (SBRT). Though OLIGO-BC1 and SABR-COMET have indicated the potential benefits of MDT for oligometastases, NRG-BR002 revealed no significant difference in progression-free survival (PFS). As a definitive conclusion to this clinical question has not been reached, there is an increasing demand for phase III trials focusing on breast cancer (BC). We planned the JCOG2110, also called as OLIGAMI trial . Design: OLIGAMI trial is a multi-institutional, two-arm, open-label, randomized controlled phase III trial being conducted with the participation of 50 hospitals belonging to Japan Clinical Oncology Group. After the first registration, all patients will be performed in a 12-week, subtype-specific, systemic therapy consisting of CDK4/6 inhibitors with hormonal therapy for luminal BC, docetaxel with trastuzumab and pertuzumab for HER2-positive BC, chemotherapy with immune checkpoint inhibitors for triple-negative BC expressing PD-L1, and olaparib for cases harboring BRCA mutations. For other triple-negative BC, chemotherapy will be administered. If this 12-week systemic therapy dose not cause any progression or complete response, patients proceed to second registration for randomization; arm A continues same systemic therapy alone, and arm B performs MDT followed by same systemic therapy. The MDT will involve either RT or surgery, and RT will involve mainly SBRT and partly conventional RT. Eligibility criteria: OLIGAMI trial will encompass all subtypes of advanced BC. The key criteria of the first registration are as follows: 1) Histologically diagnosed as invasive BC. Biopsy from oligometastases is desirable but not required. 2) Diagnosed with advanced BC with oligometastases by neck to pelvis enhanced CT, FDG-PET, and brain enhanced MRI. 3) Oligometastases defined as: (i) Maximum diameter of each tumor is 3 cm or less. (ii) Total number of 3 or less. (iii) In case of brain metastasis, maximum diameter is 2 cm or less and asymptomatic. 4) The patient with local recurrence is included. 5) De novo stage IV BC is included. The criteria of secondary registration are as follows: 1) The planned number of courses of systemic therapy has been performed. 2) No progression or new distant metastasis by response evaluation. 3) At least one oligometastaseis remains. Specific Aims: OLIGAMI trial aims to confirm the superiority of MDT to systemic therapy for oligometastases of BC. The primary endpoint is overall survival (OS) after randomization, while the secondary endpoints include OS after first registration, PFS, progression site (oligometastases vs. non-oligometastases), PFS specifically related to MDT (restricted arm B), proportion of adverse events and serious adverse events, and the non-progression proportion of health-related quality of life. Statistical methods: The sample size was calculated as 268 to detect 12% of 5-year OS difference with one-sided alpha of 0.05, power of 70%, 3 years of accrual, and 5 years of follow up. Therefore, we assumed the planned sample size for second registration for randomization as 270. We set the number of first registration as 340, assuming that there may be some patients with progression or complete response after the systemic therapy for 12 weeks. Present accrual and target accrual: The patient accrual will start in August 2023. Enrolment of 340 patients for first registration is planned over a 3-year accrual period. Contact information: Principal investigator, Toshiyuki Ishiba, MD. Ph.D. ishiba0313@gmail.com Citation Format: Toshiyuki Ishiba, Ikuno Nishibuchi, Fumitaka Hara, Keita Sasaki, Ryo Sadate, Yuta Sekino, Ryunosuke Machida, Haruhiko Fukuda, Takahiro Kogawa, Tomomi Fujisawa, Yasuaki Sagara, Yoichi Naito, Kaori Terata, Yukinori Ozaki, Akihiko Shimomura, Takehiko Sakai, Chizuko Kanbayashi, Tsuguo Iwatani, Hideo Shigematsu, Kenji Tamura, Takashi Mizowaki, Michio Yoshimura, Naoto Shikama, Tadahiko Shien, Hiroji Iwata. A Randomized Controlled Trial of Metastasis-directed Therapy for Oligometastases in Breast Cancer (OLIGAMI trial; JCOG2110) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-19-01.

Abstract 4068: In vitro masked effect, in vivo anti-tumor activity and toxicology study of KGX101, an interleukin-12 prodrug, in monotherapy or in combination with anti-PD-L1 antibody

Abstract Interleukin-12 (IL-12) has long been limited in its clinical use due to its short half-life (t1/2) and dose-related toxicity, despite its remarkable ability to activate effector functions in T cells and natural killer (NK) cells. To address these challenges, we engineered an IL-12 prodrug called KGX101. In KGX101, the C-terminus of IL-12 is fused with ADCC-impaired IgG1 Fc to extend its half-life. Meanwhile, the N-terminus is concealed with its corresponding receptor soluble domains, IL-12Rβ1 and IL-12Rβ2, using tumor-specific protease cleavable linkers. This innovative design prevents systemic immune system overactivation. Once the linker is cleaved by tumor microenvironment (TME)-specific proteases, KGX101 functions like IL-12, effectively stimulating T cells and NK cells, reshaping the TME, and displaying significant potential in cancer therapy. To confirm KGX101's masking effect, we conducted IFNγ induction efficacy tests using peripheral blood mononuclear cells (PBMCs) from three donors. KGX101 demonstrated a 300 to 2500-fold reduction in activity compared to unmasked IL-12-Fc. Importantly, the masking effect of KGX101 was nearly abolished after protease digestion, affirming its mechanism of action. To further establish KGX101's effectiveness, we conducted in vivo antitumor studies in hPBMC xenograft mouse models using human colorectal cancer HCT116 and PD-L1-overexpressed human malignant melanoma A375. Mice were subcutaneously implanted with a specific mixture of cancer cells and hPBMCs, and then intravenously injected with PBS or KGX101 at various dose levels twice a week for 4-5 cycles. Compared to the PBS control group, KGX101 demonstrated up to a 42% tumor growth inhibition (TGI) in the HCT116 model at 0.18 mg/kg and a 76% TGI in the hPD-L1-A375 model at 0.06 mg/kg. Analysis of tumor-infiltrating lymphocytes (TILs) revealed that KGX101 increased the percentage of T cells in the tumor environment in a dose-dependent manner. We also evaluated the combination of KGX101 with an anti-PD-L1 antibody in an HCT116/hPBMC xenograft mouse model, which showed limited response to anti-PD-L1 monotherapy. The TGI% for KGX101 at 0.06 mg/kg, anti-PD-L1 antibody at 1 mg/kg, and their combination were 36.56%, 6.93%, and 66.22%, respectively, demonstrating a promising antitumor synergy. In terms of pharmacokinetics, a single dose of KGX101 at 0.06 mg/kg and 0.18 mg/kg in the HCT116/hPBMC xenograft mouse model resulted in a serum half-life ranging from 52.75 to 64.87 hours, while the t1/2 in Cynomolgus monkeys was approximately 3 days. In a 4-week repeat dose toxicity study in Cynomolgus monkeys, the highest non-severely toxic dose (HNSTD) of KGX101 was determined to be 0.1 mg/kg. The results from nonclinical toxicology studies support the potential of KGX101 as a well-tolerated therapy for the First-in-Human (FIH) clinical trial. Citation Format: Shumin Yang, Nuo Li, Jing Wang, Li Ma, Yi Zhao, Hui Chen, Haixiang Wu, Weidong Jiang. In vitro masked effect, in vivo anti-tumor activity and toxicology study of KGX101, an interleukin-12 prodrug, in monotherapy or in combination with anti-PD-L1 antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4068.

Long-Term Efficacy of Ritlecitinib up to Month 24 From the ALLEGRO Phase 2b/3 and Long-Term Phase 3 Clinical Studies in Alopecia Areata

Introduction: Ritlecitinib demonstrated efficacy and safety to Week 48 in patients aged ≥12 years with alopecia areata (AA) in ALLEGRO-2b/3 (NCT03732807). ALLEGRO-LT (NCT04006457) is an ongoing, phase 3, open-label study investigating the long-term safety and efficacy of ritlecitinib in AA. We report updated interim efficacy results of ritlecitinib up to Month 24 from ALLEGRO-2b/3 and ALLEGRO-LT.&#x0D; Methods: Patients aged ≥12 years with AA and ≥50% scalp hair loss who rolled-over to ALLEGRO-LT from ALLEGRO-2b/3 were included. Data are reported for patients who received: 1) daily ritlecitinib 50-mg with a 4-week 200-mg daily loading dose (“200/50-mg”); 2) daily ritlecitinib 50-mg with no loading dose (“50-mg”). Outcomes include the proportions of patients with response (based on Severity of Alopecia Tool [SALT] score ≤20, SALT ≤10, and Patients’ Global Impression of Change [PGI-C] score of “moderately improved” or “greatly improved”) through Month 24, and the proportions of patients sustaining SALT ≤20 response from Month 12 through Month 24. Observed and imputed (modified last observation carried forward [mLOCF]) data, to account for missing values, are reported (data cutoff: December 9, 2022).&#x0D; Results: The 200/50-mg and 50-mg groups included 194 and 191 patients; 127 (65.5%) and 111 (58.1%) were ongoing at the data cutoff. SALT ≤20 response rates in the 200/50-mg and 50-mg groups increased from Month 12 (45.9% and 45.1% [observed]; 41.8% and 40.3% [mLOCF]) to Month 24 (63.1% and 60.8% [observed]; 50.8% and 46.1% [mLOCF]). SALT ≤10 response rates increased between Months 12 and 24 for the 200/50-mg group (39.4% to 51.1% [observed]; 35.6% to 40.9% [mLOCF]) and 50-mg group (34.2% to 50.8% [observed]; 30.9% to 37.7% [mLOCF]). Of SALT ≤20 responders at Month 12, 92.8% (200/50-mg) and 79.7% (50-mg) (observed) sustained this response through Month 24. PGI-C response rates were maintained from Month 12 (200/50-mg: 69.4% [observed], 65.3% [mLOCF]; 50-mg: 61.6% [observed], 57.7% [mLOCF]) to Month 24 (200/50-mg: 76.4% [observed], 65.4% [mLOCF]; 50-mg: 70.0% [observed], 56.6% [mLOCF]).&#x0D; Conclusion: Ritlecitinib 50-mg (with or without a 200-mg loading dose) demonstrated clinically meaningful and sustained clinician- and patient-reported efficacy through Month 24, which supports its long-term use in patients aged ≥12 years with severe AA.

A Phase IIa Multicenter, Randomized, Vehicle-Controlled, Dose Escalating Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of CBT-001 Ophthalmic Solution in Patients With Primary or Recurrent Pterygium

PurposeTo evaluate the safety and efficacy of CBT-001, a multi-target tyrosine kinase inhibitor (MKI) eyedrop, for pterygia. DesignPhase 2 clinical trial. Stage 1 was a single center, open-labeled, vehicle-controlled study. Stage 2 was a multicenter, randomized, double-masked, vehicle-controlled trial. ParticipantsPatients with primary or recurrent pterygia. Main Outcome MeasuresThe primary efficacy endpoint was lesion vascularity based on masked grading of photographs by an independent reading center. Other endpoints included dimensions of pterygia and safety. MethodsIn Stage 1, 24 eyes of 24 patients received one drop of CBT-001 in a dose escalation fashion (0.02%, 0.05%, and 0.2%) to determine the maximally tolerated dose based on adverse events and blood drug levels. In Stage 2, subjects were randomly assigned to receive the maximally tolerated dose of CBT-001 or vehicle dosed three times a day (TID) for 4 weeks with a 20-week follow up. ResultsIn Stage 1, the plasma maximum concentration (Cmax) values for all doses of CBT-001 were at or below the limit of detection (0.01 ng/mL). The most commonly reported adverse events were mild foreign body sensation and irritation. CBT-001 0.2% was evaluated in Stage 2. Baseline demographic characteristics were similar between patients receiving CBT-001 (n = 25) and vehicle (n = 23). After 4 weeks of dosing, mean change from baseline in pterygium vascularity scores was –0.8 ± 0.7 (mean ± standard deviation) in subjects receiving CBT-001 0.2% and 0.0 ± 0.5 in subjects receiving vehicle (P < 0.001; 95% confidence interval [CI]: -1.12, -0.40). Pterygium vascularity scores remained significantly decreased, after the 4-week dosing period, at weeks 8 and 16, but not at week 24. Mean changes from baseline in the length of the pterygia were also significantly lower in subjects receiving CBT-001 compared to vehicle at weeks 2, 4, and 8 (P≤0.014). The most commonly reported adverse events were ocular, mild in severity, resolved after therapy, and did not result in discontinuation. ConclusionsCBT-001 0.2% decreased pterygia vascularity and lesion length after 4 weeks of dosing with a prolonged effect after dosing. The drug was well tolerated with minimal detected systemic drug levels.