Functional cure induced by tenofovir alafenamide plus peginterferon-alpha-2b in young children with chronic hepatitis B: a case series study.

BACKGROUND AND AIMS: Data on the safety and effectiveness of tenofovir alafenamide (TAF) plus peginterferon-alpha (Peg-IFN-α) in children with chronic hepatitis B (CHB) are lacking. The current study aimed to present the characteristics of four pediatric CHB patients who obtained a functional cure by using TAF and Peg-IFN-α. METHODS: In this case series study initiated in May 2019, ten children who had no clinical symptoms or signs received response-guided (HBV DNA undetectable, hepatitis B e antigen [HBeAg] loss or seroconversion, and hepatitis B surface antigen [HBsAg] loss or seroconversion) and functional cure-targeted (HBsAg loss or seroconversion) TAF (25 mg/d, orally) plus Peg-IFN-α-2b (180 µg/1.73m2, subcutaneously, once weekly) in combination (9/10) or sequential (1/10) therapy. The safety and effectiveness of these treatments were monitored. RESULTS: As of April 2024, four out of ten children obtained a functional cure after a mean of 31.5 months of treatment, and the other six children are still undergoing treatment. These four cured children, aged 2, 4, 8, and 6 years, were all HBeAg-positive and had alanine aminotransferase levels of 80, 47, 114, and 40 U/L; HBV DNA levels of 71200000, 93000000, 8220, and 96700000 IU/mL; and HBsAg levels of 39442.8, 15431.2, 22, and 33013.1 IU/mL, respectively. During treatment, all the children (10/10) experienced mild or moderate adverse events, including flu-like symptoms, anorexia, fatigue, and cytopenia. Notably, growth retardation (8/10) was the most significant adverse event; and it occurred in three cured children (3/4) treated with combination therapy and was present to a low degree in the other cured child (1/4) treated with sequential therapy. Fortunately, all three cured children recovered to or exceeded the normal growth levels at 9 months posttreatment. CONCLUSIONS: TAF plus Peg-IFN-α-2b therapy is potentially safe and effective for pediatric CHB patients, which may provide important insights for future clinical practice and study designs targeting functional cures for children with CHB.

Efficacy and safety outcomes in Japanese patients with low-risk polycythemia vera treated with ropeginterferon alfa-2b.

Polycythemia vera (PV) is a Philadelphia chromosome-negative myeloproliferative neoplasm characterized by clonal erythrocytosis. A phase 2 study reported that ropeginterferon alfa-2b is a well-tolerated and effective treatment for PV in Japanese patients. This post hoc analysis of the phase 2 data further evaluated outcomes in patients at low risk of thrombosis (low-risk PV). Among 20 patients with low-risk PV, 60.0% (12/20) and 85.0% (17/20) achieved < 45% hematocrit by weeks 24 and 52, respectively. The proportion of responders with complete hematologic response (CHR) was 60.0% (12/20) at week 52, and the median time to response was 11.9 months. The mean JAK2 V617F allele burden decreased from 75.8% at baseline to 53.7% at week 52. No patient experienced thrombosis or bleeding episodes. All patients experienced treatment-emergent adverse events (TEAEs) related to ropeginterferon alfa-2b, but no grade ≥ 3 TEAEs or deaths related to ropeginterferon alfa-2b occurred, and no new safety concerns arose. This analysis indicated that ropeginterferon alfa-2b may be an effective treatment option for Japanese patients with low-risk PV.

The Topical Novel Formulations of Interferon α-2в Effectively Inhibit HSV-1 Keratitis in the Rabbit Eye Model and HSV-2 Genital Herpes in Mice.

Herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) are widespread human pathogens that establish chronic latent infections leading to recurrent episodes. Current treatments are limited, necessitating the development of novel antiviral strategies. This study aimed to assess the antiviral efficacy of novel topical formulations containing interferon alpha-2b (IFN α-2b) against HSV-1 and HSV-2. The formulations, Oftalmoferon® forte (eye drops) and Interferon Vaginal Tablets, demonstrated potent antiviral effects against HSV-1 and HSV-2 in Vero cells, respectively, with concentration-dependent inhibition of viral replication. Subsequently, their efficacy was tested in animal models: HSV-1 keratitis in the rabbit eye model and HSV-2 genital herpes in mice. Oftalmoferon® forte effectively treated HSV-1 keratitis, reducing clinical symptoms and ulcerations compared to virus control. Interferon Vaginal Tablets showed promising results in controlling HSV-2 genital herpes in mice, improving survival rates, reducing clinical signs, weight loss and viral replication. The novel IFN α-2b formulations exhibited significant antiviral activity against HSV infections in cell culture and animal models. These findings suggest the potential of these formulations as alternative treatments for HSV infections, particularly in cases resistant to current therapies. Further studies are warranted to optimize treatment regimens and assess clinical efficacy in humans.

Effectiveness and safety of interferon α-2a combined with phototherapy for patients with early-stage mycosis fungoides - a single-arm prospective study in 13 patients.

Background: Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma.Objectives: This study was conducted to evaluate efficacy and safety of interferon (IFN) α-2a combined with phototherapy for early-stage MF.Methods: Thirteen patients with early-stage MF received subcutaneous injections of IFN α-2a at 3 million IU combined with phototherapy three times per week for 6 months. Treatment efficacy was measured by changes in body surface area (BSA) score and modified severity-weighted assessment tool (mSWAT) score at 1, 3, and 6 months after treatment. Histopathologic examinations of skin lesions were performed before and after treatment.Results: After 3 months of treatment, all 13 patients achieved a partial response, and BSA and mSWAT scores were significantly lower than those at baseline (p < 0.001). After 6 months, BSA and mSWAT scores were significantly lower than those at baseline (p < 0.001) and after 3 months (p < 0.05). Eleven patients achieved complete remission and two patients achieved a partial response (overall response rate, 100%). Histopathologic examination showed a significant decrease in the number of atypical lymphocytes in both epidermis and dermis. No severe adverse effects occurred.Conclusion: IFN α-2a in combination with phototherapy may be an effective and safe alternative modality for early-stage MF.

Unusual presentation of ocular surface squamous neoplasia in a young healthy patient: A case report.

PURPOSE: To report an unusual case of ocular surface squamous neoplasia (OSSN) associated with human papilloma virus (HPV)-16 infection with an atypical morphology in a young otherwise healthy patient. CASE DESCRIPTION: A 17 year-old healthy male was referred to our department for evaluation of a corneal infiltrate with anterior stromal neovascularization in the right eye. One year before, the patient underwent an excision of a corneo-conjunctival lesion that was located inferiorly in the same eye. Histopathological analysis had shown moderate and severe dysplasia of the conjunctival epithelium and resulted positive for HPV-16. We performed a diagnostic incisional biopsy of the limbal conjunctiva and of the corneal epithelium for histological examination and molecular testing for HPV and Chlamydia by using polymerase chain reaction (PCR). Histopathologic evaluation demonstrated low-grade dysplasia of conjunctiva. PCR testing of the corneal epithelium was positive for HPV-16, similarly to the first biopsy performed by another centre. The patient was successfully treated with topical interferon alfa-2b (1,000,000 IU/ml) for a total of six months. After the treatment, the corneal infiltrate improved dramatically with regression of neovascularization and improvement of corneal transparency and vision. DISCUSSION: The present report described an atypical presentation of HPV-related OSSN due to its unusual morphology, young age of onset and absence of associated comorbidity. CONCLUSION: Conservative treatment with topical interferon-alpha 2b could be used to treat successfully HPV-16 positive OSSN, with no corneal irregularity or potential loss of vision compared to surgical excision.

Pharmacodynamic of Recombinant Human Interferon Alpha-2b Nasal Drops and Effective Prophylaxis Against SARS-COV-2 Infection.

The recombinant human interferon alpha-2b (IFN-α2b) nasal drop formulation (Nasalferon) was studied as prophylaxis for SARS-CoV-2. Healthy volunteers between 19 and 80 years of age received 0.5 million international units of IFN in one drop (0.05 mL ) in each nostril, twice a day, for 10 consecutive days. The nondetection of SARS-CoV-2 by real-time polymerase chain reaction was the primary outcome variable. Several IFN-α biomarkers, including intranasal gene expression and innate immune effector activity, were increased in participants who received intranasal IFN-α2b. The study included 2,930 international travelers and 5,728 persons who were their close contacts. The subjects were treated with Nasalferon in January 2021, and 9,162 untreated travelers were included as controls. COVID-19 rate in treated subjects was significantly lower than in untreated subjects (0.05% vs. 4.84%). The proportion of travelers with COVID-19 decreased from 60.9% to 2.2% between December 2020 and February 2021. Furthermore, 1,719 tourism workers also received Nasalferon, and no cases of SARS-CoV-2 infection were detected, whereas 39 COVID-19 cases (10.6%) were reported in 367 untreated subjects. The main adverse events associated with the use of intranasal IFN-α2b were nasal congestion, headache, and rhinorrhea. Our prophylactic health interventions study demonstrates that the daily administration of Nasalferon for 10 days decreases the risk of developing COVID-19 in healthy volunteers. [Figure: see text].

Reserve drug as first-line management: Topical interferon α-2b for vernal keratoconjunctivitis.

PURPOSE: To elucidate the efficacy and safety profile of interferon α-2b in vernal keratoconjunctivitis (VKC). METHODS: In this prospective interventional study, VKC patients fulfilling the inclusion and exclusion criteria were included and their signs and symptoms were scored based on the Clinical Scoring System. Patients were treated with topical interferon α-2b eye drop (1 MIU/ml) QID dosing for 6 weeks. Changes in symptoms and signs were evaluated at 2, 4, 8 weeks and 6 months after initiating treatment. A higher score meant severe disease, and a decline in score meant improvement in clinical signs and symptoms. Categorical variables were presented in number and percentage (%) and continuous variables as mean ± standard deviation (SD). Post-medication total subjective symptom score (TSSS) and total objective sign score (TOSS) were compared with baseline, and a P- value of <0.05 was considered significant. Possible ocular and systemic complications were evaluated. RESULTS: The study included 40 patients (32 male and eight female) with a mean age of 8.05 ± 2.33 years. Mean baseline TSSS and TOSS were 6.71 ± 0.564 and 6.59 ± 0.262, respectively, which reduced to 2.71 ± 0.011 ( P = 0.040) and 2.96 ± 0.210 ( P = 0.032), respectively, at 4 weeks and further reduced to 0.42 ± 0.552 and 0.47 ± 0.434, respectively, at 8 weeks. After 6 months of stopping the drug, mean TSSS and TOSS did increase to 2.80 ± 0.820 ( P = 0.044) and 2.50 ± 0.520 ( P = 0.030), respectively, but was still statistically significant improvement compared to the baseline. Also, no ocular or systemic side effects were observed anytime during the study period. CONCLUSION: Eye drop interferon α-2b (1 million IU/ml) is a safe and effective option as first-line monotherapy for VKC. No side effects and recurrence were observed for 6 months.

Exposure-efficacy and exposure-safety analyses of ropeginterferon alfa-2b treatment in patients with polycythaemia vera.

AIMS: To investigate the exposure-response (E-R) relationship, including exposure-efficacy and exposure-safety, of ropeginterferon alfa-2b treatment in patients with polycythaemia vera (PV). METHODS: Based on the results of the phase II trial A20-202 regarding ropeginterferon alfa-2b in patients with PV, E-R analyses were performed to evaluate the efficacy and safety of the given dosing regimen. The E-R analyses were based on logistic and linear regression and the relationship between exposure to ropeginterferon alfa-2b and key efficacy and safety variables. The key efficacy variables included complete haematologic response (CHR) and reduction of the driver mutation JAK2V617F. The safety variable was treatment-related adverse events (TRAEs). RESULTS: A clear relationship between the exposure to ropeginterferon alfa-2b and CHR was observed, with an increase in drug exposure resulting in an increased probability of achieving CHR. Similar CHR probabilities were observed in the third and fourth quantiles of the average concentration at Week 24. The results from the exposure-JAK2V617F model indicated that the JAK2V617F allele burden decreased with increasing exposure to ropeginterferon alfa-2b and baseline body surface area. Exposure-safety analysis revealed a risk of AEs associated with transaminase abnormalities, which were not associated with clinical significance. CONCLUSIONS: Our analyses have shown that patients with PV treated with ropeginterferon alfa-2b had an increased probability of achieving CHR and a molecular response with acceptable safety risks at the 250-350-500 µg titration dosing regimen. This study has provided the relevant data for the application of a biologics licence of ropeginterferon alfa-2b for PV treatment in China.

Long-term follow-up of patients with high-risk facial basal cell carcinoma treated with interferon.

BACKGROUND: Surgery is the treatment of choice for patients with basal cell carcinoma (BCC). When surgery is not a choice, only radiotherapy is recommended for patients with high-risk facial BCC. Interferon could be an acceptable therapeutic option for these patients. OBJECTIVE: To evaluate the long-term clinical response to interferon therapy in patients with high-risk facial BCC. METHODS: Patients with high-risk facial BCC were treated with perilesional injections of alpha-2b+ gamma interferons. Those with incomplete clinical response were reevaluated, their residual tumors excised, and declared cured. Patients treated with interferon and those treated with interferon plus surgery were followed for five years. Time to recurrence and the emergence of a new facial BCC were estimated by Kaplan-Meier survival analysis. Adverse events were documented. RESULTS: This study included 195 participants; 143 (73.3%) showed a complete response (95% CI 67.2‒80.1). Patients developed recurrence after a mean of 55 months (95% CI 53.8‒57.4). The estimated rate of recurrence was 12.3% (95% CI 7.4‒17.1). Patients developed a new BCC after a mean of 52.7 months (95% CI 50.4‒54.9). The estimated rate for development of a new BCC was 20.0% (95% CI 14.4‒25.9). Fifteen (7.7%) patients abandoned the study during follow-up. Adverse events were frequent but moderate or mild; fever and local pain were the most frequent. STUDY LIMITATIONS: Observational cohort design without a control group for comparison. CONCLUSIONS: Perilesional injections of alpha-2b+ gamma interferons in patients with facial high-risk BCC offer a satisfactory cure rate after five years of follow-up with an acceptable safety profile.

Preemptive Interferon-α Therapy Could Protect Against Relapse and Improve Survival of Acute Myeloid Leukemia Patients After Allogeneic Hematopoietic Stem Cell Transplantation: Long-Term Results of Two Registry Studies.

For allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients, preemptive interferon-α (IFN-α) therapy is considered as a useful method to eliminate the minimal residual disease (MRD). Our purpose is to assess the long-term efficacy of preemptive IFN-α therapy in acute myeloid leukemia (AML) patients following allo-HSCT based on two registry studies (#NCT02185261 and #NCT02027064). We would present the final data and unpublished results of long-term clinical outcomes with extended follow-up. We adopted polymerase chain reaction (PCR) and multiparameter flow cytometry (MFC) to monitor MRD, and a positive result of bone marrow specimen examined by either of them would be identified as the MRD-positive status. Subcutaneous injections of recombinant human IFN-α-2b were performed for 6 cycles, and prolonged IFN-α therapy could be permitted at the request of patients. The median cycles were 3.5 (range, 0.5-30.5) cycles. A total of 9 patients suffered from grade ≥3 toxicities (i.e., infectious: n = 6; hematologic: n = 3). The 6-year cumulative incidences of relapse and non-relapse mortality following IFN-α therapy were 13.0% (95% confidence interval [CI], 5.4-20.6%) and 3.9% (95%CI, 0.0-17.6%), respectively. The probability of disease-free survival at 6 years following IFN-α therapy was 83.1% (95%CI, 75.2-91.9%). The probability of overall survival at 6 years following IFN-α therapy was 88.3% (95%CI, 81.4-95.8%). The cumulative incidences of total chronic graft-versus-host disease (cGVHD) and severe cGVHD at 6 years following IFN-α therapy were 66.2% (95%CI, 55.5-77.0%) and 10.4% (95%CI, 3.6-17.2%), respectively. Multivariable analysis showed that an alternative donor was associated with a lower risk of relapse and the better disease-free survival. Thus, preemptive IFN-α therapy could clear MRD persistently, prevent relapse truly, and improve long-term survival in AML patients following allo-HSCT.

Intravesical sequential gemcitabine and docetaxel versus bacillus calmette-guerin (BCG) plus interferon in patients with recurrent non-muscle invasive bladder cancer following a single induction course of BCG.

INTRODUCTION: Repeat BCG induction remains an option for select non-muscle invasive bladder cancer (NMIBC) patients who fail initial therapy. Alternative salvage intravesical regimens such as Gemcitabine and Docetaxel (Gem/Doce) have been investigated. We aimed to compare the efficacy BCG plus interferon a-2b (BCG/IFN) and Gem/Doce in patients with recurrent NMIBC after a single prior BCG course. METHODS: The National Phase II BCG/IFN trial database and multi-institutional Gem/Doce database were queried for patients with recurrent NMIBC after one prior BCG induction course, excluding those with BCG unresponsive disease. Stabilized inverse probability treatment weighted survival curves were estimated using the Kaplan-Meier method and compared. Propensity scores were derived from a logistic regression model. The primary outcome was recurrence free survival (RFS); secondary outcomes were high-grade (HG) RFS and risk factors for treatment failure. RESULTS: We identified 197 BCG/IFN and 93 Gem/Doce patients who met study criteria. Patients receiving Gem/Doce were older and more likely to have HG disease, CIS, and persistent disease following induction BCG (all P < 0.01). After propensity score-based weighting, the adjusted 1- and 2-year RFS was 61% and 53% after BCG/IFN versus 68% and 46% after Gem/Doce (P = 0.95). Adjusted 1- and 2-year HG-RFS was 60% and 51% after BCG/IFN versus 63% and 42% after Gem/Doce (P = 0.68). Multivariable Cox regression revealed that Gem/Doce treatment was not associated with an increased risk of failure (HR = 0.97, P = 0.89) as compared to BCG/IFN. CONCLUSION: Patients with recurrent NMIBC after a single induction BCG failure and not deemed BCG unresponsive had similar oncologic outcomes with Gem/Doce and BCG/IFN in a post-hoc analysis. Additional prospective studies are needed.

Interferon-α2b induced anemia in severe coronavirus disease 2019 patients: a single centered, retrospective study.

BACKGROUND: The current outbreak of coronavirus disease 2019 (COVID-19) has rapidly spread throughout the world. During treatment, we found that the majority of patients had a decrease in hemoglobin (Hb). Interferon-α2b (IFN-α2b) was the primary suspected drug that was related to Hb reduction. Thus, the study aimed to investigate whether IFN-α2b could induce Hb reduction in severe patients with COVID-19 and its potential mechanism. MATERIAL AND METHODS: A total of 50 patients who were admitted to the First Affiliated Hospital of Harbin Medical University with severe COVID-19 infection were enrolled from February 12th to 24th, 2020. The demographics, baseline characteristics, clinical data, and therapeutic regimen were collected retrospectively. The patients were divided into two groups according to the declined use of IFN-α2b on day 14. The Hb levels on admission, day 7, day14, and day 21 were collected and analyzed. The primary endpoint was the level of Hb on day 21. RESULTS: A total of 31 patients in the IFN-stop group and 19 patients in the non-IFN-stop group were reviewed. The age, gender, comorbidities, clinical symptoms, nutritional status, disease severity, complications, and other factors of the patients were compared, no difference was found between the IFN-stop group and the non-IFN-stop group. The Hb levels of all patients significantly decreased on day 7 compared with that on admission (p < .0001). In the IFN-stop group, the Hb level was increased in 7 days after IFN-α2b was stopped (p = .0008), whereas no difference was found between day 14 and day 21 in the non-IFN-stop group (p = .3152). CONCLUSIONS: IFN-α2b was associated with Hb reduction in the treatment of severe patients of COVID-19. Clinicians should be aware of the high incidence of Hb reduction for patients treated by IFN-α2b.

Data-driven analysis of the kinetics of the JAK2V617F allele burden and blood cell counts during hydroxyurea treatment of patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis.

BACKGROUND: Hydroxyurea (HU) treatment of patients with essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) (MPNs) normalizes elevated blood cell counts within weeks in the large majority of patients. Studies on the impact of HU upon the kinetics of the JAK2V617F allele burden, leukocyte, and platelet counts over time are scarce. PURPOSE: Using data-driven analysis as a novel tool to model the kinetics of the JAK2V617F allele burden and blood cell counts over time during treatment with HU. MATERIAL AND METHODS: Using serial measurements of JAK2V617F and correlation analysis of routine hematological values (the Hb-concentration, leukocyte count, platelet count, and lactic dehydrogenase), we present a detailed description and analysis of the kinetics of the JAK2V617F, leukocyte, and platelet counts and lactic dehydrogenase in 27 patients (PV = 18; ET = 7; PMF = 2), who were followed in the Danish randomized trial (DALIAH). To further analyze the JAK2V617F kinetics, we use a machine learning clustering algorithm to group the response patterns. RESULTS: Response patterns were highly heterogeneous, with clustering resulting in 3 groups and 3 outliers. In the large majority of patients, HU treatment was initially associated with a modest decline in the JAK2V617F allele burden in concert with a decline in leukocyte and platelet counts. However, HU did not induce a sustained and continuous decrease in the JAK2V617F allele burden. CONCLUSION: Using data-driven analysis of the JAK2V617F allele burden, leukocyte, and platelet kinetics during treatment with HU, we have shown that HU does not induce a sustained decrease in the JAK2V617F allele burden and neither induces sustained normalization of elevated cell counts in MPN patients. Our results may explain why MPN patients during treatment with HU still have a substantially increased risk of thrombosis.

Therapeutic approaches for SARS-CoV-2 infection.

Therapeutic approaches to COVID-19 treatment require appropriate inhibitors to target crucial proteins of SARS-CoV-2 replication machinery. It's been approximately 12 months since the pandemic started, yet no known specific drugs are available. However, research progresses with time in terms of high throughput virtual screening (HTVS) and rational design of repurposed, novel synthetic and natural products discovery by understanding the viral life cycle, immuno-pathological and clinical outcomes in patients based on host's nutritional, metabolic, and lifestyle status. Further, complementary and alternative medicine (CAM) approaches have also improved resiliency and immune responses. In this article, we summarize all the therapeutic antiviral strategies for COVID-19 drug discovery including computer aided virtual screening, repurposed drugs, immunomodulators, vaccines, plasma therapy, various adjunct therapies, and phage technology to unravel insightful mechanistic pathways of targeting SARS-CoV-2 and host's intrinsic, innate immunity at multiple checkpoints that aid in the containment of the disease.

Efficacy and safety of interferon α-2b spray for herpangina in children: A randomized, controlled trial.

OBJECTIVES: The treatment of acute herpangina is inconsistent. We aim to evaluate the effectiveness and safety of interferon α-2b spray versus Ribavirin for this disease. METHODS: A randomized, controlled trial was conducted in eight hospitals in China between 2016 and 2018. 668 patients (1-7 years old) were randomized into an experimental group (treated with Interferon α-2b spray) or control group (received Ribavirin Aerosol). Body temperature returning to normal within 72 h and remaining so for 24 h was the primary outcome; release of oral herpes and adverse events were the secondary outcomes. RESULTS: (1) The average age of onset was 2.5 years old. (2) After 72 h treatment, body temperature of 98.5% patients in experimental group and 94.3% in control group returned to normal and remained so for 24 h (P = 0.004). The differences were greater at 48 h treatment (95.2% vs. 85.9%, P < 0.001) and at 24 h (77.5% vs. 66.5%, P = 0.001). (3) The rate of improved oral herpes in the experimental group was higher than that in control group (46.7% vs.37.1%, P = 0.011). No adverse reaction occurred. CONCLUSIONS: Local application of recombinant interferon α-2b spray showed better efficacy for acute herpangina in children. It was safe for use.

Pharmacokinetics and Pharmacodynamics of Ropeginterferon Alfa-2b in Healthy Japanese and Caucasian Subjects After Single Subcutaneous Administration.

BACKGROUND AND OBJECTIVES: Ropeginterferon alfa-2b is a novel monopegylated recombinant interferon alfa-2b for the treatment of patients with polycythemia vera. The objectives of this study were to evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of ropeginterferon alfa-2b in healthy Japanese subjects compared with Caucasian subjects. METHODS: In this multicenter, parallel-group phase I study, a cohort consisting of six Japanese and six Caucasian subjects was designated to receive a single subcutaneous dose of ropeginterferon alfa-2b (100, 200, 300, and 450 µg). Pharmacokinetic and pharmacodynamic parameters, and immunogenicity were evaluated. Safety was assessed throughout the study. RESULTS: Cohort 4 (450-µg dose) was not initiated because the primary objective of this study was achieved based on the three completed cohorts. A total of 36 enrolled subjects (18 Japanese and 18 Caucasian) in three cohorts were included in the safety, pharmacokinetic, and pharmacodynamic analysis sets. Ropeginterferon alfa-2b exposure in terms of the area under the serum concentration-time curve (AUC) from time zero extrapolated to infinity and the AUC from time zero to the time of the last quantifiable concentration was approximately 1.7-fold and two-fold higher in Japanese subjects than in Caucasian subjects, respectively. Across the same dose range, the maximum serum concentration was approximately 1.25-fold higher in Japanese subjects than in Caucasian subjects. The time to reach the median maximum serum concentration was similar between ethnicities (approximately 96-111 h). The terminal half-life was 48-57 h in Japanese subjects and 31-75 h in Caucasian subjects. The slope of the relationship between dose and drug exposure was greater than 1 in both ethnicities. The dose-dependent induction of beta-2 microglobulin and neopterin expression was observed in both ethnicities, and the two groups showed similar pharmacodynamic parameters. At the end of the study, 22.2% of Japanese subjects and 11.1% of Caucasian subjects developed anti-ropeginterferon alfa-2b-binding antibodies. The neutralizing capacity of these antibodies was not tested. Ropeginterferon alfa-2b up to 300 µg was safe and well tolerated, with no unexpected safety findings based on previous experiences with ropeginterferon alfa-2b and other forms of interferon. CONCLUSIONS: Ropeginterferon alfa-2b exposure was higher in Japanese subjects than in Caucasian subjects. The increase in ropeginterferon alfa-2b exposure was greater than the dose proportion in the dose range of 100-300 µg. Ropeginterferon alfa-2b was safe and well tolerated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03546465, registered on 6 June, 2018.

Neoadjuvant Pembrolizumab and High-Dose IFNα-2b in Resectable Regionally Advanced Melanoma.

PURPOSE: Neoadjuvant immunotherapy may improve the clinical outcome of regionally advanced operable melanoma and allows for rapid clinical and pathologic assessment of response. We examined neoadjuvant pembrolizumab and high-dose IFNα-2b (HDI) therapy in patients with resectable advanced melanoma. PATIENTS AND METHODS: Patients with resectable stage III/IV melanoma were treated with concurrent pembrolizumab 200 mg i.v. every 3 weeks and HDI 20 MU/m2/day i.v., 5 days per week for 4 weeks, then 10 MU/m2/day subcutaneously 3 days per week for 2 weeks. Definitive surgery followed, as did adjuvant combination immunotherapy, completing a year of treatment. Primary endpoint was safety of the combination. Secondary endpoints included overall response rate (ORR), pathologic complete response (pCR), recurrence-free survival (RFS), and overall survival (OS). Blood samples for correlative studies were collected throughout. Tumor tissue was assessed by IHC and flow cytometry at baseline and at surgery. RESULTS: A total of 31 patients were enrolled, and 30 were evaluable. At data cutoff (October 2, 2019), median follow-up for OS was 37.87 months (range, 33.2-43.47). Median OS and RFS were not reached. Radiographic ORR was 73.3% [95% confidence interval (CI): 55.5-85.8], with a 43% (95% CI: 27.3-60.1) pCR rate. None of the patients with a pCR have had a recurrence. HDI and pembrolizumab were discontinued in 73% and 43% of patients, respectively. Correlative analyses suggested that intratumoral PD-1/PD-L1 interaction and HLA-DR expression are associated with pCR (P = 0.002 and P = 0.008, respectively). CONCLUSIONS: Neoadjuvant concurrent HDI and pembrolizumab demonstrated promising clinical activity despite high rates of treatment discontinuation. pCR is a prognostic indicator.See related commentary by Menzies et al., p. 4133.