FormalPara Key Summary Points

Why carry out this study?

Human respiratory syncytial virus (HRSV) is the leading cause of lower respiratory tract infection, especially in children and older people. However, no effective treatment is currently available.

Type I interferons (IFNs) are a group of cytokines with antiviral effects. GB05, human IFNα1b inhalation solution, is a novel dosage form of IFNα1b developed for the treatment of HRSV; however, it has not been investigated clinically for the adequate dosage and safety characteristics in humans.

In this randomized, placebo-controlled, and dose-escalation phase I trial, we hypothesized that GB05 would be safe and tolerated within certain dose ranges.

What was learned from the study?

Nebulized GB05 exhibited favorable safety, tolerability, and pharmacokinetic profiles in healthy adult volunteers after a single dose or multiple doses ranging from 0.2 million IU to 1.8 million IU.

Low blood concentration of IFNα1b suggests a better lung uptake of GB05 and explains the low rate of adverse events.

Overall, the pharmacokinetic and safety results of GB05 support further clinical investigation in patients infected with RSV.

Introduction

Human respiratory syncytial virus (HRSV) is the leading cause of serious acute lower respiratory tract infection (LRTI), especially for young children and elderly people. There are 33 million occurrences of HRSV-related LRTI in children under the age of five worldwide each year. Of those cases, 3.6 million require hospitalization, and 26,300 in-hospital deaths have occurred [1]. In addition, no reduction in morbidity, hospitalization, and mortality has been observed over time [1]. The pathogenic mechanisms of HRSV infection are relatively complicated, involving comprehensive effects of causative factors, airway epithelial cell-related factors, immune system responses, nervous system responses, host factors, and environmental factors [2]. Despite the burden of HRSV-associated diseases, there is no effective treatment by far.

Current treatment against HRSV infection is mainly supportive and symptom-relieving. Supportive treatments include oral or intravenous hydration, maintaining airway patency and oxygen therapy [3]. As a result of a lack of efficacy evidence especially for infants, symptomatic clinical treatments such as bronchodilators and corticosteroids against airway obstruction are debatable, and should not be used routinely in children [3,4,5,6]. Ribavirin, a nucleoside analogue that inhibits the replication of DNA and RNA viruses, is an FDA (US Food and Drug Administration)-approved broad-spectrum antiviral drug for RSV infection. However, the high cost and potential adverse side effects limit ribavirin’s use especially in young children [7]. Moreover, FDA-approved RSV vaccines were both reported to notably increase the risk of developing Guillain-Barré syndrome [8, 9]. In general, we still lack adequate, safe, affordable, and effective therapeutics against RSV infection.

Interferons (IFNs) are a class of cytokines with broad-spectrum antiviral, anti-tumor, and immunomodulatory effects, consisting of type I, II and III subtypes with their respective receptors and functions. According to gene and protein structures, type I IFNs are also divided into IFNα, IFNβ, IFNε, IFNκ, and IFNω, among which IFNα plays an important role in the control of viral infections. IFNα1b deficiency will lead to declined antiviral capacity of the body. Studies showed a significant lower IFNα secretion in RSV-infected infants under 12 months compared with older children or healthy adults [10, 11], suggesting a demand for supplementing exogenous IFNα in the early stage of RSV infection, especially for infants, to boost the immune function and prevent the spread of viral infection. It also contributes to the prevention and treatment of RSV infection by inducing the production of endogenous interferon [12, 13].

Currently, there is no clinical study on nebulized IFNs inhalation solution globally. Though intramuscular IFNα injection has been marketed, the route of delivery limits its therapeutic applicability in young children and the elderly. Preclinical research demonstrated that nebulized inhaled IFNα1b had better efficacy and fewer side effects than traditional intramuscular injection of IFNα1b [14]. Nevertheless, there is thus far no commercially available IFN product formulated for nebulized inhalation, and there are strong unmet medical needs. As the lesion site of RSV-LRTI disease is located in the lower respiratory tract and lungs, medications in the form of small-sized aerosols not only can be effectively delivered but also enhance the efficacy, especially for children and the elderly [15]. Therefore, we developed GB05 to satisfy these clinical demands.

The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics (PK) of GB05 after a single dose or multiple doses in healthy volunteers. To our knowledge, it is the first reported clinical study on nebulized human IFNα1b inhalation solution, which acts as a foundation for the subsequent clinical developments of GB05.

Methods

Study Design and Selection Criteria

This is a randomized, double-blind, placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD) phase I study conducted in the Third Hospital of Changsha in China from January 7, 2023 to April 21, 2023. The Human Interferon Alfa-1b Inhalation Solution (GB05) was manufactured according to FDA guidelines and supplied by Kexing Biopharm Co., Ltd [16].

The study protocol and informed consent forms were approved by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) of the Third Hospital of Changsha (Approval number CS3-2022EC-065). This study was conducted in accordance with the Helsinki Declaration of 1964 and its later amendments. All participants provided written informed consent for this study.

As a first-in-human clinical trial, the dose range settings of GB05 were based on the no observed adverse effect levels (NOAELs) originating from the long-term GB05 toxicological studies conducted in cynomolgus macaques, in which the NOAEL was 14.602 μg kg−1 day−1 (126,100 IU kg−1 day−1). On the basis of preclinical dose studies, four groups were set up for the SAD study: the proposed initial single dose was 0.2 million IU, followed by 0.6, 1.2, and 1.8 million IU. For the MAD study, 1.2 million IU and 1.8 million IU groups were then given multiple consecutive doses after the single dose, i.e., 1.2 million IU bid (daily dose of 2.4 million IU), 1.8 million IU bid (daily dose of 3.6 million IU) (Fig. 1a).

Fig. 1
figure 1

Study designs. a The scheme of dose escalation design of SAD (blue box) and MAD (purple box). b Intervention schemes. SAD single ascending dose, MAD multiple ascending dose, D day

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Eligible volunteers were healthy Chinese adults aged 18–45 years with a normal body mass index (19.0–26.0 kg/m2). Key exclusions from the study included volunteers who have a history within 3 months of any surgery or planned surgery during the trial, respiratory system diseases, ocular diseases, thyroid-related diseases, drug allergies, cannot tolerate nebulized inhalation, and other criteria that would affect the absorption, distribution, metabolism, and excretion of drugs.

Randomization and Masking

The randomization of GB05 and placebo groups was performed by an independent statistician who was not involved in the trial. Random numbers were generated for volunteers with a randomization sequence generator called PROC PLAN of SAS 9.4 (SAS Institute Inc, Cary, NC). In this study, eligible volunteers were randomized respectively among the four dose groups, with a ratio of 4:1 between GB05 and placebo in all groups.

The investigational drug for each volunteer was packaged in sealed, identical boxes to conceal the intervention allocation. The independent statistician affixed the appropriate number to the package according to the drug coding table. The independent statistician will keep random number tables concealed until the end of the study.

Intervention

In this study, both GB05 and placebo solutions were provided by Kexing Biopharm Co., Ltd., produced following GMP standards. For the first and second groups, each volunteer was given the corresponding dose of nebulized GB05 or placebo solution in the morning of day 1, and only a single dose was administered during the trial. For the third and fourth groups, each volunteer was administered two doses with the corresponding dosage of GB05 or placebo solution at an 8-h interval each day from day 4 to day 7, and a final dose in the morning of day 8. In general, the MAD groups were administered for five consecutive days, with a total of nine doses during the trial (Fig. 1b).

Safety and Tolerability Assessments

Safety and tolerability of GB05 were assessed on the basis of adverse events (AEs)—significant clinical changes in the vital signs, physical examination, 12-lead electrocardiogram (ECG), clinical laboratory tests (routine blood test, blood chemistry, coagulation function, routine urine test, thyroid function, complement C3), and pulmonary function tests after administration. All AEs were assessed and classified during the trial according to Common Terminology Criteria for Adverse Events 5.0 (CTCAE 5.0). AEs were monitored throughout the study and were evaluated by the investigator for the association with GB05.

Dose escalation stopping criteria were set according to CTCAE 5.0. Dose escalation for the group would be stopped (a) if the same treatment-emergent adverse event (TEAE; AEs that happen within the administration period), greater or equal to level 2, happens among more than half of the volunteers, or (b) if any TEAE, greater or equal to level 3, happens among more than one-third of the volunteers in the same dosage group. If any serious adverse event (SAE; important medical events that occurred after treatment, such as death, life-threatening, permanent or serious disability or loss of function) related to treatment occurs in any volunteer, administration for the volunteer would be terminated.

The drug will be considered tolerated if none of the criteria were met during the study.

Pharmacokinetic Assessments

Serial blood samples for PK evaluation were collected from all volunteers at specified time points. For SAD groups, samples were taken 0.5 h pre-dose on day 1 and at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, and 48 h after administration. For MAD groups, we specified day 3 as time point 0, samples were taken 1 h pre-dose on day 6 (1 dose), day 7 (2 doses), and day 8 (1 dose), 1 h pre-first and second dose on, and then at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 48, 120, 144, and 168 h after day 8 administration. Blood samples for PK analysis were collected into labelled 4-mL serum separator tubes and allowed to clot. Samples were centrifuged and supernatants (serum) were stored at − 80 °C.

The bioanalytical analysis for PK samples was performed by United-Power Pharma Tech (Shanghai) Co., Ltd. Serum concentration of IFNα1b was determined using a validated enzyme activity method with a concentration range from 10 to 640 pg/mL, and PK parameters were calculated. Briefly, blank microplates were pre-coated with anti-interferon alpha 1 antibody (Abcam, ab20200). After blocking and washing were performed, diluted serum (1:4) and the positive (Kexing Biopharm), negative, and blank controls were added. After incubation and washing were performed, recombinant anti-interferon alpha 1 antibody (Abcam, ab242952) was added, followed with Peroxidase AffiniPure Donkey Anti-Rabbit IgG (H + L) (Jackson ImmmoResearch, EPR18694-27). TMB (3,3′,5,5′-tetramethylbenzidine) solution was added to each well and incubated for 15 min. The reaction was stopped by adding stop solution to each well and the optical density (OD) at 450 nm was determined with an ELISA plate reader. OD values of each concentration point were collected and processed with the SoftMax Pro 6.5.1 GxP software. The standard curve is generated by Watson LIMS software (Version 7.5) for each plate, using a 5-PL (Marquardt) model with 1/Y weighting factor.

Immunogenicity Assessment

Immunogenicity assessment of GB05 was conducted via anti-drug antibody (ADA) assay. ADA positive samples would then be analyzed for titer and neutralizing antibodies (NAb). The number and percentage of volunteers with positive immunogenicity (ADA and NAb) should be described if the data allowed. For volunteers with positive immunogenicity, the time of onset and duration should be further described.

Study Endpoints

The primary endpoint is safety and tolerability, assessed by AEs and incidence, TEAEs, adverse drug reactions (ADRs, any harmful or unexpected reaction that may be related to GB05 administration), SAEs, and TEAEs that lead to study discontinuation from the study.

The secondary endpoint is PK and immunogenicity. For plasma PK parameters of SAD administration: maximum concentration (Cmax), the time taken to reach the maximum concentration (Tmax), area under plasma concentration–time curve from time 0 to the minimum detectable concentration (AUC0–t), and, if data were available, area under the curve from time 0 to infinity ∞ (AUC0–∞), half-life (t1/2), elimination rate constant (Ke), apparent distribution volume (Vd), mean residence time (MRT), and clearance rate (CL), were calculated.

For plasma PK parameters of MAD administration: steady-state trough concentration (Css_min), steady-state maximum concentration (Css_max), average steady-state plasma concentration (Css_av), and, if data were available, fluctuation coefficient (DF) and fluctuation amplitude [(Cmax,ss − Cmin,ss)/Cmin,ss], were calculated.

For the first and second dose groups, immunogenicity was evaluated within 1 h before day 1 administration, then at day 9 ± 1 day, day 16 ± 1 day, and day 23 ± 2 days. For the third and fourth groups, immunogenicity was evaluated within 1 h before day 1 administration, then at day 18 ± 1 day, day 25 ± 2 days, and day 32 ± 2 days.

Statistical Analyses

The statistical methods of this study are descriptive statistics rather than hypothesis tests, and the sample size was chosen on the basis of common tolerability or PK study cohort. Safety set (SS) refers to all volunteers randomized and who received investigational drugs with records of safety assessments. Full analysis set (FAS) refers to all randomized volunteers who received the investigational drug. PK concentration set (PKCS) refers to all volunteers randomized and who received investigational drugs with at least one post-dose plasma drug concentration data collection during the trial. PK parameter set (PKPS) refers to all volunteers randomized and who received investigational drugs with at least one effective PK parameter during the trial.

PK analysis was performed on the basis of the non-chamber ventricular model with WinNonlin software (Certara USA Inc, version 8.2 or above), and other analyses were performed using SAS (version 9.4 or above) software. AEs during the study were coded according to the ICH Medical Dictionary for Regulatory Activities (MedDRA24.1 or above version). The data were expressed as mean ± standard deviation or as numbers with proportions. P values < 0.05 were regarded as statistically significant.

Results

Volunteers and Demographic Data

In this study, 41 adult volunteers were eligible including 6 alternatives, among 170 volunteers screened. Finally, 35 healthy adult volunteers were successfully enrolled, and 33 finished the trial; two from the fourth group withdrew after the second dose on day 6. Volunteers were distributed in the order they signed the informed consent form in each dose group (Fig. 2). Enrolled volunteers included 22 (62.9%) men and 13 (37.1%) women. The age of volunteers ranged from 20 to 42 years, and the corresponding body mass index ranged from 19.5 to 25.5 kg/m2. The demographic information of all the enrolled volunteers is shown in Table 1. In general, the demographic characteristics of the volunteers were well balanced between groups.

Fig. 2
figure 2

Volunteers disposition. The PK analysis (PKCS and PKPS) included 26 volunteers with effective plasma concentration, and the safety analysis (SS) included all 35 volunteers. PK pharmacokinetics, PKCS PK concentration set, PKPS PK parameter set, SS Safety Set. *Two volunteers dropped out on day 6 after the second dose

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Table 1 Demographic profile of enrolled volunteers
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All 35 volunteers enrolled in this study received investigational drugs during the trial. No serious protocol violations that affected PK or caused unmeasurable parameters were observed among volunteers. No volunteer had a pre-dose concentration higher than 5% of Cmax and no concomitant medication happened. Cmax was not observed at the first sampling time and there were no post-blood treatment or transportation errors before biological samples testing.

All 35 volunteers were included in FAS and SS, and 26 volunteers were included in PKCS and PKPS analyses, with 2 volunteers in the 0.2 million IU group not included because of lack of effective plasma concentration. For the safety analysis set, all 35 volunteers were included in the single-dose SS and 20 volunteers were included in the multiple-dose SS (Fig. 2).

Safety and Tolerability Analyses

The number and percentage of volunteers who experienced AEs are summarized according to the AEs classified by System Organ Class Preferred Term during treatment (Tables 2 and 3).

Table 2 Summary of adverse events at each dose level in the SAD study
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Table 3 Summary of adverse events at each dose level in the MAD study
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In the SAD study, seven AEs occurred in 6 of the 35 volunteers (6/17.1%). Increased blood thyroid-stimulating hormone happened once in the placebo group (1/12.5%). No AE occurred in the 0.2 million IU dose group. Dizziness happened once in the 0.6 million IU dose group (1/12.5%). AEs in the 1.2 million IU dose group included decreased white blood cell count (2/25%), increased prothrombin time (1/12.5%), and upper respiratory infection (1/12.5%). The AE in the 1.8 million IU dose group was decreased white blood cell count (1/12.5%). All AEs were at level 1/2 or mild and resolved spontaneously without treatment.

In the MAD study, 12 AEs occurred in 6 of the 20 volunteers (6/30%). In the 1.2 million IU dose group, AEs included decreased white blood cell count (2/25%), increased prothrombin time (1/12.5%), increased alanine aminotransferase (1/12.5%), increased aspartate amino transferase (1/12.5%), oropharyngeal pain (1/12.5%), throat irritation (1/12.5%), and nausea (1/12.5%), respectively. AEs in the 1.8 million IU dose group were increased blood thyroid-stimulating hormone (1/12.5%), increased free triiodothyronine (1/12.5%), upper respiratory infection (1/12.5%), and fever (1/12.5%). All AEs were at level 1/2 or mild and subsided without treatment. Besides, two volunteers stopped dosing because of upper respiratory tract infection and fever during the MAD study.

No SAE or death that led to withdrawal from the SAD or MAD study was observed. On the basis of the dose escalation stopping criteria described before, all doses of nebulized GB05, including the highest (1.8 million IU), were tolerated for the volunteers. No clinically meaningful changes were reported during the study. All AEs were reported to the IRB/IEC of the Third Hospital of Changsha and were followed up to recovery or improvement. In summary, within the dose range of 0.2–1.8 million IU, nebulized GB05 were safe and well tolerated for healthy adult volunteers.

Pharmacokinetic Properties

The PK parameters and plasma concentration–time profile of IFNα1b in the SAD study are shown in Table 4 and Fig. 3, respectively. Following nebulized inhalations of 0.2–1.8 million IU GB05 in healthy adult volunteers, the median Tmax of IFNα1b in serum was 3.50–7.00 h. The average clearance rate constant (λz) range was 0.0853–0.1394 L/h. The CL barely changed with the dose increase, with the mean value ranging from 98,247.6 to 143,303.3 ml/h. The volume of distribution (Vz/F) decreased slightly with the increase of dose, and the mean range was 103,7381–1,337,868 mL. The elimination half-life (t1/2) was 5.4062–8.8072 h, and the MRT range was 6.3780–8.8330 h. Cmax (11.300–172.375 pg/mL), AUC0–t (21.500–1897.950 h pg/mL), and AUC0–∞ (516.80–2273.32 h pg/mL) were all increased across the dose range. The proportion of increase was higher than that of dose increase, and the proportional dose response relationship analysis result did not support a definite linear relationship between Cmax, AUC0–t, AUC0–∞, and the dose of GB05.

Table 4 Descriptive statistics of PK parameters of IFNα1b in the SAD study
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Fig. 3
figure 3

Mean plasma concentrations versus time profiles following a single dose of GB05 in healthy volunteers on a linear scales and b semilogarithmic scales. Blood samples were taken 0.5 h pre-dose (− 0.5 h) on day 1 and at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, and 48 h after administration. PK of 48 h time point was too low to be detectable and was not shown on the graph. h hour

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The PK parameters and plasma concentration–time profiles in the MAD are shown in Table 5 and Fig. 4. After volunteers inhaled 1.2 million IU and 1.8 million IU GB05 twice daily, the average Css_min of IFNα1b was 84.000 pg/mL and 148.850 pg/mL, respectively. The mean values of Css_max were 323.38 pg/mL and 669.33 pg/mL, the mean values of Css_av were 208.08 pg/mL and 392.95 pg/mL, and the mean values of DF were 115.329% and 134.222%, respectively. The range [(Cmax,ss − Cmin,ss)/Cmin,ss] values were 3.2015 and 4.2283, respectively. The results of the MAD steady-state analysis indicated that the 1.8 million IU dose group could reach steady-state after continuous administration twice daily for 3 days (6 times), at an interval of 8 h every day.

Table 5 Descriptive statistics of PK parameters of IFNα1b in the MAD study
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Fig. 4
figure 4

Mean plasma concentrations versus time profiles following multiple doses (9 doses) of GB05 in healthy volunteers on a linear scales and b semilogarithmic scales. Day 3 was specified as time point 0 for MAD study. After 3 days of washout period, blood samples were taken 1 h pre-dose on day 6 (78 h on x-axis), 1 h pre-first and second dose on day 7 (96 h and 104 h on x-axis), 1 h pre-dose on day 8 (119 h on x-axis), and then at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, and 48 h after day 8 administration. h hour

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Immunogenicity

None of the volunteers had a positive ADA test result. Therefore, the NAb analysis was not applicable.

Discussion

This first-in-human randomized, double-blind, placebo-controlled, dose-escalation phase I clinical trial conducted in healthy adult volunteers demonstrated that nebulized GB05 developed by Kexing BioPharm Co., Ltd. is safe and well tolerated after SAD or MAD administrations.

In respect to the safety assessment, hardly any AE or SAE event was observed in the 0.2 million IU group, and AEs were observed mainly in higher dose groups. All AEs were mild with no unexpected safety issues observed. The most frequent AEs in this study include decreased white blood cell count, fever, nausea, upper respiratory infection, increased blood thyroid-stimulating hormone, oropharyngeal pain, and throat irritation, which are common AEs according to previously reported clinical data in healthy volunteers or patients treated with IFNα injections [15,16,17]. All AEs were supposed to be related to GB05 before unblinding. For instance, decrease in white blood cell count was linked to the important immunoregulatory function of IFNα1b on margination of leukocytes into splenic white pulp [18]. After unblinding, one volunteer in the placebo group was observed with increased blood thyroid-stimulating hormone, which might be related to personal living habit fluctuation. This indicates that not all AEs were related to GB05 administration. Two volunteers in the highest dose group discontinued the study on day 5 and day 6 after drug administration as a result of AEs, and both recovered later without treatment, suggesting 1.8 million IU is approaching the maximal tolerated dose (MTD). In all the dose groups, the AEs that occurred had not reached the termination criteria (below dose limiting toxicity), thus all the doses are considered tolerated.

According to published data, particle size plays an important role in lung deposition, along with particle velocity and settling time [19]. Larger particles between 10 and 15 µm deposit mostly in the upper airways, those in the 5–10 µm range reach the large bronchi, and those in the 1–5 µm range penetrate to the lower airways and lung periphery [19]. As the lesion site of LRTI is located in the lower respiratory tract and lungs, nebulized GB05 could be delivered to the lesion site with high local concentration and less systemic exposure. This may contribute to reducing the systemic exposure and AE risks of affecting other tissues and organs, improving medication safety in young children with LRTI.

Nebulized GB05 has an average particle size of 3 μm in diameter, suitable for long-term deposition in the lungs for its therapeutic roles. This was evidenced by the plasma PK results from this study. After a single administration in healthy adult volunteers, the maximum blood concentration of nebulized GB05 was 1.06 IU/ml in the 1.8 million SAD group. This concentration is much lower (about 13%) than that of administration via intravenous or intramuscular injections according to published data, where the blood concentration of IFNα was 42–45.8 IU/ml when 10 million IFNα was injected [20], indicating that GB05 may be mainly accumulated in the lungs rather than in the blood. This was supported by the excellent safety and tolerability profile of GB05 in this study.

As a major antiviral subtype among IFN families, IFNα1b has attracted the attention of researchers for use against HRSV-related LRTI in children [21]. Administration of IFNα1b that forms aerosols through nebulization has the advantages of rapid onset, fewer adverse reactions, and high compliance especially for children [15]. Drugs in the form of nebulized aerosols can be locally directed to alveoli, narrow airways, and other lesions with high efficiency and reduced side effects [22]. Therefore, nebulized inhalation of IFNα1b against HRSV-related LRTI in children has been recommended by the National Formulary and the Standardized Management Guidelines for Children’s Nebulization Center [23, 24].

Manufactured according to FDA guidelines for inhalation solution [16], GB05 paved the way for nebulized IFNs inhalation solution with optimized particle size and distribution for better safety and efficacy against RSV infection, especially in children. Though IFNα1b has been applied to treat various viral infections in the form of injections, no systematic clinical study has been conducted to investigate its safety and efficacy in the form of nebulized, inhaled solution [15, 17, 21, 25]. Meanwhile, GB05 was formulated without antioxidants and preservatives that IFNα1b injections may contain, reducing the potential risks of causing AEs such as respiratory muscle paralysis, allergy, and myasthenia [26, 27]. The advantages of GB05 will be further investigated in the following clinical studies.

In summary, we have demonstrated that GB05 is safe and well tolerated with favorable PK properties in healthy adults. Limitation exists in this study where the lung PK was not explored simultaneously with plasma PK to validate the lung deposition of GB05, which was addressed in the subsequent clinical trial. We knew that inclusion in the study of healthy children and older volunteers would be beneficial for the future evaluation of GB05. However, volunteers under 18 are a vulnerable population who cannot consent for themselves. According to FDA guidelines, subjects recruited should be 18 years of age or older [28]. Besides, National Medical Products Administration (NMPA; the Chinese agency for regulating drugs and medical devices) regulations require that the subjects for phase I study should mostly be healthy adults rather than children, the elderly, or other vulnerable groups [29]. Thus, children and the elderly were excluded from this study. By making full use of adult research data, we could extrapolate from adults to target pediatric or elderly populations according to the homogeneity of data characteristics. The results from this study also contributed to offering dose guidance for the phase II study, to further investigate the efficacy and safety of GB05 in children with moderate to severe RSV-related LRTI.

Conclusions

This trial confirms that nebulized GB05 is safe and well tolerated, with favorable PK profiles in healthy adult volunteers. The blood concentration was low after GB05 nebulization, suggesting a better lung uptake of GB05 while reducing the AE risk of affecting other organs. In conclusion, the safety data and PK profile from this study supports the subsequent clinical development in patients with HRSV-related LRTI.