Nanoencapsulated Sirolimus Plus Pegadricase (NASP) in Uncontrolled Gout: Current Status and Future Directions

Abstract

Uncontrolled gout (UG) is a progressive arthropathy that develops as a consequence of sustained hyperuricemia. Recombinant uricases can profoundly lower serum urate (SU) and reverse the clinical manifestations of uncontrolled gout. However, therapeutic uricases are highly immunogenic and can provoke the development of anti-drug antibodies (ADAs), resulting in a loss of effect and potentially severe allergic reactions. Pegloticase is currently the only US Food and Drug Administration-approved uricase indicated for the treatment of UG. The Food and Drug Administration recently approved the co-administration of methotrexate with pegloticase to inhibit ADA formation and enhance the efficacy and tolerability of pegloticase. Nanoencapsulated sirolimus plus pegadricase (NASP) is a novel every-4-week treatment delivered as a sequential two-component infusion consisting of nanoencapsulated sirolimus immediately followed by pegadricase, a novel PEGylated uricase. NASP mitigates ADA formation by promoting uricase-specific immunotolerance, thereby obviating the need for systemic immunomodulatory drugs. Phase I trials demonstrated that NASP inhibited ADA development, allowing sustained pegadricase control and SU lowering for up to 30 days. The dose-finding (phase II) study showed NASP (nanoencapsulated sirolimus 0.1–0.15 mg/kg and pegadricase 0.2 mg/kg) reduced ADA development and supported durable SU lowering. The phase II COMPARE trial demonstrated that monthly NASP was as effective as twice-monthly pegloticase in achieving SU targets at 6 months. Combined phase III DISSOLVE trial data confirmed that NASP significantly lowered SU and increased SU responses in participants with UG. All phase I–III trials demonstrated that NASP was generally well tolerated with no specific safety signals. Overall, NASP has demonstrated robust and durable SU lowering, which ultimately reduced disease burden, supporting positive health-related quality-of-life outcomes. This review summarizes the clinical development of NASP with particular reference to the targeted immunotolerizing strategy that diminishes its immunogenicity. Video abstract available online.

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Video Abstract

Supplementary Information

The online version contains supplementary material available at 10.1007/s40265-025-02267-w.

Key Points

Nanoencapsulated sirolimus plus pegadricase (NASP) is a novel every-4-week treatment for uncontrolled gout (UG) delivered as a sequential two-component infusion of nanoencapsulated sirolimus (NAS), immediately followed by pegadricase, a PEGylated uricase.

NASP establishes targeted uricase-specific immunotolerance via NAS and mitigates anti-uricase antibody formation.

Data from phase I–III trials show robust efficacy and safety of NASP in UG.

Introduction

Gout is a chronic, systemic, progressive, inflammatory arthritis caused by sustained hyperuricemia resulting in monosodium urate crystal deposition in joints and soft tissues [1]. Gout affects ~ 12 million people in the USA; it is estimated that 2–6% of these patients have uncontrolled gout (UG) [2–5].

Here, we have defined uncontrolled gout (UG) as manifesting with frequent gout flares, active synovitis and/or non-resolving tophi. It results from a failure to achieve an acceptable target serum urate (SU) despite treatment with oral urate-lowering therapies (ULT) [3, 6, 7]. Uncontrolled gout may lead to an erosive and deforming arthropathy, extensive tophaceous deposits, and significant functional impairment [1, 3, 4].

Uncontrolled gout is associated with (i) a higher risk of comorbidities than conventional gout [8], (ii) increased use of medical resources and opioid painkillers [8, 9], and (iii) costs related to work presenteeism and absenteeism [10]. Current guidelines recommend managing hyperuricemia in symptomatic gout to achieve a therapeutic SU target of < 6.0 mg/dL or < 5.0 mg/dL in more severely affected patients [6, 7]. Uricase treatment is recommended for patients who cannot achieve urate-lowering targets or carry a high disease burden despite the use of oral ULT, for example, uricosurics and xanthine oxidase inhibitors [6, 7].

The uricase enzyme converts uric acid to soluble and readily excreted allantoin. Humans lack functional uricase, which predisposes them to developing hyperuricemia and gout [11–14]. Therapeutic recombinant uricases, derived from other animal species or microorganisms, can be used to compensate for the absence of endogenous uricase. However, because these enzymes are non-self, they are highly immunogenic [15, 16].

Anti-drug antibodies (ADAs) can limit or even nullify drug activity and provoke immune reactions, including anaphylaxis; consequently, ADAs are a frequent cause of treatment failure for many biologics [16, 17]. Modification by conjugation with polyethylene glycol (PEG) prolongs the therapeutic half-life of uricase when compared with the unmodified enzyme [16]. Nevertheless, ADAs can develop against uricase, the PEG moiety, or the combined PEGylated product, in over 90% of treated patients. Anti-drug antibodies may lead to infusion reactions or a loss of therapeutic benefit [18–20].

Two uricases, rasburicase and pegloticase, have regulatory approval, and one uricase (pegadricase) is being evaluated in clinical trials (Table 1 of the Electronic Supplementary Material [ESM]) [19, 21–24]. Currently, pegloticase is the only US Food and Drug Administration (FDA)-approved uricase indicated for the treatment of chronic gout in adult patients refractory to conventional therapy [6, 21]. Pegloticase can substantially lower SU levels, resulting in the accelerated resolution of tophaceous deposits [25, 26]. However, in phase III clinical trials, 58% of patients receiving pegloticase (8 mg) every 2 weeks did not achieve a sustained response to treatment because of anti-pegloticase ADA formation [20]. Furthermore, high-titer anti-pegloticase ADAs were associated with infusion reactions and anaphylaxis in 26% and 5% of participants, respectively, treated with pegloticase infusions every 2 weeks [18, 20, 27]. Richette et al. reported the off-label use of rasburicase, which is indicated for tumor lysis syndrome [28], to manage tophaceous gout [29]. However, rasburicase is infrequently used for gout because of its high risk of triggering flares and hypersensitivity reactions, as well as the lack of a validated treatment regimen [30, 31].

These findings prompted approaches to reduce therapeutic risks and enhance efficacy, including the concurrent use of systemic immunomodulatory drugs [32]. In 2022, the pegloticase label was revised to recommend the co-administration of methotrexate; this regimen markedly increased response rates, lowered ADA formation, and reduced infusion reactions in patients with UG [21, 33]. Other antiproliferative agents that act by inhibiting purine or pyrimidine synthesis (azathioprine, leflunomide, and mycophenolate mofetil) can also prevent ADA formation if they are administered before or concurrently with the first dose of uricase and continued throughout treatment. [32, 34, 35]. However, the use of immunomodulatory agents in conjunction with uricase treatment is complicated by (i) the increased risk of adverse events (AEs), including renal dysfunction, mucocutaneous ulcers, and hematologic effects, (ii) the large number of comorbidities, for example, cardiovascular disease and hypertension, in patients with gout, and (iii) non-compliance with oral immunomodulators [8, 36].

Nanoencapsulated sirolimus (NAS) was developed to induce targeted tolerance to immunogenic therapies [19, 37, 38], offering a strategy that maintains normal immune function, unlike broad immunomodulation. Extensive preclinical studies confirm that NAS can mitigate ADA formation across a wide range of these therapeutics [38–40]. Uricase, a highly immunogenic enzyme in humans, was selected as a proof-of-concept model to assess the ability of NAS to prevent ADA development in early-phase clinical trials of hyperuricemia and UG [19, 23, 24]. Here, we describe the clinical development of nanoencapsulated sirolimus plus pegadricase (NASP), an investigational treatment for UG.

Development of NASP

NASP is a novel every-4-week treatment for UG delivered as a sequential two-component infusion of NAS immediately followed by pegadricase. NASP was formerly referred to as SEL-212.

• (i)NAS is a nanosized particle with a biodegradable poly(lactic acid) (PLA) polymer matrix core surrounded by a hydrophilic PLA-PEG outer layer [39], as shown in Fig. 1a. This group of polymers has been used in approved products for over 30 years [39]. NAS nanoparticles contain sirolimus, an approved immunomodulatory drug that is commonly used as prophylaxis for organ rejection [41]. During the clinical development of NASP, NAS was previously called SEL‑110, synthetic viral particle‑rapamycin, or ImmTOR^® owing to its encapsulated sirolimus formulation.
• (ii)Pegadricase is a PEGylated recombinant uricase derived from Candida utilis [42], as shown in Fig. 1b. Pharmacokinetic studies in non-human primates and rodents demonstrated that pegadricase had a longer in vivo half-life than the non-PEGylated enzyme [43]. Pegadricase was previously known as SEL-037, pegsiticase, and uricase PEG-20.

Fig. 1.

Representations of a nanoencapsulated sirolimus (NAS) and b pegadricase. PEG polyethylene glycol, PLA poly(lactic acid). Illustration of nanoencapsulated sirolimus plus pegadricase ©Sobi 2023

NASP: Focus on Mechanism of Action

NAS prevents ADA formation toward biologics such as pegadricase by inducing immunological tolerance [19, 37, 44]. Briefly, NAS induces regulatory T cells to co-administered pegadricase, providing tolerance without affecting the immune response to other antigens.

NAS Selectively Accumulates in Lymphoid Tissues

Viral surveillance and recognition are central to an effective immune response. Because of their size, shape, and charge, nanoparticles are preferentially internalized by antigen-presenting cells (APCs) [45, 46]. To maximize immune cell uptake and enable directed distribution to lymphoid organs, NAS was designed to mimic viral particle size [39], facilitating sirolimus delivery to the site of antigen presentation and thereby inducing targeted immunotolerance [39]. Studies across multiple disease models confirmed that NAS accumulated in the liver, spleen, and other lymphoid tissues following intravenous delivery [45, 47, 48]. In contrast, orally administered sirolimus, which has extensive biodistribution [49], does not reach sufficient concentrations in the lymphoid tissues to induce tolerogenic APCs [37–39, 45, 47, 48].

Sirolimus Induces Tolerogenic APCs via mTOR Inhibition

Following uptake by APCs, PLA-based nanoparticles like NAS are hydrolyzed in the acidic intracellular milieu, thus releasing sirolimus [39]. Sirolimus inhibits the mammalian target of rapamycin (mTOR) pathway, a cellular signaling system that impacts multiple biological processes, including immune function [50]. In vitro and in vivo studies demonstrated that sirolimus treatment elicits dendritic cells/APCs with a tolerogenic phenotype due to inhibition of mTOR [51, 52]. Antigen-presenting cells are a key immunotherapeutic target because of their ability to drive self-tolerance and their role in antigen presentation to T cells [39, 47].

Tolerogenic APCs Induce Regulatory T Cells That Attenuate ADA Production

Tolerogenic APCs induce regulatory T cells to co-administered pegadricase and promote uricase immunotolerance by suppressing effector immune responses by T cells, and B-cell antibody production [39]. The induction of tolerance maintains circulating pegadricase levels, mitigates ADA formation, and enables durable SU lowering [19]. This was demonstrated in a uricase-deficient mouse model, where the sequential administration of NAS, followed by pegadricase, inhibited ADA formation and normalized SU levels [38].

NAS Mediates Targeted Immune Tolerance

The induction of targeted immune tolerance by NAS is supported by evidence from several disease models: (i) NAS induced or expanded regulatory T cells specific for the sequentially administered antigens, [47, 53] including pegadricase [38]. (ii) Tolerance is transferred by transplanting splenocytes from treated animals into naïve recipients [45, 53, 54]. (iii) NAS maintained specific immune tolerance despite subsequent antigen exposure [38]. However, the repeated administration of highly immunogenic therapies is likely to necessitate additional NAS treatment [23, 55]. (iv) Perhaps most importantly, despite being tolerized toward a specific antigen, animals remained able to respond immunologically to unrelated antigens, for example, ovalbumin [45] or keyhole limpet hemocyanin [47].

NAS Initiates a Time-Dependent Tolerogenic Window

Delivering NAS provides a temporal window for tolerance induction against co-administered antigens [39], implying that the mechanism of action is not merely the slow release of sirolimus mediating chronic immunosuppression [39]. Furthermore, free (non-encapsulated) sirolimus did not induce the same tolerogenic response as NAS [38, 39, 47]. Therefore, NAS is administered first, followed by pegadricase within 30 min. Overall, the mechanism by which NASP treatment enables pegadricase-specific immunotolerance is depicted in Fig. 2.

Fig. 2.

Mechanism of action of nanoencapsulated sirolimus plus pegadricase. 1. Nanoencapsulated sirolimus (NAS) is distributed to the liver, spleen, and other lymphoid organs. Pegadricase is serially administered. NAS and pegadricase colocalize within antigen-presenting cells (APCs). 2. Sirolimus is released, inducing a tolerogenic APC phenotype via the inhibition of mammalian target of rapamycin (mTOR). 3. Tolerogenic APCs promote targeted immunomodulation through the induction of regulatory T cells, which mediate effector cell inhibition and mitigate the production of anti-drug antibodies (ADAs). IV intravenous

Overview of Clinical Studies

Here, we provide a detailed summary of findings from the phase I and II programs and their influence over the design of phase III, clinical, randomized controlled trials (Fig. 3) for NASP [19, 23, 24].

Fig. 3.

Overall clinical trial program. Summary of study designs, populations, and global enrollment across phases I–III. NASP nanoencapsulated sirolimus plus pegadricase, SU serum urate

Phase I Trials

Two phase I trials of NASP were conducted. The first, phase Ia, determined the effect of a single ascending dose of pegadricase alone, and the second, phase Ib, was in two parts: part A, which examined the effect of a single ascending dose of NAS or placebo, and part B, which examined the effect of escalating doses of NAS in combination with an unvarying dose of pegadricase [19].

Phase Ia Trial

A phase Ia, open-label, sequential, ascending single-dose, 30-day study (NCT02464605) of pegadricase was conducted in 22 participants with hyperuricemia (SU >6.0 mg/dL). The primary trial endpoints were safety and tolerability, and its secondary endpoints were uricase activity and the immunogenicity of pegadricase. Five treatment cohorts received a single intravenous infusion of pegadricase in various doses (0.1, 0.2, 0.4, 0.8, or 1.2 mg/kg), where all treatment cohorts comprised five patients except the 1.2-mg/kg treatment group, which included two participants. The enrollment of subjects was halted in the highest pegadricase dose (1.2-mg/kg) cohort because the duration of SU lowering was not increased beyond that observed in the lower dose cohorts.

Pegadricase was highly immunogenic, as expected, and all participants developed anti-uricase antibodies (Fig. 4a). Despite the development of these antibodies, pegadricase was well tolerated at all doses. Treatment with pegadricase alone mediated a considerable (but transient) reduction in SU levels, which returned to baseline between day 7 and day 30 in most participants (Fig. 4c).

Fig. 4.

Phase Ia, effect of a single ascending dose of pegadricase in patients with hyperuricemia. Panels show a anti-uricase immunoglobulin G (IgG) levels, b serum uricase activity, and c serum urate levels, up to 30 days post-infusion. Mean (± standard deviation) in n = 5 participants per cohort receiving doses of either 0.1, 0.2, 0.4, or 0.8 mg/kg of pegadricase or n = 2 participants receiving 1.2 mg/kg of pegadricase. Figure adapted from Sands et al., CC-BY 4.0 license [19]

However, in one patient (of the five) receiving the 0.4-mg dose of pegadricase, SU lowering was maintained. This individual had a low anti-uricase antibody titer of 1:120. In contrast, the other participants in the cohort developed titers greater than 1:1000, which implied that the development of anti-uricase ADAs limits SU lowering.

Phase Ib Trial

A phase Ib (NCT02648269) single ascending dose, 30-day study of NASP (composed of both double-blind and open-label components), designed to evaluate the safety of NASP (primary endpoint) and its ability to prevent anti-uricase ADA formation (secondary endpoint), was conducted in 62 patients with hyperuricemia (64 participants were enrolled and treated, but two participants withdrew consent). In phase Ib part A, 26 patients were treated with ascending doses of NAS alone (0.03, 0.1, 0.3, and 0.5 mg/kg) or placebo (Fig. 5a). As expected, no change in SU levels was noted following treatment with NAS alone (cohorts A–D, Fig. 5b). NAS was well tolerated at doses up to 0.3 mg/kg. Most treatment-emergent AEs (TEAEs) were mild or moderate in severity and not deemed to be related to NAS. At 0.5 mg/kg, the highest dose tested, two participants developed stomatitis (a known side-effect of sirolimus); these were the only two cases classified as serious AEs (SAEs).

Fig. 5.

Phase Ib trial design and serum urate (SU) levels. a Schematic of cohorts for both phase Ib trial parts A and B. Two participants in cohort C (0.3 mg/kg of nanoencapsulated sirolimus [NAS]) were enrolled and treated, but withdrew consent. b SU over time. The colored lines are the mean SU levels for the cohort. The dotted black lines represent 6.0 mg/dL of SU. Figure adapted from Sands et al., CC-BY 4.0 license [19]

In phase Ib part B, 36 patients were treated with pegadricase (0.4 mg/kg) alone or in combination with ascending doses of NAS (0.03, 0.1, 0.15, 0.3 mg/kg) [Fig. 5a]. The addition of increasing doses of NAS to pegadricase resulted in a dose-dependent effect on SU reductions (cohorts F–I, Fig. 5b). All patients treated with pegadricase and NAS doses of 0.15 and 0.3 mg/kg maintained SU levels of < 6.0 mg/dL up to day 30 (cohorts H and I, Fig. 5b). Conversely, participants administered pegadricase with lower NAS doses of 0.03 and 0.1 mg/kg (cohorts F and G, Fig. 5b) showed diminishing SU control and an elevation in SU levels from approximately day 14 post-NASP administration. Durable reductions in SU levels correlated with the inhibition of anti-uricase immunoglobulin G antibody formation and sustained uricase activity. In all cohorts, NASP was well tolerated. No life-threatening TEAEs or deaths were reported. No drug-related SAEs were observed at the higher doses of NAS (0.15 or 0.3 mg/kg) combined with pegadricase.

Overall, phase I trials demonstrated that a single dose of NAS followed by pegadricase resulted in a dose-dependent inhibition of anti-uricase antibody development, enabling sustained enzyme activity and profound lowering of SU levels. NASP and its components were generally well tolerated.

Phase II Trials

Phase II: Dose-Finding Trial

Subsequently, a study was conducted to ascertain the optimal dosing combination of NAS and pegadricase to support the ongoing NASP clinical trial program. The “dose-finding” study (NCT02959918) was an open-label phase II trial that enrolled 152 participants with symptomatic gout and elevated SU levels ≥ 6.0 mg/dL [23].

Key inclusion criteria were an SU level of ≥ 6.0 mg/dL and one or more of the following clinical manifestations: one or more tophus or one or more gout flare within the last 6 months or diagnosis of gouty arthritis based on a principal investigator’s diagnosis or medical history (e.g., chronic synovitis due to gout). Participants received infusions of NAS in various doses (0.05–0.15 mg/kg) given during the first three or all five of the 28-day treatment periods (TPs), with infusions (0.2 or 0.4 mg/kg) of pegadricase for all five of the 28-day TPs (Fig. 1 of the ESM). Treatment duration consisted of five consecutive TPs, with drug infusions occurring on day zero of each TP and a 28-day period between doses.

Trial endpoints were safety and tolerability, immunogenicity, and drug pharmacokinetics (including sirolimus concentrations). Safety was assessed by monitoring AEs, vital signs, clinical evaluations, and laboratory testing. The formation of ADAs and SU levels were also measured. Tophi were monitored using dual-energy computed tomography (DECT) scans, which were performed on a subset of 34 participants (from cohorts 10–13, 15, and 17) at baseline, and 27 of these patients had one or more follow-up scans at TP3 and/or TP5/end of study. Evaluable participants were defined as those receiving a full first dose who did not discontinue study treatments because of any measure other than drug effectiveness or drug-related safety.

Efficacy

The serial infusion of NAS, immediately followed by pegadricase, prevented ADA formation, enabling profound SU lowering and reductions in urate burden, as evidenced by DECT scans and tophi assessments. The administration of pegadricase without NAS resulted in transient reductions in SU, which were not sustained beyond 30 days in most patients. The loss of SU lowering was attributed to ADA formation and the consequent loss of uricase activity. Anti-drug antibody formation was reduced with increasing doses of NAS, with greater ADA reductions noted at ≥0.1 mg/kg than for lower doses. Furthermore, higher anti-uricase antibody titers ≥1:1080 correlated with loss of SU lowering. Serum urate (< 6.0 mg/dL) lowering was achieved in 66% (21/32) of evaluable participants at week 20 after five doses of pegadricase at 0.2 mg/kg and NAS at doses of 0.1–0.15 mg/kg (Fig. 2c of the ESM). The DECT scans showed the total body and per joint tophus volume decreased from baseline to TP3, which correlated with reductions in SU and ADA levels. Further decreases in volumes were observed from TP3 to TP5/end of study in all participants evaluated using a DECT scan at baseline and at least one follow-up scan (n = 27). An example of one patient’s serial scans is shown in Fig. 3 of the ESM. Compared with other combinations, NAS in doses of 0.15 mg/kg followed by pegadricase at 0.2 mg/kg resulted in the best control of SU levels (Fig. 2 of the ESM) and the lowest ADA production.

Safety

Every 4-week administration of pegadricase at 0.2–0.4 mg/kg with or without NAS at 0.05–0.15 mg/kg was well tolerated overall, with no safety signals regarding clinical laboratory results, vital signs, and electrocardiogram readings. No deaths occurred. Drug-related TEAEs were generally deemed mild or moderate and comparable to those obtained in phase I trials and the established safety profile of sirolimus. The most frequently reported TEAEs related or possibly related to NASP in TPs 1–3 were gout flares (23.6%), anemia (10.5%), headache (7.2%), leukopenia (7.2%), hypertriglyceridemia (6.6%), stomatitis (6.6%), and infusion-related reactions (3.9%).

Overall, the dose-finding study demonstrated that sequential infusions of NAS and pegadricase lowered SU and were well tolerated without serious safety concerns. The greatest level of SU lowering and lowest ADA formation were obtained using doses of NAS at 0.15 mg/kg and pegadricase at 0.2 mg/kg. The dose combination selected for the COMPARE and phase III DISSOLVE trials was based on the dose-finding study outcomes.

Phase II: COMPARE Trial

COMPARE (NCT03905512) was a phase II, 6-month, randomized, open-label, head-to-head trial designed to compare the efficacy of every 4-week NASP with pegloticase every 2 weeks in 170 patients with refractory gout. Key inclusion criteria were patients with documented refractory gout, SU ≥ 7.0 mg/dL, and at least one of the following disease manifestations: one or more tophus or three or more gout flares within the last 18 months or a diagnosis of gouty arthritis based on a principal investigator’s diagnosis or medical history [24].

Participants stopped ULT 7 days prior to study drug administration. Both trial arms received premedication consisting of oral prednisone (40 mg) approximately 24 h prior to infusion, oral fexofenadine (180 mg) at approximately 12 h and 2 h prior to infusion (two doses), and intravenous methylprednisolone (40 mg) approximately 1 h prior to infusion. NASP comprised serial infusions of NAS at 0.15 mg/kg, followed (within 15 min of completion) by pegadricase at 0.2 mg/kg every 4 weeks. The second treatment arm was an 8-mg dose of pegloticase monotherapy infused every 2 weeks. The primary endpoint compared the percentage of patients receiving NASP versus pegloticase who achieved a response defined as a maintained reduction of SU < 6.0 mg/dL for ≥ 80% of the time during months 3 and 6 combined. Key secondary endpoints included (i) the percentage of responders during months 3 and 6 individually and (ii) the absolute/percentage reduction of mean SU during months 3 and 6 combined and month 6 alone, and (iii) safety and tolerability. Safety and secondary laboratory and clinical endpoints, including gout flare frequency and the number of tender and/or swollen joints, were also documented.

Efficacy

NASP did not meet the primary objective of demonstrating statistical superiority over pegloticase during months 3 and 6 combined. However, the NASP arm achieved a higher percentage of responders (53.0%, n = 44 NASP vs 46.0%, n = 40 pegloticase, p = 0.181) that reached and maintained an SU of <6.0 mg/dL for ≥80% of the time (months 3 and 6 combined). During month 3, significantly (p = 0.017) more patients receiving NASP (69.9%, n = 58) versus pegloticase (54.0%, n = 47) were responders. In month 6, a numerical difference in responders treated with NASP (54.2%) versus pegloticase (47.1%) was observed (p = 0.179).

Safety

Treatment-emergent AEs were reported in 78.2% of participants treated with pegloticase and 89.2% with NASP (Table 1). Most events were mild to moderate in severity. The proportion of participants who experienced SAEs, treatment-related SAEs, and infusion-related reactions were similar between NASP and pegloticase treatments. Stomatitis, which included the related conditions aphthous ulcer, cheilitis, mouth ulceration, oral mucosal blistering, tongue ulceration, mucosal inflammation, mucosal ulceration, and nasal ulcer, occurred in 9.6% (n = 8) of participants treated with NASP. The most common treatment-related AEs documented in the NASP and pegloticase arms were gout flares (32.5% and 23.0%), infusion reactions (15.7% and 11.5%), and headache (4.8% and 0%), respectively. Treatment-related SAEs occurred in 2.4% (n = 2) [infusion-related anaphylaxis and infusion reactions] and 3.4% (n = 3) [infusion-related anaphylaxis, infusion reactions, and hypotensive emergency] of participants administered NASP and pegloticase, respectively. Overall, NASP was effective and had a favorable safety profile; NASP treatment had a low incidence of infusion-related anaphylaxis. Exposure to pre-infusion glucocorticoids was reduced by 26% in the NASP cohort because of its every-4-week infusion (compared with the every-2-week administration of pegloticase).

Table 1.

Summary of TEAEs and treatment-related TEAEs in ≥ 2% of participants (safety population)

Participants with ≥ 1 TEAE	NASP N = 83 n (%)	Pegloticase (Krystexxa™) N = 87 n (%)
TEAE	74 (89.2)	68 (78.2)
Treatment-related TEAE	45 (54.2)	34 (39.1)
Serious TEAE	7 (8.4)	8 (9.2)
Treatment-related serious TEAE	2 (2.4)	3 (3.4)
TEAE of special interest	63 (75.9)	59 (67.8)
TEAE leading to study drug withdrawal	10 (12.0)	15 (17.2)
TEAE leading to death	0	0
TEAE of infusion reaction	15 (18.1)	15 (17.2)
Treatment-related TEAEs in ≥ 2% of participants
Participants with ≥ 1 related TEAEs	45 (54.2)	34 (39.1)
Gout flare	27 (32.5)	20 (23.0)
Infusion-related reaction	13 (15.7)	10 (11.5)
Headache	4 (4.8)	0
Hypertriglyceridemia	3 (3.6)	2 (2.3)
Aphthous ulcer	2 (2.4)	0
Hyperglycemia	2 (2.4)	1 (1.1)
Hypophosphatemia	2 (2.4)	0
Back pain	2 (2.4)	0

Adapted from Baraf et al., CC-BY-NC license [24]

N total number, n number with event, NASP nanoencapsulated sirolimus plus pegadricase, TEAE treatment-emergent adverse event

Phase III: DISSOLVE Trials

DISSOLVE I and II were replicate, randomized, double-blind, placebo-controlled, phase III trials of NASP designed to demonstrate its safety and efficacy in patients with gout refractory to conventional therapy. Topline results were recently reported [56]. Two dose concentrations of NAS (0.15 mg/kg [high dose] or 0.1 mg/kg [low dose]) were evaluated, and one dose of pegadricase (0.2 mg/kg) [Fig. 6]. Participants were randomized 1:1:1 into three study arms (high-dose or low-dose NASP or placebo) [Fig. 6]. DISSOLVE I was a US trial (NCT04513366), and DISSOLVE II was a global trial (NCT04596540). DISSOLVE I and II included a screening phase and a double-blind treatment phase of six 28-day TPs. The DISSOLVE I trial had a 6-month blinded extension to allow for additional efficacy and safety monitoring (Fig. 6). Patients who discontinued the study drug were part of the intent-to-treat population and included in the efficacy endpoint.

Fig. 6.

DISSOLVE I and II trial design. Primary endpoint: the percentage of patients who have serum urate (SU) < 6.0 mg/dL for ≥ 80% of the time during weeks 21–24 (treatment period [TP] 6). Secondary endpoints include changes from baseline to week 24 in SU levels, SF-36 physical component summary score, resolution of tophi, joint tenderness, gout flare incidence during weeks 1–12 and weeks 12–24, and safety (treatment-emergent adverse events, adverse events of special interest, and serious adverse events). *Patients were dosed at the start of each 4-week period as indicated by the arrows. E4W every 4 weeks, HD high dose, IV intravenous, LD low dose, NAS nanoencapsulated sirolimus, NASP nanoencapsulated sirolimus plus pegadricase

Key inclusion criteria were refractory gout defined as SU ≥ 7.0 mg/dL and failure to normalize SU and control symptoms with any xanthine oxidase inhibitor, either allopurinol or febuxostat at the medically appropriate dose or for whom these drugs are contraindicated; and one of the following disease manifestations: one or more tophus or three or more gout flares in the previous 18 months or a diagnosis of gouty arthritis, based on a principal investigator’s diagnosis or medical history. The primary endpoint was defined as the percentage of participants who achieved and maintained SU < 6.0 mg/dL for ≥ 80% of the time during weeks 21–24 in the active treatment groups versus placebo, which was also defined as the response rate.

Efficacy

For the primary endpoint, 51%, 43%, and 8% of participants achieved SU responses in the high-dose, low-dose, and placebo-treated arms, respectively (Fig. 7) [56].

Fig. 7.

Response rates with nanoencapsulated sirolimus plus pegadricase versus placebo, combined DISSOLVE I and II intent-to-treat (ITT) population. ^aResponders were defined as subjects with (serum urate) levels < 6 mg/dL for at least 80% of the time during treatment period 6 (weeks 21–24). ^bRisk difference (RD) versus placebo [97.5% confidence interval] and p-value for each treatment group are indicated above the high-dose (HD) and low-dose (LD) columns. Missing response data in weeks 21–24 were multiply imputed. Mantel–Haenszel testing was performed with randomization stratum of tophus presence (yes/no), where applicable, with a two-sided error rate α = 2.5% for the two comparisons of the study drug against placebo. Two-sided Chi-square testing with a type 1 error rate alpha of 2.5% was applied to adjust for the two comparisons against placebo

Combined DISSOLVE I and II data confirm that NASP significantly lowered SU and significantly increased the SU response in a population with UG [56].

Safety

The safety and tolerability of NASP were assessed by clinical monitoring, AEs, and laboratory testing. Table 2 details the combined DISSOLVE I and II AEs [56]. Infusion-related reactions occurred (within 1 h) in 3.4%, 4.5%, and 0% of participants treated with NASP high dose, low dose, and placebo, respectively [56]. Stomatitis occurred in eight (9.2%) patients treated with a high dose, three patients (3.4%) with a low dose, and no patients with placebo (pooled data from DISSOLVE I and II trials [56]); all cases were deemed to be mild/moderate, and none resulted in patient withdrawal.

Table 2.

Summary of AESIs^a,b

Safety set, patients, n (%)	Combined data: DISSOLVE I and II
	High dose (N = 87)	Low dose (N = 88)	Placebo (N = 90)
≥ 1 Treatment-emergent AESIs	56 (64.4)	59 (67.0)	49 (54.4)
Gout flares	37 (42.5)	39 (44.3)	39 (43.3)
Infections (including viral)	20 (23.0)	16 (18.2)	15 (16.7)
COVID-19c	5 (5.7)	5 (5.7)	6 (6.7)
Infusion-related AEs (24 h)	7 (8.0)	6 (6.8)	2 (2.2)
Infusion reactions (1 h) including anaphylaxisd	3 (3.4)	4 (4.5)	0 (0)
Hypertriglyceridemiae	6 (6.9)	4 (4.5)	6 (6.7)
Stomatitisf	8 (9.2)	3 (3.4)	0 (0)
Renal and urinary disordersg	1 (1.1)	2 (2.3)	3 (3.3)
Pulmonary embolism	0 (0)	1 (1.1)	0 (0)
Leukopenia	0 (0)	2 (2.3)	0 (0)

AEs adverse events, AESIs adverse events of special interest, COVID-19 coronavirus disease 2019, FDA Food and Drug Administration, IRs infusion reactions

^aSafety data shown are during the first 24 weeks during DISSOLVE I and DISSOLVE II [56]. Events occurring during the extension phase of the DISSOLVE I trial are excluded

^bAESIs included in the protocol as agreed with the FDA; no other treatment-emergent AEs ≥ 5%

^cThere were no other individual infections > 2%

^dIRs (1 h) are included in the infusion-related AEs (24 h)

^eDyslipidemia/hypertriglyceridemia/hyperlipidemia

^fStomatitis/oral ulcer/aphthous ulcer; 67% mild, 33% moderate

^gIncludes microalbuminuria and renal impairment

A post-hoc analysis of DISSOLVE participants, with UG and chronic kidney disease (CKD), demonstrated that NASP reduced SU in most participants with CKD stage 3 (CKD 3) at week 24. The proportion of patients with CKD 3 who responded to high dose and low dose NASP versus placebo was 52% (p = 0.0041), 61% (p = 0.0004), and 10%, respectively. There was also a trend toward an estimated glomerular filtration rate improvement in NASP-treated patients with CKD 3 compared with those receiving placebo [57]. Full publication of DISSOLVE I and II data will be forthcoming.

Discussion

Patients with UG requiring uricase-based therapy would benefit from alternative treatment strategies that achieve rapid and sustained reductions in SU levels and attenuate ADA formation while preserving broader immune function. The introduction of NASP, a novel immunotolerizing agent, and uricase would augment a therapeutic class that currently contains only one approved treatment for UG.

Anti-drug antibody development can reduce uricase efficacy and increase the risk of infusion reactions. Studies of NASP’s  mechanism of action indicate that targeted immune tolerance could reduce uricase immunogenicity without suppressing the wider immune response [38, 45, 47, 53, 54].

The induction of targeted immunotolerance by NASP effectively maintained circulating pegadricase levels, mitigated ADA formation, and enabled durable SU lowering. Treatment with NASP was also associated with a reduction in tophus burden and tender joints when compared with placebo. Importantly, patients with UG reported clinically meaningful improvements in pain, physical, and mental quality-of-life indicators. Effective SU control in patients with UG ultimately supports health-related quality-of-life outcomes [58, 59].

NASP was generally well tolerated. However, stomatitis (a known side effect of sirolimus) was observed, and its severity appeared to be related to the dose of NAS. Earlier clinical trials employed higher NAS doses (up to 0.5 mg/kg in phase I studies) than in the phase III DISSOLVE trials (up to 0.15 mg/kg), where only mild-to-moderate stomatitis was reported in < 10% of participants.

Limitations and Further Work

• (i)The COMPARE head-to-head trial was conducted before the FDA approved the combination therapy of pegloticase and methotrexate. Therefore, the efficacy and safety of NASP treatment in UG versus a combination of pegloticase and methotrexate (or other immunomodulators) remain unknown.
• (ii)An important clinical question is whether ADAs from pegloticase treatment cross-react with NASP. Unlike pegloticase, where ADAs primarily target the PEG moiety [18], the ADA response to pegadricase predominantly targets the uricase component [19]. Phase I studies demonstrated that anti-PEG antibodies were transient, occurring only in a subset of patients who developed anti-uricase immunoglobulin G [19], and that NAS could inhibit this response [19]. Additionally, pegadricase is a recombinant urate oxidase derived from the yeast Candida utilis, whereas pegloticase is derived from mammalian uricases, potentially leading to distinct ADA profiles [19]. Overall, while cross-reactivity is not expected, definitive studies have not been conducted.

Conclusions

Overall, the positive results obtained throughout the NASP development program support its potential as an every-4-week treatment option in patients with UG. NASP is an all-in-one therapeutic option where both the immunomodulator and the uricase are sequentially infused within 30 min, allowing for administration during the same appointment. The use of NAS in the NASP development program introduces an innovative approach that could provide valuable insights into modulating ADA formation in other therapies with potential immunogenicity.

Supplementary Information

Below is the link to the electronic supplementary material.

Funding

Medical writing and editorial assistance were funded by Sobi.

Declarations

Conflicts of Interest

Herbert S.B. Baraf: Arthrosi, Olatec, Sobi, Otsuka, Pacira. Naomi Schlesinger: Amgen, Arthrosi, Novartis, Olatec, Protalix, Shanton, Sobi, Scilex, Avalo. Vibeke Strand: AbbVie, Alpine, Alumis, Amgen, AstraZenecaBayer, Blackrock, BMS, Boehringer Ingelheim, Celltrion, Citryll, Contura, Fortress Biotech, Genentech/Roche, GSK, Inmedix, Janssen, Kiniksa, Lilly, Novartis, Omeros, Pfizer, RAPT, Regeneron, R-Pharm, Samsung, Sandoz, Sanofi, Scipher, Setpoint, Sobi, Spherix, Synact, Takeda, Urica, Vertex.

Ethics Approval

This extended review presents information from phase I–III clinical studies of NASP. All study protocols were approved by an ethics committee or institutional review board at each participating center.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Availability of Data and Material

The datasets analyzed during the current study are available from the corresponding author on reasonable request. Sobi is committed to responsible and ethical sharing of data on the participant-level and summary data for medicines and indications approved by the European Medicines Agency and/or FDA, while protecting individual participant integrity and compliance with applicable legislation. Data access will be granted in response to qualified research requests. All requests are evaluated by a cross‐functional panel of experts within Sobi, and a decision on sharing will be based on the scientific merit and feasibility of the research proposal, maintenance of personal integrity, and commitment to publication of the results. To request access to study data, a data-sharing request form (available on www.sobi.com) should be sent to medical.info@sobi.com. Further information on Sobi’s data sharing policy and process for requesting access can be found at: https://www.sobi.com/en/policies.

Code Availability

Not applicable.

Authors’ Contributions

All authors meet the International Committee of Medical Journal Editors’ criteria for authorship for this article. All authors were responsible for manuscript conceptualization, writing the original draft, and reviewing and editing the final manuscript draft. All authors take responsibility for the manuscript as a whole and have given their approval for this version to be published.