Abstract
Mucopolysaccharidosis type I (MPS I) causes systemic accumulation of glycosaminoglycans due to a genetic deficiency of α-L-iduronidase (IDUA), which results in progressive systemic symptoms affecting multiple organs, including the central nervous system (CNS). Because the blood-brain barrier (BBB) prevents enzymes from reaching the brain, enzyme replacement therapy is effective only against the somatic symptoms. Hematopoietic stem cell transplantation can address the CNS symptoms, but the risk of complications limits its applicability. We have developed a novel genetically modified protein consisting of IDUA fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa; JR-171), which has been shown in nonclinical studies to be distributed to major organs, including the brain, bringing about systemic reductions in heparan sulfate (HS) and dermatan sulfate concentrations. Subsequently, a first-in-human study was conducted to evaluate the safety, pharmacokinetics, and exploratory efficacy of JR-171 in 18 patients with MPS I. No notable safety issues were observed. Plasma drug concentration increased dose dependently and reached its maximum approximately 4 h after the end of drug administration. Decreased HS in the cerebrospinal fluid suggested successful delivery of JR-171 across the BBB, while suppressed urine and serum concentrations of the substrates indicated that its somatic efficacy was comparable to that of laronidase.
Keywords: mucopolysaccharidosis type I, enzyme replacement therapy, lepunafusp alfa, blood-brain barrier, anti-transferrin receptor, transcytosis, neuronopathy, neurodegeneration, neurocognitive impairment
Graphical abstract
Neuronopathy in mucopolysaccharidosis I has not been amenable to conventional enzyme replacement therapy due to the blood-brain barrier, which blocks drug delivery into the brain. Herewith presented are first-in-human data with lepunafusp alfa, designed to overcome this challenge, suggestive of its tolerability and somatic and central efficacy.
Introduction
Mucopolysaccharidosis type I (MPS I) is an autosomal recessive hereditary lysosomal storage disorder caused by a deficiency of α-L-iduronidase (IDUA), a lysosomal enzyme involved in the breakdown of glycosaminoglycans (GAGs), which leads to systemic accumulation of GAGs, in particular heparan sulfate (HS) and dermatan sulfate (DS).1 GAG accumulation results in multiple symptoms, including deafness, otitis media, bone or joint deformity, obstructive respiratory disorder, cardiac valvulopathy, and central nervous system (CNS) symptoms.2 Based on age at onset, clinical manifestations, severity, and disease progression, MPS I is classified into three forms: Hurler syndrome, Hurler-Scheie syndrome, and Scheie syndrome. Hurler syndrome is considered to be the most severe form. The estimated prevalence of MPS I is 0.11–3.62 per 100,000 live births across 20 countries. Its prevalence in Japan, the United States, and Brazil is reported as 0.23, 0.34, and 0.24 per 100,000 live births, respectively.3 A study of 987 patients with MPS I showed that Hurler syndrome, Hurler-Scheie syndrome, and Scheie syndrome accounted for 60.9%, 23.0%, and 12.9% of the patients, respectively.4
The two currently available therapies for MPS I are hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT); one of these is selected for each individual patient after the comparative risks and benefits are weighed.5 HSCT is indicated for young patients predicted, based on genotype and family history, to have severe disease with no or minimal cognitive decline. In patients thus treated, metabolic correction and enzyme production in the CNS are believed to be achieved by trafficking of macrophage and microglia.6 Successful engraftment following transplantation is reported to bring about long-term effects, and, when introduced early, HSCT may stabilize and prevent the deterioration of psychomotor functions due to neuronopathy.2 However, the effect of HSCT against the CNS symptoms can be less prominent than that against the peripheral/somatic symptoms.7 HSCT can also be accompanied by serious and sometimes severe complications, such as graft-versus-host disease and infections, although the post-transplant survival rate has improved recently.8 Potential human leukocyte antigen incompatibility between recipients and donors also limits the applicability of the treatment.
ERT provides exogenous enzymes that bind to the mannose-6-phosphate receptors (M6PRs) for their intracellular uptake. Laronidase (solution for intravenous infusion, Aldurazyme), the first enzyme preparation approved in the United States and Europe in 2003, is indicated for patients with the Hurler and Hurler-Scheie forms of MPS I and for patients with relatively moderate to severe symptoms of Scheie syndrome. The clinical study results and post-marketing experience with laronidase over more than 10 years have shown improvements in cardiopulmonary functions, ability to walk, hepatosplenic volumes, joint function, visual acuity, and quality of life. However, laronidase does not cross the blood-brain barrier (BBB) and cannot, therefore, address neuronopathy.2
HSCT is recommended for cognitively intact (i.e., non-neuronopathic) patients younger than 2 years of age, while ERT is indicated for neuronopathic patients and all patients older than 2 years of age (international consensus).5 The European consensus panel also recommends HSCT for Hurler syndrome diagnosed before 2.5 years of age.9 Thus, the treatment options for neuronopathic MPS I are still limited given the age limit for the effectiveness of HSCT and the risks associated with its use, albeit having been reduced. It is clear, then, that there is an urgent medical need for a safe and effective treatment for MPS I that can address both the somatic and CNS symptoms.
Lepunafusp alfa (JR-171) is a genetically modified fusion protein consisting of IDUA and the Fab fragment of a specific antibody against human transferrin receptor 1 (hTfR). It binds to both hTfR and M6PR and is thereby delivered to somatic/peripheral cells, while it is also transported to the cerebral parenchyma via hTfR on the endothelium of the brain capillaries that constitute the BBB.10,11 Our nonclinical studies showed that intravenously administered JR-171 was distributed widely across the major organs, including the brain, and that it also reduced HS and DS concentrations in the CNS and peripheral tissues alike, clearly indicating successful delivery of the drug through the BBB. No safety concerns were noted in the repeat-dose toxicity studies in monkeys.12
On the basis of these nonclinical findings, it was deemed appropriate to proceed to a first-in-human study of JR-171 as a phase 1/2 clinical trial to evaluate its safety, pharmacokinetics, and efficacy in patients with MPS I.
Results
The study evaluated the safety, pharmacokinetics, and exploratory efficacy of JR-171 following weekly intravenous administration at escalated doses in two consecutive parts (Figure 1): part 1 targeted 4 patients older than 18 years given the test drug at doses of 0.1, 1.0, 2.0, and 4.0 mg/kg, and part 2 examined 14 patients aged 2 to 18 years administered with the drug at three doses (1.0, 2.0, and 4.0 mg/kg). The baseline demographics and clinical characteristics of the enrolled patients are shown in Table 1. All the patients in the study, except one in 4.0 mg/kg group in part 2, received prior ERT with laronidase, including one patient in the 2.0 mg/kg group in part 2 who received HSCT prior to laronidase treatment.
Figure 1.
Trial profile of phase 1/2 study of JR-171
Table 1.
Demographic and baseline characteristics
| Parameter | Part 1 |
Part 2 |
All |
|||
|---|---|---|---|---|---|---|
| n = 4, n (%) | Dose-escalation, n = 2, n (%) | 2.0 mg/kg, n = 6, n (%) | 4.0 mg/kg, n = 6, n (%) | Total, n = 14, n (%) | n = 18, n (%) | |
| Age at the time of informed consent (years) | ||||||
| N | 4 | 2 | 6 | 6 | 14 | 18 |
| Mean ± SD | 46.8 ± 13.6 | 9.0 ± 7.1 | 11.0 ± 6.0 | 12.3 ± 11.4 | 11.3 ± 8.3 | 19.2 ± 17.8 |
| Sex | ||||||
| Male | 0 | 1 | 3 | 5 | 9 | 9 |
| Female | 4 | 1 | 3 | 1 | 5 | 9 |
| Ethnicity | ||||||
| Asian (Japanese) | 2 | 2 | 0 | 0 | 2 | 4 |
| Asian (non-Japanese) | 0 | 0 | 0 | 0 | 0 | 0 |
| Asian (total) | 2 | 2 | 0 | 0 | 2 | 4 |
| Native American or Alaska Native | 0 | 0 | 0 | 0 | 0 | 0 |
| African American | 0 | 0 | 0 | 2 | 2 | 2 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 | 0 | 0 |
| Caucasian | 2 | 0 | 6 | 3 | 9 | 11 |
| Other | 0 | 0 | 0 | 1 | 1 | 1 |
| Country | ||||||
| Brazil | 2 | 0 | 5 | 5 | 10 | 12 |
| Japan | 2 | 2 | 0 | 0 | 2 | 4 |
| United States | 0 | 0 | 1 | 1 | 2 | 2 |
| Phenotype | ||||||
| Hurler | 0 | 0 | 5 | 2 | 7 | 7 |
| Hurler-Scheie | 0 | 2 | 0 | 3 | 5 | 5 |
| Scheie | 4 | 0 | 1 | 1 | 2 | 6 |
| Prior use of laronidase (%) | ||||||
| + | 4 (100.0) | 2 (100.0) | 6 (100.0) | 5 (83.3) | 13 (92.9) | 17 (94.4) |
| – | 0 (0) | 0 (0) | 0 (0) | 1 (16.7) | 1 (7.1) | 1 (5.6) |
| HSCT treatment (%) | ||||||
| + | 0 (0) | 0 (0) | 1 (16.7) | 0 (0) | 1 (7.1) | 1 (5.6) |
| – | 4 (100.0) | 2 (100.0) | 5 (83.3) | 6 (100.0) | 13 (92.9) | 17 (94.4) |
| Intellectual disabilities/cognitive impairment (%) | ||||||
| + | 0 (0) | 1 (50.0) | 5 (83.3) | 4 (66.7) | 10 (71.4) | 10 (55.6) |
| – | 4 (100.0) | 1 (50.0) | 1 (16.7) | 2 (33.3) | 4 (28.6) | 8 (44.4) |
| MPS I-related concurrent disease (%) | ||||||
| + | 4 (100.0) | 2 (100.0) | 6 (100.0) | 6 (100.0) | 14 (100.0) | 18 (100.0) |
| – | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| MPS I-related past history (%) | ||||||
| + | 0 (0) | 0 (0) | 2 (33.3) | 3 (50.0) | 5 (35.7) | 5 (27.8) |
| – | 4 (100.0) | 2 (100.0) | 4 (66.7) | 3 (50.0) | 9 (64.3) | 13 (72.2) |
| Prior laronidase-related IAR (%) | ||||||
| + | 1 (25.0) | 0 (0) | 1 (16.7) | 1 (16.7) | 2 (14.3) | 3 (16.7) |
| – | 3 (75.0) | 2 (100.0) | 5 (83.3) | 5 (83.3) | 12 (85.7) | 15 (83.3) |
HSCT, hematopoietic stem cell transplantation; IAR, infusion-associated reaction; MPS I, mucopolysaccharidosis type I; SD: standard deviation.
In part 2, the first 2 subjects received JR-171 at doses escalating from 1.0 to 2.0 and 4.0 mg/kg, while the other 12 subjects were randomized at a ratio of 1:1 to be administered the drug at either 2.0 or 4.0 mg/kg. Four subjects (3 from the 2.0 mg/kg group and 1 from the 4.0 mg/kg group) treated in part 2 did not complete all 12 administrations due to adverse events unrelated to the test drug (respiratory infections including COVID and cardiac failure). Each of these 4 subjects received at least 8 doses.
Tables 2 and 3 summarizes the adverse drug reactions observed during the study period. In part 1, 2 patients reported back pain as an adverse event, while 1 patient developed erythema, an infusion-associated reaction, as an adverse drug reaction. The adverse events that occurred in part 2 were upper respiratory tract infection, influenza, increased transaminase, rash, and pyrexia, and the observed adverse drug reactions were diarrhea, rash, urticaria, and pyrexia. In part 2, two serious adverse events were observed, both unrelated to JR-171: bronchial aspiration (n = 1) and cardiac failure (n = 1); the former was fatal. One patient in the 2.0 mg/kg group showed a slight increase in cerebrospinal fluid pressure in the second spinal tap, which lacked relevant symptoms and normalized in the third tap; hence, the increase was considered a nonserious, isolated phenomenon. Overall, the proportions of subjects who experienced adverse events or adverse drug reactions were comparable between the 2 doses (2.0 and 4.0 mg/kg) in part 2. The pharmacokinetic parameters from parts 1 and 2 are summarized in Table S1.
Table 2.
Adverse drug reactions (part 1)
| Part 1 | |||
|---|---|---|---|
| System organ class |
n = 4 |
||
| Preferred term | No. of subjects | % | No. of events |
| Any adverse drug reactions | 1 | 25.0 | 3 |
| Skin and subcutaneous tissue disorders | 1 | 25.0 | 3 |
| Erythema | 1 | 25.0 | 3 |
Medical Dictionary for Regulatory Activities Terminology Dictionary, v.25.1.
Table 3.
Adverse drug reactions (part 2)
| Part 2 | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| System organ class |
2.0 mg/kg, n = 6 |
4.0 mg/kg, n = 8 |
Total, n = 14 |
||||||
| Preferred term | No. of subjects | % | No. of events | No. of subjects | % | No. of events | No. of subjects | % | No. of events |
| Any adverse drug reactions | 1 | 16.7 | 3 | 3 | 37.5 | 7 | 4 | 28.6 | 10 |
| Gastrointestinal disorders | 0 | 0.0 | 0 | 1 | 12.5 | 1 | 1 | 7.1 | 1 |
| Diarrhea | 0 | 0.0 | 0 | 1 | 12.5 | 1 | 1 | 7.1 | 1 |
| Skin and subcutaneous tissue disorders | 1 | 16.7 | 1 | 1 | 12.5 | 3 | 2 | 14.3 | 4 |
| Rash | 1 | 16.7 | 1 | 0 | 0.0 | 0 | 1 | 7.1 | 1 |
| Urticaria | 0 | 0.0 | 0 | 1 | 12.5 | 3 | 1 | 7.1 | 3 |
| General disorders and administration site conditions | 0 | 0.0 | 0 | 1 | 12.5 | 3 | 1 | 7.1 | 3 |
| Pyrexia | 0 | 0.0 | 0 | 1 | 12.5 | 3 | 1 | 7.1 | 3 |
| Investigations | 1 | 16.7 | 2 | 0 | 0.0 | 0 | 1 | 7.1 | 2 |
| CSF pressure increased | 1 | 16.7 | 1 | 0 | 0.0 | 0 | 1 | 7.1 | 1 |
| Transaminases increased | 1 | 16.7 | 1 | 0 | 0.0 | 0 | 1 | 7.1 | 1 |
Medical Dictionary for Regulatory Activities Terminology Dictionary, v.25.1.
Analysis of the pharmacokinetic data revealed a dose-dependent increase in the plasma concentrations of JR-171, which reached Cmax around the end of drug administration in both parts 1 and 2 (Figure 2). JR-171 was detected in the cerebrospinal fluid (CSF) of 3 patients in part 1 at week 4 following dose escalation to 4 mg/kg and also in 1 patient in the 2.0 mg/kg group in part 2 and in 2 in the 4.0 mg/kg group at week 12.
Figure 2.
Time courses of plasma drug concentrations for 4 doses of JR-171 (parts 1 and 2)
SD, standard deviation; EOA, end of administration.
HS concentrations in the CSF decreased in all subjects after treatment with JR-171, while DS concentrations in the CSF decreased in all but 1 subject treated with JR-171 in parts 1 and 2, respectively. (Figure 3).
Figure 3.
Changes in the substrate levels in the cerebrospinal fluid (CSF) (parts 1 and 2)
HS, heparan sulfate; DS, dermatan sulfate; SD, standard deviation.
HS and DS concentrations in the urine decreased in the part 1 subjects at week 5 and in the part 2 post-HSCT subjects and those switched from laronidase at week 13 (Figure 4). A subject naive to laronidase taking JR-171 at a dose of 4.0 mg/kg in part 2 showed a marked decrease in urinary DS concentration at week 13 and stable urinary HS concentrations between weeks 8 and 13.
Figure 4.
Changes in urinary HS and DS concentrations
HS, heparan sulfate; DS, dermatan sulfate.
Serum HS concentrations decreased from baseline while serum DS concentrations remained relatively stable in the part 1 subjects at week 5, as well as among the switched or post-HSCT part 2 subjects at week 13 (Figure 5). In the subject naive to laronidase dosed at 4.0 mg/kg JR-171 in part 2, their serum HS concentration decreased from weeks 2 to 6 and remained stable thereafter until week 13, while significant reductions in serum DS concentration were noted at week 13, with a relative change of −81.5% from baseline.
Figure 5.
Changes in serum HS and DS concentrations
HS, heparan sulfate; DS, dermatan sulfate.
The study also evaluated anti-drug antibodies, as they can affect the safety and efficacy of enzyme products. Table S2 summarizes developments of anti-IDUA antibodies, while Table S3 shows both anti-JR 171 antibodies and neutralizing antibodies against M6P and transferrin receptors through part 2 of the trial. The presence or novel development of anti-IDUA antibodies or anti-JR-171 antibodies as well as neutralizing antibodies did not seem to affect overall efficacy in terms of pharmacokinetic parameters, pharmacodynamic effects in substrate reductions, and severity/frequency of infusion-associated reactions (IARs).
In terms of adjusted liver and spleen volumes, no substantial change was observed in any of the subjects in part 1 or in the switched or post-HSCT subjects in part 2, whereas the subjects naive to laronidase showed marked decreases in volume (Figure 6). Cardiac evaluation in part 2 revealed that left ventricular posterior thickness and interventricular septal thickness were both slightly increased at week 13 from baseline in the switched or post-HSCT subjects. Other echocardiographic parameters remained relatively stable during the study (details are given in Table S4). The 6 min walk test results improved from baseline at week 13 in some of the subjects in part 2 (Figure S1). Clinical neuropsychiatric and behavioral changes observed by investigators, nurses, family members, and caregivers have been collected and summarized as narrative reports (Table S5). The changes noted in 6 subjects include improvements in obstructive sleep apnea, gross motor functions, verbal communication, and agitation.
Figure 6.
Changes in liver and spleen volumes of the subjects in part 2
Discussion
This article presents the results of the first-in-human study of JR-171 in patients with MPS I, in which the safety, tolerability, and exploratory efficacy of the drug were examined. No safety issues necessitated discontinuation of treatment for any of the enrolled subjects, although some of the IARs commonly associated with ERT with laronidase (erythema, urticaria, rash, pyrexia, and diarrhea) were also observed in this study at frequency and severity levels comparable to those reported for laronidase. Therefore, the safety profile of JR-171 seems to be similar to that of laronidase, but this needs to be further corroborated in an ongoing extension study and an upcoming pivotal phase 3 study.
Pharmacokinetic analysis showed, firstly, a clear proportional dose-response relationship for the weekly doses of 2.0 and 4.0 mg/kg based on the decreases we observed in the urine, serum, and CSF substrate levels. Secondly, the lack of significant differences in Cmax and AUC0-t between parts 1 (single administration) and 2 (repeated administrations) suggests that the drug is duly eliminated and unlikely to accumulate enough to affect its efficacy and safety. This also means that anti-drug antibodies against JR-171 are either nonexistent or are too limited to significantly affect the pharmacokinetic parameters. On the basis of these findings, we deem weekly doses of 2 and 4 mg/kg JR-171 appropriate for further testing in late-phase clinical development. Also, one weekly administration seems to be able to provide sufficient drug exposure and efficacy.
HS and DS concentrations in the CSF decreased from baseline throughout the study, which suggests successful delivery of the drug through the BBB to reduce intracerebral substrate accumulations that are duly reflected in the CSF.10 This replicates the evidence of drug delivery through the BBB found with pabinafusp alfa, which utilizes the same mechanism of TfR-mediated transcytosis to treat MPS II.11,13 Also, some positive changes in neurocognition and behavior (e.g., attention, gross motor functions, sleep apnea, and snoring) were observed clinically in 7 patients in part 2. These findings, albeit not quantifiable, may be interpreted as tangible clinical manifestations suggestive of the drug’s efficacy in ameliorating neuronopathy after the drug is delivered into and widely distributed across the brain, which will allow the multifaceted neuropsychiatric symptoms resulting from the affected higher brain functions14 to be addressed. This juxtaposition of quantifiable CNS biomarker improvements and clinically observed positive changes in CNS-related symptoms was also seen in the clinical trials of pabinafusp alfa used to treat patients with MPS II.15,16,17,18 We look forward to further consolidation of these promising results with JR-171 in an upcoming pivotal study on its efficacy against the CNS symptoms of MPS I.
Reductions in urine HS and DS levels and serum HS levels were observed in all subjects, whereas serum DS concentrations remained stable after JR-171 treatment. After 12 weeks of JR-171 treatment, the subjects who had been switched from laronidase or were post-HSCT showed a greater than 30% reduction in the mean relative change from baseline in urinary HS and DS concentrations, along with a more than 28% decrease in the mean relative change from baseline in serum HS concentration. These results suggest that the efficacy of JR-171 against somatic symptoms is comparable to that of laronidase. This needs to be verified in the long-term extension study and pivotal phase 2/3 study of JR-171. As no significant improvements in the somatic endpoints were observed in this 13 week study, long-term monitoring of these endpoints is being conducted in the extension study, while the pivotal study will provide more robust data on the effects of JR-171 on somatic symptoms.
There are several limitations to this study. First, it was an open study with no comparator arm. Second, the study duration was 12 weeks, which was sufficient to show rapid reductions in HS concentrations in the CSF but not long enough to substantiate the neurodevelopmental effects of the drug. A longer comparative study with laronidase is expected to address these limitations and help establish the efficacy of JR-171 against CNS disorders, in particular, progressive neurocognitive impairments to be quantitatively and qualitatively examined by established neuropsychological and neurodevelopmental scales.
In conclusion, weekly intravenous administration of JR-171 at doses of 2.0 or 4.0 mg/kg for up to 12 weeks was safe and well tolerated. The efficacy of JR-171 against the CNS symptoms of MPS I was suggested by the marked decrease in substrate concentrations observed in the CSF, along with the positive neurocognitive and behavioral changes seen in some of the subjects. Its somatic efficacy was also shown by the reductions in serum and urinary substrate concentrations in both the naive subjects and the subjects switched from laronidase alike, suggesting that the efficacy of JR-171 against somatic symptoms is comparable to that of laronidase. An ongoing extension study is taking place to substantiate the safety and efficacy of the drug beyond 13 weeks of treatment. It should also provide more data to corroborate the correlation between JR-171-induced reductions in substrate concentrations and improvements in clinical symptoms. Overall, we believe that the positive results of this phase 1/2 study warrant a pivotal phase 2/3 study to confirm the long-term safety and efficacy of JR-171.
Materials and methods
Study design
This was a phase 1/2, open-label, multicenter, multinational study to evaluate the safety, pharmacokinetic (PK), and preliminary efficacy of JR-171 in patients with MPS I (ClinicalTrials.gov: NCT04227600).19 The study was conducted at 6 sites in the United States, Brazil, and Japan and complied with the Declaration of Helsinki. The protocol and procedures regarding informed consent were reviewed and approved by the institutional review board of each participating institution. All patients or their legal guardian(s) submitted a signed, informed consent form prior to enrollment.
The study consisted of a 4 week period (part 1) and a 12 week period (part 2), which were preceded by an observation period of 12 weeks for the patients who switched from previous ERT with laronidase.
Participants and procedures
A total of 18 patients were enrolled in the study, 4 in part 1 and 14 in part 2. In part 1, subjects in Japan and Brazil aged 18 years or older were enrolled to receive 4 weekly intravenous administrations of JR-171 in a dose-escalating manner (0.1, 1.0, 2.0, and 4.0 mg/kg). In part 2, subjects in the United States aged ≥2 years along with subjects in Japan and Brazil of any age were enrolled to receive 12 weekly intravenous administrations of JR-171. One subject in the 6–17 years age group and one aged ≤5 years were given the drug at three doses in a dose-escalating manner (1.0, 2.0, and 4.0 mg/kg), followed by the others, who were subsequently given fixed doses of either 2.0 or 4.0 mg.
Randomization and masking
In part 2, subjects without previous HSCT treatment were stratified by their phenotype (Scheie or other than Scheie), and an Interactive Response Technology system was used to randomize them into one of two treatment groups (2.0 or 4.0 mg/kg/week JR-171), except for the two subjects assigned to receive JR-171 in a dose-escalating manner. The subjects with previous HSCT treatment were allocated without stratification by their phenotype.
This was an open-label study with no masking.
Outcomes
The primary endpoints were safety evaluations, which included adverse events, adverse drug reactions, anti-drug antibodies, and IARs, as well as data from laboratory tests and electrocardiography.
PK evaluations were performed as the secondary endpoints at all dosing points in part 1 of the study and at 3 dosing points in part 2. The time points for blood sampling were before dosing, 1 h after the start of dosing, immediately after the end of administration, and then 3, 6, and 21 h afterward.
In our evaluation of efficacy, we focused on drug delivery to the CNS as measured by reductions in the substrate concentrations in the CSF and CSF opening pressure. CSF was obtained by lumber puncture prior to the first administration in each part of the study (week 4 in part 1 and week 12 in part 2). HS and DS levels were quantified as described previously in the studies on MPS II.11,12 To evaluate efficacy against somatic symptoms, serum and urine HS and DS concentrations and 6 min walk distances were measured. Additionally, subjects underwent computed tomography to assess hepatomegaly. Echocardiography was used to evaluate cardiac structures and functions.
Statistical analysis
Safety analyses were performed on the safety set, which included all subjects who gave informed consent. All adverse events were coded into the preferred term (PT) and system organ class (SOC) according to the latest version of the Medical Dictionary for Regulatory Activities (MedDRA) v.25.1 (developed by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use). Information on all adverse events and adverse drug reactions (number of subjects, incidence proportion with a two-sided 95% confidence interval [CI], and number of events) were recorded separately, depending on whether the events occurred before or after the first dose of JR-171.
PK parameters were calculated for each subject using a noncompartment model analysis. In estimating the parameters, plasma drug concentration data were adjusted by baseline values, and the actual blood collection time was used. PK was analyzed in the PK set, which included subjects for whom data on plasma drug concentrations after JR-171 administration were available.
Efficacy was assessed in the full analysis set, which included subjects for whom data on at least one exploratory endpoint after JR-171administration were available. Descriptive statistics of efficacy endpoints were calculated. Statistical analysis was performed with the SAS v.9.4 statistical software package (SAS Institute, Cary, NC, USA).
Data and code availability
The data generated in this study are presented within the article and its supplemental information files. Other data are available upon request.
Acknowledgments
The authors are grateful to all the investigators and patients for their contributions and commitment to the study. We also acknowledge with gratitude the helpful suggestions and guidance concerning neurodevelopmental assessment provided by Elsa Shapiro of the University of Minnesota, Minneapolis, and we thank Satoshi Saito, Tsubasa Hirayama, and Tsuyoshi Kurihara of JCR Pharmaceuticals for their support at various stages of the study. Special thanks are due to Timothy Minton of Keio University, Tokyo, for his immense editorial help.
Author contributions
S.S., T.I., and S.K. conceived and designed the study, and all other authors assisted in its design. R.G., A.M.M., P.H., T. Hamazaki., T.K., and R.K. conducted the trial as its principal investigators. N.T., H.M., and Y.S. drafted the manuscript. T.I. designed and conducted all statistical analyses. K.M., H.S., and T. Hirato. were responsible for the PK assay. All authors were involved in the interpretation and critical review of the data, and all approved the final version prepared by Y.S. All authors had full access to the data used in the study, and the corresponding author had final responsibility for the completion of the manuscript and the decision to submit it for publication.
Declaration of interests
This clinical trial was funded by JCR Pharmaceuticals. The funder participated in the design of the trial, the collection, analysis and interpretation of the data, and the writing of the report; it also dealt with all the regulatory requirements for carrying out the trial. The funder is also the sole intellectual property holder as well as the manufacturer of lepunafusp alfa. P.H. has received consulting fees/other remuneration from Aeglea, Alexion Pharmaceuticals, ArmaGen, Audentes, AVROBIO, BioMarin Pharmaceutical, Capsida Biotherapeutics, Chiesi, Denali Therapeutics, Edigene, Enzyvant, Fondazione Telethon, Grace Science, Inventiva Pharma, JCR Pharmaceuticals, Orphazyme, Paradigm Biopharma, PTC Therapeutics, Novel Pharma, Orchard Therapeutics, Rallybio, REGENXBIO, Renoviron, Sangamo Therapeutics, Saliogene, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical and has received research support from Alexion Pharmaceuticals, Adrenas, ArmaGen, Amicus, Ascendis, ASPA, Azafaros, BioMarin Pharmaceutical, Calcilytics, Denali, Enzyvant, Homology, Inventiva Pharma, JCR, Orphazyme, Prevail, QED, RegenXbio, Sangamo Therapeutics, Swedish Orphan Biovitrum, Takeda, and Ultragenyx Pharmaceutical. R.G. has conducted consultancy for JCR Pharmaceuticals and has been awarded grants and research support from JCR, Sanofi, Cyco, Takeda, Azakalos, Paradigm, and Regenx Bio. A.M.M. has conducted consultancy for, and has been awarded grants and research support from, JCR Pharmaceuticals. T.Hamazaki. has conducted consultancy for JCR Pharmaceuticals and has been awarded grants and research support from BioMarin. T.K. has conducted consultancy for JCR Pharmaceuticals and has been awarded grants and research support from Sumitomo Pharma and Takeda Pharmaceuticals. R.K. has conducted consultancy for JCR Pharmaceuticals. All other authors are employed by JCR Pharmaceuticals.
Footnotes
Supplemental information can be found online at https://doi.org/10.1016/j.ymthe.2024.01.009.
Supplemental information
References
- 1.Munoz-Rojas MV S.A., Giugliani R. In: Mucopolysaccharidoses Update. Tomatsu L.C.S., Giugliani R., Harmatz P., Scarpa M., Węgrzyn G., Orii T., editors. Nova science publishers; 2018. Mucopolysaccharidosis type I: Clinical features, biochemistry, diagnosis, genetics, and treatment; pp. 143–164. [Google Scholar]
- 2.Tylki-Szymanska A. 2nd Edition. Wiley Blackwell; 2022. Mucopolysaccharidosis Type I (MPS I) [Google Scholar]
- 3.Khan S.A., Peracha H., Ballhausen D., Wiesbauer A., Rohrbach M., Gautschi M., Mason R.W., Giugliani R., Suzuki Y., Orii K.E., et al. Epidemiology of mucopolysaccharidoses. Mol. Genet. Metab. 2017;121:227–240. doi: 10.1016/j.ymgme.2017.05.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Beck M., Arn P., Giugliani R., Muenzer J., Okuyama T., Taylor J., Fallet S. The natural history of MPS I: global perspectives from the MPS I Registry. Genet. Med. 2014;16:759–765. doi: 10.1038/gim.2014.25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Muenzer J., Wraith J.E., Clarke L.A., International Consensus Panel on Management and Treatment of Mucopolysaccharidosis I Mucopolysaccharidosis I: management and treatment guidelines. Pediatrics. 2009;123:19–29. doi: 10.1542/peds.2008-0416. [DOI] [PubMed] [Google Scholar]
- 6.de Vasconcelos P., Lacerda J.F. Hematopoietic Stem Cell Transplantation for Neurological Disorders: A Focus on Inborn Errors of Metabolism. Front. Cell. Neurosci. 2022;16 doi: 10.3389/fncel.2022.895511. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Hampe C.S., Wesley J., Lund T.C., Orchard P.J., Polgreen L.E., Eisengart J.B., McLoon L.K., Cureoglu S., Schachern P., McIvor R.S. Mucopolysaccharidosis Type I: Current Treatments, Limitations, and Prospects for Improvement. Biomolecules. 2021;11 doi: 10.3390/biom11020189. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Lum S.H., Miller W.P., Jones S., Poulton K., Ogden W., Lee H., Logan A., Bonney D., Lund T.C., Orchard P.J., Wynn R.F. Changes in the incidence, patterns and outcomes of graft failure following hematopoietic stem cell transplantation for Hurler syndrome. Bone Marrow Transpl. 2017;52:846–853. doi: 10.1038/bmt.2017.5. [DOI] [PubMed] [Google Scholar]
- 9.de Ru M.H., Boelens J.J., Das A.M., Jones S.A., van der Lee J.H., Mahlaoui N., Mengel E., Offringa M., O'Meara A., Parini R., et al. Enzyme replacement therapy and/or hematopoietic stem cell transplantation at diagnosis in patients with mucopolysaccharidosis type I: results of a European consensus procedure. Orphanet J. Rare Dis. 2011;6:55. doi: 10.1186/1750-1172-6-55. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Sato Y., Minami K., Hirato T., Tanizawa K., Sonoda H., Schmidt M. Drug delivery for neuronopathic lysosomal storage diseases: evolving roles of the blood brain barrier and cerebrospinal fluid. Metab. Brain Dis. 2022;37:1745–1756. doi: 10.1007/s11011-021-00893-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Sonoda H., Takahashi K., Minami K., Hirato T., Yamamoto T., So S., Tanizawa K., Schmidt M., Sato Y. Treatment of Neuronopathic Mucopolysaccharidoses with Blood–Brain Barrier-Crossing Enzymes: Clinical Application of Receptor-Mediated Transcytosis. Pharmaceutics. 2022;14 doi: 10.3390/pharmaceutics14061240. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Kida S., Koshimura Y., Yoden E., Yoshioka A., Morimoto H., Imakiire A., Tanaka N., Tanaka S., Mori A., Ito J., et al. Enzyme replacement with transferrin receptor-targeted alpha-L-iduronidase rescues brain pathology in mucopolysaccharidosis I mice. Mol. Ther. Methods Clin. Dev. 2023;29:439–449. doi: 10.1016/j.omtm.2023.05.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Sonoda H., Morimoto H., Yoden E., Koshimura Y., Kinoshita M., Golovina G., Takagi H., Yamamoto R., Minami K., Mizoguchi A., et al. A Blood-Brain-Barrier-Penetrating Anti-human Transferrin Receptor Antibody Fusion Protein for Neuronopathic Mucopolysaccharidosis II. Mol. Ther. 2018;26:1366–1374. doi: 10.1016/j.ymthe.2018.02.032. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Sato Y., Okuyama T. Novel Enzyme Replacement Therapies for Neuropathic Mucopolysaccharidoses. Int. J. Mol. Sci. 2020;21 doi: 10.3390/ijms21020400. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Okuyama T., Eto Y., Sakai N., Minami K., Yamamoto T., Sonoda H., Yamaoka M., Tachibana K., Hirato T., Sato Y. Iduronate-2-Sulfatase with Anti-human Transferrin Receptor Antibody for Neuropathic Mucopolysaccharidosis II: A Phase 1/2 Trial. Mol. Ther. 2019;27:456–464. doi: 10.1016/j.ymthe.2018.12.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Okuyama T., Eto Y., Sakai N., Nakamura K., Yamamoto T., Yamaoka M., Ikeda T., So S., Tanizawa K., Sonoda H., Sato Y. A Phase 2/3 Trial of Pabinafusp Alfa, IDS Fused with Anti-Human Transferrin Receptor Antibody, Targeting Neurodegeneration in MPS-II. Mol. Ther. 2021;29:671–679. doi: 10.1016/j.ymthe.2020.09.039. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Giugliani R., Martins A.M., So S., Yamamoto T., Yamaoka M., Ikeda T., Tanizawa K., Sonoda H., Schmidt M., Sato Y. Iduronate-2-sulfatase fused with anti-hTfR antibody, pabinafusp alfa, for MPS-II: A phase 2 trial in Brazil. Mol. Ther. 2021;29:2378–2386. doi: 10.1016/j.ymthe.2021.03.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Giugliani R., Martins A.M., Okuyama T., Eto Y., Sakai N., Nakamura K., Morimoto H., Minami K., Yamamoto T., Yamaoka M., et al. Enzyme Replacement Therapy with Pabinafusp Alfa for Neuronopathic Mucopolysaccharidosis II: An Integrated Analysis of Preclinical and Clinical Data. Int. J. Mol. Sci. 2021;22 doi: 10.3390/ijms222010938. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.2022. Phase I/II Study of JR-171 ㏌ Patients with Mucopolysaccharidosis Type I.https://clinicaltrials.gov/study/NCT04227600?cond=MPS%20I&intr=JR-171%20%5C(lepunafusp%20alfa%5C)&rank=2 [Google Scholar]
Associated Data
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Supplementary Materials
Data Availability Statement
The data generated in this study are presented within the article and its supplemental information files. Other data are available upon request.