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US-20260124283-A1 - METHODS FOR TREATING FARBER DISEASE

US20260124283A1US 20260124283 A1US20260124283 A1US 20260124283A1US-20260124283-A1

Abstract

Methods of treating Farber disease using particular doses and pharmacokinetic profiles are disclosed.

Inventors

  • ERIC GAUKEL
  • Brante SAMPEY

Assignees

  • ACERAGEN, INC.

Dates

Publication Date
20260507
Application Date
20250321

Claims (20)

  1. 1 . A method of treating Farber disease in a human subject in need thereof, the method comprising administering to the human subject purified recombinant human acid ceramidase (rhAC) in activated form at a dose of about 1 mg/kg to about 10 mg/kg.
  2. 2 . The method of claim 1 , wherein the dose is about 1 mg/kg to about 5 mg/kg.
  3. 3 . The method of claim 1 , wherein the dose is about 1 mg/kg.
  4. 4 . The method of claim 1 , wherein the dose is about 2 mg/kg.
  5. 5 . The method of claim 1 , wherein the dose is about 2.5 mg/kg.
  6. 6 . The method of claim 1 , wherein the dose is about 5 mg/kg.
  7. 7 . The method of claim 1 , wherein the dose is about 10 mg/kg.
  8. 8 . The method of claim 1 , wherein the purified recombinant human acid ceramidase (rhAC) in activated form is RVT-801, wherein RVT-801 comprises a recombinantly produced acid ceramidase (rhAC) purified to a purity of at least 95% activated form by a process comprising the steps of subjecting the recombinantly produced acid ceramidase to at least two chromatography steps selected from i) cation exchange chromatography; ii) hydrophobic interaction chromatography (HIC); and iii) anion exchange chromatography; and further subjecting the rhAC in solution to one or more viral inactivation steps, wherein in the one or more viral inactivation steps the rhAC solution is titrated to a pH of 3.7 or less.
  9. 9 . The method of claim 8 , wherein the recombinantly produced acid ceramidase is subjected to three chromatography steps consisting essentially of i) cation exchange chromatography; ii) hydrophobic interaction chromatography (HIC); and iii) anion exchange chromatography.
  10. 10 . The method of claim 8 , wherein the one or more viral inactivation steps is performed before the chromatography steps.
  11. 11 . The method of claim 8 , wherein the one or more viral inactivation steps is conducted before one of the at least two chromatography steps.
  12. 12 . The method of claim 8 , wherein the one or more viral inactivation steps is conducted before at least two of the at least two chromatography steps.
  13. 13 . The method of claim 8 , wherein the titration to pH 3.7 is performed with citric acid.
  14. 14 - 15 . (canceled)
  15. 16 . The method of claim 1 , wherein the purity of the purified recombinant human acid ceramidase (rhAC) in activated form is at least 95% by weight.
  16. 17 - 21 . (canceled)
  17. 22 . The method of claim 1 , wherein the dose in a human adult subject is about 0.8 mg/kg.
  18. 23 . The method of claim 1 , wherein the dose in a human child is about 1.2 mg/kg.
  19. 24 - 40 . (canceled)
  20. 41 . The method of claim 1 , wherein the purified recombinantly produced acid ceramidase has no detectable acid sphingomyelinase activity.

Description

RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 17/736,690, filed May 4, 2022, which is a continuation of U.S. patent application Ser. No. 17/489,096, filed Sep. 29, 2021, which is a continuation of Ser. No. 16/263,700, filed Jan. 31, 2019, which claims the benefit to and priority of U.S. Provisional Application No. 62/625,763, filed on Feb. 2, 2018, each of which are incorporated herein by reference in their entirety. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on Dec. 14, 2025, is named 771330.500013_SL.xml and is 10,831 bytes in size. BACKGROUND Farber disease, a lysosomal storage disorder (LSD), is a condition that was first described in 1952 in a 14-month-old infant with granulomatous lesions on multiple joints and evidence of lipid storage. Over the ensuing decade other similar cases were described, all of which demonstrated similar lesions and often exhibited a characteristic “hoarse” cry or voice due to the presence of lesions on the larynx. The involvement of other organ systems in some of these patients, including the lung, liver, spleen and central nervous system (CNS), also was noted. Previously, treatment for Farber disease patients has been symptomatic and principally aimed at reducing pain. Hematopoietic stem cell transplantation (HSCT) has been undertaken in a limited number of patients, and overall the outcome has been positive provided that the transplant procedure itself was successful. Successfully transplanted patients exhibit significant reduction in pain, increased motility and mobility, and in some cases shrinking and complete resolution of the subcutaneous nodules. However, successful transplantation requires histocompatible donor cells, and exposes patients to invasive and potentially dangerous immunosuppressant regimes. One alternative to HSCT is gene therapy in which autologous donor cells are transduced with a vector expressing the therapeutic protein, obviating the need for histocompatible donors. This approach has been evaluated in a Farber disease knock-in mouse model and resulted in reduction of tissue ceramides and macrophage infiltration. However, there continues to be a need for improved therapies for treating Farber disease. Previous studies in a murine model of severe Farber disease have established a broad therapeutic dose range for recombinant human acid ceramidase (“rhAC”), where efficacy was characterized based on reduction of accumulated tissue ceramide and reduction of pro-inflammatory cytokines. The disclosures in International Application No. PCT/US18/13509 filed Jan. 12, 2018 (published as WO 2018/132667 on Jul. 18, 2018), and in He et al., 2017 (February), “Enzyme replacement therapy for Farber disease: Proof-of-concept studies in cells and mice,” BBA Clin. 13 (7): 85-96, are hereby incorporated by reference in their entirety. However, these studies did not establish exposure targets. Prediction of a human equivalent dose (HED) from a therapeutic dose determined during nonclinical studies in the murine model of severe Farber disease requires an understanding of the enzyme's pharmacokinetics (“PK”) and tissue distribution (“TD”). The present subject matter fulfills such needs, as discussed herein. SUMMARY OF THE INVENTION Juvenile, healthy CD-1 mice are considered the parental strain of the Farber mouse (Farber disease mouse model used in this description and Examples). FIG. 3 shows that the juvenile CD-1 mouse rhAC (RVT-801) pharmacokinetic profile is similar to the Farber mouse experimental rhAC activity profile in circulation. This indicates that the juvenile CD-1 mouse provides an appropriate approximation of the Farber mouse PK, and as such, CD-1 mice were used to characterize the murine pharmacokinetics of RVT-801, since Farber mice are frail, difficult to mate, and not numerous enough to conduct a full PK assessment. Thus, based on a small number of Farber mice and with limited overlapping data points between strains, the data reported in the description and Examples herein suggest that systemic rhAC (e.g., RVT-801) exposure in CD-1 mice approximates that in Farber mice, and may represent the minimum systemic levels of rhAC in Farber mice following a single dose of RVT-801 administered intraperitoneally. Recombinant human AC (e.g., RVT-801) has been shown in the description and Examples to distribute extensively to tissues associated with ceramide accumulation in a Farber disease murine model (e.g., liver, spleen, and lung). Measurement of systemic levels of recombinant human AC (e.g., RVT-801) could, therefore, potentially underestimate exposure in relevant tissue of human subjects suffering from Farber disease. Thus, relying on simple allometry to scale a dose in nonclinical species to humans may not provide adequate estimates of tissue exposure to impa