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EP-4237411-B1 - AVACOPAN AND RELATED COMPOUNDS OF FORMULA (I) FOR USE IN THE TREATMENT OF HIDRADENITIS SUPPURATIVA IN PATIENTS HAVING A HURLEY SCORE OF STAGE III

EP4237411B1EP 4237411 B1EP4237411 B1EP 4237411B1EP-4237411-B1

Inventors

  • LI, SHIJIE
  • SINGH, RAJINDER
  • SCHALL, THOMAS J.
  • STAEHR, PETER

Dates

Publication Date
20260506
Application Date
20211027

Claims (8)

  1. A compound, which is of Formula I , or is a pharmaceutically acceptable salt thereof, for use in a method of treating Hidradenitis Suppurativa (HS) in a subject in need thereof, wherein said subject has been diagnosed with HS, having a Hurley score of Stage III, and receives 30 mg of the compound twice daily, wherein each R 1 is independently selected from the group consisting of CH 3 , CF 3 , CH 2 CH 3 , Cl, 1-pyrrolidine, -O-CH(CH 3 ) 2 , and CH 2 OH; and each R 2 is independently selected from the group consisting of CH 3 and F.
  2. The compound for use of claim 1, wherein the compound is selected from the group consisting of or a pharmaceutically acceptable salt thereof.
  3. The compound for use of claim 1 , wherein the compound is or a pharmaceutically acceptable salt thereof.
  4. The compound for use of claim 1 , wherein the compound is Avacopan, having the formula or a pharmaceutically acceptable salt thereof.
  5. The compound for use of any one of claims 1 to 4 wherein the subject receives treatment for 12 weeks.
  6. The compound for use of any one of claims 1 to 4 wherein the subject receives treatment for 26 weeks.
  7. The compound for use of any one of claims 1 to 4 wherein the subject receives treatment for 52 weeks.
  8. The compound for use of any one of claims 1 to 4 wherein the subject receives chronic treatment.

Description

BACKGROUND OF THE INVENTION Hidradenitis suppurativa (HS), also called acne inversa, is a chronic inflammatory skin disease characterized by inflammatory nodule, abscess, sinus and fistula formation, and scarring of the skin, most commonly in apocrine gland rich areas such as the axilla, inframammary area, inguinal area, perineum, and perianal area. In its moderate and severe forms, HS is debilitating and causes significant discomfort, pain, anxiety and depression, as well as impairment of quality of life. The exact cause of HS has not been identified, although genetic defects in the gene encoding for gamma-secretase have been described in subjects with HS. Potential target proteins include Notch, E-cadherin, and nicastrin. Notch plays an important role in hair follicle development, and a defect in Notch may lead to formation of epidermal cysts, dysregulation of normal T-cell mediated immune responses, and suppression of Toll-like receptor-4-induced pro-inflammatory macrophage mediated cytokine responses (Radtke et al, 2010; Wang et al, 2010). Smoking and obesity have been associated with HS (Prens and Deckers, 2015) as well as, excessive sweating, androgen dysfunction, or possible genetic causes. Some reports suggest that HS is, at least in part, a neutrophil mediated disease. Current therapy for subjects with HS includes local and systemic antibiotics, pain medication, and anti-TNF-α agents such as adalimumab. Other drugs such as cyclosporin A, dapsone, and isotretinoin have been used with limited success (Napolitano et al, 2017). Despite the treatment options available, most patients only partially and/or temporarily respond. A recent treatment option advanced in US2018/0280530 and US2018/028425 is the use of a C5a targeting antibody to treat patients suffering from HS. C5a is known to be a potent chemotactic anaphylatoxin, and the binding of C5a to C5aR modulates leucocyte trafficking, migration, and activation. However, targeting C5a directly with an antibody disrupts not only the C5a/C5aR axis, but also disrupts C5a binding to the C5L2 receptor. The C5a/C5L2 pathway includes beneficial biological functions including limiting or suppressing the pro-inflammatory response caused by C5a (Gerard et al. J Biol Chem. 2005. 280(48):39677-80, Wang et al. J Immunol. 2013. 191(8):4001-9). In fact, disrupting the C5a-C5L2 pathway has been shown to exacerbate inflammation resulting in a more severe reaction to C5a. (Xiao et al. J Am Soc Nephrol. 2014. 25(2):225-31, Karsten et al., Front Immunol. 2018, 15;9:488). Thus, the direct targeting of C5a involves blocking signaling pathways associated with mitigating C5a response. Moreover, antibody treatments carry other disadvantages such as the need for intravenous delivery, the potential for patients to develop human anti-chimeric antibodies (HACAs), the need for patients to travel to a medical center to receive treatment, and reduced patient compliance. As such, there remains a need in the art to identify and develop orally available compounds useful in the treatment of Hidradenitis Suppurativa (HS) and related cutaneous neutrophilic inflammatory diseases that do not block the C5a/C5L2 axis, thereby preserving the beneficial functions of the C5L2 pathway. US 2018/282425 and US 2018/280530 relate to inhibitors of C5a activity and their use in the treatment of cutaneous, neutrophilic, inflammatory diseases in a subject. WO 2020/112961 relates to solid solution capsule formulations and methods of treating individuals suffering from or susceptible to a disease or disorder involving pathologic activation of C5a receptors. BRIEF SUMMARY OF THE INVENTION The present disclosure provides a compound, which is of Formula I , or is a pharmaceutically acceptable salt thereof, for use in a method of treating Hidradenitis Suppurativa (HS) in a subject in need thereof, wherein said subject has been diagnosed with HS, having a Hurley score of Stage III, and receives 30 mg of the compound twice daily, wherein each R1 is independently selected from the group consisting of CH3, CF3, CH2CH3, Cl, 1-pyrrolidine, -O-CH(CH3)2, and CH2OH; and each R2 is independently selected from the group consisting of CH3 and F. Other objects, features, and advantages of the present invention will be apparent to one of skill in the art from the following detailed description and figures. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows a schematic of the Phase II study design. DETAILED DESCRIPTION OF THE INVENTION I. General The current disclosure provides compounds and dosing regimens for the treatment of Hidradenitis Suppurativa and specific patient populations thereof. The compounds in the methods described herein specifically target C5aR and do not disrupt the C5a-C5L2 interaction. Advantageously, the C5aR inhibitors disclosed in this applicaiton effectively modulate neutrophil migration and activation by blocking the C5a-C5aR interaction while not blocking the C5a-C5L2 axis. Without being bound to any p