A Study in Participants With Anti-NMDAR Encephalitis and Anti-NMDAR Autoantibody-Associated Psychiatric Disease

Inclusion Criteria69

• Individuals eligible to participate in Cohort A must meet all the following criteria:
• The participant is a male or female who is of legal age to provide informed consent per local regulations, and ≤65 years of age at the time of informed consent. For the purposes of this study, the minimum age is 19 years in South Korea and 18 years in Australia.
• The participant, or their legally authorized representative (LAR), must be willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to any research-related procedures. For participants who are unable to sign the consent form themselves, informed consent must be obtained from their LAR in accordance with local regulations and ethical guidelines.
• The participant, or their LAR, must ensure willingness and ability to comply with all study procedures to the extent possible, as determined by the Investigator.
• The participant has a diagnosis of ANRE according to the Graus et al criteria (Graus et al, 2016), with symptom onset >9 months to ≤36 months (or ≤120 months with Sponsor approval) prior to Week 0, Day 0.
• The participant has a positive cell-based assay result for CSF anti-NMDAR IgG autoantibody within 9 months of Week 0, Day 0. Participants without a positive CSF anti-NMDAR IgG autoantibody result within 9 months of Week 0, Day 0 may undergo a LP at Screening prior to the first study drug administration to confirm the presence of anti-NMDAR IgG autoantibodies in CSF (see Section 7.6.4.6.1).
• Note: If the participant has a documented history of positive anti-NMDAR IgG autoantibodies in CSF >9 months of Week 0, Day 0, they may be considered for inclusion in the study with confirmed positive anti-NMDAR IgG autoantibodies in serum at Screening at the discretion of the Investigator in collaboration with the Sponsor (see Section 7.6.4.6.1).
• Participants treated with IVIG must have completed treatment at least 7 days prior to Week 0, Day 0.
• Participants previously treated with immunotherapy must be receiving a stable dose (per Investigator discretion) for ≥1 month before Week 0, Day 0.
• Participants who are taking psychiatric medications (anti-depressants and antipsychotics) must remain on stable background psychiatric medications for at least 4 weeks prior to Week 0, Day 0 and for at least the first 6 weeks after Week 0, Day 0.
• Adequate disease burden as defined as any one of the following (a to c) at Screening and Week 0, Day 0:
• a. Two of the following: i. WAIS-IV immediate recall score <7 ii. TMT-A >40 seconds iii. RAVLT score <7 b. BDI-II total score ≥20. c. EQ 5D-5L score "moderate" or higher on at least 3 of the 5 items. Exceptions may be granted on a case-by-case basis in consultation with the Sponsor.
• No active malignancy (see Section 7.6.3.3) or residual teratoma. Prior teratoma must be fully resected ≥1 week before Week 0, Day 0 with no evidence of recurrence per work-up (imaging and tumor markers).
• Note: Discovery of a contralateral teratoma after study initiation will not be considered a protocol deviation. The event must be reported, managed per standard of care, and reviewed with the Sponsor Medical Monitor.
• Participants must have undergone appropriate cancer screening prior to study enrollment. The specific series of investigations used for each participant will occur according to the judgment of the treating Investigator (for example, MRI or CT of the chest, abdomen, and pelvis, and pelvic ultrasound for female participants) to exclude the presence or recurrence of an underlying neoplasm, such as ovarian teratoma or other malignancy. Documentation of imaging results must be available in the source documents.
• Sexually active female participants of childbearing potential and male participants with female partner(s) of childbearing potential must be willing to use a highly effective method of contraception during the study (from the time of providing consent) until at least 90 days after the last study drug administration, or longer if required by local regulations.
• In South Korea, contraception must be continued for 6 months after the last study drug administration in accordance with MFDS requirements.
• Examples of highly effective methods of contraception are provided in Appendix 1. The contraceptive methods used for male and female participants must be documented in the source documents.
• Female participants of childbearing potential must have a negative pregnancy test at Screening and be willing to have additional pregnancy tests during the study. Females considered not of childbearing potential include those who are surgically sterile (surgical bilateral oophorectomy, bilateral salpingectomy, or hysterectomy) confirmed by medical history or are post-menopausal (i.e., no menstrual bleeding for more than 2 years without an alternative medical cause and confirmation with more than 1 follicle stimulating hormone \[FSH\] measurement of at least >40 IU/L \[or higher per local institutional guidelines\]).Women of non-childbearing potential are not required to use any contraceptive method (see Appendix 1).
• Male participants must agree not to donate sperm, and female participants must agree not to donate eggs from the first study drug administration and until at least 90 days after the last dose of the study drug, or longer if required by local regulations.
• In South Korea, male participants must refrain from donating sperm for 6 months after the last study drug administration in accordance with MFDS requirements.
• Compliance with these restrictions must be documented at Screening and confirmed throughout the study.
• Individuals eligible to participate in Cohort B or C must meet all of the following criteria:
• The participant is a male or female who is of legal age to provide informed consent per local regulations, and ≤65 years of age at the time of informed consent. For the purposes of this study, the minimum age is 19 years in South Korea and 18 years in Australia.
• The participant, or their LAR, must be willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to any research-related procedures. For participants who are unable to sign the consent form themselves, informed consent must be obtained from their LAR in accordance with local regulations and ethical guidelines.
• The participant, or their LAR, must ensure willingness and ability to comply with all study procedures to the extent possible, as determined by the Investigator.
• The participant has a diagnosis of ANRE according to the Graus et al criteria (Graus et al, 2016), with symptom onset ≥4 months and ≤9 months (Cohort B) or ≥0 months and <4 months (Cohort C) prior to Week 0, Day 0.
• Participants with ANRE symptoms as assessed by the mRS with a score of ≥3 during Screening and Week 0, Day 0.
• The participant has a positive cell-based assay result for CSF anti-NMDAR IgG autoantibody within 9 months for Cohort B and 4 months for Cohort C prior to Week 0, Day 0. Participants without a positive CSF anti-NMDAR IgG autoantibody result within 9 months for Cohort B and 4 months for Cohort C of Week 0, Day 0 may undergo a LP at Screening prior to the first study drug administration to confirm the presence of anti-NMDAR IgG autoantibodies in CSF (see Section 7.6.4.6.1).
• Note: If the participant documented history of positive anti-NMDAR IgG autoantibodies in CSF >9 months for Cohort B and >4 months for Cohort C, they may be considered for inclusion in the study with confirmed positive anti-NMDAR IgG autoantibodies in serum at Screening at the discretion of the Investigator in collaboration with the Sponsor (see Section 7.6.4.6.1).
• Participants treated with IVIG must have completed treatment at least 7 days prior to Week 0, Day 0.
• Immunotherapy:
• Cohort B: Participants previously treated with immunotherapy must be receiving a stable dose (per Investigator discretion) for ≥1 month before Week 0, Day 0.
• Cohort C: Participants may receive ART5803 regardless of previous or ongoing immunotherapy treatment status (per the Investigator's discretion).
• Participants who are taking psychiatric medications (anti-depressants and anti psychotics) must remain on stable background psychiatric medications for at least 4 weeks prior to Week 0, Day 0 and for at least the first 6 weeks after Week 0, Day 0.
• Participants treated with plasmapheresis must have completed treatment at least 1 day prior to Week 0, Day 0.
• Participants receiving steroids must be on a stable dose or a predefined taper regimen for at least 2 weeks prior to Week 0, Day 0.
• No active malignancy (see Section 7.6.3.3) or residual teratoma. Prior teratoma must be fully resected ≥1 week before Week 0, Day 0 with no evidence of recurrence per work-up (imaging and tumor markers).
• Note: Discovery of a contralateral teratoma after study initiation will not be considered a protocol deviation. The event must be reported, managed per standard of care, and reviewed with the Sponsor Medical Monitor.
• Participants must have undergone appropriate cancer screening prior to study enrollment. The specific series of investigations used for each participant will occur according to the judgment of the treating Investigator (for example, MRI or CT of the chest, abdomen, and pelvis, and pelvic ultrasound for female participants) to exclude the presence or recurrence of an underlying neoplasm, such as ovarian teratoma or other malignancy. Documentation of imaging results must be available in the source documents.
• Sexually active female participants of childbearing potential and male participants with female partner(s) of childbearing potential must be willing to use a highly effective method of contraception during the study (from the time of providing consent) until at least 90 days after the last study drug administration, or longer if required by local regulations.
• In South Korea, contraception must be continued for 6 months after the last study drug administration in accordance with MFDS requirements.
• Examples of highly effective methods of contraception are provided in Appendix 1. The contraceptive methods used for male and female participants must be documented in the source documents.
• Female participants of childbearing potential must have a negative pregnancy test at Screening and be willing to have additional pregnancy tests during the study. Females considered not of childbearing potential include those who are surgically sterile (surgical bilateral oophorectomy, bilateral salpingectomy, or hysterectomy) confirmed by medical history or are post-menopausal (i.e., no menstrual bleeding for more than 2 years without an alternative medical cause and confirmation with more than 1 FSH measurement of at least >40 IU/L \[or higher per local institutional guidelines\]).Women of non-childbearing potential are not required to use any contraceptive method (see Appendix 1).
• Male participants must agree not to donate sperm and female participants must agree not to donate eggs, from the first study drug administration and until at least 90 days after the last dose of the study drug, or longer if required by local regulations.
• In South Korea, male participants must refrain from donating sperm for 6 months after the last study drug administration in accordance with MFDS requirements.
• Compliance with these restrictions must be documented at Screening and confirmed throughout the study.
• Individuals eligible to participate in Cohort D must meet all of the following criteria:
• The participant is a male or female who is of legal age to provide informed consent per local regulations, and ≤65 years of age at the time of informed consent. For the purposes of this study, the minimum age is 19 years in South Korea and 18 years in Australia.
• The participant, or their LAR, must be willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to any research-related procedures. For participants who are unable to sign the consent form themselves, informed consent must be obtained from their LAR in accordance with local regulations and ethical guidelines.
• The participant, or their LAR, must ensure willingness and ability to comply with all study procedures to the extent possible, as determined by the Investigator.
• The participant has persistent psychotic symptoms for at least 2 months prior to Screening and Week 0, Day 0 as evaluated by the Investigator.
• The participant has marked deterioration of functioning in one or more areas, such as occupational, social, or personal care or hygiene.
• The participant has the documented presence of:
• Anti-NMDAR autoantibodies in CSF within 6 months of Week 0, Day 0; or
• Positive CSF anti-NMDAR autoantibody within 12 months of Week 0, Day 0 and positive serum anti-NMDAR autoantibody during Screening (see Section 7.6.4.6.1).
• Participants treated with IVIG must have completed treatment at least 7 days prior to Week 0, Day 0.
• Participants previously treated with immunotherapy must be receiving a stable dose (per Investigator discretion) for ≥1 month before Week 0, Day 0.
• Participants who are taking psychiatric medications (anti-depressants and anti psychotics) must remain on stable background psychiatric medications for at least 4 weeks prior to Week 0, Day 0 and for at least the first 6 weeks after Week 0, Day 0.
• Adequate disease burden as defined as both of the following:
• a. Participant must have a Positive and Negative Syndrome Scale (PANSS) total score ≥70 and a PANSS item score ≥4 (moderate) on 2 or more of the following PANSS items: delusions, conceptual disorganization, hallucinations, suspiciousness, and unusual thought content at Screening and Week 0, Day 0.
• Exceptions may be granted on a case-by-case basis in consultation with the Sponsor.
• Sexually active female participants of childbearing potential and male participants with female partner(s) of childbearing potential must be willing to use a highly effective method of contraception during the study (from the time of providing consent) until at least 90 days after the last study drug administration, or longer if required by local regulations.
• In South Korea, contraception must be continued for 6 months after the last study drug administration in accordance with MFDS requirements.
• Examples of highly effective methods of contraception are provided in Appendix 1. The contraceptive methods used for male and female participants must be documented in the source documents.
• Female participants of childbearing potential must have a negative pregnancy test at Screening and be willing to have additional pregnancy tests during the study. Females considered not of childbearing potential include those who are surgically sterile (surgical bilateral oophorectomy, bilateral salpingectomy, or hysterectomy) confirmed by medical history or are post-menopausal (i.e., no menstrual bleeding for more than 2 years without an alternative medical cause and confirmation with more than 1 FSH measurement of at least >40 IU/L \[or higher per local institutional guidelines\]).Women of non-childbearing potential are not required to use any contraceptive method (see Appendix 1).
• Male participants must agree not to donate sperm and female participants must agree not to donate eggs, from the first study drug administration and until at least 90 days after the last dose of the study drug, or longer if required by local regulations.
• In South Korea, male participants must refrain from donating sperm for 6 months after the last study drug administration in accordance with MFDS requirements.
• Compliance with these restrictions must be documented at Screening and confirmed throughout the study.