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

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is one of the most common causes of autoimmune encephalitis. The disease is caused by the development of autoantibodies against the amino (N)-terminal domain (NTD) of the NMDAR subunit 1 (NR1) that bind and cross link the receptors, leading to receptor internalization and loss of function.

Arialys has developed a monovalent (one-armed) antibody, ART5803, that binds to the NTD of the NMDAR NR1 subunit without causing NMDAR inhibition, activation, or receptor internalization, while simultaneously blocking the ability of the pathogenic anti-NMDAR autoantibodies to bind to the receptor. There is also an increasing body of data supporting the potential link between broader psychiatric diseases and the presence of autoantibodies against the NMDAR.

7.3.1 Inclusion Criteria Individuals in Cohort A (participants with chronic ANRE) must meet all of the study inclusion criteria in Section 7.3.1.1. Individuals enrolled in Cohort B or Cohort C (participants with subacute or acute ANRE) must meet all of the study inclusion criteria in Section 7.3.1.2. Individuals in Cohort D (participants with anti-NMDAR autoantibody associated psychiatric disease) must meet all of the study inclusion criteria in Section 7.3.1.3.

Eligibility for participation in this study will be determined solely based on the participant meeting all protocol-defined inclusion and exclusion criteria. The legally authorized representative (LAR), where applicable, may provide informed consent on behalf of a participant who lacks the capacity to provide consent in accordance with local regulations; however, the LAR does not independently satisfy eligibility criteria. A participant who does not meet all required inclusion and exclusion criteria will not be enrolled in the study, regardless of the availability or status of an LAR.

7.3.1.1 Cohort A Inclusion Criteria The criteria below must be applied to all participants screened for Cohort A (participants with chronic ANRE) of the study.

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.

7.3.1.2 Cohort B and Cohort C Inclusion Criteria The criteria below must be applied to all participants screened for Cohort B (participants with subacute ANRE) or Cohort C (participants with acute ANRE) of 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.

7.3.1.3 Cohort D Inclusion Criteria The criteria below must be applied to all participants screened for Cohort D (participants with anti-NMDAR autoantibody-associated psychiatric disease) of 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.

7.3.2 Exclusion Criteria Individuals (Cohorts A, B, C, or D) will not be eligible to participate in the study if they meet any of the exclusion criteria.

• The participant is pregnant or breastfeeding at Screening or planning to become pregnant (self or partner) at any time during the study.
• The participant has used an investigational product (IP) or investigational medical device within 30 days or 5 half-lives of the other IP (whichever is longer) prior to Screening or is required to use any investigational agent prior to completion of all scheduled study assessments.
• The participant has used an NMDAR modulator other than the study drug (e.g., ketamine, memantine, dextromethorphan, amantadine, ifenprodil, phencyclidine, acamprosate, D-cycloserine) from within 5 half-lives of the NMDAR modulator prior to Week 0, Day 0.
• The participant has previous exposure to ART5803 or other antibody that targets NMDAR.
• Participant has any condition that, in the opinion of the Investigator, would interfere with the evaluation or administration of the IP, interpretation of participant safety or study results, or would make participation in the study an unacceptable risk.
• Participant with coexisting CNS demyelinating disorders (e.g., multiple sclerosis), known positivity to other autoantibodies associated with autoimmune encephalitis, or any significant history of a psychiatric or neurologic disorder other than ANRE should undergo consultation with the Sponsor Medical Monitor on a case-by-case basis for eligibility determination. MOG antibody positivity may be permitted on a case-by-case basis if the condition is clinically inactive and not expected to confound study assessments.
• The participant has a confirmed positive test for hepatitis B serology (hepatitis B surface antigen and core antigen) and/or hepatitis C polymerase chain reaction at Screening.
• The participant has a known history of allergy or reaction to any component of the investigational agent (ART5803), or history of anaphylaxis following any biologic therapy.
• The participant has a history (within 12 months prior to Screening for Cohorts A, B, or C) or current (for Cohort D) alcohol abuse or drug addiction, defined as moderate or severe substance use disorder per Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition, or any pattern of alcohol or substance use that, in the Investigator's judgment and after discussion with the