Safety and Pharmacokinetics of LPX-TI641 in Rheumatoid Arthritis and Psoriatic Arthritis

Inclusion Criteria:

1. Subject has signed an Informed Consent Form (ICF) prior to any study-specificprocedures being performed

2. ≥ 18 years old, irrespective of their race and ethnicity.

3. Body Mass Index (BMI) 18.0-35.0 kg/m2, inclusive, at screening.

4. Participants are willing and able to adhere to study protocol requirements includingbut not limited to scheduled outpatient visits, inpatient hospital stay, laboratorytests, and 12-lead ECGs.

5. A. Diagnosis of RA and meeting the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for RA atleast 3 months prior to screening AND Active disease defined by ≥ 6 tender out of 68joints and ≥ 6 swollen out of 66 swollen joint count at both screening and Day 1. AND Participants received conventional synthetic disease-modifying antirheumaticdrug (csDMARD) therapy for ≥ 3 months and on a stable dose for ≥ 4 weeks prior tothe first dose of study drug. The csDMARD allowed include methotrexate (MTX) (≤ 25mg/week), sulfasalazine (3 grams a day), hydroxychloroquine (≤400mg/day),chloroquine (≤250mg/day), and leflunomide (≤ 20mg/day) or intolerance to csDMARD asassessed by the investigator OR B. PsA diagnosis of at least 3 months duration priorto the date of first screening with Classification of Psoriatic Arthritis (CASPAR)confirmed diagnosis at Screening. Have active psoriasis defined by at least 1psoriasis lesion >= 2 cm diameter in areas other than the axilla orgroin. AND Active disease defined by ≥ 3 tender out of 68 joints and ≥ 3 swollen out of 66swollen joint count at both screening and Day 1. AND Participants received standard doses of NSAIDS for ≥4 weeks or csDMARDS (MTX ≤ 25mg/week), sulfasalazine (3 grams a day), and leflunomide (≤ 20mg/day),administered for ≥ 3 months and on a stable dose for ≥ 4 weeks prior to the firstdose of study drug or intolerance to NSAIDS or DMARDs as assessed by theinvestigator. Other traditional DMARDS not listed as a prohibited concomitantmedication may be considered after discussion with the Study physician.

6. The subject must be judged to be in good health by the investigator to participatein the study, based on clinical evaluations, including laboratory safety tests,medical history, physical examination, vital signs and 12-lead ECG competed at thescreening visit and prior to the first dose of study drug.

7. Female subject is postmenopausal (at least 1 year; to be confirmed by folliclestimulating hormone (FSH) if less than 2 years since last menstrual period),permanently sterilized (e.g. tubal occlusion, hysterectomy, bilateral salpingectomyor if of childbearing potential and engaged in sexual activity that can result inpregnancy must agree to use any two of the highly effective contraception methodslisted below. Male participants with a partner of childbearing potential must alsoagree to use any two of the highly effective contraception methods listed belowbetween the both of them. This criterion must be followed from screening visit to 6weeks after the last dose in females and for 90 days after the last dose for males. a. The following applies to all female participants with childbearing potential andfemale partners of male volunteers enrolled in the study. i. Implantable progestogen-only hormone contraception associated with inhibition ofovulation. ii. Intrauterine device. iii. Intrauterine hormone-releasing system. iv. Bilateraltubal occlusion. v. Combined (estrogen- and progestogen-containing) hormonalcontraception associated with inhibition of ovulation:

8. Oral

9. Intravaginal

10. Transdermal

11. Injectable vi. Progestogen-only hormone contraception (oral or injectable) isassociated with inhibition of ovulation. vii. Vasectomized partner viii. Sexual abstinence -this is considered a highlyeffective method only if defined as refraining from heterosexual intercourse duringthe entire period of risk associated with the study intervention. The reliability ofsexual abstinence needs to be evaluated about the duration of the study and thepreferred and usual lifestyle of the participant. ix. A combination of male condoms with either cervical cap, diaphragm, or spongewith spermicide (double-barrier methods) b. The following applies to all maleparticipants in the study: i. Sexual abstinence- this is considered a highlyeffective method only if defined as refraining from heterosexual intercourse duringthe entire period of risk associated with the study intervention. The reliability ofsexual abstinence must be evaluated for the study and the participant'spreferred and usual lifestyle. ii. A combination of male condoms with either cervical cap, diaphragm, or spongewith spermicide (double-barrier methods). iii. Vasectomy

12. Negative serum B-human chorionic gonadotropin test at screening (for all females)and negative urine pregnancy at randomization (Day 1) (females of childbearingpotential) prior to administration of investigational product.

Exclusion Criteria:

• Any subject who meets any of the following criteria will not qualify for entry intothe study:

1. History of clinically significant medical conditions or any other reason thatin the opinion of the PI would interfere with subject's participation in thisstudy

2. History of clinically significant per the PI's opinion drug or alcohol abusewithin the last 6 months

3. Pregnant or lactating women or women currently undergoing infertilitytreatments or women who intend to become pregnant during the time of studyenrollment.

4. Any known history of malignancy within 5 years other than other than completelytreated non-metastatic basal cell carcinomas or squamous cell carcinomas of theskin or localized carcinoma in situ of the cervix.

5. Any known history of a rheumatologic, autoimmune or cutaneous disease otherthan RA (except secondary Sjögren's syndrome), or PSA.

6. Significant systemic involvement secondary to RA/PsA (active vasculitis,pulmonary fibrosis, or Felty's syndrome).

7. Currently have non-plaque forms of psoriasis e.g. erythrodermic, guttate orpustular with the exception of nail psoriasis which is allowed.

8. Receipt of an investigational therapy less than 3 months or 5 drug-eliminationhalf-lives (whichever is longer) prior to first administration of studytreatment and during the study

9. Receipt of any of the following excluded therapies:Any cell depleting therapy including but limited to anti-CD4, anti-CD5,anti-CD3, rituximab, ocrelizumab, or ofatumumab.Have received prior tsDMARDs including but not limited to inhibitors of Januskinase (JAK), Bruton tyrosine kinase, or tyrosine kinase 2, includingbaricitinib, tofacitinib, upadacitinib, filgotinib, ibrutinib, or fenebrutinib.Have received prior immunomodulatory bDMARDs including, but not limited toadalimumab, golimumab, ustekinumab, secukinumab, tocilizumab, abatacept,belimumab, anifrolumab or other inhibitors of TNF, IL-6, IL-23, or IL-17Receipt of any other conventional DMARDs (not allowed per inclusion criteria 3)within less than 5 half-lives, prior to screening visit.

10. Lack of response to > 1 therapeutic agent targeting tumor necrosisfactor.

11. If on prednisone, subject must be on stable dose, not to exceed equivalent of 10mg of prednisone per day (RA and PsA), and dose must be stable for ≥ 4 weeksprior to Day 1. No injected corticosteroids 8 weeks prior to first dose ofstudy drug (e.g intraarticular, intramuscular, or intravenous)

12. Use of psoriasis treatments:

13. Oral or topical retinoids 2 weeks prior to Day 1 and throughout the study

14. Topical treatments (steroids, or JAK inhibitors) within 2 weeks prior toDay 1 and throughout the study

15. PUVA or UVB phototherapy within 4 weeks prior to Day 1 and throughout thestudy.

16. No high potency opioid analgesics 2 weeks prior to baseline and during study.Analgesic dose must remain stable throughout from screening through completionof the study.

17. COVID-19:The subject has COVID-19 positive status (confirmed by clinical signs andsymptoms and a positive SARS-CoV-2 NAAT or rapid antigen COVID test) at anytime during the screening period.OR has had recent COVID-19 vaccination including a booster dose in the past 30days prior to screening OR has received anti-viral therapy intended to preventCOVID-19 such as nirmatrelvir/ritonavir, remdesivir, molnupiravir, interferons,anti-SARS-CoV-2 monoclonal antibodies, IVIG SARS-CoV-2, COVID-19 convalescentplasma, etc. within the past 30 days prior to screening

18. Subject has clinical or laboratory evidence of active or latent tuberculosis (TB) infection at screening as assessed by QuantiFERON-TB-Gold or a purifiedprotein derivative skin test or equivalent (or both if required per localguidelines) and chest X-ray. Chest X-rays taken within 2 months prior toscreening may be used instead of during screening if there is documentationshowing no evidence of infection or malignancy as read by qualified physician.

19. Any active or recurrent infection within the past 4 weeks prior to screeningrequiring IV or oral antibiotics.

20. Laboratory values of the following at the Screening Visit:Hemoglobin < 9 g/dL for males and < 8.5 g/dL for femalesWBC <3.5X109/L; Absolute neutrophil count (ANC) < 1500cells/µL, (or < 1200 cells/µL for Black participants of Africandescent) Aspartate aminotransferase or alanine aminotransferase > 2.0 x the upper limit of normal (ULN) or bilirubin >= ULN; Bilirubin >ULN Serum creatinine > 1.5 x the ULN; Platelets < 100,000 cells/[mm^3] (10^9/L); Clinically significant abnormalscreening laboratory results as evaluated by the Investigator

21. Acutely worsened renal function within past 3 months prior to screening orestimated creatinine clearance <60ml/min by CKD-EPI creatinineequation

22. Participants with a history of active or latent TB will be excluded from thestudy, unless documentation of complete TB treatment, consistent with localcountry guidelines, can be provided.

23. Subject has any clinically significant finding on 12-lead ECG at screening oradmission. NOTE: QTc(F) interval of >450 msec in male participantsor >470 msec in female participants will be the basis for exclusionfrom the study. ECG may be repeated once for confirmatory purposes if initialvalues obtained exceed the limits specified.

24. Subject with positive results for HBsAg (hepatitis B surface antigens) and/orHBcAb (Hepatitis B core antibodies) and/or HCV Ab (hepatitis C antibodies),and/or HIV Ab (human immunodeficiency virus antibodies).

25. Blood loss of >250 mL or donated blood within 56 days or donatedplasma within 7 days of screening.

26. Recent vaccination with live attenuated vaccines such as influenza, measles,mumps, and rubella (MMR), Herpes zoster, varicella, yellow fever, Rotavirusvaccine, etc., or inactivated vaccines such as Hepatitis A, rabies vaccine,etc. in the past 30 days.

27. History of infection 1) requiring hospitalization or parenteral antimicrobialtherapy within 3 months prior to Day 1 or 2) treated with oral antimicrobialtherapy within 2 weeks prior to Day 1.

28. Subject is investigative site personnel, sponsor personnel, or a member oftheir immediate families (spouse, parent, child or sibling whether biologicalor legally adopted).