Zetomipzomib (KZR-616)

Zetomipzomib (KZR-616) is a first-in-class, selective immunoproteasome inhibitor for a range of autoimmune diseases. Immunoproteasomes play an important role in regulating the normal function of the immune system and when inhibited, multiple pathways involved in inflammatory cytokine production and immune effector cell activity – including macrophages, B cells and T cells – are also inhibited. Since the pathways regulated by immunoproteasomes are involved in the pathogenesis of many autoimmune diseases, zetomipzomib offers a “pipeline in a drug” approach, with the potential to be a treatment option for a broad range of autoimmune conditions.

Most approaches for treating autoimmune diseases focus on suppressing the immune system, like steroids, or targeting a single immune signal to help counter the chronic inflammatory state that is often present. Zetomipzomib, however, can broadly modulate the immune system when it is dysregulated. This candidate has the potential to act as a steroid sparing agent, which would fill a major unmet need in the autoimmune treatment landscape.

Lupus Nephritis

A Chronic Autoimmune Kidney Disease

Lupus Nephritis (LN) is a disease involving inflammation of the kidneys and represents a serious complication of systemic lupus erythematosus (SLE or lupus), a systemic autoimmune disease that occurs when the body’s immune system attacks its own tissues and organs. LN and SLE are chronic, extremely debilitating and progressive diseases that carry an increased risk of death.

SLE affects ~322,000 people in the U.S., and ~50% of people living with SLE will develop LN.

Kidneys remove waste from blood and control body fluid levels. LN occurs when the body’s immune system attacks the kidneys, causing inflammation in the kidneys and preventing performance of vital functions.

Blood in urine
High blood pressure
High levels of a waste product called creatinine in the blood
Foamy urine (due to excess protein in urine)
Swelling of hands, ankles or feet

Gender

Women are more likely to get SLE (9/10). Men with SLE are at a higher risk of developing lupus nephritis.

Race or Ethnicity

Blacks, Hispanics/Latinos and Asian Americans are more likely to have LN than Caucasians. The prognosis for patients with LN is worse in Blacks and Hispanics.

There are limited effective treatments for LN. While steroids and other immunosuppressive drugs can help manage severe LN by slowing or stopping the immune system from attacking healthy cells, they can have serious side effects and don’t work for about 50% of patients.

References:
1. mayoclinic.org/diseases-conditions/lupus-nephritis/symptoms-causes/syc-20354335 | 2. mayoclinic.org/diseasesconditions/lupus-nephritis/diagnosis-treatment/drc-20446438 | 3. icer-review.org/wp-content/uploads/2020/08/ ICER_Lupus-Nephritis_Revised-Scope_092920.pdf | 4. cdc.gov/lupus/facts/detailed.html | 5. lupus.org/resources/ doctors-who-treat-lupus

Autoimmune Hepatitis

A Complex Autoimmune Liver Disease With Increasing Prevalence

Autoimmune Hepatitis (AIH) is a rare, chronic disease in which the immune system attacks the liver and causes inflammation and tissue damage, severely impacting patients’ physical health and quality of life. This condition affects all ages, genders and ethnicities, with lifelong maintenance therapy required to avoid relapse and burdensome adverse effects.¹ If left untreated, AIH can lead to cirrhosis, liver failure and hepatocellular carcinoma.⁷

In the United States, AIH affects approximately 140,000 individuals, with prevalence rates increasing.⁶

The liver processes an individual’s blood, breaking down the nutrients and chemicals the blood carries. AIH occurs when an individual’s immune system attacks its liver, causing significant inflammation and tissue damage as well as severely impacting the liver’s function.⁷

Symptoms/signs and their severity vary from person to person and can include²:

Fatigue (experienced by 85% of patients)
Poor sleep
Jaundice
Abdominal discomfort/pain
Skin rashes
Itchy skin
Nausea
Poor appetite
Joint pain
Enlarged liver (hepatomegaly) and/or spleen (splenomegaly)
Risk of liver fibrosis and eventually liver scaring (cirrhosis)

Preexisting Conditions

Patients that have other autoimmune conditions have a higher chance of developing another autoimmune disease such as AIH.²

Gender

AIH affects all genders but affects females 4 times as often as males.²

Environmental Factors

Various medications (e.g., nitrofurantoin and minocycline) and several viruses (e.g., Epstein-Barr virus, cytomegalovirus, herpes, hepatitis A, B, and C and parvovirus B19) have been linked to AIH. Additional environmental factors that are associated with AIH include significant stress and chemical exposures.⁷

AIH patients require life-long maintenance therapy to avoid relapse and the burdensome adverse effects of this condition. Standard of care (SOC) for AIH is chronic, immunosuppressive treatment with corticosteroids and other immunosuppressive agents like azathioprine.⁷ While steroids and other immunosuppressive drugs can help manage AIH, these treatments may have life-altering side effects – including osteoporosis, high blood pressure, diabetes and fatigue – and increase an individual’s risk of infection and malignancies.³ Following treatment using current SOC, approximately 35% of patients do not go into remission, and approximately 50-87% of adults who go into remission relapse once treatment is discontinued.⁵ If left untreated, autoimmune hepatitis can result in cirrhosis, liver failure and hepatocellular carcinoma.³ There is a significant unmet medical need for effective AIH treatments that reduce the use of chronic immunosuppression.

References:
1. https://liverfoundation.org/for-patients/about-the-liver/diseases-of-the-liver/autoimmune-hepatitis/ | 2. https://rarediseases.org/rare-diseases/autoimmune-hepatitis/ | 3. https://www.niddk.nih.gov/health-information/liver-disease/autoimmune-hepatitis | 4. https://www.mayoclinic.org/diseases-conditions/autoimmune-hepatitis/diagnosis-treatment/drc-20352158#:~:text=Preparing%20for%20your%20appointment,in%20liver%20diseases%20(hepatologist). | 5. Mack et al. Hepatology. 2020;72(2):671-722. | 6. Terziroli Beretta-Piccoli et al. Cell Mol Immunol. 2022;19(2):158-176| 7. https://www.aihep.org/what-is-autoimmune-hepatitis