Foralumab (TZLS-401)

Foralumab is a fully human anti-CD3 monoclonal antibody, designed to modulate the immune system by targeting the CD3 epsilon subunit of the T cell receptor complex. This mechanism aims to induce regulatory T cells (Tregs), offering potential therapeutic benefits in autoimmune, inflammatory, and neurodegenerative diseases.

Development History

• Origin and Licensing: Foralumab was in-licensed by Tiziana Life Sciences from Novimmune in December 2014. ​
• Early Clinical Trials:
  • Intravenous Administration: Initial studies involved intravenous dosing in patients with moderate to severe active Crohn's disease. However, this approach did not demonstrate significant efficacy. ​
  • Oral Administration: Subsequent development focused on an enteric-coated capsule formulation for oral delivery. A Phase 1 trial in healthy volunteers demonstrated that oral Foralumab was well-tolerated up to a 5 mg dose, with no drug-related safety issues. ​
  • Nasal Administration: Tiziana developed a nasal spray formulation in collaboration with Brigham and Women's Hospital. A Phase 1 trial in healthy volunteers showed that nasal Foralumab was well-tolerated and modulated immune biomarkers, notably at the 50 µg dose. ​

Recent Developments with Intranasal Foralumab

• Multiple Sclerosis (MS):
  • Foralumab is being evaluated in a randomized, double-blind, placebo-controlled, multicenter dose-ranging Phase 2 study for non-active secondary progressive multiple sclerosis (SPMS). The study aims to assess safety, tolerability, and effects on microglial activation using PET imaging over a 12-week treatment period. ​
  • Additionally, under the FDA's Expanded Access Program, individual SPMS patients have received intranasal Foralumab, with clinical improvements measured by the Expanded Disability Status Scale (EDSS), MFIS and a reduction of Microglial activity seen on PET scans. ​
• COVID-19:
  • In a pilot study conducted in Brazil, nasal Foralumab was administered to patients with mild to moderate COVID-19. The treatment demonstrated a reduction in lung inflammation and blood inflammatory biomarkers, with improved lung CT scan results compared to the control group. ​
• Alzheimer's Disease:
  • The FDA has approved a Phase 2 trial to assess nasal Foralumab in Alzheimer's disease, focusing on safety, cognitive function, and microglial activation over a six-month period. ​
  • The FDA has also allowed an Expanded Access Program to allow a patient with Moderate Alzheimer’s to take intranasal foralumab.
• ALS
  • The ALS Association has awarded a grant to Tiziana to fund a 20-patient clinical trial titled “Modulation of ALS neuroinflammation by nasal anti-CD3 monoclonal Antibody”.

Intranasal foralumab's development reflects a strategic shift towards non-invasive administration routes, such as nasal delivery, to modulate immune responses effectively while minimizing systemic side effects. Its potential applications span a range of diseases characterized by immune dysregulation, with ongoing clinical trials exploring its efficacy and safety profiles.

Milciclib (TZLS-201)

Milciclib is a potent, small molecule inhibitor of multiple cyclin-dependent kinases (CDKs), tropomycinreceptor kinases and Src family kinases controlling cell growth and malignant progression of cancer. Milciclib has demonstrated safety and tolerability in 316 patients with advanced solid cancers in Phase 1 and 2 studies and also exhibited positive clinical responses. In two, successfully completed, Phase 2 thymic cancer trials, Milciclib successfully increased overall survival and met both primary and secondary endpoints. 

In July and September 2019, we reported positive Phase 2a safety, tolerability and efficacy data of Milciclib as a monotherapy in 28 patients with advanced HCC. The results, presented at ASCO2020, warrants further clinical development. Strong genetic and pharmacological evidence suggests that pan-CDKs inhibitors might have potential to suppress the multiple tumorigenic pathways that are activated due to activation of KRAS gene. Clinical data from a Phase I dose-escalation study with combination of milciclib with gemcitabine showed significant disease stabilization and suggested that milciclib can reverse gemcitabine-resistance in NSCLC refractory solid tumors. The clinical response in the NSCLC patient was particularly very promising. Company is exploring the combination of milciclib and gemcitabine in NSCLC subjects with pan KRAS-positive mutations.

TZLS-501

Tiziana's Anti IL-6R mAb (TZLS-501), a fully human mAb binds to both membrane-bound and soluble forms of IL-6R, an inflammatory cytokine driving chronic inflammation associated with autoimmune disease and cancer, reducing circulating levels of the IL-6 cytokine. Anti-IL-6R antibody can potentially be used in combination with Foralumab or other anti-inflammatory and anti-infective agents as therapy for idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS), multiple myeloma, arthritis, lupus and oncology indications. Excessive production of IL-6 is regarded as a key driver of chronic inflammation and is believed to be associated with severe lung damage and chronic fibrosis observed with acute and chronic respiratory illness.

The Company is scaling GMP manufacturing of its anti-IL-6R mAb concurrently with developing a hand-held nebulizer technology for direct delivery of the antibody into the for treatment of patients with IPF, a rare disease indication.