ANYARA

ANYARA is a tumor targeting immunotherapy that enhances the ability of the immune system to recognize and kill the tumor. Since October 2016, Active Biotech has a licensing agreement with NeoTX Therapeutics Ltd. for the worldwide development and commercialization of ANYARA for cancer therapy.

Mode of Action and Therapy Concept

ANYARA, a Tumor Targeting Superantigen (TTS), is a fusion protein containing the Fab-fragment of an antibody that targets the tumor-associated 5T4 antigen, expressed in a high number of solid tumors. The antibody part is fused with an engineered bacterial superantigen that activates T-cells, expressing a particular set of T-cell receptors.

ANYARA activates T lymphocytes and targets them to the 5T4-expressing tumors, resulting in massive effector lymphocyte infiltration into the tumor and tumor cell killing.

Mode of Action for ANYARA

ANYARA enhances tumor recognition

Immune checkpoint inhibitors are drugs that unleashes an immune system attack against tumor cells. Despite recent success with such drugs, the immune system’s ability to recognize the tumor is still a key challenge. Emerging clinical data highlight the need to improve recognition of the tumor to optimize the benefit of checkpoint inhibition, e.g. PD-1 therapy. ANYARA enhances the ability of the immune system to recognize the tumor and data from experimental tumor models show synergistic activity on tumor growth when combining ANYARA with a PD-1 inhibitor.

Clinical Trials

Clinically, the previous development of ANYARA has mainly focused on cancer forms with a high medical need. Phase 1 studies have been performed in patients with advanced non-small cell lung cancer, renal cell carcinoma and pancreatic cancer. Based on the phase 1 results, a phase 2/3 trial in combination with interferon alpha in patients with renal cell carcinoma was performed. The study demonstrated a favorable safety profile, but did not achieve its primary endpoint of showing a prolonged overall survival in the patient population.

Currently, preparations are ongoing for a clinical trial with ANYARA in combination with a PD-1 inhibitor in patients with various solid cancer forms, which are refractory or marginally responsive to anti-PD-1 therapies, with the trial to start second half of 2018.

ANYARA enhances tumor recognition

Phase 1 in solid tumors

Completed

In the clinical phase 1 trials, ANYARA was studied both as a single agent and in combination with an established tumor therapy – docetaxel (Taxotere®) – in patients with advanced lung cancer, renal cell cancer or pancreatic cancer (Borghaei et al, 2009; ClinicalTrials: NCT00056537 and NCT00132379). The results showed that ANYARA was well tolerated both as monotherapy and in combination with docetaxel. The phase 1 results also showed proof-of-concept in terms of increased immunologic activity, including systemic increase of inflammatory cytokines, expansion of ANYARA reactive T cells and induction of infiltrating T cells.

Phase 2/3 in renal cell cancer

Completed

Results from the ANYARA phase 2/3 clinical study in patients with advanced renal cell cancer were announced in January 2013 (Hawkins et al, 2016; Elkord et al, 2015). The study encompassed 513 patients and was designed to evaluate the effect of ANYARA in combination with interferon-alpha, compared with interferon-alpha alone. The phase 2/3 study did not achieve its primary endpoint showing a prolonged overall survival in the patient population. However, in a hypothesis-generating subgroup analysis, the 25% of patients with low to normal levels of baseline IL-6 and expected anti-superantigen antibody levels, showed a statistically significant treatment advantage on both overall survival (p=0.02, HR=0.59) and progression free survival. In North America and Western Europe, this subgroup accounts for 40-50% of the total number of advanced renal cell cancer patients. The safety profile was good and in line with previous observations.

Key Publications

Naptumomab Estafenatox induces T cell recognition, turning anti-PD-1 unresponsive “cold” tumors into “hot” responsive tumors. Azulay M, Lifshits S, Fridman A, Hedlund G, Törngren M, Shahar M. Poster presentation at AACR Annual Meeting 2018. View the complete poster here.

A Randomized Phase II/III Study of Naptumomab Estafenatox + IFNα versus IFNα in Renal Cell Carcinoma: Final Analysis with Baseline Biomarker Subgroup and Trend Analysis. Hawkins R, Gore M, Shparyk Y, Bondar V, Gladkov O, Ganev T, Harza M, Polenkov S, Bondarenko I, Karlov P, Karyakin O, Khasanov R, Hedlund G, Forsberg G, Nordle Ö, Eisen T. Clin Cancer Res. 2016; 22(13): 3172-81

Immunological response and overall survival in a subset of advanced renal cell carcinoma patients from a randomized phase 2/3 study of naptumomab estafenatox plus IFN-α versus IFN-α. Elkord E, Burt DJ, Sundstedt A, Nordle Ö, Hedlund G, Hawkins R. Oncotarget. 2015; 6(6): 4428-39

Naptumomab Estafenatox: targeted Immunotherapy with a Novel Immunotoxin. Eisen T, Hedlund G, Forsberg G, Hawkins R. Curr Oncol Rep. 2014; 16: 370

The tumor targeted superantigen ABR-217620 selectively engages TRBV7-9 and exploits TCR-pMHC affinity mimicry in mediating T cell cytotoxicity. Hedlund G, Eriksson H, Sundstedt A, Forsberg G, Jakobsen BK, Pumphrey N, Rödström K, Lindkvist-Petersson K, Björk P. PLoS One. 2013; 8(10): e79082

Monotherapeutically Nonactive CTLA-4 Blockade Results in Greatly Enhanced Antitumor Effects When Combined With Tumor-targeted Superantigens in a B16 Melanoma Model. Sundstedt A, Celander M, Eriksson H, Törngren M, Hedlund G. J Immunother. 2012; 35(4): 344–53

Tumor-Targeted Superantigens, in Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges. Hedlund G, Forsberg G, Nederman T, Sundstedt A, Dahlberg L, Tiensuu M, Nilsson, M. (ed S. R. Schmidt) 2013; p365-381, John Wiley & Sons, Inc., Hoboken, NJ, USA

Naptumomab estafenatox: a new immunoconjugate. Robinson MK, Alpaugh KR, Borghaei H. Expert Opin Biol Ther. 2010; 10: 273-79

Naptumomab estafenatox, an engineered antibody-superantigen fusion protein with low toxicity and reduced antigenicity. Forsberg G, Skartved N-J, Wallén-Öhman M, Carlsson-Nyhlen H, Behm K, Hedlund G, Nederman T. J Immunother. 2010; 33: 492-9

Phase I dose escalation, pharmakokinetic and pharmacodynamic study of naptumomab estafenatox alone in patients with advanced cancer and with docetaxel in patients with advanced non small-cell lung cancer. Borghaei H, Alpaugh K, Hedlund G, Forsberg G, Langer C, Rogatko A, Hawkins R, Dueland S, Lassen U, Cohen RB. J Clin Oncol. 2009; 27: 4116-23