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9 April 2024

Avacta Group plc

("Avacta" or the "Group" or the "Company")

Avacta Therapeutics Reports Data from the Ongoing Phase 1 Clinical Trial of AVA6000 at the AACR Annual Meeting Demonstrating Clinical Proof-of-Concept Showing Multiple Patient Responses

AVA6000 delivers high concentrations of doxorubicin to the tumor microenvironment ("TME") relative to plasma, resulting in significant antitumor activity in patients whose tumors have over-expression of Fibroblast Activation Protein ("FAP")

FAP-enabled release of doxorubicin directly in the TME results in a favorable safety profile, tumor responses and a wider therapeutic index compared to standard doxorubicin dosing 

Further development at the recommended dose for expansion is planned in 2H 2024 in specific tumor types with high FAP expression and anthracycline sensitivity

Avacta Group plc (AIM: AVCT), a life sciences company developing innovative, targeted oncology drugs and powerful diagnostics, today announces the presentation of interim results from the Phase 1 clinical trial of peptide drug conjugate AVA6000 at the American Association for Cancer Research ("AACR") annual meeting in San Diego, USA.

The results to date show that AVA6000, the first peptide drug conjugate in the Avacta pipeline, has a favorable safety profile with concentration of the warhead in the TME resulting in multiple responses in patients with high levels of Fibroblast Activation Protein ("FAP^high"), thus delivering clinical proof-of-concept for AVA6000 and proof-of-mechanism for the proprietary pre|CISION^TM drug delivery platform.

Professor Udai Banerji, Lead Investigator for the AACR poster and the Co-Director of the Drug Development Unit at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, commented:

"The trial of AVA6000 shows an opportunity to be able to localize an already effective chemotherapeutic agent to tumors using innovative technology and biomarker strategies, resulting in reduced side effects. I am enthusiastic about the early findings and I'm looking forward to completing the Phase 1 trial and moving it to the next stage in development."

Dr Alastair Smith, Chief Executive Officer of Avacta, commented:

"The data being presented at AACR support our continually growing confidence in the pre|CISION™ peptide drug conjugate platform.

"We have already observed compelling evidence in the ongoing clinical studies of AVA6000 that the platform delivers a step change in the tolerability levels compared with standard doxorubicin. The data we are presenting today demonstrate that the derived doxorubicin is being achieved through tumor cleavage, validating the platform further and giving us great confidence in the future efficacy studies.

"The positive data we are continuing to observe supports our belief that pre|CISION™ could be a game changer in cancer treatment, allowing patients to achieve better outcomes with reduced side effects both with doxorubicin and potentially other more potent warheads."

Christina Coughlin MD, PhD, Head of Research and Development at Avacta, added:

"Antibody drug conjugates have been a key focus of oncology research given their known antitumor effects in multiple solid tumors. The proof-of-concept data presented today with AVA6000 suggest that the peptide drug conjugate drug class has several key advantages, particularly the tumor-specificity of the release of doxorubicin through targeting FAP and simplicity of the manufacturing process which results in significant savings in the cost of goods.

"Today's clinical data demonstrate that treatment of patients with metastatic cancers with AVA6000 results in tumor responses with favorable tolerability in patients whose tumors over-express FAP (FAP^high).  Importantly, many of the patients had experienced disease progression with prior lines of therapy.  We believe these data support the further development of AVA6000 in a specific set of indications with higher FAP expression and sensitivity to anthracyclines. We look forward to providing further updates from the Phase 1 clinical trial in due course ahead of completion and moving to the next stage of development, and updates to the Avacta pipeline implementing these results in new programs."

pre|CISION^TM technology

Many solid tumors have higher levels of FAP compared with healthy tissues. Avacta's pre|CISION^TM technology is designed to leverage the tumor-specificity of FAP expression by rendering a therapeutic warhead inert with the bound peptide moiety attached to the warhead, until it encounters FAP and is cleaved, releasing active warhead into the TME. FAP targeted release of the warhead specifically in the TME aims to reduce damage to healthy tissues and systemic side effects, improving the tolerability for patients and allowing optimization of the dosing schedule to improve efficacy.

Data demonstrate clinical proof of concept for AVA6000 with multiple patient responses

Seven dose cohorts (n=42) were completed in the Phase 1a Arm 1 of the trial with a dosing schedule of every three weeks ("Q3W") at the time of the data cut-off on March 11, 2024. All 42 patients enrolled were evaluable for safety (primary outcome measure) and for efficacy (secondary outcome measure). At the time of the data cut-off, enrollment continues in the every two weeks ("Q2W") Phase 1 Arm 2 dose cohort.

For analysis of the efficacy, cancer indications were categorized as FAP^high (soft tissue sarcoma and salivary gland cancer) or FAP^mid (pancreatic cancer, colorectal cancer, lung cancer and other malignancies). Patients with indications considered FAP^low were excluded from the trial. Among patients with FAP^high cancers (n=15), 2 partial responses and 3 minor responses were observed, including:​

·      A durable confirmed partial response in a 60-year-old male patient with the diagnosis of undifferentiated pleomorphic sarcoma with duration of response of 34 weeks. This patient had progressed on prior therapy and imaging studies demonstrate near complete resolution of pleural metastases with a reduction of 74% in the sum of longest diameters per RECIST version 1.1;

·      An unconfirmed partial response in a 79-year-old male patient with salivary gland cancer with deepening of response to a 57% decrease in the sum of diameters;

·      Two patients with dedifferentiated liposarcoma with minor responses of >12% reduction in the sum of diameters; and

·      All four responders above remain on study at the time of the data cutoff.

Meaningful stable disease of longer than 16 weeks and/or response was observed in 10 patients resulting in a disease control rate of 10/15 (67%).  No responses were observed among patients with FAP^mid indications (n=27) and stable disease >16 weeks was observed in 10 patients for a disease control rate of 10/27 (37%). 

Treatment with AVA6000 was well tolerated and a reduction in AVA6000-related treatment-emergent toxicities as compared with standard dose doxorubicin was noted with respect to both severe and mild to moderate toxicities. Regarding severe toxicities (grade 3-4), a steep reduction in neutropenia was observed when compared to standard dose doxorubicin (with AVA6000, 16.7% of patients reported severe neutropenia vs 49% with standard dose doxorubicin). There were no cases of febrile neutropenia in the AVA6000 trial compared to 16.5% of patients receiving doxorubicin alone.  Reductions were observed as well in toxicities that impact quality of life (any grade), including nausea (reported by 33.3% of patients with AVA6000 vs 67% with doxorubicin) and mouth sores (mucositis, 7.1% with AVA6000 vs 41% with doxorubicin). Other toxicities with reductions include musculoskeletal pain, loss of appetite and constipation. Two dose limiting toxicities were observed (cardiac failure and neutropenia/thrombocytopenia), but in both cases the dose cohorts were expanded and deemed safe.

Thus, the safety profile of AVA6000 administered on a once every three weeks basis was favorable compared to standard dose doxorubicin and the first arm of the Phase 1 did not identify a maximum tolerated dose.

Pharmacokinetic and pharmacodynamic modelling in the trial demonstrate that AVA6000 delivers a high concentration of doxorubicin to the tumor microenvironment relative to plasma, as designed in the pre|CISION™ platform. This concentration of the warhead in the TME results in antitumor activity in tumors with reported high expression of FAP. In addition, exposure-response modelling and comparison with serum FAP suggests the derived, free doxorubicin is generated by tumor cleavage of AVA6000 versus peripheral blood cleavage.

Based on this very favorable three-weekly dosing safety profile, Avacta continues to enroll patients in the two-weekly dosing safety study. The combined data from the three-weekly and two-weekly studies will provide information to allow Avacta to define the dose and schedule to be used in efficacy studies.

Patients can be dosed in parallel in the two-weekly dose escalation study and Avacta remains on track to begin the dose expansion efficacy study in the second half of 2024 in the US. The data from the expansion study will be used to inform the optimal choice of a single indication for the Phase 2 efficacy study which will follow the expansions, subject to FDA approval.

-Ends-

For further information from Avacta Group plc, please contact:

About Avacta Group plc - https://www.avacta.com

Avacta Group is a UK-based life sciences company focused on improving healthcare outcomes through targeted cancer treatments and diagnostics.

Avacta has two divisions focused on therapeutics and diagnostics.

Avacta Therapeutics: a clinical stage oncology biotech division harnessing proprietary therapeutic platforms to develop novel, highly targeted cancer drugs.

Avacta Diagnostics: focused on supporting healthcare professionals and broadening access to diagnostics.

Avacta has two proprietary platforms, pre|CISION™ and Affimer^®.

The pre|CISION™ platform is a highly specific substrate for fibroblast activation protein (FAP) which is upregulated in most solid tumours compared with healthy tissues. The pre|CISION™ platform harnesses this tumour specific protease to activate pre|CISION™ peptide drug conjugates and pre|CISION™ antibody/Affimer® drug conjugates in the tumour microenvironment, reducing systemic exposure and toxicity, allowing dosing to be optimised to deliver the best outcomes for patients.

The lead pre|CISION™ programme AVA6000, a peptide drug conjugate form of doxorubicin, is in Phase 1 studies. It has shown a dramatic improvement in safety and tolerability in clinical trials to date compared with standard doxorubicin and preliminary signs of clinical activity in multiple patients.

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