REG - Avacta Group PLC - Avacta Reported Updated Phase 1 Data of AVA6000

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16/09/2024 07:00

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RNS Number : 2330E  Avacta Group PLC  16 September 2024

 

 

 
 

16 September 2024

 

Avacta Group plc

 

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

 

Avacta Reported Updated Phase 1 Clinical Data of AVA6000 at the European
Society for Medical Oncology (ESMO) Congress Demonstrating Multiple Ongoing,
Durable Responses in Solid Tumors

 

AVA6000 is safe and well-tolerated in both study arms: every three weeks (Q3W)
and every two weeks (Q2W) dosing, with an early lack of serious cardiac safety
signal and preliminary evidence of efficacy

 

Multiple ongoing and durable RECIST responses observed in patients with
FAP(high) and doxorubicin sensitive diseases including in patients with
stroma-only expression of FAP

 

pre|CISION-enabled doxorubicin (AVA6000) results in multiple fundamental
changes in the pharmacokinetics of released doxorubicin in plasma and tumor
versus conventional doxorubicin

Avacta Group plc (AIM: AVCT), a life sciences company developing innovative,
targeted cancer treatments and powerful diagnostics, has presented updated
data from the ongoing Phase 1a trial of AVA6000 in patients with FAP-positive
solid tumors at the 2024 European Society for Medical Oncology (ESMO)
Congress, in Barcelona, Spain.

The results, presented on Saturday September 14, demonstrate that AVA6000 is
well-tolerated across the every 2 weeks and every 3 weeks dosing schedules
with early evidence of efficacy supported by ongoing and durable RECIST
responses in patients with FAP(high) disease. AVA6000 is the first peptide
drug conjugate (PDC) in the Avacta pipeline and consists of doxorubicin
conjugated with a peptide moiety that is specifically cleaved by Fibroblast
Activation Protein (FAP) in the tumor microenvironment (TME).

Professor Chris Twelves, Lead Investigator and Professor of Medicine,
University of Leeds, commented:

"The AVA6000 data presented at ESMO continue to demonstrate encouraging
efficacy with several ongoing, durable responses. The observed efficacy aligns
with a highly favorable safety profile including a lack of the significant
cardiac toxicity that is often seen with doxorubicin treatment.

"The mechanism of action of the pre|CISION™ peptide drug conjugates with the
observed warhead release in tumors with lower FAP activity together speak to
the potential of this platform to treat a broad range of solid tumor patient
populations with clinical needs that are not being met. I am looking forward
to working with the Company, colleagues and patients on the continued
development of AVA6000."

Christina Coughlin MD, PhD, Chief Executive Officer of Avacta, added:

"With nearly six months of added follow-up, these compelling data strengthen
the clinical validation for AVA6000 and the pre|CISION(TM) drug delivery
platform to challenge current drug delivery methods and expand the reach of
highly potent therapeutics using peptide drug conjugates.

"We believe our platform has the potential to revolutionize cancer treatment
by enabling patients to achieve improved outcomes with fewer side effects by
leveraging the tumor specific enzyme FAP to protect normal tissues from toxic
drugs. The observation of warhead release in the tumor even in the setting of
lower FAP activity is highly encouraging for our pipeline. We are excited to
move our Company into the next stage of development, implementing these
findings of this drug release mechanism across our innovative pipeline."

Trial Results Summary

As at the latest  data cut-off date, ten dose cohorts (n=57) have completed
the Phase 1a trial under the Arm 1 dosing schedule of every three weeks
("Q3W") and the Arm 2 dosing schedule of every two weeks ("Q2W"). In total, 57
patients were enrolled and are evaluable for safety (primary outcome measure)
and 49 patients formed the efficacy evaluable dataset (secondary outcome
measure).

Efficacy data

Cancer indications were categorized based on published data regarding both
immunohistochemistry and FAPI-PET studies 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. Patients had a median of two prior
systemic cancer therapies (range 0-7) with 65% including cytotoxic exposure.
Reduction in the sum of longest diameters (SLD) is used to measure response
per RECIST 1.1 with partial responses of >30% reduction and minor responses
of between >10% and <30% reduction.

·      Among patients with FAP(high) cancers (n=23), three partial
responses and four minor responses were observed, including:

o  A durable, confirmed partial response at 12 weeks in a 79-year-old male
patient with progressive salivary gland cancer (SGC). After an initial minor
response (22% reduction in SLD), the observed durable PR is ongoing despite
patient discontinuation due to lifetime maximum dosing (duration of response
>18 weeks, with 46.2% reduction in SLD). Tumor histology demonstrates no
expression of FAP in tumor cells with only stromal cell expression noted.

o  A minor response (14.6% reduction in SLD at first 8-week scan) in a
65-year-old female patient with SGC who remains on the trial. This patient was
dosed in the 250 mg/m2 Q2W cohort of the trial and had progression on a prior
line of therapy. This patient continues on study. Similarly, the histology
shows FAP-negative tumor cells and FAP expression only in the stromal
compartment.

o  A partial response (40.5% reduction in SLD) in a 55-year-old male patient
with dedifferentiated liposarcoma who had progressed on two prior lines of
therapy in the metastatic setting. After an initial minor response this
patient experienced a partial response with SLD change of -40.6%. The patient
experienced new lesions at their latest follow-up scan.

·      Eight patients remain on study in the Phase 1a cohorts with a
diagnosis of FAP(high) cancers

Among patients with FAP(mid) cancers (n=26), two minor responses were
observed.

Safety and Pharmacokinetics Data

Treatment with AVA6000 continues to be well-tolerated with the addition of the
Q2W dosing regimen (Arm 2) with a favorable safety profile and reduction in
severe and mild-to-moderate treatment-emergent toxicities as compared with
conventional dose doxorubicin. A maximum tolerated dose has not been
identified in either arm of the trial.

·      Severe (CTCAE grade 3 or 4) neutropenia was observed in 14% of
AVA6000 patients vs 49% treated with conventional dose doxorubicin (comparison
made to a Ph III trial where doxorubicin monotherapy is the comparator arm in
a similar patient population).(1) There were no cases of febrile neutropenia
in the AVA6000 trial compared to 16.5% of patients receiving conventional
doxorubicin alone in a similar patient population(1)

·      The observed cardiac safety profile of AVA6000 compares favorably
to conventional dose doxorubicin, with low incidence of left ventricular
ejection fraction (LVEF) changes (LVEF dysfunction 12.3% v. 48.4% with
conventional doxorubicin(1,2)) and no grade 3 or 4 severe cardiac events
reported

·      Reductions were observed in toxicities that impact quality of
life including nausea, mouth sores, decreased appetite, constipation and
vomiting and similar reductions were observed with both the Q3W and Q2W dosing
schedules.as compared to conventional doxorubicin dosing(1)

·      No new dose limiting toxicities were observed and neither arm has
determined an MTD

Treatment with AVA6000 results in multiple fundamental changes in the PK of
released doxorubicin (compared to conventional doxorubicin administration(3))
including:

·      Extension of the plasma half-life by ~40%

·      Reduction of approximately 40-50% in both C(max) and the
peripheral volume of distribution, suggesting AVA6000-released doxorubicin
demonstrates a more limited distribution into normal tissues versus
conventional doxorubicin(4,5)

Tumor biopsies taken 24 hours after the first dose of AVA6000 reveal
additional insights regarding the role of FAP, in that the level of FAP
positivity in the tumor appears not to correlate with the level of released
doxorubicin in the TME (n=9).  This lack of correlation indicates that lower
levels of FAP activity are sufficient for warhead release.  These data
provide evidence for targeting of the FAP(mid) tumor types with novel
warheads.

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.

References

(1)Tap WD, et al. Effect of Doxorubicin Plus Olaratumab vs Doxorubicin Plus
Placebo on Survival in Patients With Advanced Soft Tissue Sarcomas: The
ANNOUNCE Randomized Clinical Trial. JAMA. 2020;323(13):1266-1276. doi:
10.1001/jama.2020.1707

(2)Jones, RL et al. Prospective evaluation of doxorubicin cardiotoxicity in
patients with advanced soft tissue sarcoma in the ANNOUNCE Phase III
randomized trial. Clin Ca Res 2021;27:3751-66. doi:
0.1158/1078-0432.CCR-20-4592

(3)Villalobos VM, et al. Pharmacokinetics of doxorubicin following concomitant
intravenous administration of olaratumab (IMC-3G3) to patients with advanced
soft tissue sarcoma. Cancer Med. 2020;9(3):882-893. doi: 10.1002/cam4.2728

(4)Kontny N et al, Population pharmacokinetics of doxorubicin: establishment
of a NONMEM model for adults and children older than 3 years, Cancer Chemother
Pharmacol 2013;71(3):749-63.  doi: 10.1007/s00280-013-2069-1

(5)Pérez‐Blanco JS et al, Population pharmacokinetics of doxorubicin and
doxorubicinol in patients diagnosed with non‐Hodgkin's lymphoma, Br J Clin
Pharmacol. 2016; 82(6): 1517-1527

 

-Ends-

 

 

For further information from Avacta Group plc, please contact:

 

 Avacta Group plc                                      Tel: +44 (0) 1904 21 7070

 Christina Coughlin, CEO                               www.avacta.com (https://avacta.com/)

 Michael Vinegrad, Group Communications

 Director

 Peel Hunt (Nomad and Broker)

 James Steel / Chris Golden / Patrick Birkholm         www.peelhunt.com (http://www.peelhunt.com/)

 ICR Consilium

 Mary-Jane Elliott / Jessica Hodgson / Sukaina Virji   avacta@consilium-comms.com (mailto:avacta@consilium-comms.com)

 

 

 

 

About Avacta Group plc - www.avacta.com (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 Therapeutics: a clinical stage oncology biotech division harnessing
proprietary therapeutic platforms to develop novel, highly targeted cancer
drugs.

 

Avacta Diagnostics focuses 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 tumors compared
with healthy tissues. The pre|CISION™ platform harnesses this tumor specific
protease to activate pre|CISION™ peptide drug conjugates and pre|CISION™
antibody/Affimer® drug conjugates in the tumor microenvironment, reducing
systemic exposure and toxicity, allowing dosing to be optimised to deliver the
best outcomes for patients.

 

The lead pre|CISION™ program AVA6000, a peptide drug conjugate form of
doxorubicin, is in Phase 1 studies. It has shown an 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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