AVA6103
Avacta's second pre|CISION-platform peptide-drug conjugate — a fibroblast activation protein (FAP)-cleavable peptide linker masking exatecan, the topoisomerase-I payload behind the deruxtecan ADC class. First patient dosed in the Phase 1 FOCUS-01 trial (NCT07454642) on March 31, 2026. Human safety and pharmacokinetic data arrived in September 2026: across 19 patients through the first three dose levels, Avacta reported zero neutropenia and a plasma profile it interprets as the conjugate sitting in a tumour 'drug reservoir'. No efficacy data yet, and no peer-reviewed publication of any kind.
AVA6103 is Avacta's second masked-chemotherapy conjugate: exatecan — the same payload family behind Enhertu — chemically locked behind a peptide that only the tumour-stroma enzyme FAP can cut. The Phase 1 trial opened in March 2026 and the first human data landed in September: through three dose levels in 19 patients, zero neutropenia, against 64% at the maximum tolerated dose of unmasked exatecan. That looks remarkable, and it may be, but the trial is still climbing in dose, has not found its ceiling, and the comparison is to other trials rather than a control arm. No efficacy data until 2027, and no peer-reviewed paper on the compound exists.
What is AVA6103?
AVA6103 is Avacta Therapeutics' second clinical peptide-drug conjugate (PDC) built on the pre|CISION platform. It pairs exatecan — a topoisomerase-I inhibitor and the active warhead family used in trastuzumab deruxtecan (Enhertu), datopotamab deruxtecan, patritumab deruxtecan, and ifinatamab deruxtecan — with a fibroblast activation protein alpha (FAPα)-cleavable peptide linker that masks the payload in circulation. FAPα is a serine protease highly expressed on cancer-associated fibroblasts in many solid tumors but minimally expressed in healthy adult tissue, providing a tumor-microenvironment-selective deconjugation switch. AVA6103 is described by Avacta as a 'sustained-release' PDC, distinct from the AVA6000 (FAP-doxorubicin) chemistry by virtue of a prolonged intratumoral payload-release profile. The Phase 1 FOCUS-01 trial (NCT07454642) began enrollment on March 31, 2026, targeting pancreatic ductal adenocarcinoma, cervical/vulvar, gastric/GEJ adenocarcinoma, and small-cell lung carcinoma. Preclinical data presented at AACR 2026 (abstract #5846) reported activity across low-to-high FAP-expression patient-derived xenografts, with a higher reported tumor selectivity index than a comparator arm the company generated synthetically from a published AstraZeneca dataset — not a head-to-head trial. The registry record was revised upward on September 30, 2026 to an estimated 174 patients across nine tumor types, and enrollment is selective in a way the early coverage missed: patients are chosen on co-expression of FAP and SLFN11, a gene known to predict response to topoisomerase-1 inhibition, so the addressable population is narrower than FAP expression alone would suggest.
What AVA6103 Is Investigated For
AVA6103 is the second clinical molecule from Avacta's pre|CISION FAP-activated PDC platform, swapping the AVA6000 doxorubicin payload for exatecan — the topoisomerase-I inhibitor whose deruxtecan derivative powers the most commercially successful ADC class in oncology. The strategic rationale is clear: exatecan provides broader tumor-type relevance than anthracyclines, a strong bystander effect for heterogeneous FAP expression, and a payload that lipophilic free exatecan could never achieve as a small molecule because of dose-limiting myelotoxicity. Preclinical AACR 2026 disclosures describe a 'sustained-release' intratumoral payload profile, faster tumor penetration, and a higher tumor selectivity index than a synthetic Enhertu comparator. Phase 1 FOCUS-01 (NCT07454642) is a 144-patient open-label dose-escalation and expansion study using BOIN methodology across Q3W and Q2W schedules. Honest caveats, updated: AVA6103 still has zero peer-reviewed publications — PubMed returns nothing for AVA6103 or FAP-Exd — but the claim that no human data exists is no longer true. September and October 2026 company releases reported safety and pharmacokinetics through four dose levels in 19-plus patients, with a striking 0% neutropenia rate. That number deserves care rather than enthusiasm: it is a cross-trial comparison against historical and synthetically-generated comparator data, drawn from the three lowest dose levels of a study that is still escalating and has not declared a maximum tolerated dose. Toxicity in a dose-escalation trial is a function of where you have stopped, not of the molecule alone. Efficacy data is not expected before H1 2027. The FAP-activated PDC concept itself is still proving translational viability — AVA6000 reached Phase 1 in 2022–2023 with credible early activity in salivary gland cancer, but the broader FAP-PDC class has yet to deliver a registered therapy. AVA6103 should be understood as an early-stage platform-validation asset, not a near-term cancer therapy.
History & Discovery
Avacta (Avacta Life Sciences Ltd, part of Avacta Group plc) developed the pre|CISION platform as a peptide-drug-conjugate strategy in which a FAPα-cleavable peptide linker masks a cytotoxic payload in circulation and selectively releases it within the tumor stroma. AVA6000 (FAP-doxorubicin), the first clinical asset on the platform, entered Phase 1 in 2022–2023 and reported its first clinically meaningful activity signals — including durable responses in salivary gland cancer — through 2024–2026 conference presentations. AVA6103 was developed as the platform's second clinical molecule, pairing the same FAP-cleavable linker chemistry with exatecan rather than doxorubicin. The payload switch was driven by exatecan's positioning as the dominant ADC warhead class in oncology circa 2023–2026: trastuzumab deruxtecan (Enhertu), datopotamab deruxtecan, and the broader deruxtecan family of ADCs have validated the topoisomerase-I payload class commercially and clinically. By porting that payload onto the FAP-activated PDC chassis, AVA6103 aims to reach FAP-rich stromal tumors — pancreatic, cervical/vulvar, gastric/GEJ, and small-cell lung — that are less well served by current ADC target antigens. The first preclinical disclosures arrived at AACR 2026 (abstract #5846, presented April 21, 2026), describing tumor selectivity, payload concentration, and antitumor activity in multiple patient-derived xenograft models versus a synthetic Enhertu comparator arm. The Phase 1 FOCUS-01 trial (NCT07454642) opened enrollment with first patient dosed on March 31, 2026 across sites in Virginia, Texas and Michigan. Avacta described the design at launch as a Bayesian Optimal Interval (BOIN) dose-escalation expected to enroll approximately 144 patients — the BOIN detail comes from the company release and does not appear in the registry record. Both figures have since moved: by late 2026 the registry listed an estimated 174 patients across seven sites, adding HonorHealth in Scottsdale, Florida Cancer Specialists in Sarasota, the University of Chicago and Memorial Sloan Kettering, and nine conditions rather than the original four — colorectal cancer and hormone-receptor-positive breast carcinoma joined the pancreatic, cervical/vulvar, gastric/GEJ and small-cell lung cohorts. The first human data came on September 16, 2026, when Avacta reported that the first three dose levels — 1.5, 3 and 4.5 mg/m² — had completed enrollment with 19 patients. The hematologic profile was the point of the release: 0% neutropenia versus 22% quoted for comparable doses of Enhertu and 64% at the maximum tolerated dose of conventional exatecan, with thrombocytopenia at 5% and anemia at 16%. Pharmacokinetics showed the released peptide clearing with a 2–3 hour half-life yet still detectable at 48 hours, which the company reads as the conjugate being held in the tumor and cleaved slowly — a 'drug reservoir' — with tumor-biopsy confirmation still outstanding. At ESMO 2026 on October 23, 2026 Avacta reported enrollment complete at dose level 4 and disclosed that patients are selected on co-expression of FAP and SLFN11, a gene that predicts response to topoisomerase-1 inhibition. First efficacy data is expected in H1 2027. The corporate backdrop matters for an asset at this stage. Avacta proposed a fundraise of approximately £12.5m on October 5, 2026, reported the placing and subscription results the following day, and had trading in its shares restored on AIM on October 6, implying a prior suspension.
How It Works
Exatecan is a strong tumor-killing drug from the same family used in Enhertu (Trastuzumab deruxtecan). AVA6103 carries exatecan with a peptide 'safety lock' that only opens at tumor sites — specifically where an enzyme called FAP (fibroblast activation protein) is found on cells that surround and support tumors. The peptide gets cleaved at the tumor, releasing active drug locally with less spillover to healthy tissue.
AVA6103 is a peptide-drug conjugate consisting of exatecan linked via a FAPα-cleavable peptide bond. FAPα is a dipeptidyl-peptidase-family serine protease whose expression on cancer-associated fibroblasts is restricted to tumor stroma and sites of active fibrosis, with minimal expression in healthy adult tissues — providing the differential cleavage signal that defines the pre|CISION platform. The payload, exatecan, is a camptothecin analog roughly 10-fold more potent than SN-38 (irinotecan's active metabolite). It traps topoisomerase-I-DNA cleavage complexes, generating single-strand DNA breaks that collapse replication forks and trigger apoptosis. Exatecan as a free small molecule was abandoned in oncology development because of dose-limiting myelosuppression; payload-conjugation strategies — both ADCs (Enhertu's DXd) and now FAP-activated PDCs — were designed specifically to deliver this potency without the systemic toxicity ceiling. Avacta describes AVA6103 as a 'sustained-release' PDC, suggesting prolonged intratumoral payload availability rather than burst release. Preclinical AACR 2026 disclosures reported a tumor selectivity index roughly three-fold higher than a synthetic Enhertu comparator arm, with tumor peak concentrations more than one log greater and faster tumor penetration. These claims are sourced from a company-defined comparator within a preclinical study, not from a randomized clinical head-to-head; they should be read as platform-validation signal rather than clinical-superiority evidence.
Evidence Snapshot
Human Clinical Evidence
Early but no longer absent. First patient treated March 31, 2026 in FOCUS-01 (NCT07454642), which remains RECRUITING with an estimated 174 patients and estimated primary completion January 2029. On September 16, 2026 Avacta reported the first human safety and pharmacokinetic data: 19 patients had completed enrollment through the first three dose levels of 1.5, 3 and 4.5 mg/m². Hematologic toxicity was the headline — neutropenia 0% with AVA6103 against 22% quoted for similar doses of Enhertu and 64% at the maximum tolerated dose of conventional exatecan; thrombocytopenia 5% (1/19) against 11% and 43%; anemia 16% (3/19) against 11% and 43%. The company states dose level 3 represents roughly a 50% increase over the MTD of conventional exatecan. Pharmacokinetics showed the released peptide has a half-life of only 2–3 hours yet remains detectable in plasma to 48 hours after dosing, which Avacta interprets as the conjugate being retained in the tumor as a slowly-cleaved drug reservoir — tumor-biopsy confirmation is still pending. By October 23, 2026 enrollment had completed at dose level 4. No efficacy data exists; the company expects the first in H1 2027. Every one of these figures is company-reported, and the comparator rates are cross-trial, not randomized.
Animal / Preclinical
Preliminary. AACR 2026 abstract #5846 reports activity across multiple patient-derived xenografts spanning low-to-high FAP expression and improved tumor selectivity index versus a synthetic Enhertu comparator.
Mechanistic Rationale
Strong. FAP-stromal-targeting and topoisomerase-I payload chemistry are both individually well-characterized. Peer-reviewed FAP-precision-medicine reviews (Liu et al., Acc Chem Res 2026, PMID 42610618) and exatecan linker chemistry (Li et al., Bioorg Chem 2026, PMID 42218895) frame the platform class; parallel non-antibody exatecan conjugates such as folate-exatecan LDCs (Murugan et al., Bioconjug Chem 2026, PMID 42446968) demonstrate that non-ADC delivery of the DXd/exatecan payload family can be achieved. The translational track record of the broader FAP-PDC class in humans remains unproven.
Research Gaps & Open Questions
What the current literature has not yet settled about AVA6103:
- 01Efficacy — entirely unknown. Safety and pharmacokinetics now exist through four dose levels, but no tumor response data has been reported and none is expected before H1 2027.
- 02Whether exatecan is the right payload for a stroma-targeted conjugate. The one published FAP-cleavable programme that benchmarked payloads head-to-head (Bocci et al., J Control Release 2024, PMID 38346501) found its exatecan conjugate effective against tumor-cell-FAP models but advanced a tubulin payload instead, because that one also worked against stromal-FAP models. Stromal FAP is the whole premise of the pre|CISION platform, which makes this the most specific unanswered question about AVA6103.
- 03How much the SLFN11 requirement narrows the addressable population. Patients are enrolled on co-expression of FAP and SLFN11, not FAP alone; SLFN11 is a well-established predictor of response to topoisomerase-1 inhibitors, so a positive result in a doubly-selected population would not generalise to FAP-expressing tumors at large.
- 04Whether the tumor 'drug reservoir' interpretation is correct. The 48-hour plasma detection of a peptide with a 2–3 hour half-life is consistent with slow intratumoral cleavage, but the company has said tumor-biopsy confirmation is still pending — until that lands, the reservoir is an inference from plasma data.
- 05Linker cleavage kinetics in human tumors — whether sufficient FAPα activity exists across the targeted tumor types to drive therapeutic exatecan release.
- 06Comparative activity versus deruxtecan ADCs — the AACR 2026 comparator was synthetic, not a randomized head-to-head.
- 07Optimal tumor-type selection — pancreatic, cervical, gastric, and SCLC are being explored in parallel, with response heterogeneity expected.
- 08ILD signal monitoring — whether the topoisomerase-I payload carries the same ILD risk in a PDC format as it does in the deruxtecan ADC class.
Forms & Administration
Intravenous infusion in FOCUS-01. Investigational. Not commercially available. No compounded or research-chemical sources are legitimate.
Dosing & Protocols
The ranges below reflect protocols commonly discussed in the literature and by clinicians — not a prescription. Actual dosing for any individual should be determined by a qualified healthcare provider who knows the patient.
Typical Range
FOCUS-01 dose-escalation pending. Both Q3W and Q2W schedules are being explored using BOIN methodology.
Frequency
IV infusion every 2 or 3 weeks depending on cohort.
Timing Considerations
No specific timing requirements: can be administered at any time of day, with or without food, and is not tied to exercise timing. Consistency matters more than the specific clock — dose at roughly the same time each day (or same day each week, for weekly protocols) to keep exposure steady.
Cycle Length
Standard oncology cycle structure per FOCUS-01 protocol.
Protocol Notes
AVA6103 is in early clinical development and is not commercially available. Eligible patients in FAP-expressing solid tumors may discuss FOCUS-01 enrollment with their oncologist.
AVA6103 is investigational and Phase 1 stage. Oncology indication; specialty oncology supervision required for any clinical trial participation.
Timeline of Effects
Onset
Standard cycle response assessment — initial response evaluation typically at 6–9 weeks (2–3 cycles).
Peak Effect
To be characterized in Phase 1 expansion and any future Phase 2 cohorts.
After Discontinuation
Pharmacological clearance per exatecan PK; long-term durability data not yet available.
Monitoring & Measurement
Bloodwork & Labs
- •Complete blood count with differential before each cycle — the standard surveillance for any exatecan-class payload, where myelosuppression is the dose-limiting toxicity of the unmasked drug
Functional & Performance Tests
- •Chest imaging and active surveillance for respiratory symptoms — interstitial lung disease is a recognised class effect of the deruxtecan antibody-drug conjugates that share this payload family, and proactive monitoring is standard practice there
- •Cross-sectional imaging for response assessment on the trial's schedule
When to Test
Baseline before first dose, bloods before each cycle, imaging on the protocol schedule.
Interpretation & Notes
This describes what a trial protocol requires for a topoisomerase-1 payload, not a self-tracking regimen — AVA6103 is an intravenous investigational agent available only inside FOCUS-01. Two honest qualifications. First, no interstitial lung disease signal has been reported for AVA6103; the concern is inherited from the deruxtecan class that shares the payload family, and whether it carries over to a FAP-activated conjugate is genuinely unknown. Second, the myelosuppression that motivates routine blood counts for free exatecan is exactly what Avacta's September 2026 data did not show — 0% neutropenia through three dose levels. If that holds as the dose climbs, the monitoring burden for this conjugate may end up lighter than its payload class implies. It has not yet been tested at the top of the range.
Common Questions
How is AVA6103 different from AVA6000?
Both are FAP-cleavable peptide-drug conjugates using Avacta's pre|CISION linker. AVA6000 carries doxorubicin (an anthracycline that drives DNA damage via topoisomerase II and intercalation, with cardiotoxicity as the dose-limiting concern). AVA6103 carries exatecan (a camptothecin analog that inhibits topoisomerase I — the same payload family used in Enhertu, Trodelvy successor Datroway, and the rest of the deruxtecan ADC class). Avacta also describes AVA6103 as a 'sustained-release' chemistry, distinct from AVA6000's profile, though full mechanistic detail is not yet published.
Why exatecan instead of using a deruxtecan ADC?
ADCs deliver payload via an antibody binding a tumor-surface antigen — they require the right antigen on the tumor cell surface. FAP-activated PDCs deliver payload via cleavage at the tumor stroma, so they target the tumor microenvironment rather than tumor-cell-surface antigen expression. The pitch is that FAP-rich stromal tumors (pancreatic, cholangiocarcinoma, certain sarcomas) where current ADC targets are weak could be reached by a stroma-activated platform.
Is this approved or available?
No. AVA6103 is investigational and in Phase 1. The only legitimate access is enrollment in the FOCUS-01 trial (NCT07454642). Any non-trial source claiming to sell AVA6103 should be presumed unverified material.
Who AVA6103 Is NOT For
- •Oncology trial enrollment only — outside FOCUS-01, no legitimate access.
- •Pregnancy and breastfeeding — chemotherapy contraindication.
- •Severe baseline myelosuppression — exatecan-class payloads carry myelotoxicity risk.
- •Active or prior interstitial lung disease — class concern carried over from deruxtecan ADCs that share the topoisomerase-I payload family.
- •Known hypersensitivity to camptothecin-class drugs or peptide conjugates.
Drug & Supplement Interactions
No drug interaction profile is established. Exatecan-class payloads are partially metabolized by CYP3A4 and UGT enzymes (extrapolating from related camptothecin pharmacology), so co-administration of strong CYP3A4 modulators or UGT-affecting agents is a theoretical concern. FOCUS-01 protocol exclusions will define the practical interaction list as the program progresses.
Safety Profile
Common Side Effects
Cautions
- • Investigational — Phase 1 stage with no published human data yet
- • Oncology drug — managed under specialty oncology care only
- • Exatecan/topoisomerase-I payloads carry interstitial lung disease (ILD) signal seen across the deruxtecan ADC class — relevance to AVA6103 unknown
What We Don't Know
Human safety, tolerability, PK, and activity profile — all to be characterized in FOCUS-01 (NCT07454642).
Legal Status
United States
Investigational — not FDA-approved. Phase 1.
International
Investigational across major regulators.
Sports & Competition
Not relevant — oncology indication.
Regulatory status changes over time. Verify current local rules with a qualified professional.
Myths & Misconceptions
Myth
AVA6103's 0% neutropenia rate proves it is safer than Enhertu.
Reality
Not yet, and the comparison is not the kind that can prove it. The 0% versus 22% versus 64% figures come from 19 patients across the three lowest dose levels of a trial that is still escalating — dose level 4 completed enrollment in October 2026 and no maximum tolerated dose has been declared. The comparators are historical and synthetically-generated data from other studies, not a randomized control arm. Hematologic toxicity in a dose-escalation study is largely a function of how far up the dose range you have climbed; a clean safety profile at the bottom of the range is expected, not evidence of a better molecule. The claim becomes testable when the trial reaches its ceiling.
Myth
AVA6103 is Enhertu without the antibody.
Reality
AVA6103 shares the exatecan payload family with Enhertu's DXd, but the targeting strategy is fundamentally different. Enhertu targets HER2 on the tumor cell surface; AVA6103 targets FAP on stromal cancer-associated fibroblasts. The tumor populations that respond — and the resistance mechanisms — are not interchangeable.
Myth
Because AVA6103 uses a popular payload, it will work in many cancers.
Reality
Payload identity does not determine clinical success — delivery does. Whether AVA6103 reaches therapeutic exatecan concentrations in human tumors depends on FAPα expression density, tumor accessibility, and linker cleavage efficiency in human biology. The track record of FAP-activated drug delivery in clinical trials is still being written.
Myth
Avacta data showing AVA6103 beats Enhertu means it's already superior.
Reality
The AACR 2026 comparator was a synthetic Enhertu arm in preclinical xenografts — a useful internal benchmark, not a randomized human comparison. Preclinical superiority signals routinely fail to translate. Treat the preclinical data as platform validation, not clinical superiority.
Published Research
10 studiesTargeting Fibroblast Activation Protein for Precision Medicine.
Receptor-Targeted Folic Acid Ligand-Drug Conjugate of Exatecan Leads to Complete Tumor Regression in the Preclinical Tumor Model.
NH2-trimethyl lock (NH2-TML): a stable and effective adapter for exatecan-based antibody-drug conjugates.
A novel FAP-targeting antibody-exatecan conjugate improves immune checkpoint blockade by reversing immunosuppressive microenvironment in pancreatic cancer.
In vivo activation of FAP-cleavable small molecule-drug conjugates for the targeted delivery of camptothecins and tubulin poisons to the tumor microenvironment.
Bocci M et al., J Control Release 2024. The closest published analogue to AVA6103 that exists, and the most useful cautionary datapoint on the page: a FAP-cleavable conjugate programme that benchmarked topoisomerase-I payloads including exatecan against a tubulin payload. Exatecan performed well against tumor-cell-FAP models, but the tubulin conjugate was the one advanced to clinical development because it also worked against stromal-FAP models — and stromal FAP is precisely what AVA6103 is designed to exploit.
New Life of Topoisomerase I Inhibitors as Antibody-Drug Conjugate Warheads.
Pommier Y and Thomas A, Clin Cancer Res 2023. Short authoritative framing of why topoisomerase-I inhibitors became the dominant ADC payload class, from the field's leading topoisomerase pharmacologist — the background that explains why Avacta swapped doxorubicin for exatecan in its second conjugate.
Avacta announces first patient treated in Phase 1 FOCUS-01 trial of FAP-Exd (AVA6103), a sustained-release pre|CISION exatecan peptide drug conjugate
Avacta press release (March 31, 2026) announcing the first patient dosed in FOCUS-01 (NCT07454642) — the Phase 1 dose-escalation and expansion study of AVA6103, the company's second pre|CISION peptide-drug conjugate. Describes the asset as a 'sustained-release' exatecan PDC distinct in chemistry from AVA6000 (FAP-doxorubicin).
FOCUS-01 (NCT07454642): A Phase 1, Open Label, Dose-Escalation and Expansion Study to Evaluate Safety, Pharmacokinetics and Initial Therapeutic Activity of AVA6103
AACR 2026 #5846 — AVA6103 is a FAP-enabled pre|CISION peptide-drug conjugate delivering sustained release of exatecan in the tumor microenvironment with potent antitumor activity
Phase I AVA6000 (AACR 2024 #CT188) — A Phase I trial of AVA6000, a peptide-drug conjugate of doxorubicin selectively activated by FAP in the tumor microenvironment
Quick Facts
- Class
- FAP-Activated Peptide-Drug Conjugate
- Tier
- D
- Evidence
- Limited
- Safety
- Limited Data
- Updated
- Oct 2026
- Citations
- 10PubMed
Also known as
Tags
Evidence Score
Clinical Trials
View Clinical TrialsLinks to ClinicalTrials.gov for reference. Listing does not imply endorsement.