Akeso moves bispecific ADCs into Phase II as IO 2.0 combination strategy enters mid-stage development

Akeso, Inc. (HKEX: 9926.HK) has secured China National Medical Products Administration clearance to initiate Phase II clinical trials for two next-generation antibody-drug conjugates: AK146D1, a Trop2/Nectin4 bispecific ADC, and AK138D1, a HER3-targeting ADC. Both candidates will be evaluated in combination with Akeso’s two approved checkpoint bispecific antibodies, cadonilimab (PD-1/CTLA-4) and ivonescimab (PD-1/VEGF), across a range of advanced solid tumors. The move advances what the company calls its “IO 2.0 + ADC 2.0” platform from early-stage human trials into the larger, efficacy-oriented studies that typically define pivotal positioning. With shares trading around HK$120.70 on March 25, 2026, well below their 52-week high of HK$179.00 but roughly double the 52-week low of HK$60.60, this clinical milestone arrives as investors recalibrate expectations ahead of the company’s annual results due April 1.

Why is combining bispecific checkpoint antibodies with next-generation ADCs considered a structural advance over earlier IO plus ADC regimens?

The conventional IO plus ADC pairing that has defined oncology combination therapy over the past several years carries a fundamental limitation: standard checkpoint inhibitors release immune brakes across the entire system, while standard ADCs deliver cytotoxic payloads to any cell expressing a single target antigen. Neither component addresses the underlying problem of tumor heterogeneity, where not all malignant cells in a given patient express the same surface markers at the same density.

Akeso’s framing of “IO 2.0” rests on its two approved bispecific checkpoint antibodies. Cadonilimab simultaneously blocks both PD-1 and CTLA-4, two non-redundant immune checkpoints, while ivonescimab pairs PD-1 inhibition with anti-VEGF activity, a combination that addresses both immune suppression and the pro-angiogenic tumor microenvironment in a single molecule. The practical consequence is that each backbone already delivers a more complex immune intervention than a conventional PD-1 or PD-L1 monoclonal antibody.

Akeso is the only company globally that has secured regulatory approval for two such checkpoint bispecific antibodies. That is not a marketing assertion but a structural reality in the competitive landscape, one that matters specifically for combination strategy. To build an IO plus ADC combination that deploys a bispecific checkpoint backbone, a competitor would either need to partner with Akeso or achieve regulatory approval for its own bispecific checkpoint agents, neither of which is straightforward. Running the “IO 2.0 + ADC 2.0” combination on internally owned assets across both sides of the equation is a genuine competitive distinction.

What makes AK146D1 a structurally different ADC from the approved Trop2 and Nectin4 agents already on the market?

Sacituzumab govitecan and datopotamab deruxtecan are both approved Trop2-targeting ADCs, and enfortumab vedotin targets Nectin4 in urothelial carcinoma. All three are single-antigen monoclonal ADCs. AK146D1 is specifically engineered to bind Trop2 and Nectin4 simultaneously, making it the first bispecific ADC addressing both markers, a claim supported by the absence of any competing approved agent in that construct class as of early 2026.

The rationale for dual targeting is grounded in antigen co-expression biology. Trop2 and Nectin4 are both frequently present in epithelial-derived tumors including lung, breast, and bladder cancers, but their relative expression levels vary across patients and across tumor subpopulations within the same patient. A monoclonal ADC targeting only Trop2 will miss cells where Trop2 expression has been downregulated or lost, a known resistance mechanism. By binding to either Trop2 or Nectin4, AK146D1 theoretically maintains target engagement even when one antigen is selectively lost, which may help sustain payload delivery in tumors that would otherwise escape a single-target agent.

Phase I data characterised both AK146D1 and AK138D1 as showing potent anti-tumor activity with manageable safety profiles. That framing is standard early-stage language, and Phase II will provide the larger, more granular dataset needed to assess whether the efficacy signal is durable and whether the safety profile holds at the doses required for combination regimens. The combination context is important here: adding a bispecific checkpoint antibody to an ADC adds immune activation on top of cytotoxicity, which can amplify efficacy but can also compound toxicity if the profiles are not carefully matched.

How does AK138D1’s HER3 targeting address the resistance problem in HER2 and EGFR-driven cancers?

HER3 (human epidermal growth factor receptor 3) is structurally related to HER2 and EGFR but has historically been a more difficult drug target. Unlike HER2 and EGFR, HER3 has limited intrinsic kinase activity, which made it largely inaccessible to the tyrosine kinase inhibitor class. The ADC modality sidesteps that limitation entirely: the antibody component delivers the payload to cells expressing HER3 on their surface, irrespective of whether the receptor is enzymatically active.

The clinical relevance is that HER3 expression frequently rises in tumors that have developed resistance to established HER2 and EGFR-targeted therapies. Patients who progress on trastuzumab, pertuzumab, or EGFR inhibitors often show elevated HER3 activity as a compensatory signaling pathway. An ADC targeting HER3 in this population is therefore addressing a defined mechanism of acquired resistance rather than a de novo target of convenience. The tumor types involved, including ovarian, colorectal, melanoma, and prostate cancers, represent large, commercially significant indications where resistance to existing treatments is a major clinical problem.

The Phase II trials announced by Akeso will evaluate AK138D1 both as a standalone combination with the company’s bispecific checkpoint antibodies and potentially with its anti-CD47 agent AK117 and anti-VEGF agent AK109. The multi-backbone design creates a complex combinatorial matrix, which is both the ambition and the risk. Each combination arm requires its own dosing, scheduling, and safety monitoring, and the Phase II dataset will need to be sufficiently powered to distinguish signal from noise across multiple tumor types.

What execution risks and timeline uncertainties does the Phase II transition create for investors evaluating Akeso’s pipeline value?

Phase II clearance from China’s NMPA marks regulatory permission to enroll patients, not proof of efficacy. The gap between Phase I tolerability data and Phase II efficacy confirmation is where most oncology programs encounter unexpected headwinds, including insufficient patient responses at tolerable doses, unexpected toxicity at higher doses required for efficacy, or competitor approvals that change the standard of care before a trial completes.

For Akeso’s combination strategy specifically, the layered complexity of “IO 2.0 + ADC 2.0” creates a trial design challenge. Combinations of bispecific antibodies with ADCs are not yet well-characterised in terms of additive versus synergistic versus antagonistic interactions at the mechanistic level. Phase II will need to demonstrate not only that the combination is safe and active, but that it is meaningfully superior to either component alone in a given tumor type. That is a higher evidentiary bar than a simple monotherapy Phase II and will require enrollment of adequately powered combination arms, which takes time and resources.

Akeso is also navigating a commercial backdrop in China where the pricing environment for innovative oncology drugs has been progressively compressed through national reimbursement negotiations. Both cadonilimab and ivonescimab are commercially available in China, and their inclusion in the national reimbursement drug list has been critical to adoption. Any future commercial product emerging from the “IO 2.0 + ADC 2.0” platform will face the same pricing discipline, which limits the per-unit revenue that can be captured even from scientifically differentiated agents.

How are global ADC developers positioned relative to Akeso’s bispecific approach, and what does this mean for competitive differentiation?

The global ADC market has expanded significantly. Fifteen FDA-approved ADCs as of early 2026 cover targets including HER2, Trop2, Nectin4, BCMA, CD33, and folate receptor alpha, among others. The competitive field includes Daiichi Sankyo and AstraZeneca (multiple DXd-platform ADCs), Pfizer (via its acquisition of Seagen, including enfortumab vedotin), Gilead Sciences (sacituzumab govitecan), and a rapidly growing cohort of Chinese biotechs developing ADC programs across overlapping targets.

The bispecific ADC construct is a less crowded segment. While preclinical and early clinical bispecific ADC programs exist at multiple companies, no bispecific ADC targeting the Trop2/Nectin4 pairing has reached approval or late-stage trials as of this announcement. That creates a window of competitive exclusivity for Akeso on AK146D1, though that window is not permanent. The pace of ADC development globally means that multiple sponsors are likely exploring similar dual-targeting constructs, and the first to reach pivotal data will have significant influence over how regulators think about the category.

For the HER3-targeting AK138D1, the competitive context is somewhat more crowded. Daiichi Sankyo has advanced patritumab deruxtecan (HER3-DXd) into late-stage trials, and the data from that program will shape clinical and commercial expectations for HER3-targeted ADCs regardless of Akeso’s timeline. Akeso’s differentiation argument for AK138D1 rests on its combination with bispecific IO backbones rather than the HER3 targeting alone, which is where the trial design will need to prove incremental clinical value.

What does Akeso’s stock trajectory around HK$120 tell analysts about market pricing of the pipeline transition?

Akeso’s shares at approximately HK$120.70 on March 25, 2026, sit at roughly 67% of their 52-week high of HK$179.00 reached in August 2025. The pullback from that high reflects several forces simultaneously: a broader compression in Hong Kong-listed biotech valuations, a transition in Akeso’s commercial narrative from near-term approvals to longer-cycle pipeline catalysts, and the natural recalibration that follows a period of strong price appreciation.

The analyst consensus remains constructive. The average 12-month price target from coverage tracked by investing.com stands at approximately HK$174, implying meaningful upside from current levels. Bernstein moved to a Hold rating in mid-March 2026, a signal of caution rather than fundamental concern, and the broader analyst panel of 20 buy recommendations versus zero sell recommendations reflects confidence in the underlying pipeline trajectory. The earnings release scheduled for April 1 will provide the commercial revenue and cost data needed to assess how efficiently Akeso is converting its approved products into cash flow to fund the Phase II combination trials now commencing.

The Phase II milestone announced today is unlikely to be an immediate share price catalyst on its own, given that NMPA Phase II clearances for Chinese biotechs are a routine developmental step. The more significant catalysts will be the first interim efficacy readouts from the Phase II combination cohorts, likely 18 to 24 months away, and any out-licensing or global partnership announcements that would provide external validation of the “IO 2.0 + ADC 2.0” platform value.

Key takeaways on what Akeso’s IO 2.0 plus ADC 2.0 Phase II advance means for the company, competitors, and oncology investors

• Akeso has received NMPA clearance to advance AK146D1 (Trop2/Nectin4 bispecific ADC) and AK138D1 (HER3 ADC) into Phase II trials in combination with cadonilimab and ivonescimab, marking the first bispecific checkpoint plus bispecific ADC combination to enter mid-stage development.
• AK146D1 is the only bispecific ADC simultaneously targeting Trop2 and Nectin4. Both approved ADC agents in these pathways, enfortumab vedotin (Nectin4) and sacituzumab govitecan (Trop2), are single-antigen monoclonal constructs, leaving no approved competitor in the dual-targeting space.
• Akeso’s structural advantage is that it is the only company globally with two approved checkpoint bispecific antibodies. Competitors wishing to replicate the “IO 2.0 + ADC 2.0” combination internally would need to first develop and approve their own bispecific checkpoint agents, a multi-year regulatory process.
• HER3 targeting via AK138D1 is squarely aimed at the acquired resistance problem in HER2 and EGFR cancers. Daiichi Sankyo’s patritumab deruxtecan is the reference competitor; Akeso’s differentiation depends on demonstrating that the bispecific IO backbone adds clinically meaningful benefit beyond HER3 monotherapy ADC.
• Phase II introduces meaningfully higher execution risk than the Phase I safety assessments already completed. Combination regimens of bispecific antibodies and ADCs carry complex pharmacodynamic interactions, and powering the trials sufficiently to show combination superiority over components alone requires significant time and enrollment resources.
• China’s reimbursement pricing environment will apply to any commercial output from this platform. Scientific differentiation does not translate automatically into revenue premium under the national reimbursement negotiation framework, which constrains peak sales modeling even for genuinely novel agents.
• Shares at approximately HK$120.70 trade roughly 33% below the August 2025 high of HK$179, with analyst consensus targets clustering around HK$174. The market appears to be waiting for efficacy data catalysts rather than re-rating on regulatory milestones alone.
• The upcoming April 1 annual results will be important for assessing how much internal cash generation can fund the expanding Phase II program. The company reported a net loss of approximately HK$612 million in the most recent half-year, widening from HK$299 million previously, underlining the capital intensity of the current pipeline expansion phase.
• Beyond AK146D1 and AK138D1, Akeso is also advancing IO 2.0 combinations with personalised mRNA cancer vaccines (AK154), DNA-based therapeutics, and T-cell engagers, suggesting the company sees its bispecific checkpoint antibodies as platform combination assets rather than standalone commercial products.
• The global ADC market now has 21 approved agents as of March 2026. Competitive intensity in the ADC space is high and rising. Akeso’s defensible position lies not in ADC technology alone but in the proprietary combination of bispecific IO backbones with next-generation ADC constructs, a combination that no competitor can currently replicate with fully internal assets.