How did a Chinese bispecific top the global forecast rankings?

Akeso (09926.HK) was founded by Dr. Xia Yu in Zhongshan, Guangdong in 2012 and listed on the Hong Kong Stock Exchange in 2020. What the industry praises most is its in-house platform (Tetrabody) that reliably produces bispecific antibodies, which has already brought 7 new drugs to market, including the world’s first approved PD-1×CTLA-4 bispecific, cadonilimab (Kaitanni). In fiscal 2025, Akeso’s commercial sales revenue was about RMB 3.033 billion, up 51.48% year on year, with a full-year net loss of about RMB 1.141 billion; as of mid-2025, cash and various financial assets were about RMB 7.1 billion. These numbers position Akeso clearly: it is already a scaled biotech that can fund itself, but not yet at the size of a large pharma — which is exactly why its playbook for ivonescimab had to be “run China ourselves, borrow strength to go global”.

Ivonescimab itself is a tetravalent PD-1×VEGF bispecific: one hand presses on the immune brake PD-1, the other neutralizes VEGF in the tumor. VEGF both drives tumor angiogenesis and creates a locally immunosuppressive microenvironment, so “anti-angiogenesis + relief of immunosuppression” is designed as a synergy within a single molecule. The mechanism itself is not mysterious — bevacizumab plus PD-1 has precedent — ivonescimab’s bet is to put the two into one molecule and make efficacy better than existing immunotherapy monotherapy.

Why did Akeso dare to stake everything on “putting it into one molecule”? There is an often overlooked design ingenuity here: VEGF concentrations are naturally higher in tumor tissue than in normal tissue, and ivonescimab’s two-armed structure makes it more inclined to “cluster” and bind in VEGF-rich tumor areas, concentrating immune activation more in the tumor and in theory both enhancing efficacy and limiting off-target effects. This is the synergy logic claimed by the manufacturer, and whether it fully holds still awaits more mechanistic evidence, but it explains one thing — ivonescimab is not simply two old drugs stuck together, but an attempt to make “one plus one greater than two” at the level of molecular design. Akeso had already proven with cadonilimab, the world’s first PD-1×CTLA-4 bispecific, that its bispecific platform can produce big products, and ivonescimab is the culmination of this “immunotherapy 2.0” playbook.

At the end of 2022, Akeso made a decision that looks highly prescient in hindsight: before its global Phase 3 had read out, it licensed overseas rights to the US company Summit Therapeutics for a US$500 million upfront, up to about US$5 billion in milestones, plus low-double-digit royalties on net sales. Summit’s licensed territory initially covered the US, Canada, Europe and Japan, and was further expanded in June 2024 to Latin America, the Middle East and Africa; Akeso retains China and other unlicensed territories. This “early BD” both locked in cash and handed expensive global development and commercialization to a US-listed platform dedicated to the task — Summit’s market capitalization is now in the tens of billions of dollars.

Ivonescimab’s main battlefield is non-small cell lung cancer (NSCLC) — China has about 1.06 million new lung cancer cases a year, the most in the world, about 85% of them NSCLC. Chinese patients have two further features favorable to ivonescimab: an EGFR mutation rate as high as 40%–50% (far higher than in the West), and a very large PD-L1-positive population, meaning the patient pool is big enough whether in driver-positive later lines or PD-L1-positive first line.

But “big” is not “empty”. China has approved more than 17 PD-1/PD-L1 monoclonal antibodies; pembrolizumab and domestic tislelizumab, sintilimab, toripalimab, camrelizumab and others are all on the NRDL, and first-line lung cancer immunotherapy has long been a red ocean where the price war has driven annual treatment costs down to the RMB 10,000 level. In such a market, “no drug available” is not the problem; “better than existing immunotherapy” is the real unmet need. For ivonescimab to command a premium, it relies not on filling a gap but on proving superiority with head-to-head data — which sets it apart from most “follower” domestic immunotherapies.

The weight of these three datasets is that they were not compared against placebo but went head-to-head with current standard immunotherapy, and obtained solid overall survival benefits in both squamous and EGFR-mutant populations. For Chinese clinical experts, NRDL payers and guidelines, this is far more persuasive evidence than “yet another PD-1”. That is why ivonescimab has already been approved in China for two indications (EGFR-mutant later line in May 2024, first-line PD-L1-positive monotherapy in April 2025), with a supplemental application for first-line squamous under review, and both are on the NRDL.

Taking the valuation story apart, what really decides whether ivonescimab can deliver on “global number one” are the gates below — some already passed, some still hanging in the air.

What is most worth unpacking about ivonescimab is its rare path of “China first, global in parallel”. The usual pattern for domestic innovative drugs going abroad is China approval first, with overseas slowly following; while ivonescimab was approved in China ahead of the rest of the world, its global Phase 3 matrix (HARMONi, HARMONi-3, HARMONi-7, etc.) rolled out almost simultaneously, with Summit recruiting Western patients and interfacing with FDA. The return on this path is huge — once approved in the US and victorious in the global head-to-heads, it becomes a global immunotherapy backbone able to compete head-on with pembrolizumab; but the cost is equally real.

The first cost is extrapolability of the data. In the global HARMONi, the proportion of Chinese patients early on was high and the Western sample relatively thin; combined with overall survival not formally meeting its threshold, this makes “can China-led data persuade FDA” the biggest question mark in going global. The US review outcome will be revealed around the target date of November 14, 2026 — the most important near-term inflection point, with whether an advisory committee meeting will be held still a focus of public attention.

Worth projecting in advance are several possible outcomes of the US review: the best case is approval on schedule, with the global narrative achieved in one step; the middle case is FDA issuing a complete response letter or requesting supplementary data because of insufficient overall survival evidence, pushing US launch to after the global head-to-heads read out; the worse case is restriction to a very narrow population. These three scenarios have completely different effects on the US$25 billion NPV, which is why the date “November 2026” is watched so closely. It should be stressed that even if the US review hits a snag, it does not negate the value ivonescimab has already realized in China — it merely pushes back the timeline for “global blockbuster” and places more weight on the key readouts in 2027.

Following this logic, the US$25 billion NPV can be roughly decomposed: a considerable portion comes from the certain cash flow of a product already marketed, on the NRDL and scaling in China; a larger portion is the discounting of a chain of events that have not yet happened — “US approval + global head-to-head wins + pan-tumor expansion”. In other words, the value behind the top ranking includes both “already in hand” and “still on the way” — which is exactly why it is both enticing and not a case for blind optimism.

The second cost is the trade-off of handing the world to a partner. With a US$500 million upfront and up to US$5 billion in milestones, Akeso got Summit to bear the capital and execution of global development and commercialization; the upside is that Akeso’s cash burn is almost “desensitized” to the expansion of expensive global trials, while the downside is that pricing power, pacing and narrative in global markets are largely in the partner’s hands. Fortunately the structure gives Akeso a double hedge: two capital channels, the Hong Kong platform + Summit’s US-listed platform, and two streams of cash flow, milestone income + China product sales — even if one leg falters, the other can still hold.

Zooming in within NSCLC, ivonescimab’s breadth of coverage is what distinguishes it from most competitors:

• Spanning driver and non-driver populations. It covers EGFR-mutant later line (China’s high EGFR mutation rate naturally makes the patient pool larger), first-line PD-L1-positive monotherapy, and first-line squamous combined with chemotherapy — with positive randomized controlled results in both squamous and non-squamous disease.
• A single molecule simplifies combination. It is both an immunotherapy and anti-angiogenic in itself, saving the hassle of stacking two drugs, “PD-1 + bevacizumab”; it is given by standard intravenous infusion without complex step-up dosing, and involves none of the risks such as cytokine storm that require inpatient monitoring, so the threshold for execution at primary level is low.
• A relatively friendly testing threshold. First-line monotherapy depends on PD-L1 immunohistochemistry (widely available in major Chinese pathology centers), while first-line squamous is not restricted by PD-L1, further easing companion testing constraints.
• Gaps not yet fully proven remain. The rate of brain metastases in Chinese NSCLC is as high as 30%–40%, while ivonescimab’s published central nervous system efficacy data are limited, so “brain-penetrant benefit” should not yet be treated as an established selling point; extension to the perioperative setting (neoadjuvant/adjuvant) also still needs dedicated registration studies.

More imaginative is what lies beyond lung cancer. At ASCO 2026, ivonescimab plus chemotherapy reported a 70.8% objective response rate in a global Phase 2 in first-line microsatellite-stable colorectal cancer (a tumor historically “cold” to immunotherapy), and has already been upgraded to the global Phase 3 HARMONi-GI3 — in first-line unresectable metastatic colorectal cancer, comparing ivonescimab + mFOLFOX6 with bevacizumab + mFOLFOX6, planning to enroll about 600 patients, with progression-free survival as the primary endpoint. This means colorectal is no longer just an “early signal” but a registration-grade direction backed by real money. In addition, hepatobiliary, breast and other tumor types, as well as combinations with GSK’s B7-H3 ADC, are also being explored — together supporting the “pan-tumor platform” narrative and the source of the “option value” in the US$25 billion NPV; apart from lung and colorectal cancer, most tumor types are still early signals, not conclusions.

An often overlooked advantage: ivonescimab is produced with Akeso’s own capacity. The multi-chain assembly and purification of a tetravalent bispecific is more complex than for an ordinary monoclonal antibody, but Akeso has already brought it to commercial scale, largely defusing process scale-up risk and reducing reliance on external contract manufacturing. What needs continued attention is overseas supply — the supply chain for export markets requires coordinating cross-border logistics and technology transfer with Summit, and cold-chain and release continuity for a biologic is a link that cannot break during global scale-up. In terms of dosing and cost, it is a standard intravenous infusion with antibody-scale manufacturing costs; after NRDL entry the unit price is under pressure, and margins depend more on volume and multiple indications for dilution.

Putting cash, data readouts and competitive windows on the same timeline, the rhythm of the ivonescimab story is very dense:

November 14, 2026 — US FDA target review date. The first overseas approval milestone, and the first direct answer to “can Chinese data be extrapolated”.

Throughout 2026 — the China first-line squamous supplemental application is expected to land, and NRDL-driven uptake continues; data in colorectal, hepatobiliary, breast and other tumor types read out progressively.

H2 2026 — final progression-free survival readout for the squamous cohort of global HARMONi-3 (the interim did not reach the very high bar and continuation was recommended).

H1 2027 — progression-free survival readout for the non-squamous cohort of HARMONi-3. The binary inflection point that determines the quality of the “global blockbuster” claim.

2027 and beyond — readouts such as HARMONi-7, pan-tumor expansion and delivery of ADC combinations, benchmarked against Evaluate’s forecast peak of US$8.5 billion in 2032.

On funding, Akeso holds about RMB 7.1 billion in cash and financial assets, commercial sales are growing more than 50% a year, plus milestones released by Summit at registration and sales nodes, and expensive global development is mainly paid for by the partner — which means “money” is essentially not a rate-limiting step in the ivonescimab story. What is truly rate-limiting are two binary events that money cannot speed up: the review outcome and the global readouts.

Ivonescimab made it to the top of Evaluate’s rankings not because it has already won, but because it has got an extremely hard thing halfway done: in China, it has used two head-to-head wins to prove that “beating current immunotherapy on hard endpoints” is not empty talk — a win on progression-free survival against pembrolizumab, and an overall survival benefit against another PD-1 monoclonal antibody (with chemotherapy); globally, it has placed the same bet on the imminent FDA review and the key readouts that follow. It is the most iconic card in the narrative of Chinese innovative drugs going global — demonstrating that a domestic bispecific platform can produce a global-class asset, and putting the question of “how Chinese data will be accepted by the world” in front of everyone.

The next 12 to 18 months will either cement or rewrite the words “global number one”.