Summary

This week's feature commentaries include:

• FDA’s ODAC have decisively voted against the use of PD-1 inhibitors in PD-L1 negative patients in first-line gastric cancer and esophageal squamous cell carcinoma. Our editor Angus Liu has more on this news.
• Despite the underwhelming data from TROP2-targeted ADC Dato-Dxd, its approval is still possible. If it gets approved, the sequence of using then 4 approved ADCs would be a new challenge. More analysis by Jiamin Zhuo.
• STAT News published a feature article on Akeso, the China-based company that developed ivonescimab, the “keytruda killer”, and published all the data that sent Summit Therapeutics to $15bn. Akeso represents a small group of leading China-based biotechs that share striking similarities. Leon Tang has more on this story.

Other news includes the China story behind Dermavant's acquisition by Organon; the paradigm-shifting approval of Cobenfy for schizophrenia; and the highlights of Sino-American Pharmaceutical Professionals Association (SAPA) annual conference.

Encouraged by the recent interest rate cut, the IPO window is opening fast. BioVerse episode 14, “The Global Trends in Biotech IPOs”, will have Andre Lam from Ally Bridge Group, Daniel Parisotto from Oppenheimer & Co., Enna Weng from Freedom Capital Markets, Alex Yuen from Jefferies, and Peter E. Devlin from Jones Day to share their insights. Don’t miss this insightful webinar to learn the insights from the frontline experts and register the event here.

Many ISWTC members will attend Fierce Biotech Summit on Sep 30 and Oct 1, 2024 in Boston. Our volunteer Angus Liu will host a panel on CAT-T and fireside chat with Flagship’s BD chief, and a few ISWT members will speak at the event. We have a networking WeChat group, and please contact Angus Liu, Jiamin Zhuo, or Devin Chen to join.

Please send your questions and suggestion to partnership@iswtb.com

FDA’s ODAC votes to restrict PD-1s in stomach, esophageal cancers

Experts on the FDA’s Oncologic Drugs Advisory Committee (ODAC) have voted 10-2 and 11-2 in support of the agency’s view that the use of PD-1 inhibitors in first-line HER2-negative gastric cancer and first-line esophageal squamous cell carcinoma, respectively, is not favorable in PD-L1-negative tumors, Fierce Pharma reports. There was one abstention from the same person for both votes.

The overwhelming results make it likely that the FDA will narrow existing approvals for Bristol Myers Squibb’s Opdivo and Merck & Co.’s Keytruda, both of which currently enjoy broad labels in the two tumor types without limitations on PD-L1 expression levels. It also means that BeiGene’s two ongoing applications for Tevimbra in the indications will likely also be restricted to PD-L1-positive tumors.

The FDA started questioning whether PD-1 drugs should be used in PD-L1-negative or -low patients despite six phase 3 trials for the above drugs all showed statistically significant overall survival benefits in the intent-to-treat populations regardless of PD-L1 expressions. In stomach cancer, OS results in the PD-L1-negative subgroups were in favor of the PD-1 drugs’ chemo combinations versus chemo alone in all three trials: BMS’ CheckMate-649, Merck’s KEYNOTE-859 and BeiGene’s RATIONALE-305. In esophageal cancer, the risks of death in PD-L1-negative patients were in favor of Opdivo-chemo in CheckMate-648, the same between the two arms in KEYNOTE-590 and in favor of chemo alone in RATIONALE-306, according to the FDA’s exploratory analyses.

The FDA’s move serves as another reminder that in oncology, no detriment to OS is a minimum requirement—not a guarantee—for an approval.

As the FDA sees it, the PD-1 drugs’ benefit-risk profiles “appeared not favorable” in PD-L1-negative stomach cancer. The OS HR in that subgroup across the three stomach cancer trials were all close to 1, and the KM curves didn’t really separate between treatment arms.  (see FDA table and chart below, err: RN306 should be RN305):

For each trial, the PD-L1-negative analysis was exploratory and not statistically powered, with CI upper bound crossing 1. While the three companies argued–and the FDA acknowledged–that each calculation was not statistically reliable, the FDA argued in a briefing document that “consistency of subgroup effects over multiple trials as well as biological plausibility can increase confidence in the subgroup results.”

During the ODAC meeting, Dr. Robert Anders from Johns Hopkins University, a paid consultant for BMS, outlined the real-world challenge of a PD-L1 cutoff based on combined positive score (CPS) testing. PD-L1 expression scores may change over time, which could make “the difference between a patient receiving first-line I-O therapy or not,” he said. Besides, pointing to two research papers in stomach cancer, Anders argued that CPS is a “highly subjective” test, showing that pathologists often produce different reads from the same stomach cancer sample. 

Merck, using health records by Flatiron Health, noted in its briefing document that about 25% of first-line stomach cancer patients were not being tested for PD-L1 expression before treatment.

ODAC members appeared interested in this issue, having spent quite some time during the meeting asking for more information on CPS diagnostics. But that apparently didn’t change their view.

“When you look at the tails of where [the curves] converge, there’s less than a 1% absolute difference in this less-than-one subgroup. [...] That means you’re treating hundreds of these patients to benefit one,” Daniel Spratt, M.D., from Case Western Reserve University, said after casting his vote rejecting PD-1s in PD-L1-negative stomach cancer.

It’s also worth noting that while the FDA is poised to crack down on the PD-L1-negative use–the voting question was specifically about PD-L1 below 1–the agency was not very satisfied with the PD-1s’ performance in certain PD-L1-low subgroups, either. A vote against PD-L1-negative use doesn’t automatically mean that doctors support a favorable profile of PD-1 drugs in all PD-L1-positive cases. In fact, several ODAC members actually raised similar concerns in such populations as those with PD-L1 between 1 to 5, mirroring some existing clinical guidelines. NCCN’s stomach cancer guideline currently lists category 1 recommendations to Opdivo only in tumors with PD-L1 of at least 5, and to Keytruda 10 or above.

The situation is similar–if not worse–in esophageal cancer; after all, only one trial’s OS HR in the PD-L1-negative subgroup was below 1. (See FDA table and chart below).

The discussions around the esophageal analyses leaned heavily on how small those PD-L1-negative subgroups were. The small number of patients further reduced the reliability of the findings. But as Northwestern University’s Dr. Bill Gradishar summarized, “despite the concerns about small numbers, there was no evidence of benefit, period.”



Again, as a reminder, to get an FDA approval, it’s the sponsor’s responsibility to prove a favorable benefit-risk profile. Unclear results could subject an application to additional FDA scrutiny. – Angus Liu

Challenges in Sequencing ADCs: Cross-Resistance Learnings from Breast Cancer Treatment

Last Monday, AZN announced that its TROP2 ADC, datopotamab deruxtecan (Dato-DXd), failed to meet one of its dual-primary endpoints: OS compared to the investigator’s choice of chemotherapy in the Phase 3 TRIPOIN Breast-01 trial for HR-positive, HER2-low or HER2-negative metastatic breast cancer (mBC) patients (Press release). Despite this setback, Dato-DXd met the other dual-primary endpoint, PFS, in the same trial and remains on track for potential FDA approval, with a PDUFA date set for Q1 2025.

If Dato-DXd fortunately secures FDA approval, it will become the fourth ADC approved in the breast cancer space, joining Roche's Kadcyla, AZN/Daiichi's Enhertu, and Gilead's Trodelvy. Even if the older-generation ADC Kadcyla, with relatively lower efficacy, is excluded, physicians will still face challenges in sequencing the remaining three ADCs, which target two different antigens (HER2 and TROP2) but share the same payload class (TOP1 inhibitor). Given that BC has the most approved ADCs, lessons learned in this space could provide insights for using ADCs in the entire solid tumor field. 

A complicating factor is that the TROP2 ADCs are designed to be treatment-agnostic regarding TROP2 expression levels, and Enhertu is also approved for HER2-low patients and even aiming for HER2-ultralow patients. This overlap means there is a considerable patient population eligible for all three ADCs, yet there is little guidance on selecting the most appropriate first-line ADC or determining the optimal sequencing of these therapies.

Sequencing of ADCs will likely depend on the potential resistance patterns caused by these therapies. While cross-resistance for the same drug target (e.g., antigen escape) is better understood due to the longer history of antibody-drug use, recent studies have revealed more evidence of cross-resistance related to the payload itself, which could complicate treatment with ADCs. For instance, a study from MGH focusing on the sequential use of ADCs in mBC (the ADC-after-ADC or A3 study) presented at SABCS 2023 showed that the PFS for the first ADC (PFS1) was significantly longer than for the second ADC (PFS2) (median TTP of 5.36 months vs. 2.56 months) in 68 HER2-low patients in the U.S., suggesting better outcomes with earlier ADC use (Abelman et al., SABCS 2023). Interestingly, the second ADC showed the least response when it shared the same payload drug class as the first ADC, indicating the presence of cross-resistance related to the payload. In fact, various TOP1 resistance mutations were identified in 13% of patients in the A3 study (n=31), which is substantially higher than the 0.7% found in non-ADC-treated mBC patients (n=420) and the 0.5% observed in the TCGA database (n=1084). These mutations appeared to be acquired during the treatment with the first ADC (Abelman et al. AACR 2024)).

This cross-resistance poses a significant challenge for ADC development, especially for payloads like TOP1 inhibitors, which currently dominate the landscape, with over 100 clinical-stage assets in development. If ADCs with the same drug-class payloads fail to maintain efficacy as subsequent treatments, even when targeting different antigens or using different linker systems, physicians may opt to use only one ADC from the same payload class over the entire course of treatment. This scenario would force TOP1 payload ADCs to compete for one or two available slots in the treatment regimens for specific tumors, a competition that could significantly limit their commercial potential. Of course, more research is required to fully understand the resistance pattern, especially in the payload. However, ADC developers have to pay close attention and adjust their development plans accordingly. — Jiamin Zhuo

Akeso’s Success Reflects the Coming of Age of Some China Biotechs

Last week, STAT news published a feature article on Akeso, which is a leading China-based whose “Keytruda killer” ivonescimab showed impressive clinical benefits in a head-to-head trial against Keytruda. This data boosted their US partner Summit Therapeutics’ market cap to over $15bn, and a flattering coverage of their two executives on WSJ, Forbes, and CNBC.

In this Stat News article, Akeso CEO Michelle Xia and CFO Bing Wang recounted their impressive historic rise of the company since its inception in 2012, including their initial focus on CTLA-4, their first out-licensing deal with Merck, the first approved PD-1/CTLA-4 bispecific antibody cadonilimab in the world, and the development process of “keytruda killer” ivonescimab.

“The little known Chinese biotech”, according to STAT news article, actually has ~3,000 employees, 4 drugs on the market (including two PD-1-targeted assets), ~$300M expected revenue in 2024, and a market cap of 58.4Bn HKD (~ $7.5Bn). 

Compared with Summit’s single-asset pipeline, Akeso has a pipeline of ~50 assets, including 22 in the clinic.

Akeso’s story represents a small group of China-based biotech/biopharma companies that are ready to break into the global stage, with similar features: 

1.  Founded around 2010 by management teams that typically includes returnees (“sea turtles”) with Western education and biotech/biopharma work experiences. 
2.  Rise with the initial boost of China’s biotech investment frenzy from 2010 foundation to 2022 and the boom of some disease areas, particularly immuno-oncology.
3.  Survived the extreme price control and over-competition in China (China had ~100 PD1/L1-targeted assets in development at its peak).

When I applied the three above criteria to the China biotech universe, a few companies immediately came up:

1. BeiGene Biotech: founded in 2010 in Beijing China; 3 drugs on the market including a PD-1 mab; a large oncology-focused pipeline, and ~$22Bn market cap.
2. Innovent Biologics: founded in 2011; ~10 drugs on the market including a PD-1 mab; a highly diverse pipeline that covers oncology, I&I, ophthalmology, obesity, and others; and ~$9.2Bn market cap.
3. Shanghai Henlius Biotechnology: founded in 2009; 6 drugs on the market including a PD-1 mAb; an oncology-focused pipeline, and the first revenue-driven profitable biotech company in China.

The future of China biotech probably has arrived, but it is certainly unevenly distributed. — Leon Tang

Global Biotech News

A recent BlueView article (in Chinese) discusses the acquisition of Dermavant, a U.S. biopharmaceutical company specializing in dermatology treatments, by Organon for $1.2 billion. Dermavant's core product, Vtama cream, originally from China, has changed hands multiple times, increasing in value from $200 million to $1.2 billion. The document highlights the challenges and successes of Vtama's development, including regulatory hurdles and financial struggles. It also contrasts the different market dynamics and valuations between China and the U.S., emphasizing the role of the "newco" model in advancing pharmaceutical innovations.

The FDA has approved Cobenfy, a new schizophrenia drug developed by Karuna Therapeutics, now part of Bristol Myers Squibb. This drug, combining xanomeline and trospium chloride, is the first in over 30 years to offer a new mechanism of action by targeting cholinergic receptors instead of the traditional dopamine receptors. This approval marks a significant advancement in schizophrenia treatment, potentially offering better outcomes for patients who have not responded well to existing therapies.

The Sino-American Pharmaceutical Professionals Association hosted their annual conference in New Brunswick last week, and ~100 ISWT members spoke or attended the conference. Read the conference highlights on SAPA’s Linked website.

The Editorial Team

BioVerse episode 14, “The Global Trends in Biotech IPOs”, will have Andre Lam from Ally Bridge Group, Daniel Parisotto from Oppenheimer & Co., Enna Weng from Freedom Capital Markets, Alex Yuen from Jefferies, and Peter E. Devlin from Jones Day to share their insights. Don’t miss this insightful webinar to learn the insights from the frontline experts and register the event here.

The Partnering Corner

This corner was designed to foster collaboration among the readers and the participating companies. Currently, we have ISWT BioAdvisory that are looking for licensor or licensee opportunities.