With an FDA target decision date set for next week, BeiGene and Novartis’ tislelizumab has a real chance of becoming the first China-developed PD-1 cancer immunotherapy to reach the U.S.—about eight years after the class’s leaders nabbed their first nods.
If approved, tislelizumab would be BeiGene’s second commercial product in the U.S. after an original go-ahead for blood cancer med Brukinsa in late 2019.
Although both drugs are latecomers to their megablockbuster competitors, BeiGene is lining up combination approaches—including a Novartis-partnered TIGIT inhibitor—and novel standalone molecules that the company believes could be early movers or best-in-class contenders, BeiGene’s global R&D head, Lai Wang, Ph.D., said. And with new technologies, the company is on track to deliver 10 new drugs a year starting from 2024, Wang said in a recent interview with Fierce Biotech.
"We were late in the game," but …
BeiGene and Novartis are now looking at a July 12 FDA action date for tislelizumab’s application in previously treated advanced esophageal squamous cell carcinoma (ESCC).
Wang acknowledged that second-line ESCC isn’t going to be a big indication for tislelizumab, which has been approved in China for other much larger diseases such as newly diagnosed non-small cell lung cancer (NSCLC). Not to mention, Merck’s Keytruda and Bristol Myers Squibb’s Opdivo have recently both broken into front-line ESCC.
“Let’s admit it, we were late in the game in the PD-1/PD-L1 space,” Wang said, pointing out tislelizumab didn’t enter the clinic until 2015 and only regained global rights from Celgene in 2019. But BeiGene designed tislelizumab in a way that it believes can reserve the T cells in the tumor microenvironment to eventually have better therapeutic effect, he added.
Tislelizumab can be more competitive in areas such as newly diagnosed stomach cancer or front-line ESCC, where it’s closer to the first movers, Wang argued. In front-line ESCC, BeiGene and Novartis just unveiled phase 3 data showing tislelizumab, used in combination with chemo, cut the risk of death by 34% versus chemo alone regardless of PD-L1 expression levels.
“PD-1 is not going to be the ultimate solution for all the indications,” Wang said. BeiGene sees tislelizumab as the backbone for many future combinations that can offer further benefit over PD-1 monotherapies.
“I truly believe that’s one of the major reasons why Novartis wants to work with us, because they do need a PD-1 as a combination partner also for their pipeline product,” Wang said. Otherwise, it has to buy Keytruda as the partner drug, which could push up the clinical development cost greatly, he noted.
TIGIT remains in play despite Roche's setback
BeiGene has already designed several drugs that hold potential as combination partners with tislelizumab. Among them is anti-TIGIT antibody ociperlimab, which has also been licensed to Novartis through a potentially $1 billion deal inked in late 2021.
But two back-to-back phase 3 flops of Roche’s tiragolumab in lung cancer have brought doubt over the entire TIGIT class.
The TIGIT story remains very much alive, Wang argued. For one thing, while tiragolumab’s phase 3 SKYSCRAPER-01 NSCLC trial missed its tumor progression mark, Roche has recorded a positive trend toward a significant improvement in patient survival at the interim analysis.
Wang believes tiragolumab, used alongside Roche’s PD-L1 inhibitor Tecentriq, still has a fair chance of eventually hitting the key overall survival endpoint that could support an FDA approval.
As for ociperlimab, “we do believe that PD-1 is a better combination partner in lung cancer versus a PD-L1 [inhibitor],” Wang said, given past clinical results from Keytruda and Tecentriq. Keytruda enjoys huge commercial success because it “had a wonderful clinical development [program] especially in lung cancer,” Wang added.
While years late in the PD-1/L1 space, BeiGene and Novartis are in the front row of TIGIT players. Ociperlimab’s phase 3 AdvanTIG-302 NSCLC trial started a year ago. It’s similar to Roche’s SKYSCRAPER-01 in that they both limit patient recruitment to those with high PD-L1 expression of at least 50%. By comparison, Merck launched the KEYVIBE-003 trial also about a year ago to test Keytruda and Merck’s TIGIT candidate vibostolimab in a broader patient population who test positive for PD-L1.
In addition, the phase 3 AdvanTIG-301 trial pitting ociperlimab and tislelizumab against AstraZeneca’s Imfinzi in newly diagnosed stage 3 unresectable NSCLC, a market currently dominated by the AZ PD-L1 inhibitor.
So far, BeiGene has treated over a thousand patients for the TIGIT molecule in various tumor types. It’s now expecting additional early- or midstage data readouts in the next six to 12 months, which Wang said will provide a broader view about what TIGIT means for different tumor types.
“We’re going to continuously adjust our development plan based on both internal data as well as external data,” Wang said of the TIGIT drug.
Broad oncology pipeline with first-in-class contenders
Besides TIGIT, BeiGene has licensed Asia-Pacific rights—excluding Japan—to two drugs that are now being paired with tislelizumab in phase 3 trials. They are Mirati Therapeutics’ multikinase inhibitor sitravatinib and Zymeworks’ HER2-targeted bispecific antibody zanidatamab.
The company also has other self-developed drugs that hold promise as monotherapy or add-ons to tislelizumab. These include a potentially first-in-class HPK1 inhibitor dubbed BGB-15025.
HPK1 is an intracellular immune checkpoint that regulates TCR signaling. By inhibiting HPK1, the drug may prevent T-cell exhaustion, Wang explained. With preclinical evidence suggesting this mechanism can enhance PD-1 activity, BeiGene is currently in phase 1 dose escalation testing of BGB-15025.
Another early-stage molecule that Wang said makes a good combination partner with many other drugs including tislezliumab is an OX40 agonist coded BGB-A445. OX40 is an immune costimulatory receptor.
The BeiGene OX40 drug is unique in that it doesn’t disrupt the interaction between OX40 and its ligand, Wang explained. Existing OX40 drugs, which are ligand-competitive, have shown limited response at relatively low doses. By preserving the original ligand engagement—and hence anti-tumor immunity—the BeiGene candidate can be given at higher doses and could theoretically get better anti-tumor efficacy, the company suggests.
BeiGene has already recorded promising early clinical data for BGB-A445 as a monotherapy, which Wang said is “extremely critical, and that makes the development pathway much easier” for the drug either alone or in combination.
BeiGene’s internal research capabilities have expanded tremendously in the past three years from about 200 preclinical scientists to more than 800 today, Wang said. The company has brought on some new technology platforms—including bispecific, trispecific, antibody-drug conjugate—and it’s building up a cell therapy unit. Wednesday, BeiGene also unveiled a research pact with Chinese biotech InnoRNA focused on mRNA therapeutics.
“All industries are driven by technology and the market,” Wang said. “For our industry, market will always be there—it’s about technology.”
As new technologies open up new opportunities, BeiGene is heavily investing in its internal discovery engine. The company is now on track to churn out about 10 new molecule entities per year starting in 2024, Wang said.