By making an example of Eli Lilly and partner Innovent Biologics’ practically denied application for PD-1 inhibitor Tyvyt, the FDA is sounding the alarm for companies working on “me-too” cancer drugs. The public display of FDA disapproval through an advisers’ meeting invites serious soul-searching for those latecomers.
The FDA’s harsh stance against Tyvyt shows it’s serious about improving diversity in clinical trials, which is effectively erecting a major roadblock for many Chinese companies seeking U.S. expansions, SVB Leerink analyst Daina Graybosch, Ph.D., wrote in an investors’ note Friday.
For the PD-1/L1 class specifically, the FDA and its external expert panel have spelled out an overwhelmingly negative opinion toward the use of a single-country, ex-U.S. registrational trial and an outdated comparator arm. That could spell trouble for future contenders, Graybosch said, including not just several Chinese firms and their Western partners but also existing players such as a partnership between Regeneron and Sanofi.
Trial diversity could be a major hurdle for Chinese biopharmas
Lilly and Innovent used the phase 3 Orient-11 trial for Tyvyt’s application in newly diagnosed nonsquamous non-small cell lung cancer. Problem is, the study was conducted solely in China, raising the question of whether the outcome could be applied to a U.S. population. As Graybosch sees it, Orient-11 was a perfect example for the FDA to pick on, because the trial design, execution, and FDA communication all had issues.
Despite the China-only nature, panelists at Thursday’s advisory committee meeting appeared to have acknowledged that a benefit in Asian patients could generally be translated to other ethnicities given existing experience with the PD-1 inhibitor class, Graybosch noted. But the FDA contended that trial diversity was also about policy and healthcare equity than just one outcomes analysis.
Ensuring racial and ethnic diversity is gaining attention among U.S. policymakers. But requiring a U.S. representation in multiregional clinical trials “will likely put a kibosh on expansion of many Chinese biotechs into the U.S. market, without a multinational partner,” Graybosch said.
One thing Graybosch didn’t spell out is that by running clinical trials in China at relatively low operational costs, many biopharmas including Lilly and Innovent are angling for a discounted price on the U.S. market. Lilly, for example, promised a roughly 40% discount for Tyvyt relative to marketed PD-1s. But global trials are markedly more expensive to run and would potentially erode the cost edge Chinese players could provide.
Requirement for large, gold-standard multiregional trials could benefit Big Pharma companies as they have the resources to address the trial diversity issue and can be “aggressive in running studies across indications to lock down territory,” Graybosch observed.
But as the FDA has alluded to, there will be exceptions—or as the agency put it, “regulatory flexibility”—with innovative therapies. This means drugs for rare diseases or disorders that disproportionately affect particular ethnic groups may enjoy some leniency. But these are inevitably small niche settings. Coherus Biosciences and Junshi Biosciences’ application for their PD-1 inhibitor toripalimab in nasopharyngeal carcinoma falls in this category. The indication, with an FDA breakthrough designation, is under review based on China-only trials.
Other PD-1/L1 applications could be in jeopardy
But not all other PD-1/L1 applications are like toripalimab’s. Besides the lack of diversity, the FDA and the advisory committee also took issue with the fact that Orient-11 compared Tyvyt’s combination with chemo against chemo alone, but when the study was started, Keytruda had already replaced chemotherapy as the new standard-of-care in the U.S. As they see it, Tyvyt should instead be compared with an existing rival PD-1 rather than chemo.
That stance raises several problems for other PD-1/L1 programs in development.
First, running trials in China allows those latecomers to pit their candidates against an old therapy. Novel drug approvals in the emerging market generally lag those in the U.S., but the gap is narrowing these days. Running head-to-head trials involving a newer therapy would again push up the cost of a clinical trial and thus further diminish the potential pricing edge Chinese players could provide.
Secondly, Graybosch has compiled a long list of registrational trials of checkpoint inhibitors in NSCLC alone that utilize a chemotherapy control arm and could be in trouble in light of the Tyvyt case. These include Regeneron and Sanofi’s phase 3 Empower-Lung3 trial, which the pair is using in the hope to win approval for Libtayo—alongside chemo—in front-line NSCLC, with an FDA decision expected by September. That global study was launched in March 2018, five months before Orient-11.
Toripalimab also has a China-only front-line NSCLC phase 3 dubbed Choice-01, which also has all the same problems as Tyvyt’s Orient-11.
It’s not just PD-1’s chemo comparisons that are at risk. Graybosch also pointed to a combo of Arcus Bioscience’s investigational PD-1 zimberelimab and Gilead Sciences-partnered anti-TIGIT antibody domvanalimab in the phase 3 ARC-10 trial in NSCLC patients bearing high levels of the PD-L1 biomarker. While the combo is being pitted against zimberelimab alone, the zim arm is being compared to chemo. Therefore, the combo's approval hinges on the FDA accepting that zim's improvement over chemo is sufficient.
Arcus designed ARC-10 in close consultation with the FDA, according to Arcus management cited by Berenberg analyst Zhiqiang Shu, Ph.D., in a separate note Friday. Because of its chemotherapy arm, the trial was conducted outside of the U.S.
The FDA’s requirement for noninferiority trials would likely make things difficult for companies pursuing an indication where a PD-1/L1 is already approved and could serve to consolidate the market for existing players, Graybosch said.
Given the many hurdles, “we would not be surprised to see biotechs (re)line up at Merck’s door to avoid the whole mess by combining their novel therapies with [Keytruda],” Graybosch wrote.