The Trouble with TIGITs: Big Pharma's $6B Gamble Faces Setbacks

In recent months, the pharmaceutical industry has witnessed a series of setbacks in the development of anti-TIGIT antibodies, once hailed as the future of immuno-oncology. This article explores the challenges facing TIGIT-targeted therapies and the implications for the pharmaceutical companies that have invested heavily in this approach.

The Rise and Fall of TIGIT Enthusiasm

The excitement surrounding TIGIT (T cell immunoreceptor with Ig and ITIM domains) inhibitors began with promising early-stage results, particularly from Roche's phase 2 Cityscape trial. This study showed that Roche's tiragolumab, when combined with the PD-L1 blocker Tecentriq, doubled the tumor response rate in metastatic lung cancer patients compared to Tecentriq alone.

However, the initial enthusiasm has been dampened by recent developments:

• BeOne Medicines (formerly BeiGene) discontinued development of ociperlimab due to disappointing phase 3 outlook.
• GSK halted development of belrestotug, partnered with iTeos, after lackluster phase 2 results in non-small cell lung cancer (NSCLC).
• Roche, despite a caveated phase 3 win in esophageal cancer, has stopped most tiragolumab trials.

The $6 Billion Question: What Went Wrong?

Industry experts, including Daina Graybosch, Ph.D., senior research analyst at Leerink Partners, attribute the TIGIT setbacks to several factors:

1. Over-enthusiasm: The impressive phase 2 results led to a "simplistic approach" in developing TIGIT candidates.
2. Unrealistic expectations: The industry failed to anticipate more modest benefits in larger trials.
3. Fc-enabled vs. Fc-silent antibodies: Many companies opted for Fc-enabled antibodies, which showed promise in mice but led to toxicity issues in humans.

Dr. Graybosch explains, "People went for Fc-competent because it worked best in mice. They couldn't help themselves, even though they knew there was some risk of depleting T effector cells that are actually what you need to fight your tumor."

The Last TIGITs Standing

While many TIGIT programs have been shelved, some pharmaceutical companies are still pursuing this target with a more measured approach:

1. AstraZeneca's rilvegostomig: A TIGIT/PD-1 bispecific antibody with mutated Fc function, potentially reducing toxicity.
2. Arcus Biosciences and Gilead's domvanalimab: An Fc-silent TIGIT inhibitor currently in phase 3 trials for NSCLC and gastrointestinal cancers.

Puja Sapra, Ph.D., SVP for Biologics Engineering and Oncology Target Discovery at AstraZeneca, remains optimistic about rilvegostomig's prospects. She cites preclinical studies showing that their bispecific molecule has better responses than a combination of individual agents.

Similarly, Gilead's Chief Medical Officer Dietmar Berger, M.D., Ph.D., believes in the potential of domvanalimab, emphasizing its Fc-silent character as a key differentiator.

While the future of TIGIT inhibitors remains uncertain, the industry's experience serves as a cautionary tale about the risks of over-enthusiasm in drug development. As companies reassess their approaches, the coming months and years will reveal whether the remaining TIGIT candidates can overcome the challenges that have plagued their predecessors.