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| Holbrook Kohrt |
The immuno-oncology arena is seeing a new player enter the hottest game in R&D. And some of the biggest companies in biopharma are pushing into early-stage studies, spawning a fresh rivalry as researchers jockey for the lead position in what promises to be a hotly contested race.
The target is 4-1BB, a member of the TNF receptor family which has demonstrated multiple abilities to spur a T cell or natural killer cell attack on cancer. In a Reuters feature today, veteran biotech writer Bill Berkrot covers how an early setback in 4-1BB research--where a high dose in an early study triggered signs of liver toxicity, the kiss of death for many drugs--has been countered with lower (safer) dosing by some of the scientific pioneers in the field.
As a result, notes Berkrot, Pfizer ($PFE) has evidently taken the lead in mounting early trials and gathering the first, impressive human data, with the powerhouse team at Bristol-Myers Squibb ($BMY) close behind while Johnson & Johnson ($JNJ) and AbbVie ($ABV) are gearing up with their own programs.
"What they have shown are some pretty phenomenal responses in patients … where you would not expect the drug to work very well" because the patients had stopped responding to any available treatments, Stanford's pioneering 4-1BB specialist Holbrook Kohrt told Reuters.
Immuno-oncology may look to outsiders like it has only a brief, explosive history. But all these programs can be traced back for years as investigators worked out how the immune system can be brought in to fight cancer. Currently the big initial focus is on checkpoint inhibitors which allow T cells to attach to cancer cells and destroy them by dismantling a stealth mechanism used by cancer cells to avoid detection.
4-1BB antibodies, though, work through multiple mechanisms to rev up an attack. Writing recently in Frontiers in Oncology, Todd Bartkowiak and Michael Curran from M.D. Anderson Cancer Center in Houston explored the evidence that 4-1BB (CD-137) offered a pathway to expand and focus an attack by CD8-positive cytotoxic T cells. CD4-positive cells can also be brought into the game while natural killer cells (NK) can benefit as well. The effect on regulatory T cells is still being studied.
The checkpoint inhibitors are dominated by Bristol-Myers and Merck ($MRK), with Roche ($RHHBY) and AstraZeneca ($AZN) playing catch-up among the closest competition in the clinic. With analysts breathing fire over a truly revolutionary way to treat a wide variety of cancers, with forecasts of a market that could be worth $30 billion to $40 billion a year, a host of competitors are hot on the leaders' heels. And of them all, Pfizer--which has been a laggard in the clinic--has the most to gain if it can close the gap.
Pfizer spent $850 million on the largest upfront in biopharma history to partner with Merck Serono on a checkpoint drug. Its 4-1BB drug PF-05082566 (PF-2566) has also been partnered with Merck's Keytruda in a Phase I study. And a full slate of early studies is now in the works.
Back at ASCO, researchers noted that in a small proof-of-concept study Pfizer's drug spurred an overall response rate of up to 29% in one arm with a duration of more than two years and a progression-free survival rate of 66% at 6 months. And Reuters adds that nearly 40% of the 38 patients involved benefited from the drug. Those kinds of numbers get attention, even from such small patient groups, especially as developers are now prepared to devote some huge sums to accelerate cancer R&D straight into late-stage testing as early as possible.
Given the track record in immuno-oncology, the handful of players now in the game are likely to be quickly joined by a host of competitors looking to leap ahead with their own programs that hope to exploit the latest insights on cancer.
- here's the Reuters piece