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Several events that happened last week are worthy of our comprehensive analysis. Although the mechanism of the PCSK9 antibody Repatha is highly reliable, it did not achieve the expected efficacy in the Fourier trial of 27,000 people; the hormone drug, recombinant relaxin Serelaxin, failed in a larger phase III clinical trial after seeing a survival advantage in a phase III clinical trial; and Parkinson’s Although the pathology of PD is complex, Safinamide, which has poor selectivity, has become the first new PD drug in 10 years. These events show that our understanding of diseases and judgment of drugs are still at a relatively low level. How to find new drugs at this level of technology is a strategic issue that needs to be considered.
Drug source analysis
For new mechanism drugs, it is almost impossible to predict their success rate before the second phase of clinical trials. Even in the third phase of clinical trials, there is still a 50% chance of failure, and new mechanism drugs may have a higher failure rate. Early data are difficult to predict the final efficacy and safety, and IO drugs can even cause temporary pseudo-growth of tumors in responders. Unexpected effects like Entresto lowering blood sugar, Jardiance alleviating heart failure, and unexpected toxicity of Vioxx are even more unpredictable. So no matter how dazzling the animal test results are, how outstanding the activity and selectivity are, new drugs that can change the standard therapy are difficult to distinguish from failed drugs until they are close to the market.
There are two schools of thought in the pharmaceutical world when it comes to this conundrum. One advocates perseverance, the so-called pick the winners. This point of view holds that no project can be successful without picking up a few layers of skin, so you should not be disturbed by failure signals, just treat yourself as a pawn crossing the river. The task is to constantly find the way forward. This strategy is more suitable for relatively mature projects with relatively low risks. An extreme case is me-too drugs. If the target has been confirmed, as long as you persist, you will definitely find a drug that can be marketed. Of course, if you are a new target of Roy Vagelos, you can also use this strategy.
The other advocates planting widely and harvesting little, the so-called kill the losers. This school of thought believes that since we cannot judge the possibility of success in early projects, we should diversify project selection to the greatest extent, and then pay close attention to which projects will gradually win as data accumulates. Not only the targets should be diversified, but also the scope of mechanisms should be diversified. Taking anti-cancer as an example, strategies can be divided into directly killing tumor cells or indirectly killing tumors by changing the environment. This in turn can be subdivided into cytotoxicity, targeted therapy, hormonal therapy, angiogenesis, tumor metabolism, epigenetics, immunotherapy, etc. The key to this strategy is not to be lenient when the project needs to be terminated, otherwise the total investment will soon exceed anyone’s capacity. The more unknown the field, the more important this strategy is. In extreme cases, if the preclinical data cannot predict the clinical performance at all, then each project can only be tested in the clinic.
The famous baseball player Ted Williams subdivided his batting zone into many areas. He knew his hit rate for each area. Of course, he also considered other factors such as ball speed, spin, score situation, and weather. The same is true for new drugs. Many factors, such as compound quality, biological pathway, disease field, treatment modality, and comparison with standard therapy, affect its success rate. With the accumulation of data, it gradually enters Williams’ hitting zone after a baseball is pitched. Whether you believe in killing the losers or picking the winners, you have to have an accurate judgment on the possibility of hitting the incoming ball.
So at a deep level, the skills required for these two strategies are very similar. A good drug hunter will not be fooled by superficial prosperity, but will not ignore any real progress, even a small one. It’s like finding a piece from a pile of boulders at the foot of the mountain and moving it up the mountain. The master will be very sensitive to which piece is loose. Inexperienced people believe that every stone is easy to move under the hillside with many people.
