Failures in cardiovascular trials don't invalidate CRP as a biomarker. Like phospho-ERK in oncology, CRP indicates pathway activity, acting as a 'smoke detector'. Success depends on hitting the right upstream target (the 'fire'), not just silencing the downstream signal. Any successful drug will ultimately lower CRP.
Early concerns about molecular glue degraders stemmed from thalidomide's notorious toxicity. Monterosa convinced partners of its modality's safety by proving mono-selectivity not just in tunable biochemical assays, but in comprehensive cellular assays measuring degradation against thousands of other proteins, demonstrating true cellular specificity.
Instead of pursuing broad, expensive trials common in areas like cardiovascular disease, smaller biotechs can succeed by focusing. They use imaging, genetics, and proximal biomarkers to identify and enroll a highly specific patient population whose disease is still modifiable, enabling much smaller and more targeted clinical trials.
Contrary to expectations that major trial failures would deter investment, large pharmaceutical companies are accelerating efforts in atherosclerotic cardiovascular disease. They are initiating new Phase 2 trials with novel mechanisms like NLRP3 inhibitors, signaling a strong underlying belief in the pathway and a continued strategic commitment to the indication.