News and Insights
When a clinical trial disappoints, leadership begins with what comes next
September 25, 2026
Amyloid, Lp(a) and HDL remind us that clinical trials test more than medicines. They test what we believe about disease.
When a major clinical trial fails, the first numbers we often see are financial. A company can lose billions in market value. Analysts revise revenue projections. Investors question pipeline strength. Years of investment are suddenly described as having been lost. Those consequences are real, but they tell only part of the story.
A clinical trial also represents something far more consequential: one of science’s most rigorous tests of what we believe about human disease and industry’s willingness to invest, take risks and help answer the questions that can change people’s lives.
Clinical trials test medicines and scientific hypotheses. Behind a molecule entering Phase III may lie decades of research across academia, government, foundations and industry. Pharmaceutical and biotechnology companies assume much of the financial and operational risk of turning those discoveries into medicines and testing them in thousands of patient volunteers. Sometimes that investment confirms what we hoped we knew; sometimes human biology tells us something different.
An unexpected clinical result matters far beyond one company or medicine because people’s lives remain on the line. Patients and families are waiting for better answers, better treatments and more time together. When a trial challenges what science believed about a disease, the lesson cannot end with a missed endpoint. Understanding what happened, what we learned and where the science should go next becomes part of the responsibility to those who volunteered for the research and those still waiting for hope to become medicine.
The recent Phase III setback for Novartis’ pelacarsen offers one such moment. The complicated history of amyloid in Alzheimer’s disease offers another, while an earlier cardiovascular experiment involving HDL provides an especially perplexing third. Their larger lesson is not that science failed, but rather that science was tested.
Amyloid: A hypothesis meets human biology
For decades, amyloid beta represented one of the great hopes and great scientific questions in Alzheimer’s disease. Amyloid plaques are a defining feature of a disease that progressively takes memory, independence and, ultimately, pieces of a person from the people who love them. If reducing amyloid could slow that progression, the implications for patients and families would be profound. Aducanumab became a major test of whether that scientific hope could translate into meaningful human benefit.
Biogen’s two large Phase III studies, EMERGE and ENGAGE, together enrolled more than 3,200 people with early Alzheimer’s disease. Both demonstrated that aducanumab could reduce amyloid levels, yet the clinical results were conflicting. EMERGE reported less clinical decline at the high dose for its primary endpoint; however, ENGAGE did not reproduce this result.
The results presented a question far more complex than whether one drug had succeeded: What was the relationship between removing amyloid and changing the course of Alzheimer’s disease? The answer did not turn out to be simply that amyloid was irrelevant.
Lecanemab later reduced amyloid and modestly slowed cognitive and functional decline in people with early Alzheimer’s disease. Eli Lilly’s donanemab added further evidence. The significance was larger than the numbers: targeting amyloid could affect the course of disease, not simply what appeared on a brain scan.
The scientific journey did not end. It changed direction. Which forms of amyloid matter? When should treatment begin? Which patients benefit, and what roles do tau, inflammation, vascular disease and other processes play? A disappointing drug program can force science to question what it thought it knew, sharpen the search and pursue a better path to patients.
Lp(a): Causation does not guarantee a successful intervention
Cardiovascular medicine is confronting a similar scientific challenge. Lipoprotein(a), or Lp(a), is a genetically influenced risk factor for cardiovascular disease, including heart attack and stroke. Decades of population and genetic research strongly support something even more important: high Lp(a) is not simply associated with cardiovascular disease; it can help cause it.
That evidence led to a critical test: If high Lp(a) helps cause cardiovascular disease, could lowering it protect people from heart attack, stroke and other cardiovascular events? Novartis’ Lp(a)HORIZON trial put that question to the test with pelacarsen in people already living with cardiovascular disease.
The Phase III study enrolled more than 8,000 people. Pelacarsen lowered Lp(a), but Novartis announced on September 4th that the study did not meet its primary endpoint of reducing cardiovascular death, nonfatal myocardial infarction, nonfatal stroke and urgent coronary revascularization requiring hospitalization.
That result does not erase decades of genetic evidence that high Lp(a) can help cause cardiovascular disease. It presents science with a harder question: If Lp(a) contributes to disease, why didn’t lowering it reduce cardiovascular events in this trial? The answer may reshape when, how and in whom Lp(a) is targeted, opening another path toward treatments that can change people’s lives.
Perhaps intervention must occur earlier. Perhaps duration or degree of reduction matters. Perhaps some patients benefit more than others, or biological consequences accumulated over decades cannot be undone simply by lowering circulating Lp(a) later in life. Those are questions, not conclusions, and the complete Lp(a)HORIZON data will need to be examined repeatedly before researchers can responsibly distinguish among them.
That is precisely why a Phase III result matters even when the expected endpoint is not achieved. One door may close while several new scientific ones open.
HDL: When the biomarker looked better but patients did not
Cardiovascular medicine had seen a striking scientific assumption tested before. For years, the balance between “good” HDL cholesterol and “bad” LDL cholesterol helped shape our understanding of cardiovascular risk. If higher HDL was associated with protection, could dramatically raising it with a medicine protect patients? Evacetrapib put that long-held premise to the test.
The ACCELERATE trial enrolled more than 12,000 patients with high-risk vascular disease. At three months, evacetrapib increased mean HDL cholesterol by 133.2 percent and decreased mean LDL cholesterol by 31.1 percent. On paper, the biomarker impact looked impressive; however, patients did not experience an expected benefit.
After some 26 months, the primary cardiovascular endpoint occurred in 12.9 percent of patients receiving evacetrapib and 12.8 percent of patients receiving placebo. The ratio was 1.01, and the trial was terminated early for lack of efficacy.
The experiment did more than disappoint. It shattered decades of assumptions. Raising HDL through this intervention did not reduce cardiovascular events, forcing medicine to rethink the relationship between “good” cholesterol and cardiovascular protection. Science is not static; its willingness to challenge what we believe is how medicine advances. The question is: Who carries the responsibility and risk of putting those beliefs to the test?
Who actually does this science?
There is a temptation to neatly divide medical discovery into basic and applied science categories. The ecosystem is far more interdependent, with government, academia, foundations, patient organizations and industry contributing different capabilities to a shared scientific enterprise.
Government scientists pursue fundamental questions. Academic medical centers turn discoveries into hypotheses and early clinical research. Foundations and patient organizations champion unmet needs and clinical trial participation. Industry brings the resources, expertise and scale needed to turn promising science into medicines and test whether they actually improve people’s lives.
Industry takes on an essential challenge: turning a promising biological hypothesis into a medicine that can be safely tested in people. That journey requires drug discovery, toxicology, manufacturing, regulatory science and clinical expertise, often representing years of work before a large-scale trial even begins.
Then comes the ultimate test: human biology. Companies may invest billions of dollars and enroll thousands of patient volunteers across hundreds of research centers without knowing whether the scientific premise will hold. Successful medicines reflect the investment of many candidates that never reach patients, which is why a negative trial should be viewed not only in terms of what was lost but also in terms of what science gained.
Industry funds some of the largest tests of scientific hypotheses, committing enormous capital without knowing whether human biology will cooperate. Success can produce a medicine; disappointment can redirect science. Both are part of an industry pioneering longer, healthier human lives, and that story deserves to be told.
Science and communication are interwoven
Science, investment and communication form a helix. Science creates possibilities. Investment enables the testing of people’s resources. Communication ensures that what is learned, especially when the answer disappoints, can be questioned, challenged, and built upon. Each is essential to turning discovery into progress.
Success has a powerful vocabulary: breakthrough, approval, lives changed and investment rewarded. Disappointment is reduced to missed endpoint, pipeline setback, billions lost and hopes dashed. Those consequences are real, but they can bury something equally valuable: what one of the largest and most expensive experiments on a scientific hypothesis just taught us.
A missed endpoint should ignite questions, not end the conversation. What happened biologically and clinically? Where did expectations and outcomes diverge? What assumptions should now be challenged, and what should the next study do differently? The value of a trial lies not only in whether a medicine worked, but in whether what was learned helps propel the next scientific advance.
That knowledge must move. Researchers need it to challenge assumptions, clinicians to understand what the findings mean and patients and families to know that their participation mattered. Negative findings are not simply disclosures; they are fuel for discovery. Science and communication must work together to turn disappointment into knowledge, knowledge into better questions and better questions into the next opportunity to improve people’s lives.
The people behind the data
A missed endpoint does not have to define the mission. What happens next can. Industry has invested capital, assembled scientific expertise, and partnered with thousands of patient volunteers to test an important hypothesis. When the expected answer does not come, that is not the moment to retreat. It is the moment to lead.
Leadership means owning the next question: What did we learn, and where does science go from here? Researchers, clinicians, investors and, most importantly, patients and families deserve that answer. Industry can turn disappointment into discovery by sharing what was learned, challenging assumptions and helping chart the next path forward. That is not managing failure. It is demonstrating what scientific leadership looks like.
A failed endpoint should never mean lost knowledge
A missed endpoint does not end the story. It can clarify the direction. For industry leaders, scientists and communicators, this is not the moment to scramble into defensive positions. You still own something enormously valuable: the knowledge gained, the assumptions challenged and the possibilities now coming into view.
Own that conversation. Bring science, leadership and communications together around what was learned and what it makes possible. Explain what surprised you, what you now understand differently and where the evidence points next. This is a learning organization at its best: not defending yesterday’s assumptions but allowing new knowledge to shape tomorrow’s decisions. A disappointing result is a moment of scientific leadership, demonstrating that progress is not only finding the answer you hoped for. Sometimes it is discovering a better question.
We owe stakeholders more than a press release announcing that an endpoint was missed. We owe them the fullest possible value of what was learned. Billions of dollars can test a scientific hypothesis, but investment alone cannot advance science. Progress occurs when evidence changes understanding, unexpected findings are shared and the next experiment begins with greater knowledge than the one before it.
That is the leadership opportunity. Industry can own the conversation about what science now makes possible. By turning unexpected results into better questions, clearer direction and the next generation of research, biopharma demonstrates the value of being a learning industry, one willing to put enormous resources and reputation behind ideas that may improve or extend human life.
Championing what comes next can strengthen the reputation of an industry willing to take an idea and a hope from the research bench, assume the risk of testing it in people and move science closer to the patient’s bedside or medicine chest. The expected answer may not always come. The responsibility and the opportunity are to make sure every answer moves us forward. That is the promise of science and the societal value of biopharma.
POSTED BY: Gil Bashe
