Endpoints for geroscience clinical trials: health outcomes, biomarkers, and biologic age

Current work to identify biomarkers is not aligned with the goal of accelerating the evaluation of promising interventions.

“Thus, current work to identify biomarkers is not aligned with the goal of accelerating the evaluation of promising interventions.”

• AssumptionRests on an assumption: There is neither consensus nor a process to generate consensus on what constitutes an acceptable endpoint for a geroscience-based prevention trial.

Hip bone mineral density (BMD) is an example of a valid surrogate marker.

“Bone density (BMD) of the hip is an example of a valid surrogate marker.”

• cites [13] Black DM, et al. Diabetes Endocrinol. 2020;8(8):672–82. https://doi.org/10.1016/S2213-8587(20)30159-5. sourceNot checked — no full text of the source

Using validated surrogate biomarkers instead of clinical outcomes would substantially reduce the size, duration, and cost of clinical trials.

“Using biomarkers instead of clinical outcomes would substantially reduce the size and the duration of clinical trials.”

• Also stated in: § Introduction · hedged

  “The availability of validated surrogate biomarkers would obviate the need conduct large, lengthy, and costly trials to establish treatment efficacy.”

Meaningful health endpoints for geroscience trials would be ascertainable by interview and simple tests.

“In general, meaningful health endpoints for geroscience trials would be ascertainable by interview, for example, about activities of daily living for disability, and by questions combined with simple tests, such as gait speed and change in body weight, for frailty.”

To be a valid surrogate, the biological effect of the treatment, the change in the marker, and change in the health outcome must all line up in the same causal pathway.

“Thus, the biological effect of the treatment, the change in the marker, and change in the health outcome must all line up in the same causal pathway (Fig. 1).”

A large meta-analysis combining all clinical trials demonstrated a strong correlation (R2 = 0.73) between change in hip BMD and reduction in risk of hip fracture.

“The large meta-analysis combining all clinical trials demonstrated a strong (R2 = 0.73) correlation between change in hip BMD and reduction in risk of hip fracture (Fig. 2a) connecting the parts of the causal pathway (Fig. 2b) and validating hip BMD as a surrogate marker.”

• cites [13] Black DM, et al. Diabetes Endocrinol. 2020;8(8):672–82. https://doi.org/10.1016/S2213-8587(20)30159-5. sourceNot checked — no full text of the source

Trials with incident clinical outcomes are conducted in participants who are older and at high risk of the outcome to increase the number of aging-related events.

“To increase the number of aging-related events, trials with incident clinical outcomes are conducted in participants who are older and have high risk of the outcome.”

A predictive marker is not necessarily a surrogate marker.

“However, a predictive marker is not necessarily a surrogate marker.”

If all or the vast majority of items in a composite endpoint reflect the effect of the treatment, inclusion of all such endpoints can increase the frequency of the endpoint and reduce the sample size required to detect change in that index.

“If all, or the vast majority of, items reflect the effect of the treatment, then inclusion of all such endpoints can increase the frequency of the endpoint thereby reducing the sample size required to detect change in that index.”

The results of trials with incident clinical outcomes conducted in older high-risk participants would generalize to a small fraction of the people who could benefit from such interventions earlier in life.

“The results, however, would generalize to a small fraction of the people who could benefit from such interventions changes earlier in life.”

Showing that change in a predictive marker is associated with change in the health endpoint strengthens the possibility but does not reliably show that the predictive marker is a true surrogate marker.

“Showing that change in the predictive marker is associated with change in the health endpoint strengthens the possibility but does not reliably show that the predictive marker is a true surrogate marker.”

Trials with biomarker endpoints could afford to enroll a broader population at lower risk of a clinical outcome, thereby extending the generalizability of the results of a treatment trial to more people.

“Besides relatively low cost, such trials could afford to enroll a broader population at lower risk of a clinical outcome, thereby extending the generalizability of the results of a treatment trial to more people.”

Demonstrating that a predictive biomarker predicts a health outcome provides support that the property measured by the marker may be a cause of the outcome.

“Demonstrating that predictive biomarkers, such as quantity of Tau on brain scans, predicts the health outcome, such as incidence of the diagnosis of Alzheimer’s disease (AD), and provides support that the property measured by the marker may be a cause of the outcome.”

Response biomarkers provide proof of concept that a treatment has a desired biological effect on target mechanisms of aging or their manifestations.

“Especially in the development of treatments, response biomarkers, such as senescence associate secretory phenotype (SASP) biomarkers, provide proof of concept that the treatment has a desired biological effect on target mechanisms of aging (killing senescent cells) or on their manifestations (e.g., 19).”

A new treatment that slows a measurement of "biological age" that is not a true surrogate is likely to be widely used but ineffective or even harmful.

“A new treatment that slows a measurement of “biological age” that is not a true surrogate is likely to be widely used but ineffective or even harmful.”

• AssumptionRests on an assumption: There is an intense thirst for treatments to slow aging.

The ACCORD result taught that intensive treatment must have other effects, besides change in HbA1c, that are not on the causal pathway, resulting in increased risk of CVD.

“This result taught that intensive treatment must have other effects, besides change in HbA1c, that are not on the causal pathway, that resulted in the increased risk of CVD.”

The assumption that a biomarker that predicts the health endpoint is a surrogate is sometimes wrong and misleading.

“The assumption is sometimes wrong and misleading.”

Trials that have found reduction in brain amyloid have consistently failed to have beneficial effects on cognitive function or risk of dementia.

“Consistently, trials that have found that reduction in brain amyloid have failed to have beneficial effects on cognitive function or risk of dementia [16].”

• cites [16] Panza F, Lozupone M, Logroscino G, Imbimbo BP. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat Rev Neurol. 2019;15(2):73–88. https://doi.org/10.1038/s41582-018-0116-6. sourceNot checked — no full text of the source

Using biological age as the endpoint of a trial is likely to produce misleading results about its effects on health outcomes if the treatment, biological age, and health outcome are not part of the same causal pathway.

“In this case, using biological age as the endpoint of a trial is likely to produce misleading results about its effects on health outcomes.”

If the treatment, epigenetic age, and health outcome are not part of the same causal biological pathway, a treatment may alter "biological age" without affecting the causal mechanism that changes the endpoint.

“If not, a treatment may alter “biological age” without affecting the causal mechanism that changes the endpoint (Fig. 1).”

Fasting glucose and HbA1c levels predict the risk of cardiovascular disease.

“Those levels predict the risk of cardiovascular disease.”

• cites [14] ACCORD Study Group. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011;364(9):818–28. https://doi.org/10.1056/NEJMoa1006524. sourceCheck pending

If an epigenetic clock reflects multiple biological mechanisms, the overall clock is likely to be less sensitive to interventions that influence only one.

“If an epigenetic clock reflects multiple biological mechanisms, the overall clock is likely to be less sensitive to interventions that influence only one.”

Commonly used epigenetic clocks are highly correlated with calendar age.

“Epigenetic age has become the most popular approach; derived from patterns of DNA methylation, commonly used epigenetic clocks are highly correlated with calendar age.”

• cites [17] Brinkley TE, Justice JN, Basu S, et al. Research priorities for measuring biologic age: summary and future directions from the Research Centers Collaborative Network Workshop. GeroScience. 2022. https://doi.org/10.1007/s11357-022-00661-w. sourceCheck pending

Without an understanding of the biological mechanisms, it is uncertain and unlikely that biological age will be a valid surrogate marker for treatments that target a specific process of aging.

“Without an understanding of the biological mechanisms, it is uncertain and unlikely that biological age will be a valid surrogate marker for treatments that target a specific process of aging.”

Intensive hypoglycemic treatments such as oral hypoglycemics and insulin substantially reduce fasting glucose and HbA1c levels.

“For example, intensive hypoglycemic treatments, such as oral hypoglycemics and insulin, substantially reduce fasting glucose and HbA1c levels.”

• cites [14] ACCORD Study Group. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011;364(9):818–28. https://doi.org/10.1056/NEJMoa1006524. sourceCheck pending

For biological age, or specifically epigenetic age, to be a valid surrogate, the treatment, epigenetic age, and the health outcome must be part of the same causal biological pathway.

“For biological age, or specifically, epigenetic age to be a valid surrogate, the treatment, epigenetic age, and the health outcome must be part of the same causal biological pathway (Fig. 1).”

Different epigenetic clocks may have different mechanisms.

“Different epigenetic clocks may have different mechanisms [18].”

• cites [18] Raj K, Horvath S. Current perspectives on the cellular and molecular features of epigenetic ageing. Exp Biol Med (Maywood). 2020;245(17):1532–42. https://doi.org/10.1177/1535370220918329. sourceCheck pending

The concentration of amyloid in the brain is associated with the risk and progression of dementia.

“The concentration of amyloid in the brain is associated with the risk and progression of dementia.”

• cites [16] Panza F, Lozupone M, Logroscino G, Imbimbo BP. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat Rev Neurol. 2019;15(2):73–88. https://doi.org/10.1038/s41582-018-0116-6. sourceNot checked — no full text of the source

In the ACCORD trial, diabetics randomly assigned to intensive treatment that reduced HbA1c levels in fact increased the risk of CVD events.

“However, the belief that HbA1c was a surrogate marker was contradicted by findings from the ACCORD trial that diabetics randomly assigned to intensive treatment that reduced HbA1c levels in fact increased the risk of CVD events [14].”

• cites [14] ACCORD Study Group. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011;364(9):818–28. https://doi.org/10.1056/NEJMoa1006524. sourceCheck pending

It is a very long jump from findings that an epigenetic clock predicts health outcomes to validation that biological age is a surrogate marker.

“However, it is a very long jump from these findings to validation that biological age is a surrogate marker.”