integrated PK-PD biomarker in clinical trials to support drug development

what is PK/PD modeling/analysis?

application of mathematical models to characterize and predict tthe time course of drug effects

what are surrogate markers/endpoints?

a lab measurement or physical sign that is used in therapeutic trials as a substitute for a clinically meaningful endpoint that is a direct measure of how a patient feels, functions, or survives and is expected to predict the effect of the therapy

what are clinical endpoints?

• distinct measurements/analyses of disease characteristics observed in a study or clinical trial that reflect the effects of a therapeutic intervention

• most credible characteristics used in the assessment of the benefits and risks of a therapeutic intervention in randomized clinical trials

why PK/PD in drug development?

• exposure-response information is at the heart of any determination of the safety and effectiveness of drugs
• a drug can be determined to be safe and effective only when the relationship of beneficial and adverse effects to a defined exposure is known
• enable safe and effective use of a drug
• to make drug development more efficient and less costly
• improve drug development, knowledge management, and decision making
• integrate data from new clinical study with previous learnings to improve decision-making on future studies or steps
• help separate "noise" from signal

what is the PK component in the PK/PD model?

serves as the driving force for drug access to target sites and the input rates and elimination processes control both the duration of drug exposure and often the duration of drug action

what is the PD component in the PK/PD model?

• the basic PD model used widely has its origin from the Hill equation, as well as from the equation derived from receptor occupancy theory
• commonly employed for quantifying the nonlinear relationship between drug effects (E) and plasma (Cp) or biophase drug concentrations

what are the components of PK/PD models?

• PK: disposition kinetics, biophase distribution
• PD: biosensor processes, biosignal flux, transduction, response

what are the biomarkers for alzheimer's disease?

• amyloid PET
• plasma Aβ42/Aβ40
• CSF Aβ42/Aβ40
• plasma p-tau181
• CSF p-tau181
• CSF t-tau
• serum neurofilament (sNfL)

what are the clinical endpoints of AD?

• clinical dementia rating scale sum of boxes score (CDR-SB): assesses 3 domains of cognition (memory, orientation, judgment/problem solving) and three domains of function (community affairs, home/hobbies, personal care)
• AD assessment scale-cognitive subscale 14 (ADAS-Cog 14): cognitive assessment consisting of clinical ratings and cognitive tasks measuring disturbances of memory, language, and praxis
• ADCS MCI-ADL: activities of Daily Living Scale for use in Mild Cognitive Impairment

what is lecanemab PK in serum?

PK exposure was approximately dose proportional, with a serum terminal elimination half-life of ~7 days

what is lecanemab PK in CSF?

• lecanemab penetrated the blood-brain barrier and could be measured in CSF as a surrogate for CNS exposure

CSF concentration as % of its serum concentration at 24 h post dose was:

• 0.04 % after a single dose

• 0.04 - 0.08 % after monthly multiple doses

• 0.13 % at steady state after biweekly dosing

what does higher lecanemab exposure lead to?

greater reduction in plasma p-tau181 from baseline at month 18

what is the correlation between amyloid PET and clinical endpoints?

a decrease in brain amyloid was associated with treatment effects at the popoulation level for CDR-SB

why was the PK/PD model established for AD?

• to describe relationships for amyloid PET standard uptake value ratio, and two plasma biomarkers (Aβ42/40 ratio and p-tau181) in patients with early AD
• demonstrated dose-dependency in the decrease in SUVr and p-tau181 and increase in Aβ42/40 ratio, leading to the selection of 10 mg/kg bi-weekly dose in Phase 3

what did the phase 3 trial of lecanemab demonstrate?

reduced markers of amyloid in early Alzheimer's disease and resulted in a moderately less decline on measures of cognition and function than placebo at 18 months, but was associated with adverse events

what is canakinum (ACZ885)?

• for the treatment of children and adults with cryopyrin-associated periodic syndrome (CAPS): caused by a single gene mutation that leads to overproduction of interleukin-1 beta (IL-1ß), which causes sustained inflammation and tissue damage
• fully human monoclonal antibody that rapidly and selectively blocks IL-1ß
• binds to human IL1β and neutralizes its activity by blocking its interaction with IL-1 receptors, but it does not bind IL-1α or IL-1 receptor antagonist (IL-1ra)

what were the disease assessments of canakinum?

• complete response to treatment was defined as a global assessment of no or minimal disease activity by a physician, an assessment of no or minimal rash, and a value for both serum CRP and SAA was within the normal range (<10 mg per liter for both measures)
• relapse was defined as a value for either CRP or SAA of more than 30 mg per liter, accompanied by a physician's assessment of global disease activity that was greater than minimal or that was minimal and accompanied by a rash that was assessed as more than minimal
• patients performed a global assessment of their symptoms together with assessments of each of the following symptoms: fever or chills, rash, joint or muscle pain, eye discomfort or redness, fatigue, headache, and other symptoms

what was the phase 1/2a dose titration study to assess the clinical efficacy, safety, PK, and PD of canakinumab in CAPS patients?

• three different doses of canakinumab were tested - 10 mg/kg IV, 1 mg/kg IV and 150 mg SC
• following administration of the first dose, redosing was initiated upon disease flare
• amongst the biomarkers collected are C-reactive protein and Serum Amyloid A (SAA), indicators of inflammatory disease activity that are elevated in patients with CAPS
• result: rapid reduction in inflammatory biomarkers in response to a single dose

what was the demonstration of safety and efficacy of canakinumab (ACZ885) for the treatment of CAPS?

• 35 patients received 150 mg of canakinumab subcutaneously
• those with a complete response to treatment entered part 2 and were randomly assigned to receive either 150 mg of canakinumab or placebo every 8 weeks for up to 24 weeks
• after the completion of part 2 or at the time of relapse, whichever occurred first, patients proceeded to part 3 and received at least two more doses of canakinumab
• results: treatment with subcutaneous canakinumab once every 8 weeks was associated with a rapid remission of symptoms in most patients with CAPS

what is lecanemab (BAN2401)?

• treats alzheimer's disease
• humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta
• monoclonal antibody that selectively binds soluble amyloid β (Aβ) protofibrils
• the accumulation of amyloid beta plaques in the brain is a defining pathophysiological feature of AD: drug reduces amyloid beta plaques