Demonstrate Disease Modification Research Articles

Efficient use of open label extension data to support additional evidence of efficacy and disease modification hypotheses

AbstractBackgroundMany clinical trials have open label extension (OLE) phases in which all patients from the randomized controlled study go onto active treatment for some period of time. These OLEs provide the opportunity for placebo patients to have access to active treatment. Trial sponsors also want to get meaningful information from the OLE data.MethodWe evaluate the types of hypotheses that can be tested with OLE data in degenerative diseases and propose analyses aligned with these hypotheses. Challenges with OLE data are also enumerated and discussed. For these analyses, and for simplicity of examples, we are assuming that the randomized phase and the OLE phase are each 1 year in duration.Result6 key hypotheses can be addressed with OLE data. 1. Treatment effects differ during the randomized phase and the OLE, 2. Treatment groups differ at the end of the OLE, 3. The slope for placebo patients in the randomized phase differs from their slope during the OLE, 4. The slope over the entire duration of the randomized phase and the OLE phase differs between groups, 5. The slope of decline during the first 12 months of treatment combined across the original active patients and the placebo patients during the OLE phase differs from the placebo slope of decline during the original 12 month randomized phase. 6. The slope of the original placebo group differs from the original active group during the OLE phase. If a significant treatment effect is seen during the randomized phase, then hypotheses 2 and 6 can demonstrate disease modification in a pseudo staggered start analysis if they demonstrate that the treatment groups also differ at the end of the OLE phase, and are not converging during the OLE. Challenges with OLE analyses include high dropout rates, differential dropout between groups, ceiling and floor effects resulting in differing slopes (nonlinearity) during the randomized and OLE phases.ConclusionOLE phases can add to the weight of evidence for efficacy in clinical trials and can identify disease modifying effects as long as issues such as dropout and non‐linearity are accounted for.

Bone Marrow Fibrosis Changes Do Not Correlate with Efficacy Outcomes in Myelofibrosis: Analysis of More Than 300 JAK Inhibitor-Naïve Patients Treated with Momelotinib or Ruxolitinib

Introduction: Bone marrow fibrosis (BMF) is a primary pathological and diagnostic feature of myelofibrosis (MF). BMF biopsies are evaluated and scored using updated WHO criteria, which consist of four escalating grades of severity: G0-G3 (Arber et al, 2016). Although BMF grade is not featured in the IPSS or DIPSS prognostic scoring systems, several studies have associated increasing degree of BMF with poor prognosis. Current clinical research efforts in MF often assess BMF, with the ultimate intent of demonstrating disease modification. To date, limited clinical data have compared efficacy outcomes in MF such as survival or symptom, splenic, and/or anemia responses with BMF changes. Here, we present BMF data from over 300 JAK inhibitor (JAKi)-naïve patients who participated in the double-blind, randomized, Phase 3 SIMPLIFY-1 (S1) study of momelotinib (MMB), an inhibitor of JAK1, JAK2 and ACVR1, vs ruxolitinib (RUX), a JAK1 and JAK2 inhibitor. Methods: BMF biopsies were collected pre-treatment (baseline), following 24 weeks of randomized treatment (RT) with either MMB or RUX, and at Week 96 during open-label treatment with MMB. Grading was performed by local hematopathologists and included assessments of reticulin and collagen. Other efficacy assessments included MFSAF symptom scoring, spleen volume imaging, transfusion independence (TI) status, and hemoglobin (Hgb) levels. Survival was estimated using KM analysis. Results: In S1, 128 sites in N. America, Europe & APAC enrolled patients; 211/215 patients randomized to MMB and 213/217 patients randomized to RUX had baseline BMF assessments with 59% in each arm registering as G3. Of these patients, 144 and 160 on MMB and RUX, respectively, had a paired biopsy at Week 24 (W24). Of patients with a W24 paired biopsy, the proportion with stable or improved BMF was similar between treatment arms: 22% who received MMB had a ≥1G improvement compared with 23% of patients who received RUX, and 85% of patients had stable or improved BMF on MMB compared to 81% on RUX (Table 1). In the MMB arm, 87% of the patients with BMF improvement of ≥1G were also W24 TI responders (TI-R), compared to 76% of those with stable or worsening BMF. In the RUX arm, 44% of those with ≥1G improvement in BMF and 56% with stable or worsening of BMF were also W24 TI-R. Furthermore, Hgb levels were noted to increase on MMB, regardless of BMF improvement or worsening, while Hgb levels were observed to decrease on RUX in patients with both improving and worsening BMF. No association between BMF outcome and spleen or symptom outcomes was noted for MMB or RUX. In both treatment arms, no improvement in overall survival (OS) was observed for those achieving ≥1G BMF improvement (MMB HR=0.78, p=0.5203; RUX→MMB HR=1.27, p=0.4789). Although not statistically significant, those registering worsening of BMF grade trended to have improved OS compared to those with no change (MMB HR=0.570; RUX HR=0.597) or improvement (MMB HR=0.818; RUX HR=0.523). Discussion: Improvement in BMF has been pursued as an endpoint in clinical trials and presumptively linked to disease modification. However, limited clinical data have been presented to date and the correlation of BMF changes with survival and other efficacy outcomes has not been well described. Data presented here show that with both MMB and RUX approximately 20% of patients had ≥1G BMF improvement, whilst BMF was stable in >60%. Interestingly, for patients treated with MMB, Hgb levels increased and TI-R was achieved regardless of BMF changes, suggesting the previously described anemia benefit of MMB is a feature of its JAK1, JAK2, and ACVR1-mediated mechanism of action which is not reciprocated by RUX. Patients treated with RUX - even those achieving ≥2G BMF improvement - did not have improved Hgb levels, nor symptom or splenic response. Furthermore, long-term follow up of patients achieving ≥1G BMF improvement did not demonstrate OS advantage. Conclusion: These data represent the most extensive analysis to date of the correlation of BMF changes with other outcome measures in JAKi-naïve patients with MF. Of particular note, anemia improvement was not linked with BMF changes. These findings bring into question the use of BMF assessment at W24 as a surrogate for clinical benefit. The clinical significance of BMF changes needs to be carefully evaluated to better understand its role in disease modification, the pathogenesis of MF, and clinically important patient outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Role of biomarkers in evaluation, treatment and clinical studies of pulmonary arterial hypertension

Pulmonary arterial hypertension is a complex disease resulting from the interplay of myriad biological and environmental processes that lead to remodeling of the pulmonary vasculature with consequent pulmonary hypertension. Despite currently available therapies, there remains significant morbidity and mortality in this disease. There is great interest in identifying and applying biomarkers to help diagnose patients with pulmonary arterial hypertension, inform prognosis, guide therapy, and serve as surrogate endpoints. An extensive literature on potential biomarker candidates is available, but barriers to the implementation of biomarkers for clinical use in pulmonary arterial hypertension are substantial. Various omic strategies have been undertaken to identify key pathways regulated in pulmonary arterial hypertension that could serve as biomarkers including genomic, transcriptomic, proteomic, and metabolomic approaches. Other biologically relevant components such as circulating cells, microRNAs, exosomes, and cell-free DNA have recently been gaining attention. Because of the size of the datasets generated by these omic approaches and their complexity, artificial intelligence methods are being increasingly applied to decipher their meaning. There is growing interest in imaging the lung with various modalities to understand and visualize processes in the lung that lead to pulmonary vascular remodeling including high resolution computed tomography, Xenon magnetic resonance imaging, and positron emission tomography. Such imaging modalities have the potential to demonstrate disease modification resulting from therapeutic interventions. Because right ventricular function is a major determinant of prognosis, imaging of the right ventricle with echocardiography or cardiac magnetic resonance imaging plays an important role in the evaluation of patients and may also be useful in clinical studies of pulmonary arterial hypertension.

Disease Modification in Alzheimer's Disease: Current Thinking.

Alzheimer's disease (AD) has increasingly been recognized as a huge unmet medical need. Currently, there is no approved drug to cure, prevent, or even slow down the disease. It is imperative to develop disease-modifying treatments for AD to alter the underlying disease progression. This paper reviews the most up-to-date regulatory guidance on how to demonstrate disease modification and provides an overview of available methodologies and applications to clinical trials. The intent is to assist the field with future clinical trials designed to demonstrate disease-modifying effect in AD. The methodologies may be generalizable to broader neurodegenerative diseases.

Disease Modification in Alzheimer’s Disease: Current Thinking

Alzheimer's disease (AD) has increasingly been recognized as a huge unmet medical need. Currently, there is no approved drug to cure, prevent, or even slow down the disease. It is imperative to develop disease-modifying treatments for AD to alter the underlying disease progression. This paper reviews the most up-to-date regulatory guidance on how to demonstrate disease modification and provides an overview of available methodologies and applications to clinical trials. The intent is to assist the field with future clinical trials designed to demonstrate disease-modifying effect in AD. The methodologies may be generalizable to broader neurodegenerative diseases.

Will genotype drive treatment options?

Individual genetic variation can have a major impact on the clinical manifestation of a movement disorder and its response to treatment. Advances in gene discovery and increasing availability of diagnostic genetic testing have led to the identification of a growing number of patients with well-defined hereditary movement disorders. Establishing a genetic diagnosis may greatly impact patient counseling and shape therapeutic decisions. Further, assignment of a movement disorder to a specific genetic defect holds promise for the development of causal treatment approaches and individualized therapies, especially as the first gene-targeted approaches have recently entered clinical trials. However, important gaps remain, that is, genetic testing results are often inconclusive, gene-specific treatment options are still exceedingly rare, and designing clinical trials to demonstrate disease modification continues to pose a major challenge. © 2019 International Parkinson and Movement Disorder Society.

Statistical considerations in a delayed-start design to demonstrate disease modification effect in neurodegenerative disorders.

There has been a paradigm shift in diagnostic conceptualization of Alzheimer's disease (AD) based on the current evidence suggesting that structure and biology changes start to occur before clinical symptoms emerge. Consequently, therapeutic drug development is also shifting to treat early AD patients using biomarkers for enrichment in clinical trials. A similar paradigm shift is occurring for Parkinson disease. In the absence of acceptable biomarkers that could be combined with a clinical endpoint to demonstrate a disease modification (DM) effect in neurodegenerative disorders, a delayed-start design can be applied to demonstrate a lasting effect on the disease course. The delayed-start design includes two treatment periods, where in period 1, patients are randomized to receive an active treatment or placebo, and in period 2, placebo patients are switched to the active treatment while patients in the active treatment arm will continue the same treatment. The hypothesis is that patients who start the active treatment later will fail to catch up to the treatment benefit achieved by patients who receive the active treatment in both periods. A usual analytical approach has sought to demonstrate the divergence of slope during period 1 and the parallelism of slopes during period 2 as the DM effect. However, due to heterogeneity in timing and the magnitude of maximal effect among patients, nonlinear response over time could be observed within the two treatment arms in both periods. We propose an approach to evaluate the DM effect with the linearity assumption for treatment differences, but not for each arm separately.

The delayed start trial design to demonstrate disease modification: Background and prior experience

The delayed start trial design to demonstrate disease modification: Background and prior experience

Role of medial abrasion phenomenon in the pathogenesis of knee osteoarthritis

Osteoarthritis of the knee affects a large population worldwide and is associated with an extremely high economic burden largely attributable to the effects of disability, comorbid disease, and the expense of treatment. Since the initiating events that result in the cartilage degradation are poorly understood, there has been very limited success in demonstrating disease modification in clinical trials of potential therapies. Medial plica related medial abrasion phenomenon has recently been identified to have close relationship with medial compartment osteoarthritis. We hypothesized that this abrasion phenomenon will elicit lifelong interplay between pathologic medial plica and the facing medial femoral condyle and might play a role in the pathogenesis of knee osteoarthritis by both physical and chemical effects. After evaluating current evidence, we designed a study to prove that the concentrations of total protein, cartilage degrading related cytokines (tumor necrosis factor-α and interleukin-1β) and enzyme (matrix metalloproteinase-3) are higher in the medial compartment of the knee having the phenomenon of medial abrasion. The accumulating data and findings about medial abrasion phenomenon might be important for the understanding of the pathogenesis or progression of this common disease. We hope that our hypothesis will stimulate further studies verifying if medial abrasion phenomenon plays more roles in the pathogenesis of knee osteoarthritis. Further clinical observations for its appropriate treatment based on this hypothesis are also mandatory for the benefits of patients.

A novel approach to delayed-start analyses for demonstrating disease-modifying effects in Alzheimer's disease.

One method for demonstrating disease modification is a delayed-start design, consisting of a placebo-controlled period followed by a delayed-start period wherein all patients receive active treatment. To address methodological issues in previous delayed-start approaches, we propose a new method that is robust across conditions of drug effect, discontinuation rates, and missing data mechanisms. We propose a modeling approach and test procedure to test the hypothesis of noninferiority, comparing the treatment difference at the end of the delayed-start period with that at the end of the placebo-controlled period. We conducted simulations to identify the optimal noninferiority testing procedure to ensure the method was robust across scenarios and assumptions, and to evaluate the appropriate modeling approach for analyzing the delayed-start period. We then applied this methodology to Phase 3 solanezumab clinical trial data for mild Alzheimer’s disease patients. Simulation results showed a testing procedure using a proportional noninferiority margin was robust for detecting disease-modifying effects; conditions of high and moderate discontinuations; and with various missing data mechanisms. Using all data from all randomized patients in a single model over both the placebo-controlled and delayed-start study periods demonstrated good statistical performance. In analysis of solanezumab data using this methodology, the noninferiority criterion was met, indicating the treatment difference at the end of the placebo-controlled studies was preserved at the end of the delayed-start period within a pre-defined margin. The proposed noninferiority method for delayed-start analysis controls Type I error rate well and addresses many challenges posed by previous approaches. Delayed-start studies employing the proposed analysis approach could be used to provide evidence of a disease-modifying effect. This method has been communicated with FDA and has been successfully applied to actual clinical trial data accrued from the Phase 3 clinical trials of solanezumab.

A new proposal for randomized start design to investigate disease-modifying therapies for Alzheimer disease

The increasing prevalence of Alzheimer disease (AD) and lack of effective agents to attenuate progression have accelerated research and development of disease modifying (DM) therapies. The traditional parallel group design and single time point analysis used in the support of past AD drug approvals address symptomatic benefit over relatively short treatment durations. More recent trials investigating disease modification are by necessity longer in duration and require larger sample sizes. Nevertheless, trial design and analysis remain mostly unchanged and may not be adequate to meet the objective of demonstrating disease modification. Randomized start design (RSD) has been proposed as an option to study DM effects, but its application in AD trials may have been hampered by certain methodological challenges. To address the methodological issues that have impeded more extensive use of RSD in AD trial and to encourage other researchers to develop novel design and analysis methodologies to better ascertain DM effects for the next generation of AD therapies, we propose a stepwise testing procedure to evaluate potential DM effects of novel AD therapies. Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-cog) is used for illustration. We propose to test three hypotheses in a stepwise sequence. The three tests pertain to treatment difference at two separate time points and a difference in the rate of change. Estimation is facilitated by the Mixed-effects Model for Repeated Measures approach. The required sample size is estimated using Monte Carlo simulations and by modeling ADAS-cog data from prior longitudinal AD studies. The greatest advantage of the RSD proposed in this article is its ability to critically address the question on a DM effect. The AD trial using the new approach would be longer (12-month placebo period plus 12-month delay-start period; total 24-month duration) and require more subjects (about 1000 subjects per arm for the non-inferiority margin chosen in the illustration). It would also require additional evaluations to estimate the rate of ADAS-cog change toward the end of the trial. A regulatory claim of disease modification for any compound will likely require additional verification of a drug's effect on a validated biomarker of Alzheimer's pathology. Incorporation of the RSD in AD trials is feasible. With proper trial setup and statistical procedures, this design could support the detection of a disease-modifying effect. In our opinion, a two-phase RSD with a stepwise hypothesis testing procedure could be a reasonable option for future studies.

Selectin inhibitors: a patent review

Importance of the field: Selectins play a significant and well-documented role in inflammation and immune response. They initiate tethering and rolling of blood borne leukocytes leading to their activation, adhesion and subsequent extravazation into tissues. This is important for healthy immune response and tissue repair. However, dysregulation of selectins leads to exacerbation of disease. Atherosclerosis, restenosis, deep venous thrombosis and tumor metastasis are just a few of the diseases in which selectin blockade has been demonstrated to ameliorate disease pathology. Thus, selectins remain attractive targets for amelioration of disease.Areas covered in this review: Summarized here are new patents/patent applications on selectin inhibition published since our last review in 2003 and any significant changes or progress made in demonstrating clinical safety and efficacy of therapeutics covered by patents/patent applications reviewed in 2003.What the reader will gain: A comprehensive review of new developments in the field of selectin inhibition through discussion of patents/patent applications from 2003 to August 2009, reports on clinical results where available and selected literature.Take home message: The field of selectin inhibition has matured significantly in recent years in the ability to inhibit selectin/ligand interactions with drug-like molecules and to demonstrate disease modification in human trials.

P-196: A mathematical comparison of a “randomized withdrawal” clinical trial design and a parallel groups design to demonstrate disease modification in Alzheimer’s disease (AD)

Demonstration of disease modification in clinical studies of drugs treating different indications has been approached in many ways. Among the strategies proposed for AD are two approaches based on clinical outcomes: 1. the “randomized withdrawal” or “staggered start” designs, and 2. parallel group designs comparing slopes and severity of disease. This presentation demonstrates how the study designs described above compare to each other mathematically and under what circumstances they may be equivalent. A mathematical comparison of the staggered start design to the randomized withdrawal design proves that these designs and their associated analyses are mathematically equivalent. A parallel groups design is shown to be mathematically connected to a staggered start design. The conditions under which these designs test the same hypotheses are described. A parallel groups analysis can be constructed that is mathematically equivalent to analyses from these crossP-over designs. This paper proves that the “randomized withdrawal” and “staggered start” designs are in fact mathematically equivalent. A new “natural history staggered start” design based on parallel groups was proposed and was shown under certain conditions to be equivalent to the two crossP-over type designs. In these conditions it is superior, because it allows measurement of the same underlying patterns of drug effect, without the operational complications (longer trial periods, dropP-out bias, ethical concerns) introduced with the staggered start or randomized withdrawal designs.