In the USA, a rare disease is defined as one that affects no more than 200,000 individuals nationwide (a prevalence of roughly six per 10,000), and in Europe as one that affects five per 10 000, or around 250,000 individuals. Most current treatments are supportive rather than disease-modifying, leaving the majority of rare disease patients with considerable unmet medical needs.

The design and delivery of clinical trials in the rare disease arena bring specific considerations and potential pitfalls for researchers, patients, pharmaceutical companies, and regulators. Examples of trial-related questions/issues that need to be addressed include recruitment targets, dropout rates, and, ultimately, challenges of regulatory approval if the criteria for efficacy and safety are met.

As a requirement, most rare disease clinical trials are multicentre, and often multinational for sufficient patient recruitment, even in phase I and II trials. This can challenge clinical study protocol harmonization, the selection of appropriate biomarkers, ethical review, site IRB approval, indemnity, organization of clinical services, standards of care, and cultural diversity.

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Reliable imaging services help a small biotech advance the development of a novel,rare neurological disease treatment.

Additionally, while it’s true that every patient matters in all clinical trials, this takes on new meaning in studies of rare diseases. As there are not many people living with the diagnosis, finding patients and keeping them engaged in clinical trials is critical. Trial sponsors can’t risk a patient dropping out of a study because of missteps or problems with data collection and reporting during investigator visits.
As a result, the development of new treatments for rare disease poses unique challenges to clinical trial sponsors. Because these trials can’t risk anything going wrong, sponsors need experienced partners they can rely on to get it right the first time – and every time.

Below is a collection of materials that highlight Calyx’s experience in supporting rare disease clinical trials and how our scientific and technical expertise is helping researchers successfully develop novel treatments to bring new hope to patients living with rare disease.

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Contact hello@calyx.ai to learn how the expertise and experience behind Calyx’s eClinical solutions can help your rare disease trial succeed.

Advances in oncology precision medicine and therapy have increased the number of immune therapies and molecular-targeted agents for the treatment of most solid tumors. Antibody Drug Conjugates (ADCs) are one of the fastest-growing classes of cancer drugs in clinical development and have the potential to change the management of cancer patients in the clinic.

ADC construct typically involves a monoclonal antibody (mAb) covalently attached to a cytotoxic drug via a chemical linker. This chemical construction gives ADCs two advantages:

  • Highly specific/accurate targeting ability
  • Efficient lysis of cancer cells

Unfortunately, ADCs have been associated with the risk of pulmonary abnormalities, the most concerning of which is Drug-induced Interstitial Lung Disease (DI-ILD). DIILD is the term used to define a subset of ILD resulting from exposure to pharmaceutical drugs causing interstitial inflammation and possibly interstitial fibrosis.

As a result, in clinical trials investigating ADCs for the treatment of cancers, regulatory agencies around the world are asking trial sponsors to monitor for ILD toxicity. Research has shown that early detection, diagnosis, and management can prevent the worsening of ILD in these patients since in many cases the complications are reversible.

Rohit Sood PhD, VP Scientific & Medical Services, Calyx
Author:

Rohit Sood, MD, PhD, VP Scientific & Medical Services, Calyx

However, diagnosis of ILD in ADC clinical trials requires proactive longitudinal monitoring of subject health using clinical, laboratory, and radiology tools and no single tool can provide a definite diagnosis. Radiology methods such as High-Resolution Computed Tomography (HRCT) is the gold standard for the detection and characterization of ILD and, when combined with clinical and laboratory data, provides a powerful method for the accurate diagnosis of DIILD.

Integration of radiology data with clinical and laboratory tests such as pulmonary function tests and review of this information by a centralized independent joint events committee consisting of expert clinicians provides a consistent and standardized way to adjudicate DIILD cases.

Calyx Medical Imaging is actively supporting numerous clinical trials of ADC-based treatments and working with global trial sponsors to ensure their protocols support patient safety and meet regulators’ evolving expectations.

Learn how Calyx Medical Imaging can help you achieve your oncology clinical development objectives.

Advanced imaging technology is enabling us to answer critical questions as we strive to understand disease pathophysiology and inform the clinical development of new medical treatments. Here, we review how Calyx Medical Imaging is providing valuable insights intended to help researchers further understand the mechanisms in the brain that are associated with addictive behavior.

Calyx is delivering expertise in imaging within a clinical trial framework along with our partner, Ceretype Neuromedicine, Inc. to help researchers further understand the brain’s reward system through functional MRI (fMRI). The study we are currently working on aims to map out how brain mechanisms differ between people with addictive behaviors and those without and how that deviation will change over time with medication.

fMRI enables us to study neuronal activity as well as functional connectivity across the entire brain. This approach demonstrates that when nerve cells are active in certain areas of the brain, there’s an increase in blood flow to those areas, resulting in measurable changes. Moreover, if multiple brain regions are activated simultaneously, they are assumed to have a strong functional connectivity among them. Hence, fMRI allows us to look at activity within and connectivity among those brain regions responsible for mediating the physiological and cognitive processing of reward. Addiction treatments may target these regions associated with the brain’s reward network.

Participants’ brain activity can be captured while at rest or while observing images of items that depict addictions, as well as images of less addictive and/or unrelated items. Further analyses of MR images reveal the differences in brain activity and connectivity of those who are addicted compared to healthy participants. The same approach can be employed to investigate the objective change as a response to addiction treatment.

Historically, due to the complexity of image acquisition and analysis, fMRI has not been successfully used within the clinical trial framework. However, by combining Ceretype’s proven capabilities in acquiring high-quality data with a high signal-to-noise ratio and innovative data analysis pipelines with Calyx’s scientific and operational expertise, it is possible to obtain statistically significant results illustrating possible treatment effects.

Contact us to learn about Calyx Medical Imaging’s expertise and how our advanced solutions and services can help you optimize clinical trial imaging and meet your clinical development objectives.

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AUTHORS

Elif Sikoglu, PhD, Sr. Medical Director, Calyx

Alice Motovylyak, PhD, Principal Scientist, Calyx

Recent research highlights the importance of developing and utilizing cost-effective, sensitive, and specific plasma biomarkers using commercially available assays for screening subjects in Alzheimer’s Disease (AD) clinical trials. This approach overcomes limitations associated with the clinical diagnosis of AD, especially in individuals with mild cognitive impairment or dementia who exhibit typical AD symptoms lacking Aβ pathology.

There is evidence that targeting p-tau217 in blood has yielded the best results as a diagnostic and prognostic tool for assessing longitudinal change. Studies showed that the p-tau217 assay outperformed MRI and showed comparable performance with CSF biomarkers in detecting Aβ PET positivity and tau PET positivity.

Utilizing the approach recommended by Alzheimer’s Association guidelines, commercial immunoassay has shown high positive and negative predictive accuracy at screening in clinical studies.

Learn about other advances in Alzheimer’s Disease research, including why the FDA’s recognition of using medical imaging as an objective biomarker is a big step forward for the clinical development of new AD treatments.

Rohit Sood PhD, VP Scientific & Medical Services, Calyx
Author:

Rohit Sood, MD, PhD, VP Scientific & Medical Services, Calyx

A Conversation with Oliver Bohnsack, MD, PhD, MBA

In February 2022 the Journal for ImmunoTherapy of Cancer published “Comparison of tumor assessments using RECIST 1.1 and irRECIST, and association with overall survival.” This publication marks the first time immune-related criteria show a correlation with overall survival as the most meaningful endpoint in the treatment of cancer patients.

Calyx’s Head of Oncology, Dr. Oliver Bohnsack is considered one of the leading industry experts on oncology-imaging trial design and response criteria, having co-authored the immune-related response criteria (irRC, 2009), authored irRECIST (2014), and co-authored Comparison of Assessments using RECIST and irRECIST by Eggleton P. et al. (2020).

Here we discuss with Dr. Bohnsack the implications of these new response assessments, based on his contribution as a co-author of the 2022 paper, and what they mean for oncology research and treatment decision-making moving forward.

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Watch this discussion with Dr. Oliver Bohnsack and Peter Eggleton on “Solid Tumor Trials: Maintain More Patients with irRECIST

“In my opinion irRECIST easily can and shall replace outdated RECIST 1.1 on all solid tumor trials going forward.”

– Dr. Oliver Bohnsack, VP, Medical Imaging & Head of Oncology, Calyx

Q: Can you give us some background on how cancer treatment response is currently measured in clinical trials?

Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define when cancer patients improve (“respond”), stay the same (“stable”) or worsen (“progression”) during treatments. The original RECIST was published in February 2000 by an international collaboration and updated to RECIST 1.1 in 2009.

Today, most clinical trials with imaging-based response or progression as an endpoint evaluating cancer treatments in solid tumors are using RECIST 1.1.

Q: Are there limitations to using RECIST 1.1 for tumor assessment?

Yes, there are. Patients treated with immune checkpoint inhibitors (ICIs), or any other form of immune-based treatment may experience pseudoprogression, which shows – at least on imaging – a tumor burden worsening before the treatment shows efficacy in and is visible on scans. In this situation these patients will be classified as progressive disease (PD) by RECIST V.1.1 and thus could lead to inappropriate treatment discontinuation.

As a result, immune-response criteria – irRECIST (Immune-related Response Evaluation Criteria In Solid Tumors) ‒ were developed and used in many clinical trials since to better capture novel response patterns seen with immune-based treatments and T-cell therapies.

Q: How does irRECIST differ from RECIST 1.1?

The irRECIST approach allows responses not typically observed in traditional systemic treatment to be identified and better documented. The guideline describes a standard approach to solid tumor measurement and definitions for objective change in tumor size which can be used not only in immunotherapy clinical trials. Where any new lesion seen with RECIST 1.1 defines a treatment failure with documented PD, irRECIST allows for a possible continuation and further evaluation taking new lesions and the whole tumor burden into consideration.

Q. Can you tell us about the current findings outlined in the 2022 paper you contributed to?

Working with researchers from Merck Healthcare KGaA and renown clinical institutions we pooled data from 1765 patients with 12 types of advanced solid tumors treated with avelumab (an anti-programmed death ligand 1 (PD-L1) monoclonal antibody) monotherapy in the JAVELIN Solid Tumor and JAVELIN Merkel 200 trials, conducted a comparative analysis of tumor assessments by investigators according to RECIST 1.1 and irRECIST, and evaluated the correlation between progression-free survival (PFS), continued patient benefit and overall survival (OS).

The use of irRECIST identified a subset of patients with a best overall response (BOR) of progressive disease by RECIST 1.1 but an irBOR of immune-related disease control by irRECIST with a distinctive survival curve, thereby providing more clinically relevant information and better treatment decision-making options than RECIST 1.1 alone.

The publication demonstrates the benefit to a subgroup of patients in each of its various analyzed tumor indications, who otherwise would have foregone treatment and survival benefit when relying solely on RECIST 1.1 instead of irRECIST.

Q. What are the implications for sponsors of ICI trials who use RECIST 1.1 for evaluating response to treatment in studies of solid tumors?

Because immune-targeted treatment can initially cause the tumor burden to look as if it is progressing, when in fact it is not, clinical trial sponsors using RECIST 1.1 to assess treatment response may end up discontinuing patients who would otherwise remain in the study. Using RECIST 1.1 could limit sponsors from recognizing the full treatment benefit of new therapies in development, and more importantly, may prevent patients from receiving potentially beneficial treatments.

Q: What can we expect moving forward, as the industry considers these findings and their implications?

Sponsors and regulatory agencies will have to consider whether based on this data RECIST 1.1 is still appropriate to be used and advocated for as the current assessment standard for physicians, aiding them in treatment decision making and whether to continue or discontinue the current immune oncology treatment of their patients. irRECIST includes and covers all that’s embedded in RECIST 1.1 already but now takes the entire tumor burden including new tumor growth into consideration. In my opinion irRECIST easily can and shall replace outdated RECIST 1.1 on all solid tumor trials going forward.

The landscape of imaging in Myeloma patients has changed rapidly over the past few years. Routine clinical practice and clinical trial settings now utilize more advanced imaging modalities like PET-CT, whole-body MRI, and low-dose CT as compared to whole-body skeletal surveys (Xray) which were more commonly used in the past. These high-resolution imaging modalities lead to higher lesion detection rates at screening and thereby require an ongoing imaging evaluation in a predefined manner to support the efficacy analysis of a therapeutic intervention in clinical trials.

The figures below illustrate imaging presentation in myeloma patients and provide guidance on categorizing these lesions for response evaluation:

CT scans from a Myeloma Trial

Figure a) is a CT head of a patient showing a punched-out lytic lesion in the frontal bone (white arrow). Lytic lesions should be monitored qualitatively as per clinical discretion for progressive disease.

Soft tissue plasmacytoma noted in the pelvis (yellow arrows) in two different subjects: contrast-enhanced CT of pelvis (figure b) and a fused FDG PET image (figure c). Such soft tissue plasmacytoma need to be quantitatively evaluated at a predefined imaging schedule to evaluate the response of therapy along with the other lab parameters.

Regulators are looking for standardized methodologies to be applied upfront in trials to ensure the robustness of the data and its validity. We have noted a trend in the last year wherein health authorities across the globe are asking for a central review of imaging evaluation to mitigate variability in data from site imaging interpretation and across trials.

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Learn how Calyx helped a leading pharmaceutical company receive accelerated approval for a Multiple Myeloma treatment.

Calyx is a leading provider of myeloma trial imaging, having supported nearly 40 trials and 6 approved indications to date. We routinely collaborate with myeloma trial sponsors and consult on how to standardize image acquisition and support independent, harmonized imaging analysis to meet regulators’ expectations.

Our expert methodology is based on the wealth of experience gained by supporting trials over the last 25 years and engaging in scientific consultation with experts such as Dr. Shaji Kumar and Dr. Joseph Mikhael.

Contact us to explore how our scientific and medical imaging experts can partner with your team to reduce risks and deliver reliable imaging data that meets regulators’ requests and sets your development program up for success.

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