Want More Candidates For Rare Disease Trials? Turn To Genetic Testing

By Jolan Eszter Walter, MD, Ph.D., division chief, pediatric allergy and immunology programs, University of South Florida Health and Johns Hopkins All Children’s Hospital

Clinical trials for rare conditions are inherently small, yet investigators often find it challenging to meet minimum enrollment requirements. A common reason is that patients are turned away for not having a definitive diagnosis, but that’s something we can improve upon.

In this era of genome-based medical treatment, physicians can boost trial enrollment by conducting genetic testing in every patient with a clinical history that signals a rare disease — as early in the diagnostic process as possible.

Some pharmaceutical companies are supporting that effort by collaborating with genetics labs to launch sponsored programs designed to increase access to genetic testing — and, as a result, patients’ eligibility for certain investigational treatments.

For instance, Pharming Healthcare, Inc. offers no-cost genetic testing to eligible patients in the U.S. or Canada whose clinical histories suggest they might have the rare primary immunodeficiency APDS (activated PI3K delta syndrome). In addition, the program offers free testing to any blood relative of a patient whose results reveal a mutation in the PIK3CD or PIK3R1 genes. Its goal is to reduce barriers to the diagnosis and treatment of rare genetic immunodeficiencies.

By implementing this kind of testing and improving access to it, we can potentially identify a host of new candidates for rare disease trials and empower patients to understand the benefits of participating.

Accessing Genetic Testing

Early genetic testing is crucial in patients thought to have primary immunodeficiencies (PIs) because these rare conditions are difficult to recognize and, once suspected, easy to mistake for each other.

For instance, APDS is caused by variants in the PIK3CD or PIK3R1 genes that can lead to respiratory infections, viruses, cytopenias, GI issues, and lymph node enlargement.¹ But without genetic testing, the disease is often confused with Evans syndrome, monogenic combined immunodeficiencies (CIDs), common variable immune deficiency (CVID), autoimmune lymphoproliferative syndrome (ALPS), autoimmune cytopenias, or even types of cancers.^2,3

A 2020 study by the Jeffrey Modell Foundation confirmed the “utility, cost-efficiency, and critical importance” of genetic testing in patients with PIs. After providing sequencing to 158 patients, investigators determined that clinical diagnoses changed for 45% of the patients, disease management was altered for 40%, and treatment was adjusted for 36%.⁴

Because eligible patients sometimes have trouble accessing genetic testing, often for insurance-related reasons, several organizations have established programs that provide comprehensive testing at no cost. In addition to the disease state-specific navigateAPDS, these include Probably Genetic and the Broad Institute’s Rare Genomes Project.

But to truly capitalize on its benefits, we will need to close the knowledge gap within the medical community about genetic testing. While doctors at leading academic institutions are generally comfortable with this methodology, many either aren’t using it or don’t adequately understand how to implement it. To protect our patients and keep our field from being left behind, we must reverse that trend.

I’m convinced that the best way to accomplish that is through a grassroots series of intimate workshops where attendees can feel comfortable being honest about their knowledge levels and needs. I recently launched that effort with a small workshop at my facility, where medical geneticists and other primary care doctors were learning more about immunology. I’m looking forward to offering similar events in the future.

I encourage my colleagues with expertise in genetic testing to join me by offering their own workshops whenever the opportunity arises.

Establishing Trial Eligibility

While genetic testing is the first step toward establishing trial eligibility, it’s usually not the last. For instance, sequencing may reveal a variant of uncertain significance (VUS), a genetic mutation that is not conclusively linked to the individual’s symptoms — or any illness.

In these cases, physicians may be able to confirm a PI diagnosis by conducting family variant testing, functional testing, and immunophenotyping. Although the latter tests are not standard outside major academic centers, some community-based allergists/immunologists/hematologists can perform them, and efforts are underway to make them more widely available.

Trial eligibility also can depend on other factors, such as age, the severity of an illness, or a patient’s treatment history. Additional enrollment concerns hinge not on patients’ eligibility but on their interest in participating. Challenges include:

• Patient health status. When patients are feeling well, they’re typically not inclined to pursue clinical trials. As a result, innovation is mainly driven by patients who aren’t well supported by standard therapies or whose conditions have become refractory to treatment.
• The need for comprehensive care. Trials can add complexity to the lives of patients and their doctors. Patients may need to see both study investigators and their own doctors during trials to receive adequate monitoring and treatment. Meanwhile, referring physicians must find ways to communicate with study teams without breaching confidentiality.
• Awareness about trials. While patients may request a list of relevant trials to consider, most doctors are unlikely to be prepared to provide one — although they can discuss any that are brought to their attention. To learn about available studies, patients can search the database at clinicaltrials.gov.

Expanding Early Screening

To further support innovation in the rare disease space, we should implement genetic testing even before symptoms appear, and for everyone — as part of routine newborn genetic screens. Already, every baby in America is screened for hearing issues, as well as for sickle cell anemia, critical congenital heart defects, spinal muscular atrophy, and severe combined immunodeficiency (SCID).⁵

Historically, children with SCID died by age 1 because symptoms arose too late for intervention, but now we can save nearly all their lives. If newborn genetic screening and assays for all inborn errors of immunity were included in newborn screenings, we could prevent many more children from ever becoming sick.

A caveat is that newborn screening can create anxiety for parents as they anticipate signs of disease. However, I would argue that knowing what’s ahead can empower parents to better care for their children.

Ultimately, broader newborn screening would make rare diseases less rare, facilitating better-enrolled trials with the potential to drive innovation. Paired with our current approaches — from no-cost genetic testing to continuing physician education — this very early screening could vastly improve the outlook for patients facing debilitating and sometimes deadly immunodeficiencies.

References:

1. Maccari ME, Abolhassani H, Aghamohammadi A, et al. Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry. Front Immunol. 2018;9:543. doi:10.3389/fimmu.2018.00543 
2. Jamee M, Moniri S, Zaki-Dizaji M, et al. Clinical, Immunological, and Genetic Features in Patients with Activated PI3Kδ Syndrome (APDS): a Systematic Review. Clin Rev Allergy Immunol. Published online May 21, 2019. https://doi.org/10.1007/s12016-019-08738-9.
3. Rotz SJ, Ware RE, Kumar A. Diagnosis and management of chronic and refractory immune cytopenias in children, adolescents, and young adults. PBC. 2018; e27260. doi: 10.1002/pbc.27260.
4. Quinn J, Modell V, Holle J, et al. Jeffrey’s insights: Jeffrey Modell Foundation’s global genetic sequencing pilot program to identify specific primary immunodeficiency defects to optimize disease management and treatment. Immunol Res. 2020;68(3):126-134. doi: 10.1007/s12026-020-09131-x.
5. Centers for Disease Control and Prevention website. Newborn Screening Portal. Updated November 29, 2021. Accessed January 26, 2024. https://www.cdc.gov/newbornscreening/index.html.

About The Author:

Jolan Eszter Walter, MD, Ph.D, is an international expert in primary immunodeficiencies and immune dysregulation who serves as division chief of the pediatric allergy and immunology programs at University of South Florida Health and Johns Hopkins All Children’s Hospital. Her research is focused on better understanding diseases associated with the under- and overactive immune system and defining strategies for the early detection of susceptible individuals and novel approaches for precision treatment.

Note: This article was written for educational purposes and the views expressed herein are solely those of the author. Editorial support was provided by a third party and paid for by Pharming Healthcare, Inc.  No financial compensation or incentives were provided.