HemOnc Today's PharmAnalysis

HemOnc Today's PharmAnalysis

January 22, 2020
4 min read

Recommendations seek ‘similarity across trials’ of therapies for sickle cell disease

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Julie Panepinto, MD, MSPH, FAAP
Julie Panepinto

Sickle cell disease, the most common inherited red blood cell disorder in the United States, is associated with debilitating physical symptoms, including acute pain crises, joint and organ damage, diminished cognitive function and decreased life expectancy.

Despite long-standing knowledge of the molecular mechanisms of sickle cell disease (SCD), only four treatments for SCD have received FDA approval. Bone marrow transplant has been an effective curative option for some patients, but others may lack a suitable donor or face high risk for complications.

New SCD treatments, including possibly curative gene therapies, remain under development. Among them is ARU-1801 (Aruvant/Roivant Sciences), an investigational autologous gene therapy granted rare pediatric disease designation by the FDA.

Amid the recent resurgence of SCD research, clinicians and regulatory officials have recognized the need for standardization of clinical trial endpoints used to assess new therapies for the disease. To that end, the FDA and ASH organized a workshop of seven expert and patient panels that conducted literature reviews, discussed potential improvements to SCD clinical trials, and issued comprehensive recommendations for increased uniformity of clinical trial endpoints. The recommendations, published as two companion papers in Blood Advances, advocated increased use of patient-reported outcomes and biomarkers as clinical endpoints.

“Over the past few years, ASH has established and is involved in an initiative focused on SCD that includes a research collaborative and data hub, and these recommendations stemmed from that initiative,” Julie Panepinto, MD, MSPH, FAAP, professor of pediatric hematology at Medical College of Wisconsin/Children’s Wisconsin, co-chair of ASH’s Guideline Oversight Committee, and co-chair of the workshop, said in an interview with Healio. “I also think that we were very aware that, especially in terms of developing new therapeutics, it can be very helpful to have endpoints that are uniform and common across studies. It just helps to be able to compare apples to apples.”

Panepinto and colleagues reviewed the available literature on endpoints related to patient-reported outcomes (PROs), pain (non-PROs), the brain, end-organ considerations, biomarkers, assessment of cure and care in low-resource environments. Panepinto spoke with Healio about the recommendations for each of these areas and how they can more effectively guide clinical trials of SCD in the future.

Question: What scientific literature served as the basis for the panels’ recommendations?

Answer: We looked at multiple sources, with peer-reviewed journals being the largest source. We considered not only SCD-specific evidence, but evidence on other diseases that might provide information about, for example, a biomarker. We also had experts’ opinion and working knowledge of all the endpoints, and feedback from workshop members.


Q: PROs were a major area of focus in these recommendations. What did the panels consider in terms of PROs?

A: We received input not only from experts on the panels, but also from patients who were able to attend the workshop. I hope that the result — our paper — is a concise document that helps improve understanding not only of the importance of measuring PROs, but also of impact of this disease and its therapeutics on patient functioning. Because there are so many different PROs for children and adults, we pulled together what we know about the use of PROs and determined what we considered the best domains to focus on and the measures that have been used and validated among patients with SCD. The three domains the PROs panel recommended as focuses for future SCD trials included crisis/noncrisis pain; affect, including emotional impact and fatigue; and function, which encompasses social, physical and cognitive function.

Q: Can you discuss what the other panels recommended?

A: We had one panel that looked at non-PRO measurements of pain. This panel discussed whether we have anything to measure pain that can augment or complement PROs. It recommended non-PRO measurement of pain through health care utilization, use of analgesics and physical function.

Another panel focused on end-organ considerations, specifically brain, heart, lung and kidney factors. This panel discussed the importance of developing new biomarkers that determine the progression of kidney and cardiopulmonary disease.

There was a panel dedicated to care in low-resource settings. This panel looked at opportunities to expedite clinical trials in areas of the world where SCD is prevalent, such as sub-Saharan Africa. The panel also suggested collecting data on early childhood, perioperative and pregnancy-related death, as well as pediatric PROs pertaining to growth and development.

Lastly, we had a cure panel that looked at not only gene therapy but also bone marrow transplant and sought to understand what outcomes are important to measure when these treatment modalities are used. The panel emphasized the need to develop biomarkers and to follow patients over long periods of time to assess the benefits of curative treatments, and to record this information in a central database to increase understanding and use of these treatments.

Q. Where do you think future research on SCD treatment is headed?

A: We were all very excited to see the recent FDA approval of two new drugs for SCD, and there’s a lot going on in the curative realm with transplant and gene therapy. Any therapeutic procedure that can improve the health of those living with SCD is very welcome. Many clinicians are excited to see a lot happening in this area after having only one disease-modifying drug for decades. As researchers publish the results of their clinical trials, we would really love to see outcomes that are similar across studies and help us learn even more. Sometimes it seems obvious to report certain things, but when you review the literature, you realize that we’re all thinking about different things. So, if we can have a sense of doing things similarly across trials, I think it really helps advance the field. – by Jennifer Byrne


Farrell AT, et al. Blood Adv. 2019;doi:10.1182/bloodadvances.2019000882.

For more information:

Julie Panepinto, MD, MSPH, FAAP, can be reached at 701 Watertown Plank Road, Milwaukee, WI 53226.

Disclosure: Panepinto reports no relevant financial disclosures.