trnd-sickle-cell-556px - image courtesy of NIH

Sickle cell disease (SCD) is one of those frustrating conditions that has seen countless research failures and few innovations.

SCD refers to a group of inherited red blood cell disorders in which patients have an abnormal hemoglobin (hemoglobin S) resulting in red blood cells that are hard and sickle-shaped rather than flexible and round. Their rigidity and sharp edges, as well as changes in their cell membranes, cause them stick to vessel walls, blocking blood flow and preventing oxygen from reaching nearby tissues. That can lead to severe pain events that often occur without warning and frequently require hospitalization as well as numerous other complications

Despite studying this disease for more than 100 years, few treatment options for these patients. Currently, the only cure for SCD is a hematopoietic stem cell transplantation (HSCT), though this option has significant risks and donors can be difficult to find. For the rest of the patient population, hydroxyurea, a drug that increases fetal hemoglobin in red blood cells and neutralizes the abnormal hemoglobin S, is the only disease modifying medication available and approved for use in adult SCD patients. In contrast, there have been over 40 drugs approved to treat patients with HIV since the late 1980s. Hydroxyurea has toxicities that limit its use in some patients and only partially reduces the frequency of SCD complications but does not eliminate them entirely.  Most of the treatment options for SCD still focus on treating symptoms with pain killers, antibiotics, and blood transfusions to cope with anemia.

Pain comes in many forms

There are many reasons that research to date has failed to bring new treatments to market. One challenge has been the focus on number of hospitalization events as a key endpoint for efficacy.

Sickle cell patients often end up in the hospital when their pain is extreme, yet a 2008 prospective study of pain experienced by SCD patients shows that pain is a daily phenomenon that is mostly managed at home, even when relatively severe, which caused Smith to conclude that it is probably underestimated by health care providers, resulting in misclassification, distorted communication, and under treatment. It also means the primary end point for many trials – hospitalization – may not the best measure of efficacy, as healthcare utilization is a relatively infrequent choice for patients in pain.

Studies like this one, coupled with the trend toward more patient centric research initiatives, is having a positive impact on SCD trials. There are currently several seminal SCD trials underway, and many of them are using patient reported outcomes as a measure of efficacy. The US Food and Drug Administration (FDA) has also shown interest in PROs as an element of SCD studies. In 2014, the agency held a public meeting with SCD patients to gather their perspectives on the condition and available therapies as part of its Patient-Focused Drug Development initiative.

This is all good news for SCD patients, and developers working on this disease. When researchers understand what outcomes are most important to patients, and gather their feedback as part of the research, they are able to make better decisions, and develop drugs that will have the greatest impact on their quality of life.

We have already seen progress in response to this trend. In 2016, Emmaus Life Sciences submitted a New Drug Application (NDA) to the FDA for its oral pharmaceutical grade L-glutamine treatment, which demonstrated positive clinical results in a completed Phase 3 clinical trial for sickle cell anemia and sickle ß0-thalassemia. If the FDA approves the treatment, it would be the first FDA-approved medicine available for children with sickle cell disease, and the first potentially new treatment for adults and children in nearly two decades. The therapy has Orphan Drug designation in the U.S. and Europe, and also received Fast Track designation from the FDA.

If the patients won’t come to the research…

Another challenge for SCD research is the difficulty recruiting patients to trials, particularly in the US and EU. SCD affects millions of people throughout the world — but fewer than 100,000 of those patients live in the US. SCD is most common among people in sub-Saharan Africa where roughly 300,000 people are born with SCD every year. Yet drug developers worried they would not be able to manage data quality and patient safety running trials in these countries. So they ran their trials in the US and EU, which often led to big investments in sites that enrolled limited numbers of patients, causing delays and resulting in termination of some trials.

But this trend is also beginning to change, with a few developers taking the bold step of conducting SCD trials in countries where the patients are most likely to be found.

QuintilesIMS already has a strong network of sites and trained clinical research experts in the region, and we recently worked with a sponsor to conduct a pediatric SCD trial in the countries with the greatest need – and the results have been impressive. To support the research and to demonstrate the efficacy of conducting research in Africa, we opened trial sites around the world, including 31 sites in the US and six sites in Ghana and Kenya, along with a number of other global locations.

By the end of the recruiting timeline, the US sites averaged just two patients per site, while the sites in Ghana and Kenya recruited 16-30 patients per site – by far exceeding every other location. The African sites also met their targets in less time and at a much lower cost.

More importantly, we found the quality of risk management, safety and patient engagement in Africa all exceeded our expectations. They had fewer protocol violations than US sites, and the patients were more willing to fill out patient reported outcome surveys on the impact of the treatment on their quality of life than in any other country we studied.

This experience helped to break a lot of preconceived notions about the ability to conduct quality trials in emerging markets, and the value of working with partners who have site networks in countries where targeted patients populations are most prevalent.

Gene therapy is now an option

Along with overcoming obstacles, we are also seeing new innovations emerging, including early phase research into gene therapy as a treatment options for SCD. A recent report in the New England Journal of Medicine describes the first successful correction of SCD using a viral vector carrying an anti-sickling version of a hemoglobin gene. The corrective hemoglobin gene was inserted into blood stem cells that had been collected from a patient with SCD and then, after treating the patient with chemotherapy to make room for these cells in the bone marrow, the newly corrected blood stem cells were transplanted back into the patient. Fifteen months after therapy this patient is healthy with no evidence of SCD.

Newer gene editing technologies are also being explored as a way to cure patients with SCD. In September, 2016, researchers from Dana-Farber/Boston Children’s Cancer and Blood Disorders Center reported results of a precision-engineered gene therapy virus for SCD which, when inserted into blood stem cells, leads to specific alterations in the DNA within the stem cells that fix the problems caused by the sickle cell mutation. Specifically, the genome editing leads to high level expression of fetal hemoglobin within red blood cells, which prevents red blood cells from sickling. The results show, in a mouse model of sickle cell disease, that the mice treated with this genome editing therapy had markedly reduced sickle-induced red-cell damage. A clinical gene therapy trial in SCD patients utilizing this genome editing technology is expected to launch in the coming year.

All of these advances offer real promise for SCD patients, and underscore the importance of questioning our preconceived notions about how and where trials are conducted, and the importance of engaging patients in the conversation about what endpoints matter most to them. By questioning long standing methods, we can find new ways to address unmet needs, and streamline the research we conduct to achieve those goals.

Topics in this blog post: Biopharma, R&D, Oncology/Hematology