Stroke is one of the most devastating complications of this sickle cell disease; it occurs in 5 to 10% of children affected. Since the early 1990s, ultrasound to measure blood flow in arteries of the brain (transcranial Doppler) has been standard practice in management of young people with SCD; those children with reduced blood flow have, until now, been advised to receive regular transfusions of non-sickling blood, to reduce their risk of stroke. However, a treatment regimen of chronic transfusions carries risk: besides unknown infection in the blood supply (deemed low) or bacterial contamination in blood (unusual), there’s a greater probability of developing iron overload , over time. Iron overload causes problems in the heart, liver, endocrine system and other organs.
Patients entering the TWiTCH trial was stopped early, in 2014, based on clear results for hydroxyurea being at least as good as transfusion in maintaining blood flow to the brain, as measured by transcranial Doppler. (This was the primary endpoint of the trial, which enrolled over 120 children between the ages of 4 and 15 years, all with severe SCD.) Ware said there was no significant difference in the incidence of strokes between the two treatment arms, and no significant problems observed from hydroxyurea on the study, which included follow-up through two years.
“This truly is one of the abstracts that can be defined as practice-changing,” Thompson said. She’s a pediatric hematologist and professor at
Northwestern University ’s Lurie Children’s Hospital of Chicago. and was
recently elected to an ASH leadership position. She fielded several questions on safety of this treatment at the press briefing.
“These are sick kids,” Thompson considered. Sickle cell disease causes strokes, life-threatening infections, pain, organ failure and early death. “There’s a growing body of evidence that this is a safe and effective drug,” she said. “Hydroxyurea is a helpful drug for many people who have sickle cell anemia,” she said. “But it requires careful discussion with patients,” she emphasized.
“We always tell patients, or families of children, that this drug was developed for cancer and is a form of chemotherapy,” Thompson said in a later interview. “We also share with them the mounting evidence of benefit to using hydroxyurea in ameliorating or preventing sickle cell complications without any increased risk of cancer. We have to be clear about it,” she said. “If there’s any perception of deception, that can cause problems.”
“There are concerns about fertility with hydroxyurea, especially in men,” Thomson said. “Also, although we always warn girls and women not to get pregnant while on this drug, it does happen,” she added “Sometimes, it’s not on the woman’s side, but by a man who’s on the drug. In theory this could cause problems, but so far we haven’t seen birth defects.”
“Hydroxyurea (HU) has been used in clinical trials for children with sickle cell disease who are as young as 9 months and there are no unique safety concerns from those studies,” Thompson wrote in a subsequent email. The
NIH guidelines for treating sickle cell disease strongly support broader use of HU including in children. “It is likely that the label indication will include children soon,” she added.
In a second presentation at the press meeting, Dr. Barbara Cappelli reviewed results from a large international registry of 1,000 HLA-identical sibling transplants performed for patients severe SCD. The perfectly-matched allogeneic transplants were carried out between 1986 and 2013, at 88 medical centers in 23 countries, Cappelli indicated.
According to the abstract (#541), which reads (as did others) slightly differently from the presentation, the median age at transplant was 9 years. Approximately half of the transplant recipients were female, and just over half of the procedures were performed since 2007. The reasons for considering transplantation (and entering the trial) included stroke, an SCD complication called acute chest syndrome, and having painful crises requiring hospitalization. At three years after transplant, overall survival surpassed 94%, Cappelli said.
Engraftment rates were “excellent,” Cappelli said; in only 70 of 1,000 patients (7%) did the transplants not take hold of the patient’s marrow. Younger patients receiving transplants fared better than older, she indicated. With hundreds of transplanted patients out now more than 10 years (in some cases, over 20 years) after transplant, some patients might be considered cured of SCD. (Although Cappelli was reluctant to use the term “cure,” others did.)
The possibility of treating SCD by matched bone marrow transplantation is limited by several factors, Cappelli outlined. Only one in ten SCD patients has an identical sibling match, she noted; the option for transplant with such a high probability of a favorable outcome doesn’t apply to most SCD patients, who lack a perfect sibling donor. Second, many patients in developing countries lack access to healthcare facilities where bone marrow transplantation, a fairly standard procedure in modern medical centers, can be safely accomplished.
The drug works by enhancing hemoglobin’s affinity for oxygen, said Dr. Eleanor Ramos in a phone interview. She’s the chief medical officer of Global Blood Therapeutics, the study’s sponsor and product manufacturer. “We’ve observed that erythropoietin levels declined in patients who received the drug. Nothing is absolute, but this decrease in EPO strongly suggests that oxygen is being effectively delivered to tissues,” Ramos said. “This explains the observed changes in the red blood cells.” If this agent diminishes sickling and clogging of the small blood vessels, as happens in sickle cell disease, there should be less organ damage, she said.
The GBT440 study was designed to test various doses of the drug in healthy volunteers and adult patients with SCD. “So far, we have enrolled 22 adults who have sickle cell anemia in the trial,” she said. The reported findings include those 22 patients who’ve taken the drug at a set, tolerated dose for 28 days, along with 8 healthy research volunteers. (The study design calls for a 6:2 skewing in this phase.) The trial is now enrolling research subjects who will take GBT440 for as long as 90 days, Ramos said.
The protocol stipulates that everyone on the trial be monitored in a clinical research unit for the first four days of treatment. This enables researchers to watch for any potential untoward effects. It also permits close monitoring of how GBT440 is absorbed at each dose, when peak levels occur, and other aspects of its pharmacology. After the initial four days, patients can leave the unit and come back for periodic checks.
“The most common complaint we’ve observed is headache during the first week of the study, and those appear to resolve,” Ramos said. The headaches, considered grade 1 or 2 adverse events, have been mild or moderate, and have been reported by subjects receiving both the active drug and the placebo, she noted. Investigators report a total of four serious adverse events (SAEs) among the 30 subjects in this phase of the study. Three of those four were due to sickle cell crisis (a painful manifestation of SCD), and all occurred after discontinuation of the study drug (GBT440 or placebo). The other (fourth) SAE was an infection causing hemolysis; the patient was admitted to the hospital because he needed antibiotics, Ramos said. While it can’t be ascertained that the drug did not somehow contribute to that patient’s infection, patients with sickle cell disease are at increased risk; most lack functional spleens and are vulnerable to pneumonia and other infections.
“This drug is unique in that it’s a disease-modifying agent, that’s unrivaled in its ease of administration,” Ramos said. “It’s a single, daily dose oral agent,” she said. “It appears to be well tolerated.” The potential for relieving pain, and organ damage from low oxygen, is tremendous, she offered.
The ongoing clinical trial of GBT440 aims to enroll 128 patients. Results from the phase 1-2 trial will be available in 2016, Ramos said.
Finally, the Bluebird gene therapy abstract published by ASH (abstract #202) contains few details, and refers also to patients with another type of hemoglobin disorder, β-thalassemia (major), who received similar treatment. As reported at the meeting in Orlando, and consistent with information provided on the company’s website (“HGB-205 Study in beta-thalassemia major and severe sickle cell disease” and “HGB-206 Study in severe sickle cell disease”), as of mid-November 2015, a total of four SCD patients have received treatment with the lentiviral vector LentiGlobin BB305.