SCD Patients to Greet the First New Drug, the Gene Therapy to Hold Up Their Future

The Endari of Emmaus Life Sciences, Inc. was approved the marketing by FDA last week for symptom control of SCD (sickle cell disease) patients aged above 5. It is an oral L-glutamine and the first drug that can be used for pediatric patients with SCD.

The L-glutamine of Emmaus Life Sciences, Inc. used for SCD patients had received the orphan drug designation of FDA early in 2001. In the early development of this orphan drug, the FDA Office of Orphan Products Development (OOPD) offered different support to encourage the development of this new drug, and besides the policy support, OOPD’s grants program also provided grants for the exploration of the clinical use safety and effectiveness of this orphan drug. FDA Oncologic Drugs Advisory Committee voted 10 to 3 to recommend the marketing application of Endari to FDA in May this year. The final marketing approval received by this new drug seems natural, considering Endari’s positive improvement effects on SCD patients in the clinical trial.

In the pivotal Phase III clinical trial of Endari, the patients included in the randomized controlled trial were a population aged 5-58 who had painful crises caused by SCD within the 12 months prior to enrollment in the trial. The treatment was investigated and evaluated for 48 weeks. According to the trial results, the experimental group patients who received L-glutamine powder had significantly fewer hospital visits, fewer days in the hospital and fewer occurrences of acute chest syndrome (a life-threatening complication of SCD) (23.1% vs 8.6%) compared with patients who received a placebo.

SCD is one of the most common monogenic disorders in the world. The mutation of one locus of beta-globin gene encoding amino acid of SCD patients results in the finally expressed HbA protein to change to harmful HbS protein, with the red blood cells in the sickle shape, and patient body under anemia status; in the meantime, the dead sickle cells blocked the capillaries, causing painful crises and organ failure. Serious patients have been depending on blood transfusion to sustain life. Although patients could increase the quantity of the red blood cell population not becoming sickle-shaped in the body by using prophylactic antibiotics and blood transfusion, etc. from the babyhood, the organ damage brings symptoms like avascular necrosis, infection and renal failure, making the death of most patients become inevitable.

Early studies found that some adult patients with SCD could be cured through bone marrow transplantation and large-dose cyclophosphamide treatment after the operation, however, the selection of the donors matching patients, and the rejection and infection, etc. after the transplantation are enormous challenges. Such therapy is inadvisable for most SCD patients owing to many kinds of restrictions. The allogeneic hematopoietic stem cell transplantation has similar problems.

With the gene therapies going deep into the monogenic disorder research, the attempts to seek SCD gene therapy solutions are representing the future direction. In such field, the LengiGlobin gene therapy of Bluebird Bio is a typical one therein, which received the FDA breakthrough therapy designation in 2015. LentiGlobin BB305 gene therapy is a lentiviral vector which inserts anti-sickling β-globin gene into the hematopoietic stem cells (HSC) separated from a patient ex vivo in advance, then reintroduces the HSCs amplified ex vivo to the patient’s body, to reconstruct patient’s ability in synthesizing normal hemoglobin. According to early clinical trial results, some critical patients, upon treatment with LentiGlobin BB305, could sustain life without the need for blood transfusion for at least 3 months. According to the data of the Phase III clinical trial named Northstar-2 (HGB-207) issued recently, the first patient could be stopped the blood transfusion 1 month after the treatment, and his hemoglobin level was under normal state 6 months after the treatment. The expression effect of Bluebird Bio Hbat87q seems to be sufficient to inhibit patients’ hemolysis as viewed from the current results; patients who received treatment could maintain the relatively stable hemoglobin concentration of 11-12g/dL, and showed significant improvements in other indexes like specific biomarker.

To confirm whether the lentiviral would be integrated into the proto-oncogene, researchers monitored the viral integration sites, and confirmed the polyclonal response to HSCs. According to current results, the lentiviral is not associated with such risk.

If such gene therapy in development could become a safe and effective treatment method in the future, its primary advantage would be the radical solution of the pains of patients with the monogenic disorder SCD, which would be one-off solution; in addition, such therapy does not have the risk of allograft rejection and requires no matching donor, compared to the bone marrow transplantation or stem cell transplantation.

Optimistically speaking, the success of the gene therapy will hold up the future of patients with such monogenic disorders, but currently, the primary and urgent needs are to control symptoms, prolong life-span, and improve patients’ life quality, to which Endari’s marketing approval is a just-in-time solution.

By Xiaoyaowan