When Emmaus Medical Inc.'s pharmaceutical-grade amino acid L-glutamine got the FDA green light last month it became the first new treatment for sickle cell disease (SCD) to come on the market in the U.S. since chemotherapeutic agent hydroxyurea gained approval almost a decade ago. Although hydroxyurea cuts down the frequency of crises that SCD patients suffer and reduces the need for blood transfusions some patients do not respond well to the treatment. As such, there is a significant unmet need for new SCD therapies. Patients, however, may not have to wait too long for the next treatment to reach the market as several new potential medicines are currently in late stage clinical development.

For the time being, patients will certainly welcome the availability of L-glutamine, branded Endari, which should become available towards the end of the year, the company said. The drug is indicated to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years of age and older. Its mode of action, the company described, is the reduction of oxidant damage to red blood cells by improving the redox potential of nicotinamide adenine dinucleotide, a co-enzyme that has been identified as the primary regulator of oxidation. (See BioWorld, July 10, 2017.)

According to the National Institutes of Health, approximately 100,000 people in the U.S. have sickle cell disease with the condition occurring most often in African-Americans, Latinos and other minority groups.

Therapies under development

There are several new compounds that have reached late-stage clinical testing. For example, in its second quarter financial report, Gaithersburg, Md.-based Glycomimetics Inc. updated its product pipeline progress. "Our most advanced clinical development program to evaluate drug candidate rivipansel for the treatment of vaso-occlusive crisis of sickle cell diseases, is on track to complete enrollment of the phase III pivotal trial in the second half of 2018, according to our collaborator Pfizer," Rachel King, CEO noted.

Earlier phase II data on GMI-1070 (rivipansel sodium), a pan-selectin, showed patients treated with rivipansel experienced meaningful reductions in the time to reach resolution of VOC, length of hospital stay and use of opioid analgesics for pain management, in each case as compared to patients receiving placebo.

In 2011 Glycomimetics signed a deal with the New York-based pharma company is estimated to be worth as much as $340 million if all milestones are reached. (See BioWorld Today, Oct. 12, 2011.)

The dosing of the first patient in the RESET (Rivipansel: Evaluating Safety, Efficacy and Time to Discharge) study in June 2015 triggered a milestone payment from Pfizer of $35 million.

The trial will enroll at least 350 individuals with sickle cell disease, aged 6 and older who are hospitalized for a vaso-occlusive crisis. Trial participants must be receiving treatment with intravenous opioids for their vaso-occlusive crisis and must be able to receive the first dose of study drug within 24 hours of initiation of intravenous opioid therapy. The primary endpoint for the study will be time to readiness-for-discharge.

Ritu Baral, Cowen & Co. analyst said rivipansel is the company's lead program, and it "will receive meaningful royalties on sales. However, given program timelines and value, '1271 [for treatment of adults with relapsed/refractory acute myeloid leukemia (AML)] is still the main value driver and investor focus of the company."

As of June 30, 2017, Glycomimetics had cash and cash equivalents of $119.1 million thanks to generating $86.8 million in net proceeds from a public offering of common stock completed in May.

Last year South San Francisco-based Global Blood Therapeutics Inc. (GBT) reached an agreement with the FDA on the design of a pivotal phase III trial for GBT440, their experimental once-daily therapy for adults and adolescents with sickle cell disease. The trial is expected to yield top-line data in the first half of 2019. The trial will enroll up to 400 patients, age 12 and older, who have had at least one episode of vaso-occlusive crisis in the previous year. The primary efficacy endpoint will be the proportion of patients who achieve a greater than 1 g/dL increase in hemoglobin at 24 weeks of treatment vs. baseline. (See BioWorld Today, Oct. 26, 2016.)

In their second quarter financial update, company president and CEO Ted Love, said that during the period they had made "significant progress toward our goal of developing GBT440 as a potential global treatment option for SCD patients of all ages."

He reported that the company had expanded its phase IIa HOPE-KIDS 1 study into a new cohort of younger patients, age 6 to 11, based on encouraging results from a single-dose cohort in patients age 12 to 17.

The company continues to enroll patients in the phase III HOPE study, and the compound received Priority Medicines (PRIME) designation from the European Medicines Agency.

GBT's bank balance in terms of cash, cash equivalents and marketable securities totaled $290.6 million at June 30, 2017.

Novartis AG established a position in the SCD space through its acquisition of Selexys Pharmaceuticals Corp. for up to $665 million in up-front, acquisition and milestone payments. (See BioWorld Today, Nov. 22, 2016.)

The pharma company took an exclusive option to acquire Selexys in 2012 and exercised its right to acquire the company following receipt of results of the SUSTAIN study, a phase II trial evaluating the use of SelG1, an anti-P-selectin antibody, in the reduction of vaso-occlusive pain crises in SCD.

Cambridge, Mass.-based Imara Inc, which was granted FDA Rare Pediatric Disease designation for lead product IMR-687, said it is conducting a phase Ia study to evaluate the safety and pharmacokinetics of the product in healthy volunteers. If the outcome is positive, the company will initiate a phase IIa study in adult patients living with sickle cell disease later this year and initiate a phase II in pediatric patients next year. IMR-687 is an orally-administered selective phosphodiesterase 9 (PDE9) inhibitor, a potentially disease-modifying therapeutic for SCD as well as other hemoglobinopathies.

Gene therapy

Gene therapy has demonstrated some early evidence of success in sickle cell disease.

Early this year, Cambridge, Mass.-based Bluebird Bio Inc. reported treatment of the first patient under an amended study protocol in HGB-206, their phase I study of its Lentiglobin drug product in patients with severe sickle cell disease. The company reported that this study now incorporates several changes to the study protocol with the goal of increasing production of therapeutic anti-sickling hemoglobin (HbAT87Q).

At the European Hematology Association (EHA) meeting in Madrid, in June, Bluebird reported the first patient with SCD treated with gene therapy (Patient 1204) continues to show clinically meaningful improvement in symptoms of SCD and stable vector copy number and HbAT87Q in peripheral blood.

With $436.8 million in net proceeds from an equity financing, the company says its cash, cash equivalents and marketable securities of $1.2 billion are sufficient to fund their operations into 2020.

Editas Medicine Inc. reported results from its preclinical hematopoietic stem cell (HSC) program, which they say confirms the potential for CRISPR-based editing to treat sickle cell disease and beta-thalassemia. In a presentation at the American Society of Gene & Cell Therapy meeting, the company reported data demonstrating a substantial increase in fetal hemoglobin protein using a novel and potent genome editing strategy.

In studies, human HSCs were edited ex vivo and infused into mice. Four months following transplant, successful and durable repopulation of the blood system in vivo was observed.

Crispr Therapeutics AG reported that its lead hemoglobinopathies program remains on track to file a clinical trial application (CTA) in Europe by year-end, and begin clinical trials next year. At EHA the company presented data adding further support for its approach of re-creating the natural condition of hereditary persistence of fetal hemoglobin (HPFH) that is protective in sickle cell disease and in beta-thalassemia. The presentation described the ability to re-create specific HPFH gene variants in the intended target tissue, human CD34+ stem cells, and demonstrated that these gene variants increase the expression of protective fetal hemoglobin.

As of June 30, the company had $272.3 million in cash, which they expect will be sufficient to fund operating expenses and capital expenditure requirements for at least the next two years.

Capital market performance

The publicly-listed companies with SCD therapies in their product pipelines have enjoyed significant investor attention of late with six companies recording an average increase of 10 percent in their share prices during August. (See SCD public companies)

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