Potential SCD Therapies by GBT Safe in Healthy People, Trials Show

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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GBT601 and inclacumab, experimental therapies from Global Blood Therapeutics (GBT) for sickle cell disease (SCD) and associated vaso-occlusive crises (VOCs), were generally safe and showed signs of biological activity in healthy volunteers, according to data from Phase 1 clinical trials.

These findings will be presented by GBT through two posters at the 2021 American Society of Hematology (ASH) Annual Meeting & Exposition, to be held Dec. 11–14 in Georgia and online.

“We’re very excited to present new Phase 1 data from our pipeline relating to GBT601 and inclacumab — both of which we believe have the potential to be best-in-class therapies — as we work on behalf of patients to achieve our goal of transforming sickle cell disease into a well-managed chronic condition,” Kim Smith-Whitley, MD, executive vice president and head of research and development at GBT, said in a press release.

GBT601, also known as GBT021601, is the company’s potential successor to Oxbryta (voxelotor), an oral therapy from GBT that was approved in the U.S. in 2019 as the first disease-modifying treatment for SCD.

Oxbryta is currently under regulatory review in Europe for the same indication as in the U.S.: adult and pediatric patients, ages 12 and older. That therapy has been granted Priority Medicines (PRIME) designation from the European Medicines Agency.

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Both Oxbryta and GBT601 work by increasing hemoglobin’s ability to bind to oxygen, thereby preventing its clumping, or polymerization, and the subsequent sickling and destruction of red blood cells —  which is SCD’s underlying cause.

However, compared with the approved therapy, GBT601 showed greater efficacy at significantly lower doses in a mouse model of the disease.

Data from two Phase 1 clinical trials evaluating GBT’s next-generation hemoglobin S polymerization inhibitor in healthy volunteers and SCD patients will be presented in a poster titled “GBT021601, a Next Generation HbS Polymerization Inhibitor: Results of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics in Adults Living with Sickle Cell Disease and Healthy Volunteers.”

Single ascending doses of GBT601 — ranging from 50 mg to 2,200 mg — are being tested against a placebo in 63 healthy adults, ages 18–55, in one trial (NCT05036512). In the other study (NCT04983264), single and multiple ascending doses of the therapy are being given to six adults with SCD, ages 18–60.

Both trials are evaluating the therapy’s safety and tolerability. Its pharmacokinetics, or movement into, through, and out of the body, and its pharmacodynamics, which measures a therapy’s effects on the body, also are being assessed.

Additionally, the study involving patients is evaluating GBT601’s preliminary efficacy through changes in anemia and red blood cell destruction, called hemolysis.

As of July 22, 39 healthy volunteers had completed the study, 23 were still being monitored, and one had left the trial due to moving to a new geographical area. Also, the six SCD patients had received a single 100 mg dose of GBT601.

Results showed that the therapy was generally well-tolerated in adults both with and without SCD, with most adverse events (side effects) being mild to moderate in severity and with no deaths reported.

Moreover, single ascending doses of GBT601 resulted in a dose-dependent increase in hemoglobin occupancy — the percentage of hemoglobin bound to the therapy — that exceeded the increase reported for healthy volunteers given Oxbryta’s single doses within a similar range.

These data suggest that GBT601 “has the capacity to achieve a targeted [hemoglobin] occupancy and attain the desired hematological effect at low doses, therefore reducing pill burden and improving clinical outcomes for individuals living with SCD,” the researchers wrote.

Multiple-dose data from SCD patients also will be presented, and if GBT601 shows a hemoglobin occupancy “in the 30-50 percent or higher range with a maintenance dose less than 500 mg, we believe GBT601 could be a potential best-in-class therapy,” Smith-Whitley said in an emailed statement to Sickle Cell Disease News.

“What is really exciting for people living with sickle cell disease is that we believe with this level of efficacy GBT601 has the potential as a functional cure in a once-daily pill,” Smith-Whitley added.

In the second poster, “Preliminary Results of a Phase 1 Study in Healthy Subjects Administered Inclacumab, a Fully Human IgG4 Anti-P-Selectin Monoclonal Antibody in Development for Treatment of Sickle Cell Disease,” researchers will share final data from a Phase 1 trial that evaluated inclacumab in healthy adults.

Initially designed by Roche, and acquired by GBT in 2018, inclacumab is being developed as a potential best-in-class therapy to prevent and/or reduce vaso-occlusive crises known as VOCs — painful SCD-related attacks caused by blood vessel blockage.

Given directly into the bloodstream (intravenously), the antibody-based therapy works by blocking the activity of P-selectin, a protein that increases the stickiness of sickled red blood cells.

As such, inclacumab is expected to lower the risk of blood vessel obstruction, thereby reducing the rate of VOCs and post-VOC hospital readmissions in SCD patients. Previous data also suggested that the therapy may require less frequent dosing relative to once-a-month Adakveo (crizanlizumab), the first P-selectin inhibitor approved to lower VOCs frequency.

In the Phase 1 trial, 15 healthy adults were given a single inclacumab infusion at a dose of 20 mg/kg (six people) or 40 mg/kg (nine people). All but one participant completed the 29-week follow-up period (nearly seven months). The participants’ median age was 42 (range, 22–52).

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Results showed that inclacumab was generally well-tolerated, with no reports of serious adverse events, infusion-related reactions, or immune reactions. There also were no clinically significant changes in vital signs, laboratory findings, or heart measures.

The most common adverse events included headache, muscle pain, and red, itchy rash.

Notably, both doses reduced the formation of P-selectin-dependent blood cell aggregates, or clumps, as early as two hours post-treatment and for at least 12 weeks (about three months).

Antibodies against the therapy were detected at three months and thereafter in two participants given the higher dose, but a preliminary analysis showed no apparent impact on the therapy’s pharmacokinetics or safety.

These data support inclacumab’s “best-in-class potential as a medicine for quarterly dosing,” Smith-Whitley said, adding that “this would be a meaningful improvement for patients compared to monthly dosing and aligns well with a typical sickle cell disease physician practice schedule of quarterly check-ins.”

These findings also supported the launch of two pivotal placebo-controlled Phase 3 trials — GBT2104-131 (NCT04935879) and GBT2104-132 (NCT04927247) — testing inclacumab at a dose of 30 mg/kg, given every three months, to SCD patients, ages 12 and older, who have experienced between two and 10 VOCs in the previous year.

The GBT2104-131 study is assessing whether the therapy can prevent VOCs, while GBT2104-132 is evaluating whether a single inclacumab infusion given just prior to, during, or around the time of discharge can reduce readmission due to VOCs. Both studies are still recruiting patients in the U.S. and Lebanon; more information can be found here and here.

The 2021 ASH meeting will be held at the Georgia World Congress Center, in Atlanta, with all presentations also available virtually. GBT will be presenting six posters in total, all relating to SCD. Registration information for the 63rd annual meeting can be found here.