Experimental injection lowers need for blood draws in slow-growing cancer

Ionis Pharmaceuticals’ experimental injection therapy sapablursen may ease symptoms of polycythemia vera (PV) and reduce the need for blood draws to manage the slow-growing blood cancer, according to results from an international Phase 2 clinical trial.

A Phase 3 clinical trial called INTREPID (NCT07429266) is now evaluating sapablursen against a placebo in up to 250 adults with PV who require regular blood draws. The trial’s main goal is to test whether the therapy is more effective than a placebo at reducing the need for blood draws. Recruitment is ongoing at sites in the U.S. and Australia.

The Phase 2 trial results were detailed in the study “Sapablursen for Erythrocytosis Control in Patients with Polycythemia Vera,” which was published in Blood. The work was funded by Ionis, and three of its authors work at the company.

PV is a slow-growing blood cancer marked by the uncontrolled growth of blood cells, particularly red blood cells. To manage the disease, patients often require regular blood draws (phlebotomies) to remove excess blood cells.

Red blood cells use an iron-containing compound called hemoglobin to carry oxygen through the bloodstream. Sapablursen, administered as an under-the-skin injection, is designed to reduce levels of TMPRSS6, a protein that normally helps regulate how the body processes iron. Essentially, by limiting the iron available to make hemoglobin, sapablursen restricts the production of new red blood cells.

Phase 2 trial results and mechanism of action

The Phase 2 trial (NCT05143957) enrolled 50 people with PV who needed regular blood draws. A total of 49 participants were treated with sapablursen every four weeks. In the first group of participants, treatment was initially started at 120 mg per dose, but was reduced to 80 mg due to safety concerns. In the second group, treatment started at 40 mg per dose. Doses could then be adjusted based on blood cell counts.

The study’s main goal was to evaluate how treatment affected participants’ need for phlebotomies between weeks 17 (nearly four months) and 37 (about 8.5 months). Results showed that the estimated mean number of phlebotomies per year dropped from 7.8 to 2.6 in the first group and from 8.8 to 3.6 in the second. In both groups, the mean weekly phlebotomy rate was significantly reduced by about five blood draws per year.

Roughly half of patients in each group (53% in the high-dose group and 41% in the low-dose group) saw their phlebotomy rates fall by at least 90%.

Sapablursen treatment also reduced the proportion of red blood cells in the blood and increased levels of hepcidin, a protein often depleted in PV patients because TMPRSS6 suppresses its production.

Biomarker data suggested that sapablursen was reducing iron available to blood cells but not to the rest of the body — in contrast to regular phlebotomies, which remove iron from the entire body.

Symptom relief, safety, and Phase 3 trial

Over the course of the study, participants tended to report an easing of PV symptoms, as reflected by decreases in a standardized test called the Myeloproliferative Neoplasm-Symptom Assessment Form Total Symptom Score. These reductions were statistically significant in the high-dose group.

Data from the Patient Global Impression of Change scale showed that 59% of participants felt their overall health was “a little bit better” or “much better” after treatment. Participants also tended to report reductions in fatigue.

Most adverse events reported were mild to moderate in severity. The most frequent side effects included anemia or low red blood cell counts (37%), fatigue (33%), headache (20%), diarrhea (20%), and rash (20%). Injection-site reactions were reported in six patients (12%).

“Administration of sapablursen [every four weeks] was associated with a reduced phlebotomy rate, greater [control of red blood cell counts], [reduced] symptoms, and a low incidence of injection site reactions,” the researchers wrote.

Now, the three-part Phase 3 INTREPID trial will test the therapy’s safety and efficacy in a larger patient population. After the initial 32-week placebo-controlled period, participants can continue receiving sapablursen for up to 124 weeks (nearly 2.5 years).

In addition to measuring phlebotomy dependency between the sapablursen and placebo groups after 32 weeks, the trial will evaluate differences in blood-related measures, symptom control, and fatigue over one year. The study is expected to end in 2031.