APL-2 Monotherapy Holds Promise for Paroxymal Nocturnal Hemoglobinuria Patients

A new drug under development for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), a rare, acquired, life-threatening blood disease, has been shown to be beneficial in participants enrolled 2 ongoing phase 1b trials—PHAROAH and PADDOCK.

The drug in question? Apellis Pharmaceuticals Inc.’s APL-2, a first-in-class treatment developed to target C3; in fact, it has the potential to significantly improve hemoglobin (Hb) levels in eculizumab-treated patients suffering from anemia, according to the pharmaceutical company.

Currently, the only approved drug for PNH therapy is eculizumab (Solaris). However, a recent study showed that 70% of patients treated with eculizumab were anemic and had hemoglobin levels below 12.0 g/dL.

The 2 proof-of-concept clinical trials are a part of the PNH program, which allows for participants with PNH to switch therapies, going from eculizumab to APL-2 monotherapy after 1 month of co-treatment. The overarching goal is to improve hematological parameters, particularly hemoglobin.

In the PHAROAH trial, which is assessing the ability of APL-2 to benefit PNH patients on treatment with eculizumab who are severely anemic and transfusion-dependent, participants are being treated with APL-2 in addition to eculizumab. After at least 1 year of co-treatment, several patients have been switched to APL-2 monotherapy.

The 32-week data from the trial released in December 2017 included 4 out of 6 patients who remained in the study as of week 32 and received co-treatment of eculizumab and APL-2 at 270 mg/day. Key findings included the observance of no needed transfusions, a successful reduction in dosing of eculizumab, and successful weaning from eculizumab.

“It was initially very encouraging to see the significant improvements in these significantly anemic patients when APL-2 was added to Soliri,” commented Anita Hill, lead consultant for the National PNH Service at the Leeds Teaching Hospitals, In the United Kingdom, in a recent statement. “To see APL-2 maintain the same hematological benefits when dosing with Soliris was reduced in all and weaned entirely in three of four patients is impressive.”

In the PADDOCK trial, APL-2 is being evaluated for safety and efficacy in PNH patients who have not been previously treated with eculizumab. According to the data collected in April 2018, 8 patients not previously treated with eculizumab after daily subcutaneous administration with 270 mg/day of APL-2 for at least 28 days reported that APL-2 increased Hb levels and reduced lactate dehydrogenase (LDH). Additional key findings included improved hemoglobin and other anemia markers.

“The data generated by APL-2 in treatment-naïve patients with PNH are impressive compared to our experience with Soliri,” added Peter Hillmen, MB ChB, PhD, professor of experimental hematology at the University of Leeds. “The early experience of APL-2 demonstrates that inhibiting C3 controls extravascular as well as intravascular hemolysis unlike inhibition of C5 where continued extravascular hemolysis is frequently problematic.”

To date, subcutaneous APL-2 has been found to be well tolerated with cumulative systemic exposure of over 12 patient years of treatment on APL-2, according to a recent news release. Furthermore, no significant infections or thromboembolic events have been noted.

“We are especially pleased to see APL-2 monotherapy helping a range of patients, including those who are severely anemic and continue to suffer while being treated with high doses of eculizumab,” emphasized Cedric Francois, MD, PhD, co-founder and CEO of Apellis. “We are encouraged by these data that support our belief that many rare and autoimmune conditions can be treated through C3 inhibition.”