FDA Grants ALPN-101 Orphan Drug Designations in GVHD

The FDA has granted 2 Orphan Drug Designations to ALPN-101 for the prevention and treatment of acute graft-versus-host-disease.

The FDA has granted 2 Orphan Drug Designations to ALPN-101 for the prevention and treatment of acute graft-versus-host-disease (GVHD), according to Alpine Immune Sciences, Inc., the company developing the first-in-class selective dual T cell costimulation inhibitor.1

The designations will expedite the development and review of ALPN-101 in GVHD, the most frequently occurring life-threatening complication following a hematopoietic cell transplant.

“We are pleased to receive these important designations from the FDA in acute GVHD, where current standard therapies remain inadequate to prevent or control the disease,” Mitchell H. Gold, MD, executive chairman and chief executive officer of Alpine, said in a press release. “ALPN-101’s unique mechanism has the potential to serve as a groundbreaking medicine for patients suffering from a range of progressive and devastating autoimmune/inflammatory indications with little or no treatment options available to them today.

ALPN-101 simultaneously inhibits the CD28 and ICOS inflammation pathways. “CD28 and ICOS are closely related costimulatory molecules with partially overlapping roles in T cell activation likely playing a role in multiple autoimmune and inflammatory diseases,” Alpine explained in the press release.

Early data for ALPN-101 have been positive. An initial first-in-human study evaluated the safety, pharmacodynamics, and pharmacokinetics of ALPN-101 in healthy volunteers. The study included 12 cohorts of 6 patients each and randomized patients in a 2:4 ratio to ALPN-101 or placebo.

In 10 of the cohorts, patients in the experimental arms received an intravenous dose of ALPN-101, ranging from 1 μg/kg to 10 mg/kg. There were also 2 subcutaneous cohorts, in which patients on the experimental arms received a dose of either 1 mg/kg or 3 mg/kg.

The investigators reported that ALPN-101 achieved the targeted pharmacodynamic activity. Further, there were no infusion reactions, dose-limiting toxicities, or grade 3/4 adverse events (AEs). Self-limited upper respiratory tract infections and headaches were the most common AEs. There were no cases of cytokine release.

These positive findings led to the launch of the phase Ib/II BALANCE (AIS-A02) study evaluating ALPN-101 in patients with steroid-refractory acute GVHD. The study is examining ALPN-101 concurrently with salvage therapy.

Part A of the study is evaluating ascending dose levels of ALPN-101 to establish the optimal dose, with dose levels ranging from 0.001 mg/kg to a maximum of 20 mg/kg. Part B will be examining the optimal dose established in Part A. Overall, the study aims to enroll about 100 patients. The primary outcome measure is safety. Key secondary endpoints include objective response rate (ORR), duration of response, and overall survival.

The GVHD armamentarium has seen tremendous gains in recent years. In May 2019, the FDA approved ruxolitinib (Jakafi) for the treatment of adult and pediatric patients ≥12 years of age with steroid-refractory acute GVHD. The approval was based on findings from the phase II REACH1 trial, which demonstrated that the combination of ruxolitinib with corticosteroids elicited a 57% ORR at day 28 in patients with steroid-refractory acute GVHD, with a complete response rate of 31%.2

In August 2017, the FDA approved ibrutinib (Imbruvica) for the treatment of adult patients with chronic GVHD (cGVHD) following the failure of 1 or more lines of systemic therapy.

The approval was based on data from the single-arm phase Ib/II PCYC-1129 trial, in which ibrutinib induced an ORR of 67% (28/42 patients; 95% CI, 51-80) and showed clinically meaningful and durable responses in patients who failed at least 1 prior treatment for cGVHD.2 Twenty-one percent of responders had a CR and 45% had a partial response. Additionally, most responders were able to reduce steroid doses to an acceptable minimal level.


  1. Alpine Immune Sciences’ ALPN-101 Receives FDA Orphan Drug Designations for the Prevention and Treatment of Acute Graft Versus Host Disease. Published online March 18, 2020. https://ir.alpineimmunesciences.com/index.php/news-releases/news-release-details/alpine-immune-sciences-alpn-101-receives-fda-orphan-drug. Accessed March 18, 2020.
  2. FDA Approves Jakafi (ruxolitinib) for the Treatment of Patients with Acute Graft-Versus-Host Disease. Incyte. Published May 24, 2019. https://bit.ly/2WiRktX?rel=0. Accessed May 24, 2019.
  3. FDA approves treatment for chronic graft versus host disease. Published August 2, 2017. https://www.fda.gov/news-events/press-announcements/fda-approves-treatment-chronic-graft-versus-host-disease. Accessed March 18, 2020.
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