FDA Grants Fast Track Status to HPN217 for Relapsed/Refractory Multiple Myeloma

FDA

The FDA has granted a fast track designation to the BCMA-targeting Tri-specific T-cell Activating Construct (TriTAC), HPN217, for use as a potential therapeutic option in patients with relapsed or refractory multiple myeloma who have previously received at least 4 lines of therapy.¹

The safety, tolerability, pharmacokinetics (PK), and activity of the agent is currently under investigation in patients with relapsed or refractory multiple myeloma, as part of an ongoing multicenter, open-label, phase 1/2 trial (NCT04184050).²

Data from an interim report of the trial showed that HPN217 had clinical activity at higher dose levels examined, such as weekly doses of 2150 µg and 2860 µg.³ At the 2150 µg dose (n = 8), the objective response rate (ORR) with HPN217 was 63%, and the disease control rate (DCR) was 88%. At the 2860 µg dose (n = 5), the ORR and DCR with the agent were 40% and 60%, respectively. HPN217 was also found to be generally well tolerated.

“We are pleased that HPN217 has received FDA fast track designation because it highlights the serious unmet medical need for patients with relapsed/refractory multiple myeloma who received multiple lines of therapy,” Julie Eastland, president and chief executive officer at Harpoon Therapeutics, stated in a press release. “We are focused on selecting an initial dose to study in the expansion phase of the ongoing phase 1/2 clinical trial in the first half of this year as we progress HPN217 forward as an innovative new treatment option for these patients.”

A recombinant polypeptide of 50 kDa, HPN217 is comprised of the following 3 humanized antibody-derived binding domains: BCMA to bind to multiple myeloma cells, albumin to extend half-life, and CD3 for T-cell engagement. The agent was designed to allow for optimal drug exposure in target cancer tissues, extend half-life, and have strong functional stability under physiological conditions.

In vitro and in xenograft models, the drug has been found to mediate potent target tumor cell killing in a BCMA-specific manner, and in the presence of T cells. HPN217 monovalently binds to both CD3 and BCMA, thus minimizing the activation of non-specific T cells.

The trial is comprised of 2 parts: dose-escalation and -expansion. Investigators enrolled those with relapsed/refractory multiple myeloma who received at least 3 prior therapies, including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody.

In the dose-escalation portion of the research, patients were treated in either fixed-dose or step-dose cohorts. As of November 10, 2021, 37 patients received the agent, which was examined at the following weekly doses: 5 µg (n = 1), 15 µg (n = 1), 30 µg (n = 2), 90 µg (n = 1), 270 µg (n = 2), 810 µg (n = 4), 1620 µg (n = 6), 2150 µg (n = 11), and 2860 µg (n = 6).

The highest target doses examined to date included a fixed dose of 2860 µg weekly, and a step dose of 1620 µg weekly as a priming dose followed by 3240 µg weekly as the target dose. Patients were premedicated to manage cytokine release syndrome (CRS).

The key objectives of the trial were to characterize safety, PK, and identify the maximum tolerated dose (MTD) or the recommended phase 2 dose.

Among the 37 patients who received HPN217, the median age at baseline was 71 years (range, 38-78), with a duration of disease of 8 years (range, 1-20). Seventy-six percent of patients previously underwent transplantation and the number of prior systemic therapies received was 7 (range, 2-16).

Patients previously received PIs, such as bortezomib (Velcade; 92%), carfilzomib (Kyprolis; 81%), and ixazomib (Ninlaro; 27%); anti-CD38 antibodies, such as daratumumab (Darzalex; 89%) and isatuximab-irfc (Sarclisa; 27%); IMiDs, such as lenalidomide (Revlimid; 92%), pomalidomide (Pomalyst; 84%), and thalidomide (Thalomid; 30%); and BCMA-targeted therapies, such as belantamab mafodotin-blmf (Blenrep; 16%), SEA-BCMA (5%), bispecific TCE (3%), and CAR T-cell therapy (3%).

The best response achieved to the most recent regimen received was complete response (CR) in 3% of patients, very good partial response (VGPR) in 11%, partial response in 14%, minimal response in 3%, stable disease in 27%, and progressive disease in 32%. This information was missing for 11% of patients.

Data presented during the 2021 ASH Annual Meeting showed that of the 8 disease-evaluable patients who received the weekly dose of 2150 µg, 1 had a stringent CR (sCR), 1 had a VGPR, and 3 experienced PRs; this included 1 patient who previously received a BCMA-targeted agent. Notably, the 2 patients who experienced sCRs were found to have minimal residual disease negativity per next-generation flow cytometry. All patients who responded to HPN217 were still receiving study treatment at the time of the presentation.

PK data showed a dose-proportional increase in Cmax and area under the curve (AUC) was observed, as well as dose-independent clearance and volume of distribution. The median half-life for the agent was found to be 74 hours. Moreover, investigators found evidence of HPN217 accumulation; there was an approximate 1.5- to 2-fold increase in Cmax and AUC, and an approximate 2- to 3-fold increase in Clast.

Pharmacodynamics data revealed on-treatment changes in serum BCMA from baseline to cycle 1 day 15 after 2 doses of HPN217. Moreover, those who received the weekly dose of 2150 µg, who had evaluable baseline and cycle 1 day 15 measurements, all experienced a reduction in sBCMA.

Regarding safety, the most common all-grade toxicities experienced in the 37 patients who received treatment included anemia (46%), fatigue (32%), aspartate aminotransferase (AST) increase (19%), cough (19%), alanine aminotransferase (ALT) increase (16%), epistaxis (16%), headache (16%), arthralgia (16%), nausea (16%), diarrhea (16%), and dyspnea (16%).

Grade 3 or higher effects comprised anemia (38%), AST increase (14%), ALT increase (8%), fatigue (3%), arthralgia (3%), and dyspnea (3%).

One dose-limiting toxicity was reported, and this was grade 4 AST increase, which resolved. The MTD had not yet been reached. Moreover, 22% of patients experienced at least 1 event of transaminitis, and most of these events were reported on day 1 of cycle 1; all events were transient with no clinical sequalae.

Grade 1 or 2 CRS was experienced by 24% of patients, although no grade 3 CRS was reported. One patient who received HPN217 at a weekly dose of 2860 µg was given tocilizumab (Actemra) because of grade 2 CRS experienced on day 1 of cycle 1. Notably, no patients experienced immune effector cell–associated neurotoxicity syndrome with the agent.

Previously, in January 2021, the FDA granted an orphan drug designation to HPN217 for the treatment of patients with multiple myeloma.⁴

References

1. Harpoon Therapeutics receives FDA fast track designation for HPN217. News release. Harpoon Therapeutics, Inc.; March 2, 022. Accessed March 3, 2022. https://bit.ly/3IVr0ex
2. A phase 1/2 open-label, multicenter, dose escalation and dose expansion study of the safety, tolerability, and PK of HPN217 in patients with R/R MM. ClinicalTrials.gov. Updated September 10, 2021. Accessed March 3, 2022. https://clinicaltrials.gov/ct2/show/NCT04184050
3. Madan S, Abdallah A-O, Cowan AJ, et al. An interim report on a phase 1/2 study of HPN217, a half-life extended Tri-specific T Cell Activating Construct (TriTAC®) targeting B Cell Maturation Antigen for the treatment of relapsed/refractory multiple myeloma. Blood. 2021;138(suppl 1):1654. doi:10.1182/blood-2021-148176
4. Harpoon Therapeutics granted orphan drug designation from FDA for HPN217 for treatment of multiple myeloma. News release. Harpoon Therapeutics, Inc. January 13, 2021. Accessed March 3, 2022. http://bit.ly/3i8tFog