FDA Grants Fast Track Status to PRGN-3006 for Relapsed/Refractory AML

The FDA has granted a fast track designation to the multigenic autologous CAR T-cell therapy PRGN-3006 for use as a potential therapeutic option in patients with relapsed or refractory acute myeloid leukemia (AML), according to an announcement from Precigen, Inc.¹

“We are very pleased to receive the FDA’s fast track designation, which facilitates development and expedites the review process of drugs that address serious conditions and high unmet medical needs,” Helen Sabzevari, PhD, president and chief executive officer of Precigen, Inc., stated in a press release. “AML is a rapidly progressing disease with a very poor prognosis. The fast track designation will help facilitate the timely development of this program and we look forward to working more closely with the FDA to potentially bring this new and highly differentiated overnight UltraCAR-T therapy to patients.”

The UltraCAR-T product leverages the company’s non-viral Sleeping Beauty system to express a CAR that specifically targets CD33, which is known to be overexpressed on AML blasts. The therapy also expresses membrane-bound, interleukin-15 (IL-15) for stronger in-vivo expansion and persistence and contains a kill switch that can conditionally eliminate CAR T cells and allow for an improved toxicity profile.

By using an advanced overnight non-viral gene delivery manufacturing process at a medical center’s cGMP facility, without requiring ex vivo expansion, the CAR T platform may be able to overcome existing limitations with other available products. For example, current options are known to have a prolonged interval between apheresis and infusion. Moreover, lengthy ex-vivo expansion with these products is also known to result in an exhausted phenotype of T cells. The T cells for PRGN-3006 are manufactured overnight by leveraging the proprietary UltraPorator system.

PRGN-3006 was evaluated in adult patients with relapsed or recurred AML, high-risk myelodysplastic syndrome (MDS), or chronic myelomonocytic leukemia as part of a first-in-human, dose-escalation and -expansion, phase 1/1b trial (NCT03927261).²

To be eligible for enrollment, patients needed to have a Karnofsky performance status score of 60% or higher and a life expectancy of at least 12 weeks. Those who had undergone an allogeneic hematopoietic stem cell transplant (AHSCT) were permitted if at least 3 months had passed since the procedure, they had relapsed AML/MDS, and were not on treatment or prophylaxis for graft-vs-host disease for at least 6 weeks prior to PRGN-3006 administration.

Patients who had acute promyelocytic leukemia, known central nervous system leukemic involvement, an ongoing uncontrolled serious infection, human immunodeficiency virus seropositivity, or active hepatitis B or C virus, or who previously received a CAR T-cell therapy, were excluded, as were those who required drugs other than hydroxyurea to control blast counts within 2 weeks of enrollment.

Investigators set out to examine the safety of the CAR T-cell product and to identify the maximum tolerated dose administered through intravenous infusion without lymphodepletion (cohort 1) or with lymphodepletion (cohort 2). They also sought to assess in vivo persistence and antitumor activity with the agent.

Data from the trial on 15 patients with relapsed or refractory AML were shared during the 2021 ASH Annual Meeting; of these patients, 9 comprised the non-lymphodepletion cohort and 6 comprised the lymphodepletion cohort.³ Those in the non-lymphodepletion cohort had previously received a median of 4 lines of treatment (range, 1-6); those in the lymphodepletion cohort had a median of 3 lines of therapy (range, 1-7). In these cohorts, 33% and 50% of patients, respectively, had experienced failure with AHSCT.

Within the non-lymphodepletion cohort, a single infusion of the product resulted in strong dose-dependent expansion and persistence in the peripheral blood and bone marrow. Moreover, the UltraCAR-T cells were noted to be in the blood for longer than 7 months after the infusion, underscoring the ability of the cells to engraft and persist, even without lymphodepletion therapy. Between days 7 and 21, peak expansion of the cells was observed.

Three dose levels of PRGN-3006 were evaluated, and 33% of these patients were found to have stable disease in accordance with European LeukemiaNet criteria; these patients continued to have disease stability for at least 3 months. Notably, 1 patient experienced stable disease for longer than 7 months, along with a reduction in peripheral blast levels.

In the lymphodepletion cohort, encouraging dose-dependent expansion and persistence of PRGN-3006 was also noted in the peripheral blood and bone marrow. Here, UltraCAR-T cells were noted in the blood for longer than 3 months following the singular infusion, with peak expansion reported between days 14 and 21.

In this cohort, PRGN-3006 elicited an objective response rate (ORR) of 50%, with those who received the lowest dose levels experiencing a response to treatment. Specifically, those who were given dose level 1 experienced an ORR of 33% (n = 1/3) and 67% (n = 2/3) when given dose level 2. One of the patients who received the product at dose level 1 and responded went on to receive AHSCT and had ongoing survival for more than 1 year.

Regarding safety, no dose-limiting toxicities were reported with PRGN-3006. The product was found to be well tolerated overall, with a low incidence of toxicities following infusion. The adverse effects (AEs) included decreased lymphocyte count, anemia, and cytokine release syndrome (CRS).

Over 70% of the treatment-emergent toxicities experienced with PRGN-3006 were grade 1 or 2 in severity. One patient who was in cohort 1 and received PRGN-3006 at dose level 1 experienced a transient grade 3 AE in the form of CRS, although this resolved in less than 24 hours with the administration of tocilizumab (Actemra) and dexamethasone. Other patients who experienced grade 1 or 2 CRS did not need intervention and their effects resolved with standard management. Notably, no participants were noted to have experienced a significant increase in serum IL-15.

Previously, in January 2020, the FDA granted PRGN-3006 an orphan drug designation for patients with relapsed or refractory AML.⁴

References

1. Precigen receives fast track designation for PRGN-3006 UltraCAR-T in patients with relapsed or refractory acute myeloid leukemia. News release. Precigen, Inc.; April 4, 2022. Accessed April 4, 2022. https://prn.to/3u61xd0
2. PRGN-3006 adoptive cellular therapy for relapsed or refractory AML or high risk MDS. ClinicalTrials.gov. Updated October 19, 2021. Accessed April 4, 2022. https://clinicaltrials.gov/ct2/show/NCT03927261
3. Precigen announces positive interim phase 1 data for PRGN-3006 UltraCAR-T in relapsed or refractory acute myeloid leukemia. News release. Precigen, Inc.; December 13, 2021. Accessed April 4, 2022. https://bit.ly/3KaEhQX
4. Precigen receives FDA orphan drug designation for PRGN-3006 UltraCAR-T in patients with acute myeloid leukemia (AML). News release. Precigen, Inc; January 6, 2020. Accessed April 4, 2022. https://bit.ly/3uVA9O6