REGiMMUNE Corporation has presented clinical data on RGI-2001 Intravenous Infusion for the prevention of acute GVHD in the annual meeting of the American Society of Hematology on December 5 2020.

 

  • Repeat weekly doses of RGI-2001 100 μg/kg IV infusion (30min) in allogeneic bone marrow transplant is safe when given with standard GvHD prophylaxis of tacrolimus/methotrexate for the reduction and prevention of acute GvHD.
  • Plasma levels of KRN7000 were similar in each patient after the first dose and multiple doses. The half-life was approximately 36 hours.
  • No Grade III/IV GVHD has been reported. Of the seven patients, one patient developed stage 3 skin max grade II and another developed stage 1 skin max grade I acute GvHD.
  • 1 patient had mismatched unrelated ablative transplantation and did not develop acute GvHD.
  • RGI-2001 induces NKT cell responses and in turn regulatory T cells. Increases of % of Tregs/CD4+T cells may have potential in prevention of acute GVHD.   This study is active and will continue enrollment (NCT04014790).

 

REGiMMUNE Corporation, a clinical stage biotech company using its reVax technology to induce immune tolerance for cure of immune disorders and transplantation, today provided preliminary Phase 2b clinical trial of NCT04014790 “RGI-2001-003” in a poster presentation at the 62nd annual meeting of the American Society of Hematology (ASH) in San Diego.“RGI-2001-003” is an open-label, multi-center, single-arm study to evaluate six weekly doses of RGI-2001 in combination with standard of care treatment for the prevention of acute graft-vs-host-disease (aGVHD) in subjects following allogenic hematopoietic stem cell transplantation (alloHSCT). The study is conducted in U.S. transplant centers. The study included a safety run-in phase to assess the safety and tolerability of 6 weekly doses of RGI-2001 followed by an expansion phase in which the potential efficacy of 6 weekly doses of RGI-2001 in addition to standard of care for GvHD prophylaxis will be assessed. Comparison will be made to a contemporaneous control group.

The Run-In Phase data presented at ASH showed both safety and PK profile of repeat weekly doses of RGI-2001 (100 mg/kg, IV infusion) in seven subjects who underwent alloHSCT in US transplant centerswith standard GVHD prophylaxis, only one subject reported a grade II GVHD, and immune response of invariant natural killer T cells (iNKTs) and regulatory T cells (Tregs) in peripheral bloods.

 

Below are highlights of the presentation at ASH

Clinical Activity Biomarker Kinetics & aGVHD

  • All subjects were engrafted.
  • Most of subjects had iNKT response and % of Tregs/CD4+T cells increase.
  • No Grade III/IV GVHD has been reported.
  • Of the seven patients, one patient developed stage 3 skin max grade II and another developed stage 1 skin max grade I acute GvHD.
  • 1 patient had mismatched unrelated ablative transplantation and did not develop acute GvHD even without ATG treatment.

 

 

Safety

  • The most common AEs were diarrhea, fatigue, mucositis, rash, nausea, and vomiting.
  • The were no dose limiting toxicities were reported.
  • 2 subjects reported SAE- URI/GVHD of skin,fever/chills/vomiting/diarrhea and none of these were related to RGI-2001

PK

  • Blood samples were collected pre-dose, 0.5, 2, 4, 6, 8, 24, and 48 h after the first dose and pre-dose, 0.5, and 4 h post-dose on Day 14.
  • The concentration of the active ingredient, KRN7000, in plasma for all patients for day 1 and day 14 was assessed.
  • Plasma levels of KRN7000 were similar in each patient after the first dose and multiple doses.
  • Plasma half-life was approximately 36 hours.
  • Repeat weekly infusions of RGI-2001 led to generally similar exposure of the first dose Day 0 and Day 14.

 

“These are very encouraging results. We are happy to see the PK data is suggestive of good plasma concentration. Repeat dosing of RGI-2001 is safe. Notably 1 subject with mismatched unrelated ablative transplant and did not develop GVHD. The study is active in enrollment,” said Yi-Bin Chen, M.D., Associate Professor of Medicine, Harvard Medical School, Director of BMT program in Massachusetts General Hospital Cancer Center transplantation, and a principal investigator of RGI-2001-003 clinical trial.  Regimmune is very excited about the development program of RGI-2001, we will continue to advance our clinical effort in this very important prevention for prevention and reduction of acute GVHD.

 

Trial sites

  • Massachusetts General Hospital

 

About RGI-2001

RGI-2001 is a liposomal formulation of the compound known as RGI-7000.  RGI-7000 is a synthetic glycolipid composed of a galactose and a ceramide moiety linked in an α-configuration, a derivative of α-galactosylceramide (α-GalCer), a glycolipid originally extracted from a marine sponge (Natori 1993). It serves as a ligand for the CD1d molecule, expressed on antigen presenting cells (APC) (Kawano 1997, Brossay 1998). The CD1d molecule is a non-polymorphic, major histocompatibility complex (MHC) class I–like antigen-presenting molecule with an antigen-binding groove adapted for the presentation of lipid antigens (Moody 2005, Brigl 2004). When RGI-7000 is presented by CD1d, it is recognized by an invariant T-cell receptor (iTCR) expressed on invariant natural killer T (iNKT) cells, and activates iNKT cells in a CD1d-restricted manner (Taniguchi 1998). CD1d-restricted iNKT cell activation results in the rapid release of large amounts of both Th1 and Th2 cytokines, a unique property that distinguishes iNKT cells from conventional T cells, and supports their important immunoregulatory role in innate as well as adaptive immunity.　RGI-2001 is anticipated to elicit antigen-specific immune tolerance.

 

Preclinical and Phase 1/2a studies have demonstrated the biological activity of RGI-2001 as follows:

  • RGI-2001 has been shown in vitro to be effectively taken up by B cells.
  • In peripheral blood mononuclear cell (PBMC) and whole blood studies to assess cytokine induction, RGI-2001 at clinically relevant concentrations, did not induce significant levels of pro-inflammatory cytokines in either human PBMCs or whole blood, demonstrating the low potential for inducing cytokines that may play an inciting role in GvHD (e.g., IL-12, IFN-γ or TNF-α).
  • In an acute GvHD model, RGI-2001 induced host-specific tolerance by promoting significant and dose dependent expansion of donor-derived CD4+Foxp3+ Tregs following allogeneic bone marrow and whole spleen cell (WSC) transplantation. The expansion of Tregs was also associated with a significant survival benefit and improvement in clinical signs of GvHD without compromise of GvL effects.
  • Concurrent treatment of normal mice with RGI-2001 and allogeneic donor spleen cells resulted in tolerance specific to the donor alloantigens through expansion of DCreg and Treg cells in a donor-specific transfusion (DST) mouse model.
  • In the GvHD efficacy studies a highly significant survival benefit was seen in mice treated with single injections of RGI-2001 at doses as low as 0.1 μg/kg. A dose-dependent donor derived CD4+Foxp3+Treg expansion was observed at doses ranging from 0.01 to 100 μg/kg. The survival benefit in these models reached significance at approximately 0.1 ug/kg. Thus, the minimum pharmacologically active dose (PAD) in the mouse GvHD model was defined as 0.1 μg/kg based on both survival and Treg expansion.
  • The first in human (FIH) study of RGI-2001 was a Phase 1/2a multicenter, open-label, dose escalation study whose primary objective was to evaluate the safety, tolerability, and pharmacokinetic profile of a single dose of RGI-2001 in subjects undergoing alloHSCT, with radiation or non-radiation containing myeloablative or reduced intensity preparative treatments based on institutional practices. GvHD prophylaxis consisted of a calcineurin inhibitor and one of the following (based on institutional practices): methotrexate, mycophenolate mofetil, or sirolimus. The study was divided into 2 parts: Part 1 was the dose-escalation phase and Part 2 was the dose-Expansion Phase. Eligible subjects were enrolled at 7 centers. A total of 68 subjects, 57 RGI-2001 treated subjects as well at 11 control subjects participated in the study.
  • In Part 1 of the study, a total of 28 subjects with a variety of hematologic diseases received a single dose of RGI-2001, administered approximately 30 minutes after allogeneic HSCT with an unrelated peripheral blood or bone marrow donor graft. The dose ranged from 0.001 ug/kg to 100 ug/kg. Based on the results of the Part 1 study, 2 doses, were selected to further study in the Part 2 for the dose-expansion.  100 μg/kg was the maximal administered dose that had no significant toxicity and had some signal of effect. A dose 2 logs lower (at 1 μg/kg) was chosen to evaluate the potential dose response between the 1 μg/kg and 100 μg/kg doses in an effort to see a dose response in Part 2 of the study.
  • In the Part 2 dose-Expansion Phase of the study, 29 subjects receiving matched related or unrelated donor grafts were randomized to receive a single infusion of either 1.0 ug/kg or 100 ug/kg RGI-2001 administered approximately 30 minutes after allogeneic HCT. Fourteen subjects received a dose of 1.0 ug/kg and 15 subjects received a dose of 100 ug/kg of RGI-2001. An additional 11 subjects were enrolled as control subjects. A subset of subjects comprised of 4 subjects from each cohort, (8 of 29, 28%) responded to RGI-2001 by inducing a markedly increased number of cells with a Treg phenotype. The Treg had a high Ki-67 index and were almost exclusively Helios+ and Foxp3+, indicating that their accumulation was due to expansion of natural Tregs. Notably, the incidence of grade 2 to 4 GvHD in the 8 subjects who responded to RGI-2001 was 12.5%, compared with 52.4% in the 21 subjects who did not respond. No grade 3 or 4 GvHD was observed in the responder group, compared with a 9.5% incidence among nonresponders (Chen 2017).
  • The expansion of Treg cells was observed through Day 22 relative to the control group. Treg increases appeared to be inversely related to the severity of GvHD. There was no impact on myeloid or platelet engraftment noted.
  • In general, the mean Cmax was increased as the dose of RGI-2001 increased. For most cohorts and for the subjects who received either the 1 μg/kg or 100 μg/kg dose of RGI-2001 in Part 2, the median times to Tmax were between 0.5 and 0.7 hours.
  • RGI-2001 was well tolerated and without infusion reactions or cytokine release syndrome up to a dose level of 100 μg/kg administered as a single intravenous infusion in subjects who underwent allogeneic transplantation. There were no notable adverse effects across a variety of conditioning regimens and regimens for GvHD prophylaxis.
  • This study served as the proof of concept for further exploring the potential of RGI-2001 for repeat administration to reduce or prevent GvHD during the critical phase post-transplantation.

 

Orphan Drug Designation

The U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation to liposomal a-galactosylceramide (RGI-2001) for “prevention of graft versus host disease (GVHD)” on September 28, 2012.

 

Future plan

Since a dose/schedule has been determined by a safety review committee (SRC) to have acceptable safety/PH profile, enrollment will continue in the Expansion Phase and be extended to all sites. Accrual is targeted at 44 subjects who will receive open-label RGI-2001 at a dose of 100μg/kg, via 30-minute intravenous (IV) infusion on a weekly basis for 6 doses in addition to a SOC GvHD prophylactic regimen. The first dose will be administered on Day 0 at least 30 minutes after HSCT infusion. Subsequent doses will be administered weekly, on Days 7, 14, 21, 28 and 35.

 

For more information, please contact us: info@regimmune.com.