eRapa (encapsulated rapamycin) / Emtora Biosci, Biodexa Pharma - LARVOL DELTA

Biodexa Receives Orphan Drug Designation in Europe for eRapa in FAP (GlobeNewswire) - "Biodexa Pharmaceuticals PLC...announced the European Commission (EC) has granted Orphan Drug Designation for eRapa in familial adenomatous polyposis (FAP), a largely inherited precancerous disease of the colon for which there is currently no pharmaceutical intervention....The Phase 3 study of eRapa in FAP is in the final stages of implementation. It will be a double-blind placebo-controlled trial in 168 patients, randomized 2:1 drug / placebo. It is expected the study will be conducted in approximately 30 clinical sites across the US and Europe."

Orphan drug • Trial status • Rare Diseases

Phase 3 Trial of eRapa in Patients With Familial Adenomatous Polyposis (clinicaltrials.gov) - P3 | N=168 | Not yet recruiting | Sponsor: Rapamycin Holdings Inc.

New P3 trial • Genetic Disorders

Exosomal delivery of rapamycin modulates blood-brain barrier penetration and VEGF axis in glioblastoma. (PubMed, J Control Release) - "In this study, we utilized an exosome-encapsulated rapamycin (Exo-Rapa) delivery strategy, which permits the use of smaller drug dosages to achieve effects typically seen with higher dosages, thus enhancing drug efficacy. Additionally, a series of in vivo experiments have further demonstrated the permeability of Exo-Rapa across the BBB, enabling it to accumulate at tumor sites; it also ameliorates inflammatory responses in Glioblastoma multiforme (GBM) mouse models and enhances anti-tumor activity through the regulation of angiogenesis via the VEGF/VEGFRs axis. Our results indicate that MSC-derived exosomes are a potent therapeutic carrier for GBM, offering an effective strategy for enhancing drug delivery across the BBB and providing a scientific foundation for the use of exosomes in the treatment of GBM and other diseases."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Biodexa Announces Successful Outcome of a Type C Meeting with FDA Regarding the Phase 3 Program for eRapa in FAP (GlobeNewswire) - "Biodexa Announces Successful Outcome of a Type C Meeting with FDA Regarding the Phase 3 Program for eRapa in FAP; Clears the way to finalize Phase 3 protocol and recruit sites for U.S; Phase 3 substantially funded by $17.0 million CPRIT grant and $8.5 million Company match."

Commercial • FDA event • New P3 trial • Rare Diseases

Biodexa Announces Appointment of Precision for Medicine LLC as CRO for European Component of Phase 3 Study of eRapa in FAP (GlobeNewswire) - "Biodexa Pharmaceuticals PLC...today announced the appointment of Precision for Medicine, LLC ('Precision') as the clinical research organization ('CRO') to conduct the European component of the upcoming registrational Phase 3 study of eRapa in FAP. The U.S. component of the study will be conducted by LumaBridge, based in San Antonio, Texas....The planned registrational Phase 3 study of eRapa in FAP will be a double-blind placebo-controlled trial in 168 patients, randomized 2:1 drug / placebo. It is expected the study will be conducted in approximately 30 clinical sites across the US and Europe."

Commercial • New P3 trial • Rare Diseases

Biodexa Announces Allowance of U.S. Patent Covering Oral Rapamycin Nanoparticle Preparations ('eRapa') and Use (GlobeNewswire) - "Biodexa plans to initiate a Phase 3 registrational study of eRapa in Familial Adenomatous Polyposis (FAP) next quarter...Biodexa Pharmaceuticals PLC...today announced that the U.S. Patent and Trademark Office allowed has U.S. patent application No. 17/391.495 titled 'Oral Rapamycin Nanoparticle Preparations and Use' which was exclusively licensed to Biodexa by Rapamycin Holdings, Inc. d/b/a Emtora Biosciences, along with other patents, in a transaction which closed in April 2024. The patent is due to issue on March 4, 2025 and, in the absence of any patent term extensions, is expected to expire in March, 2034."

New P3 trial • Patent • Colonic Polyps • Rare Diseases

Rapamycin Reduces Noise-Induced Vestibular Loss and Improves Walking Speed in Noise Exposed Rats (ARO 2025) - "A commercially prepared pelleted chow diet containing encapsulated rapamycin or vehicle was given to rats at a dose of approximately 42 mg/kg body weight per day... These results demonstrate a protective effect on the vestibular periphery and a significant improvement in walking speed, both shortly after noise exposure and for months after discontinuation of the rapamycin diet. Taken together, these results demonstrate a measurable effect of rapamycin that may have long-term benefits for mobility and vestibular function that can be observed at the cellular level."

Preclinical • Otorhinolaryngology • mTOR

Biodexa Receives US FDA Fast Track Designation for eRapa in Familial Adenomatous Polyposis (GlobeNewswire) - "Biodexa Pharmaceuticals PLC...announced today that the US Food and Drug Administration ('FDA') has granted Fast Track designation for eRapa, a proprietary encapsulated form of rapamycin being developed for the treatment of familial adenomatous polyposis (FAP)...Today, the only treatment option is surgical resection of the colon and/or rectum. Data from the Phase 2 study of eRapa in FAP showed eRapa to be safe and well-tolerated with a median 17% reduction in total polyp burden at 12 months compared with baseline and an overall 75% non-progression rate."

Fast track • Rare Diseases

Trial of ERapa to Prevent Progression in Familial Adenomatous Polyposis Patients Under Active Surveillance (clinicaltrials.gov) - P2 | N=30 | Active, not recruiting | Sponsor: Rapamycin Holdings Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • APC

Rapamycin Reduces Carcinogenesis and Enhances Survival in Mice when Administered after Nonlethal Total-Body Irradiation. (PubMed, Radiat Res) - "Immediately after TBI, along with untreated control groups, animals were placed on chow containing different concentrations of encapsulated rapamycin (14, 40, 140 mg/kg chow). Further, there was a survival advantage when delaying the rapamycin chow by 1 month after TBI. Rapamycin is FDA-approved for human use and could be considered for use in individuals exposed to nonlethal TBI from a nuclear accident or attack or after significant therapeutic doses for cancer treatment."

Journal • Preclinical • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

Trial of eRapa to Prevent Progression in Familial Adenomatous Polyposis Patients Under Active Surveillance (clinicaltrials.gov) - P2 | N=30 | Recruiting | Sponsor: Rapamycin Holdings, Inc. dba Emtora Biosciences | Active, not recruiting ➔ Recruiting | Phase classification: P2a ➔ P2 | Trial completion date: Feb 2023 ➔ Mar 2025 | Trial primary completion date: Feb 2023 ➔ Mar 2025

Enrollment open • Phase classification • Trial completion date • Trial primary completion date • Genetic Disorders • APC

Successful mixed hematopoietic chimerism by Bcl- Inhibition and rapamycin encapsulating nanoparticles (ImmTOR) without chemotherapy or total body irradiation in nonhuman primates (TTS 2024) - "To completely eliminate the requirement of TBI or chemotherapy, we hypothesized that if allogeneic hematopoietic stem cells could be better protected from innate and adaptive inflammatory responses, allogeneic stem cells would more effectively engraft, even in the limited space created by Venetoclax...Conversely, this effect was not observer in cells treated with free rapamycin, possibly indicating the preferential uptake of antigen presenting cells and modified mechanism of action of nanoparticle encapsulated rapamycin (fig... Hematopoietic chimerism was induced by the combination of Bcl-2i and ImmTOR nanoparticles, for the first time without TBI or chemotherapy. The nanoparticles may target the antigen presenting cell preferentially and exercises the immunosuppression selectively. Immunological tolerance appears to have been achieved in one animal, but further optimization of this protocol is needed for consistent tolerance induction."

IO biomarker • Bone Marrow Transplantation • Inflammation • CD14 • CD40LG • PD-L1

PHASE IIA TRIAL OF ENCAPSULATED RAPAMYCIN (ERAPA) IN PATIENTS WITH FAMILIAL ADENOMATOUS POLYPOSIS TO REDUCE INTESTINAL POLYP BURDEN: 6 MONTH INTERIM RESULTS (DDW 2024) - "eRapa appears safe and well-tolerated in FAP. A 24% reduction in overall polyp burden was observed. Patients in Cohort 1 (0.5 mg every other day) demonstrated greatest reduction in polyp burden (32%) with fewest related AEs."

Clinical • P2a data • Colorectal Cancer • Gastrointestinal Disorder • Genetic Disorders

Nanoliposomes Encapsulated Rapamycin/Resveratrol to Induce Apoptosis and Ferroptosis for Enhanced Colorectal Cancer Therapy. (PubMed, J Pharm Sci) - "Coloading Rapa and Res into liposomes to promote apoptosis and ferroptosis in tumor cells represents a promising strategy for the treatment of colorectal cancer."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • GPX4 • SLC7A11

Subconjunctival liposomal sirolimus vs. cyclosporine or tacrolimus as treatment of keratoconjunctivitis sicca in dogs: A double-blind, randomized study. (PubMed, Vet Ophthalmol) - "In this trial, a 1 mg/mL (100 micrograms) SCJS every 2 weeks showed similar safety and efficacy profiles as daily CsA/T in dogs with KS after 14 weeks of treatment. Larger studies should be performed to further assess SCJS as an alternative treatment for KCS."

Journal • Conjunctivitis • Dry Eye Disease • Ocular Infections • Ocular Inflammation • Ophthalmology • Sjogren's Syndrome

Modulation of immunosuppressive effect of rapamycin via microfluidic encapsulation within PEG-PLGA nanoparticles. (PubMed, J Biomater Appl) - "The encapsulated rapamycin could be gradually released from three nanoparticles for more than 1 month without any noticeable burst release...Rapa&P-50 k nanoparticles could be the optimal choice for rapamycin delivery as it also achieved the most effective immunosuppressive property. Hence, this study could provide an efficient technology with superior manipulation to offer a solution for rapamycin delivery and clinical application."

IO biomarker • Journal • CD40 • CD80 • IL12A • IL1B • TGFB1

A Modular Intracellular Hierarchical-Responsive Nanocarrier Enables Dual Targeting for High Therapeutic Efficacy in Kidney Diseases (KIDNEY WEEK 2023) - "To treat acute kidney injury, the nanocarriers encapsulated rapamycin and dexamethasone acetate; for PAN, the drugs were rapamycin and captopril; and for the ccRCC model, gefitinib and glutathione were chosen as the targeted antitumor drugs. The dual-drug delivery system can flexibly adapt to treating various diseases by modifying the particle size, surface antibodies, and drugs."

Clinical • Acute Kidney Injury • Clear Cell Renal Cell Carcinoma • Nephrology • Oncology • Renal Disease

Subconjunctival Sirolimus-Loaded Liposomes for the Treatment of Moderate-to-Severe Dry Eye Disease. (PubMed, Clin Ophthalmol) - "The treatment group received three doses of subconjunctival liposome-encapsulated sirolimus and the sham group received three doses of liposomal suspension without sirolimus. Our findings suggest that sub-conjunctival sirolimus-loaded liposomes are effective in reducing both signs and symptoms of dry eye in patients with poorly controlled moderate-to-severe DED, while avoiding other topical administration adverse effects. Further investigation with a larger sample size is required to determine long-term effects."

Clinical • Dry Eye Disease • Ophthalmology • MMP9

Successful Induction of Mixed Chimerism by Bcl-2 Inhibition and Tolerogenic Rapamycin Encapsulating Nanoparticles (ImmTor) without Chemotherapy or Total Body Irradiation in Nonhuman Primates (ATC 2023) - "We previously showed a selective Bcl-2 inhibitor, Venetoclax (Bcl-2i) promoted mixed chimerism induction and renal allograft tolerance but low dose TBI was still required. ImmTOR nanoparticles of encapsulated rapamycin have been demonstrated to mitigate anti-drug antibody formation when used with biologic therapies and exhibit a donor-specific tolerogenic effect... Hematopoietic chimerism was consistently induced by the combination of Bcl-2i and ImmTOR nanoparticles without requirement of TBI. Although optimal dose of ImmTOR and requirement of other treatments remain to be defined, Bcl-2i/ImmTOR is promising approach to induce allograft tolerance via mixed chimerism."

Hematological Disorders • Transplantation • CD40LG

The reiMMAgine Study: Evaluation of the Safety, Tolerability, and Pharmacodynamics of AAV8 Gene Therapy (MMA-101) in Combination with an Immunotolerance-Inducing Nanoparticle (ImmTOR) in MUT Subtype Isolated Methylmalonic Acidemia (MMA) (ASGCT 2023) - "The study is an open-label, single dose level, single center (NIH) study of MMA-101 plus the immunomodulatory drug ImmTOR, which is nano encapsulated sirolimus. The endpoints include: 1) Safety and tolerability; 2) Pharmacodynamic response to MMA-101 assessed by reduction sMMA and an increase in the 1-13C -sodium propionate oxidation breath test; 3) Formation of AAV8 neutralizing antibodies (NAb); 4) clinical parameters including hospitalizations, metabolic crises, growth, diet, and subject-/caregiver-reported outcomes. In summary, this first-in-human clinical trial will establish the safety and efficacy of a liver-directed AAV8 gene therapy to treat subjects with mut0 MMA and assess the ability of the novel immunomodulatory drug ImmTOR to induce immune tolerance to the AAV8 vector."

Clinical • Combination therapy • Gene therapy • PK/PD data • Gene Therapies • Genetic Disorders • Hepatology • Immune Modulation • Liver Failure • Metabolic Disorders • Ophthalmology • Transplantation • APOE

Trial of eRapa to Prevent Progression in Familial Adenomatous Polyposis Patients Under Active Surveillance (clinicaltrials.gov) - P2a | N=30 | Active, not recruiting | Sponsor: Rapamycin Holdings, Inc. dba Emtora Biosciences | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • APC

Anti-coagulation and anti-hyperplasia coating for retrievable vena cava filters by electrospraying and their performance in vivo. (PubMed, Int J Pharm) - "The in vitro drug release pattern showed that the encapsulated rapamycin in the coating can be sustainably released within one month, whereas activated partial thromboplastin time (APTT) and in vitro cell culture showed that the drug eluting RVCF can effectively extend blood clotting time and inhibit smooth muscle cell (SMC) and endothelial cell (EC) proliferation, respectively...The results demonstrated that the as-prepared RVCF possessed excellent antihyperplasia properties in vivo, significantly improving the retrieval rate and extending the in vivo dwelling time in sheep. Consequently, the drug eluting RVCF has promising potential for application in the clinic to improve RVCF retrieval rates."

Journal • Preclinical • Thrombosis

[VIRTUAL] Dose finding study of AAVLSPMMUT in a mouse model of MMA and efficient suppression of anticapsid antibody responses by single and multiple administrations of ImmTOR nanoparticles (ESGCT 2021) - "ImmTOR, nanoparticleencapsulated rapamycin, combined with 1E13 vg/kg of MMA101 reduced anticapsid IgG antibody responses. Repeated administration of ImmTOR provided more durable suppression of antibodies against AAV capsid. Monthly dosing of ImmTOR has been shown to be well tolerated and effective in mitigating immunogenicity of a fungalderived uricase therapy in Phase 2 clinical trials in gout patients and is currently in Phase 3 clinical testing."

Preclinical • Genetic Disorders • Gout • Inflammatory Arthritis • Metabolic Disorders • Ophthalmology • Rheumatology

[VIRTUAL] Immune Suppression with Rapamycin May Cause Prolonged IgM Formation against AAV Vector (ASGCT 2021) - "Immune suppressive drugs such as rapamycin and cyclosporine has long been utilized to mitigate immune responses in transplantation. We sought to identify alternative nanoparticle formulations for co-delivery of lower doses of rapamycin that could effectively prevent NAb formation against AAV in liver gene transfer. We tested three nanoparticle-encapsulated rapamycin formulations (NP1-Rapa, NP2-Rapa, and NP3-Rapa) along with free rapamycin as control to prevent anti-AAV antibody formation and allow for successful AAV vector re-administration. An AAV8 vector expressing chicken ovalbumin (ova) was intravenously injected to 8-weeks old male BL/6J mice (n=6 per group) at the vector dose of 1x1011 vg per mouse on Day 0 with or without the three different NPs formulated with 50 or 200 ug of rapamycin."

Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases • Transplantation

Trial of eRapa to Prevent Progression in Familial Adenomatous Polyposis Patients Under Active Surveillance (clinicaltrials.gov) - P2a; N=30; Not yet recruiting; Sponsor: Rapamycin Holdings, Inc. dba Emtora Biosciences; Initiation date: Feb 2020 ➔ May 2020

Clinical • Trial initiation date • Genetic Disorders • APC