ALA sonodynamic therapy / INSIGHTEC, SonALAsense, Ivy Brain Tumor Center - LARVOL DELTA

Human CNS Tissue Effects in 5-ALA Sonodynamic Therapy (EANO 2026) - P1 | "Following intravenous 5-ALA (SONALA-001), tumor cells accumulate the sonosensitizer protoporphyrin IX (PpIX)... This first-in-human study establishes that 5-ALA SDT is safe from 200 to 800J and likely induces measurable, tumor-selective oxidative stress and apoptosis in human CNS tissue without evidence of normal brain injury. The presence of modest oxidative stress response in enhancing tumor tissue but not in the nonenhancing regions suggest that at 10 mg/kg dose, 5-ALA achieves cytotoxic PPIX levels only within the enhancing region. Any sonodynamic regimen intended to treat infiltrative glioma must therefore overcome this exposure limit."

First-in-human • Brain Cancer • Glioma • High Grade Glioma • Oncology • Solid Tumor • CASP3 • IDH1

Sonodynamic Therapy With SONALA-001 or 5-ALA HCL and Magnetic Resonance Guided Focused Ultrasound for the Treatment of Progressive or Recurrent Glioblastoma (clinicaltrials.gov) - P1 | N=8 | Recruiting | Sponsor: Mayo Clinic | Trial completion date: Dec 2026 ➔ Dec 2031 | Trial primary completion date: Dec 2026 ➔ Dec 2028

Trial completion date • Trial primary completion date • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Safety, feasibility and preliminary efficacy of the first-in-child phase 1/2 study of escalating dose sonodynamic therapy (SDT) using SONALA-001, an intravenous aminolevulinic acid (ALA) together with magnetic resonance imaging guided low-intensity focused ultrasound (MRgFUS) in pediatric patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG) (ISPNO 2026) - P2 | "SDT with SONALA-001 and MRgFUS is a novel and well-tolerated approach for patients with DIPG following initial radiotherapy with a promising early efficacy signal that warrants further invesigation to more fully evaluate potential therapeutic efficacy."

Clinical • MRI • P1/2 data • Brain Cancer • CNS Disorders • Diffuse Intrinsic Pontine Glioma • Glioma • Hematological Disorders • Pediatrics • Solid Tumor

Study of Sonodynamic Therapy in Participants With Recurrent High-Grade Glioma (clinicaltrials.gov) - P1 | N=10 | Terminated | Sponsor: Nader Sanai | N=30 ➔ 10 | Recruiting ➔ Terminated; Study terminated due to unavailability of the investigational product required to continue the study.

Enrollment change • First-in-human • Trial termination • Brain Cancer • Glioma • High Grade Glioma • Oncology • Solid Tumor

The heme pathway: A possible metabolic target for the treatment of hematologic cancers (ASH 2025) - "The drug, 5-aminolevulinic acid (5-ALA, SONALA-001), is the first committed intermediate in the heme biosynthetic pathway while the device provides low-intensity focused ultrasound...This would allow us to treat circulating blood in situ noninvasively and would also have the potential to treat bone marrow infiltrated with malignant cells.This research was, in part, funded by the Advanced Research Projects Agency for Health (ARPA-H). The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the United States Government."

Actinic Keratosis • Bladder Cancer • Bone Marrow Transplantation • Chronic Lymphocytic Leukemia • Dermatology • Genito-urinary Cancer • Hematological Malignancies • Leukemia • Multiple Myeloma • Myelodysplastic Syndrome • Oncology • Solid Tumor • T Acute Lymphoblastic Leukemia • PTPRC

An early clinical trial of 5-ALA sonodynamic therapy in recurrent high-grade glioma. (PubMed, Sci Transl Med) - P1 | "In this first-in-human, open-label, early clinical study (NCT04559685), safety and biological efficacy of ascending doses of MRgFUS combined with intravenous administration of 5-ALA (SONALA-001) were assessed in nine patients with recurrent high-grade glioma...This early phase clinical trial demonstrates proof of principle for 5-ALA SDT as a therapeutic modality for glioma. Further research is needed to optimize treatment parameters for clinical efficacy and to explore the potential of 5-ALA SDT in other types of cancer."

Clinical • Journal • Brain Cancer • Glioma • High Grade Glioma • Oncology • Solid Tumor

A clinical update of a first-in-human phase 0/1 trial of 5-aminolevulinic acid sonodynamic therapy (5-ALA SDT) in recurrent glioblastoma. (EANO 2025) - " In the dose escalation arm of this study, six hours prior to SDT, adult patients with recurrent GBM were administered 10mg/kg of an IV formulation of 5-ALA (SONALA-001)... This first-in-human Phase 0/1 study of a new therapeutic modality for recurrent glioblastoma patients demonstrates that 5-ALA SDT is safe at 200 to 800J and likely induces targeted cell death in GBM patients via oxidative stress. Ongoing enrollment in Arms B-E will evaluate the effect of higher dose of 5-ALA and MRgFUS parameters to obtain maximal tumor cell death and evaluate clinical efficacy."

Clinical • First-in-human • P1 data • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • CASP3 • IDH1

Sonodynamic Therapy With SONALA-001 and Magnetic Resonance Guided Focused Ultrasound for the Treatment of Progressive or Recurrent Glioblastoma (clinicaltrials.gov) - P1 | N=8 | Recruiting | Sponsor: Mayo Clinic | Not yet recruiting ➔ Recruiting

Enrollment open • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Sonodynamic Therapy With SONALA-001 and Magnetic Resonance Guided Focused Ultrasound for the Treatment of Progressive or Recurrent Glioblastoma (clinicaltrials.gov) - P1 | N=8 | Not yet recruiting | Sponsor: Mayo Clinic

New P1 trial • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Study of Sonodynamic Therapy in Participants with Recurrent High-Grade Glioma (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: Nader Sanai | Trial completion date: Dec 2025 ➔ Mar 2028 | Trial primary completion date: Jun 2025 ➔ Mar 2026

Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Glioma • Malignant Glioma • Oncology • Solid Tumor

Study of Sonodynamic Therapy in Participants with Recurrent High-Grade Glioma (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: Nader Sanai | Trial completion date: Mar 2025 ➔ Dec 2025 | Trial primary completion date: Dec 2024 ➔ Jun 2025

Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Glioma • Malignant Glioma • Oncology • Solid Tumor • CASP3

Sonodynamic therapy (SDT) using intravenous 5-aminolevulinic acid with non-ablative focused ultrasound for the treatment of diffuse intrinsic pontine gliomas in pediatrics: initial safety and outcomes the multicenter SDT-201 trial (SNO 2024) - P2 | "MRgFUS was combined with the prodrug SONALA-001 (5-ALA iv) to activate its metabolite, protoporphyrin IX, and thereby induce apoptosis within tumor cells...Preliminary analysis of twelve pediatric patients treated with SDT for DIPG demonstrates acceptable safety outcomes and promising clinical results. Additional patient enrollment and longer follow-up times are required to determine efficacy."

Clinical • Brain Cancer • CNS Disorders • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Pediatrics • Solid Tumor

A Phase 1/2 dose escalation and expansion study of sonodynamic therapy with SONALA-001 in combination with non-ablative MR-guided focused ultrasound in subjects with progressive or recurrent glioblastoma (SNO 2024) - No abstract available

Clinical • Combination therapy • P1/2 data • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

A Phase 2 Study of Sonodynamic Therapy Using SONALA-001 and Exablate 4000 Type 2.0 in Patients with DIPG (clinicaltrials.gov) - P2 | N=15 | Suspended | Sponsor: SonALAsense, Inc. | Trial completion date: Jul 2024 ➔ Oct 2024 | Terminated ➔ Suspended

Combination therapy • Trial completion date • Trial suspension • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor

A Phase 2 Study of Sonodynamic Therapy Using SONALA-001 and Exablate 4000 Type 2.0 in Patients With DIPG (clinicaltrials.gov) - P2 | N=15 | Terminated | Sponsor: SonALAsense, Inc. | N=40 ➔ 15 | Trial completion date: Aug 2025 ➔ Jul 2024 | Active, not recruiting ➔ Terminated; The study is terminated due to lack of funding but not due to safety concerns.

Combination therapy • Enrollment change • Trial completion date • Trial termination • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor

A Study of Sonodynamic Therapy Using SONALA-001 and Exablate 4000 Type 2.0 in Subjects With Recurrent GBM (clinicaltrials.gov) - P1/2 | N=8 | Terminated | Sponsor: SonALAsense, Inc. | Trial completion date: Nov 2026 ➔ Jul 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: Apr 2026 ➔ Jun 2024; Study is terminated due to funding challenges and not due to safety concerns.

Combination therapy • Trial completion date • Trial primary completion date • Trial termination • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

A Phase 2 Study of Sonodynamic Therapy Using SONALA-001 and Exablate 4000 Type 2.0 in Patients With DIPG (clinicaltrials.gov) - P2 | N=40 | Active, not recruiting | Sponsor: SonALAsense, Inc. | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor

Interim clinical, pharmacokinetic, and technical report of a phase 2 study of sonodynamic therapy (SDT) using SONALA-001 together with MR-guided low-intensity focused ultrasound (MRgFUS) in children with diffuse intrinsic pontine glioma (DIPG) (ISPNO 2024) - P2 | "SDT is an innovative and to-date well-tolerated strategy for children with DIPG post-initial radiotherapy. Sonications did not result in any adverse procedural effects. SONALA-001 exhibits rapid distribution and clearance, while PpIX PK align with metabolite formation."

Clinical • P2 data • PK/PD data • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Pediatrics • Solid Tumor

A phase 1/2 dose escalation and expansion study of sonodynamic therapy with SONALA-001 in combination with Exablate 4000 Type 2.0 MR-guided focused ultrasound in patients with progressive or recurrent glioblastoma (rGBM). (ASCO 2024) - P1, P1/2 | "Endpoints of this study are safety evaluation, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and determination of pharmacokinetic (PK) parameters. The Phase 2 portion will further characterize safety of RP2D along with evaluation of efficacy with PFS6 (mRANO), ORR, CBR, DOR, DOCR, TTR, and OS."

Clinical • Combination therapy • P1/2 data • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Interim report of a phase 2 study of sonodynamic therapy (SDT) using SONALA-001 together with MR-guided low-intensity focused ultrasound (MRgFUS) in children with diffuse intrinsic pontine glioma (DIPG). (ASCO 2024) - P2 | "SDT is a well-tolerated strategy for patients with DIPG after initial radiotherapy. SONALA-001 shows rapid distribution and clearance, and PpIX PK align with metabolite formation. Following dose escalation completion, dose-expansion will be initiated at RP2D offering further insights into safety, PK, and efficacy."

Clinical • P2 data • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Solid Tumor

Study of Sonodynamic Therapy in Participants With Recurrent High-Grade Glioma (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: Nader Sanai | Trial completion date: Mar 2024 ➔ Mar 2025 | Trial primary completion date: Dec 2023 ➔ Dec 2024

Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • CASP3

Theranostic Uses of the Heme Pathway in Neuro-Oncology: Protoporphyrin IX (PpIX) and Its Journey from Photodynamic Therapy (PDT) through Photodynamic Diagnosis (PDD) to Sonodynamic Therapy (SDT). (PubMed, Cancers (Basel)) - "This review describes the creation and evolution of ALA PDT, from the treatment of skin cancers to PDD and PDT of malignant brain tumors and, most recently, into a noninvasive form of PDT, ALA SDT. Current clinical trials of ALA SDT for recurrent glioblastoma and high-grade gliomas in adults, and the first pediatric ALA SDT clinical trial for a lethal brainstem cancer, diffuse intrinsic pontine glioma (DIPG), are also described."

Journal • Review • Bladder Cancer • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Genetic Disorders • Glioblastoma • Glioma • Oncology • Pediatrics • Skin Cancer • Solid Tumor

A Phase 2 Study of Sonodynamic Therapy Using SONALA-001 and Exablate 4000 Type 2.0 in Patients With DIPG (clinicaltrials.gov) - P2 | N=40 | Recruiting | Sponsor: SonALAsense, Inc. | Phase classification: P1/2 ➔ P2

Combination therapy • Phase classification • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor

A Study of Sonodynamic Therapy Using SONALA-001 and Exablate 4000 Type 2.0 in Subjects With Recurrent GBM (clinicaltrials.gov) - P1/2 | N=8 | Active, not recruiting | Sponsor: SonALAsense, Inc. | Recruiting ➔ Active, not recruiting | N=44 ➔ 8

Combination therapy • Enrollment change • Enrollment closed • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

SonALAsense Presents Preliminary Data From Clinical Study in Patients With Deadly Pediatric Brain Tumor (Businesswire) - P1/2 | N=27 | NCT05123534 | Sponsor: SonALAsense, Inc. | "SonALAsense...announced the presentation of positive preliminary data from the ongoing Phase 1/2 SDT-201 study in Diffuse Intrinsic Pontine Glioma (DIPG). These results were presented at the November 2023 Society for Neuro-Oncology (SNO) Annual Meeting in Vancouver, Canada. The preliminary data from Study SDT-201 shows signals of clinical activity and no safety concerns....Initial clinical activity observed in the first 5 patients showed partial responses of at least 25% reduction in tumor size in 2 (40%) patients through eight weeks post treatment and stable disease in 2 (40%) patients. Four patients treated have exceeded the median survival of 9-11 months post diagnosis. Patients treated have also maintained or improved their patient performance status."

P1/2 data • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioblastoma • Glioma • Oncology • Solid Tumor