Plus Therapeutics Stock

Plus Therapeutics, Inc. (Plus Therapeutics) is a U.S. pharmaceutical company developing targeted radiotherapeutics with advanced platform technologies for central nervous system ('CNS') cancers.

The company's novel radioactive drug formulations and therapeutic candidates are designed to deliver safe and effective doses of radiation to tumors. To achieve this, the company has developed innovative approaches to drug formulation, including encapsulating radionuclides, such as Rhenium isotopes with nanoliposomes and microspheres. The company's formulations are intended to achieve elevated patient absorbed radiation doses and extend retention times such that the clearance of the isotope occurs after significant and essentially complete radiation decay, which will contribute and provide less normal tissue/organ exposure and improved safety margins.

The company's targeted radiotherapeutic platform and unique investigational drugs have the potential to overcome these disadvantages by directing higher, more powerful radiation doses at the tumor-and only the tumor-potentially in a single treatment. By minimizing radiation exposure to healthy tissues while simultaneously maximizing locoregional delivery and, thereby, efficacy, the company intends to reduce the radiation toxicity for patients, improving their quality of life and life expectancy. The company's radiotherapeutic platform, combined with advances in surgery, nuclear medicine, interventional radiology, and radiation oncology, affords the company the opportunity to target a broad variety of cancer types.

The company's lead radiotherapeutic candidate, rhenium (186Re) obisbemeda (formerly, '186RNL'), is designed specifically to CNS cancers, including recurrent glioblastoma ('GBM'), leptomeningeal metastases ('LM'), and pediatric brain cancers ('PBC') by direct localized delivery utilizing approved standard-of-care tissue access, such as with convection-enhanced delivery ('CED') and intraventricular brain(Ommaya reservoir) catheters. The company's recently acquired radiotherapeutic candidate, Rhenium-188 NanoLiposome Biodegradable Alginate Microsphere ('188RNL-BAM') is designed to treat many solid organ cancers, including primary and secondary liver cancers by intra-arterial injection.

The company's headquarters and manufacturing facilities are in Texas and are in proximity to world-class cancer institutions and researchers. The company's dedicated team of engineers, physicians, scientists, and other professionals are committed to advancing the company's targeted radiotherapeutic technology for the benefit of cancer patients and healthcare providers worldwide and the company's pipeline is focused on treating rare and difficult-to-treat cancers with significant unmet medical needs.

In addition to its headquarters in Austin, the company has an established, GMP-validated research and development and manufacturing facility in San Antonio, Texas, tailored to produce cGMP rhenium (186Re) obisbemeda. The company has built a robust supply chain through strategic partnerships that enable the development, manufacturing and future potential commercialization of the company's products. The company's supply chain and key partners are positioned to supply cGMP rhenium (186Re) obisbemeda for ongoing and planned Phase 2 and Phase 3 clinical trials in patients with GBM, LM and PBC.

Pipeline

The company's most advanced investigational drug, rhenium (186Re) obisbemeda, is a patented radiotherapy potentially useful for patients with CNS and other cancers. Preclinical study data describing the use of rhenium (186Re) obisbemeda for several cancer targets have been published in peer-reviewed journals and reported at a variety of medical society peer-reviewed meetings. Besides GBM, LM and PBC, rhenium (186Re) obisbemeda has been reported to have potential applications for head and neck cancer, ovarian cancer, breast cancer and peritoneal metastases.

The Rhenium (186Re) Obisbemeda technology was part of a licensed radiotherapeutic portfolio that the company acquired from NanoTx, Corp. ('NanoTx') on May 7, 2020. The licensed radiotherapeutic has been evaluated in preclinical studies for several cancer targets and the company has an active award from U.S. National Institutes of Health/National Cancer Institute which is expected to provide financial support for the continued clinical development of rhenium (186Re) obisbemeda for recurrent GBM through the completion of a Phase 2 clinical trial, including enrollment of up to 55 patients. As of February 23, 2023, 26 patients had been treated in the Phase 1 clinical trial and the Phase 2 clinical trial has been initiated with the first patient treated. In addition, the company anticipates obtaining FDA IND approval for the ReSPECT-PBC clinical trial for PBC in early 2023.

On August 29, 2022, the company announced feedback from a Type C meeting with the FDA regarding Chemistry, Manufacturing and Controls ('CMC') practices. The meeting focused on the company's Current Good Manufacturing Practice ('cGMP') clinical and commercial manufacturing process for the company's lead investigational targeted radiotherapeutic, BMEDA-chelated Rhenium (186Re) Obisbemeda, for recurrent GBM.

The FDA indicated agreement with the company's proposed application of cGMP guidance for radiotherapeutics, small molecule drug products and liposome drug products for the company's novel rhenium (186Re) obisbemeda in the support of ongoing and future GBM clinical trials, manufacturing scale up, and commercialization. Alignment with the FDA includes support of the company's proposed controls and release strategy for new drug substance and new drug product. Because this product is identical for recurrent GBM and LM adult development and pediatric brain tumors, this FDA alignment and feedback will apply to rhenium (186Re) obisbemeda used in other clinical development programs, including LM and PBC.

Rhenium (186Re) obisbemeda versus External Beam Radiation Therapy for Recurrent GBM

Rhenium (186Re) obisbemeda is a novel injectable radiotherapy designed to deliver targeted, high dose radiation directly into GBM tumors in a safe, effective, and convenient manner that may ultimately prolong patient survival. rhenium (186Re) obisbemeda is composed of the radionuclide Rhenium-186 and a nanoliposomal carrier, and is infused in a highly targeted, controlled fashion, directly into the tumor via precision brain mapping and CED catheters.

ReSPECT-GBM Trial for Recurrent GBM

Interim results from the company's ongoing Phase 1/2a ReSPECT-GBM trial (ClinicalTrials.gov NCT01906385) show that the beta particle energy from the company's lead investigational drug rhenium (186Re) obisbemeda has provided preliminary positive data and utility in treating GBM and potential other malignancies. More specifically, the preliminary data from the company's Phase 1/2a ReSPECT-GBM trial suggests that radiation, in the form of high energy beta particles or electrons, can be effective against GBM. Thus far, the company has been able to deliver up to 740 Gy of absorbed radiation to tumor tissue in humans, without significant or dose limiting toxicities and with the capability to go higher if required. In comparison, current EBRT protocols for recurrent GBM typically recommend a total maximum radiation dose of about ~30-35 Gray.

In September 2020, the FDA granted both Orphan Drug designation and Fast Track designations to rhenium (186Re) obisbemeda for the treatment of patients with GBM. In November 2021, the FDA granted Fast Track designation for rhenium (186Re) obisbemeda for the treatment of LM.

Rhenium (186Re) obisbemeda is under clinical investigation in a multicenter, sequential cohort, open-label, volume and dose escalation study of the safety, tolerability, and distribution of rhenium (186Re) obisbemeda given by CED catheters to patients with recurrent or progressive malignant glioma after standard surgical, radiation, and/or chemotherapy treatment (NCT01906385). The study uses a standard, modified 3x3 Fibonacci dose escalation, followed by a planned Phase 2 expansion trial at the maximum tolerated dose ('MTD') / maximum feasible dose ('MFD') or non-dose limiting toxicity ('DLT') if MTD is not reached, to determine efficacy. The trial is funded through Phase 2 in large part by a NIH/NCI grant. These investigations have not reached DLT or MTD/MFD and the study is in its eighth dosing administration cohort. Due to the observation of a preliminary efficacy signal, the company has initiated in parallel a Phase 2, non-DLT dose trial pursuant to the funded NIH/NCI Grant. This trial will begin at the current non-DLT rhenium (186Re) obisbemeda dose and will expand exploring higher radiation doses in larger volumes to treat larger tumors. Additionally, two or more rhenium (186Re) obisbemeda administrations, if indicated, will be evaluated, and reviewed with the FDA, as well as expanded safety, imaging and efficacy data to support a planned future registrational trial. This in turn will provide a path to a registration trial.

On September 6, 2022, the company announced a summary of its Type C clinical meeting with the FDA that focused on the ReSPECT-GBM trial. The FDA agreed with the company that the ReSPECT-GBM clinical trial should proceed to the planned Phase 2. The key focus areas of clinical investigation of the Phase 2 trial will be 1) further dose exploration, including both increased dosing and multiple doses, and 2) collecting additional safety and efficacy data to inform the design of a future registrational trial. Because no DLT administered doses were observed, the FDA and the company also agreed to continue to dose cohort eight. There was further agreement with the FDA that in a planned future registrational trial, overall survival should be used as the primary endpoint. The company agreed with the FDA to hold future meeting(s) to consider the use of external data to augment the use of a control arm in the registrational trial.

At the European Society for Medical Oncology Congress, held September 9 to 13, 2022, the company presented updated data from the ReSPECT-GBM trial, which evaluated 23 adult patients with recurrent GBM across eight cohorts of increasing dose and treated over a seven-year period.

At the Society for Neuro-Oncology Annual Meeting in November 2022, the company presented patient data, which at that time included the results for 24 patients treated in the ReSPECT-GBM trial. As of the date of this report, rhenium (186Re) obisbemeda given by CED in recurrent GBM patients was observed in the trial to be feasible and well tolerated.

On January 18, 2023, the company announced that the first patient has been dosed in the ReSPECT-GBM Phase 2b dose expansion clinical trial evaluating rhenium obisbemeda for the treatment of recurrent GBM. The Phase 2b trial is expected to enroll up to 31 total patients with small- to medium-sized tumors in approximately 24 months.

ReSPECT-LM Clinical Trial for Leptomeningeal Metastases (LM)

The ReSPECT-LM Phase 1 clinical trial (ClinicalTrials.gov NCT05034497) is predicated in part upon preclinical studies in which tolerance to doses of rhenium (186Re) obisbemeda as high as 1,075 Gy was shown in animal models with LM without significant observed toxicity. Furthermore, treatment led to a marked reduction in tumor burden in both C6 and MDA-231 LM models.

Upon receiving acceptance of the company's Investigational New Drug application and Fast Track designation by the FDA for rhenium (186Re) obisbemeda for the treatment of LM, the company initiated the trial and began screening patients for the ReSPECT-LM Phase 1 clinical trial in Q4 2021.

The ReSPECT-LM is a multi-center, sequential cohort, open-label, dose escalation study evaluating the safety, tolerability, and efficacy of a single-dose application of rhenium (186Re) obisbemeda administered through intrathecal infusion to the ventricle of patients with LM after standard surgical, radiation, and/or chemotherapy treatment. The primary endpoint of the study is the incidence and severity of adverse events and dose limiting toxicities.

On March 31, 2022, the company entered into a Sales Order (the 'Sales Order') with Medidata Solutions, Inc. ('Medidata'), pursuant to which Medidata built a Synthetic Control Arm (SCA) platform that facilitates the use of historical clinical data to incorporate into the company's Phase 2 clinical trial of rhenium (186Re) obisbemeda in GBM. The Sales Order had a term of six (6) months. Work under this Sales Order has been completed.

On September 19, 2022, the company entered into a Cancer Research Grant Contract (the 'CPRIT Contract'), effective as of August 31, 2022, with CPRIT, pursuant to which CPRIT will provide the company a grant of up to $17.6 million (the 'CPRIT Grant') over a three-year period to fund the continued development of rhenium (186Re) obisbemeda for the treatment of patients with LM through Phase 2 of the ReSPECT LM clinical trial. The CPRIT Grant is subject to customary CPRIT funding conditions, including, but not limited to, a matching fund requirement (one dollar from the company for every two dollars awarded by CPRIT), revenue sharing obligations upon commercialization of rhenium (186Re) obisbemeda based on specific dollar thresholds until CPRIT receives the aggregate amount of 400% of the proceeds awarded under the CPRIT Grant, and certain reporting requirements.

Interim results showed that treatment with rhenium (186Re) obisbemeda decreased CSF tumor cell count/ml and was well tolerated by all four LM patients. rhenium (186Re) obisbemeda was administered through a standard intraventricular catheter (Ommaya Reservoir), redistributed throughout the CSF, and was retained in the leptomeninges at least through day seven. All four patients have shown prompt and durable rhenium (186Re) obisbemeda distribution throughout the subarachnoid space.

ReSPECT-PBC Clinical Trial for Pediatric Brain Cancer

In August 2021, the company announced plans for treating pediatric brain cancer at the 2021 American Association of Neurological Surgeons (AANS) Annual Scientific Meeting. In July 2021, the company reported that the company had received FDA feedback pertaining to a pre-IND meeting briefing package in which the FDA stated that the company is not required to perform any additional preclinical or toxicology studies.

Since the initial FDA feedback and receiving important adult GBM data and experience with rhenium (186Re) obisbemeda and follow-up communications with the FDA, the company plans to submit a pediatric brain tumor IND to investigate the use of rhenium (186Re) obisbemeda in two pediatric brain cancers in early 2023.

Rhenium-188 NanoLiposome Biodegradable Alginate Microsphere Technology

In January 2022, the company announced that the company licensed Biodegradable Alginate Microsphere ('BAM') patents and technology from The University of Texas Health Science Center at San Antonio ('UT Health Science Center at San Antonio') to expand the company's tumor targeting capabilities and precision radiotherapeutics pipeline. The company intends to combine its Rhenium NanoLiposome technology with the BAM technology to create a novel radioembolization technology. Initially, the company intends to utilize the Rhenium-188 isotope, 188RNL-BAM for the intra-arterial embolization and local delivery of a high dose of targeted radiation for a variety of solid organ cancers, such as hepatocellular cancer, hepatic metastases, pancreatic cancer and many others.

Preclinical data from an ex vivo embolization experiment in which Technetium99m-BAM was intra-arterially delivered to a bovine kidney perfusion model was presented at the recent 2021 Society of Interventional Radiology ('SIR') Annual Scientific Meeting. The study concluded that the technology required for radiolabeling BAM could successfully deliver, embolize and retain radiation in the target organ. 188RNL-BAM is a preclinical investigational drug the company intends to further develop and move into clinical trials. Specifically, in 2022 the company transferred the 188RNL-BAM technology from UT Health Science Center at San Antonio, and began planning to develop the drug product and complete early preclinical studies to support a future FDA IND submission. The company's intended initial clinical target is liver cancer, which is the sixth most common and third deadliest cancer worldwide.

Licensing

On June 22, 2022, the company announced a multi-year laboratory services agreement with Biocept, Inc. ('Biocept') to employ their cerebrospinal fluid ('CSF') assay, CNSide, in Plus Therapeutics' ReSPECT-LM Phase 1/2a dose-escalation trial of Rhenium-186 NanoLiposome for the treatment of patients with ('LM').

On December 31, 2021, the company entered into a Patent and Technology License Agreement (the 'UTHSA License Agreement') with UT Health Science Center at San Antonio, pursuant to which UT Heath Science Center at San Antonio granted the company an irrevocable, perpetual, exclusive, fully paid-up license, with the right to sublicense and to make, develop, commercialize and otherwise exploit certain patents, know-how and technology related to the development of BAM containing nanoliposomes loaded with imaging and/or therapeutic payloads. Therapeutic payloads may include radiotherapeutics, chemotherapeutics, or thermotherapeutics.

The company anticipates that it will initially focus on developing 188RNL-BAM as a next-generation radioembolization therapy for liver cancer, in which BAM blocks the hepatic artery segments that supply blood to the malignant tumor while also providing 188RNL radiotherapy directly to the tumor and surrounding tissue.

On March 29, 2020, the company entered into a Patent and Know-How License Agreement (the 'NanoTx License Agreement') with NanoTx, pursuant to which NanoTx granted the company an irrevocable, perpetual, exclusive, fully paid-up license, with the right to sublicense and to make, develop, commercialize and otherwise exploit certain patents, know-how and technology related to the development of radiolabeled nanoliposomes.

The licensed NanoTx portfolio benefits from proprietary nanoliposome-encapsulated technology to encapsulate radionuclides allowing direct local delivery for several cancer targets.

The licensed radiolabeled nanoliposome platform was developed by a multi-institutional consortium based in Texas at the Mays Cancer Center / UT Health Science Center at San Antonio MD Anderson Cancer Center led by Dr. Andrew Brenner, MD, PhD, who is the Kolitz Chair in Neuro-Oncology Research and Co-Leader of the Experimental and Developmental Therapeutics Program. The technology was previously owned by NanoTx and funded by both the National Institutes of Health/National Cancer Institute ('NIH'/'NCI') and the Cancer Prevention and Research Institute of Texas ('CPRIT'). There is an active $3 million award from NIH/NCI which is expected to financially support the continued clinical development of rhenium (186Re) obisbemeda for recurrent glioblastoma.

Manufacturing

The company has entered into master services agreements ('MSAs') with third parties, including Piramal Pharma Solutions, Inc. ('Piramal'), ABX Advanced Biochemical Compounds GmbH, IsoTherapeutics Group, LLC, and Radiomedix, Inc. in connection with the development, manufacture, and supply of the company's rhenium (186Re) obisbemeda drug product.

Intellectual Property

The company licenses the proprietary formulation and proprietary methods of manufacture of the nanoliposome-encapsulated radionucleotides. rhenium (186Re) obisbemeda and 188RNL are covered by U.S. Patent No. 7,718,160, (the ''160 Patent'), which will expire in December 2026. Patent term extension, codified in 35 U.S.C. §156, provides a means of recapturing time lost during the regulatory approval process. Based upon this regulation, the company will apply for patent term extension for the '160 Patent for the time equal to the regulatory review period for rhenium (186Re) obisbemeda. This has the potential to extend patent coverage for this product for up to another five years. The '160 Patent covers rhenium (186Re) obisbemeda and 188RNL and their method of manufacture. The patent family also contains granted patents in Canada (Patent No. 2,490,959), Europe (Patent No. EP1536843), and Australia (Patent No. 2003241598), which are expected to expire in May 2023.

188RNL is also covered by U.S. Patent Appl. No. 17/611,929 titled Radiotherapeutic Microspheres, to which the company has a license. This application is directed to a method of producing liposome containing alginate microspheres. This application was filed on November 17, 2021, and any patent granted from or claiming priority to it is expected to expire in May 2040, not including any patent term adjustment or patent term extension. The patent family also contains applications in Canada, Israel, India, Japan, Mexico, Saudi Arabia, Thailand, South Africa, Vietnam, the Philippines, China, European Patent Office, Brazil, Singapore, Indonesia, Malaysia, Australia, and New Zealand.

188RNL is also covered by PCT/US2022/018992 titled Loading Alginate Microspheres, to which the company has a license. This application is directed to a method for post-manufacture loading of a liposome-containing hydrogel microsphere. This application was filed March 4, 2022, and any patent granted from or claiming priority to it is expected to expire in March 2042.

The company co-owns and licenses PCT Application No. PCT/US2021/059969 and U.S. Patent Appl. No. 17/746,853, titled Radiolabeled Liposomes and Methods of Use Thereof, which are directed to methods of treating cancer comprising administering 186Re and 188Re nanoliposomes via CED. These applications were filed on November 18, 2021 and May 17, 2022, respectively, and any patents issued from or claiming priority to them are expected to expire in November 2041, not including any patent term adjustment or patent term extension.

The company co-owns and licenses PCT Application No. PCT/US2023/11564, titled Radiolabeled Liposomes and Methods of Use for Treating Leptomeningeal Metastases, which is directed to methods of treating Leptomeningeal Metastases comprising administering 186Re and/or 188Re nanoliposomes via an intraventricular reservoir. This application was filed on January 25, 2023, and any patent issued claiming priority to it is expected to expire in January 2043, not including any patent term adjustment or patent term extension.

Government Regulation and Product Approval

The company's nanoparticle oncology drug candidates must receive regulatory approvals from the EMA and the FDA and from other government authorities prior to sale of the product candidates in their respective jurisdictions.

In the United States, the company's activities are potentially subject to regulation by various federal, state and local authorities in addition to the FDA, including but not limited to, the Centers for Medicare and Medicaid Services, or CMS, other divisions of the U.S. Department of Health and Human Services (e.g., the Office of Inspector General), the U.S. Department of Justice, or DOJ, and individual U.S. Attorney offices within the DOJ, and state and local governments.

The Foreign Corrupt Practices Act obligates companies whose securities are listed in the United States to comply with accounting provisions requiring the company to maintain books and records that accurately and fairly reflect all transactions of the corporation, including international subsidiaries, and to devise and maintain an adequate system of internal accounting controls for international operations.

In addition to the foregoing, state and federal laws regarding environmental protection and hazardous substances, including the Occupational Safety and Health Act, the Resource Conservancy and Recovery Act and the Toxic Substances Control Act, affect the company's business.

History

The company was founded in 1996. It was incorporated in the state of Delaware in 1997. The company was formerly known as Cytori Therapeutics, Inc. and changed its name to Plus Therapeutics, Inc. in 2019.