Rhenium-188 P2045 (BAY86-5284, Tozaride): A Somatostatin Receptor-Targeted Agent for Pancreatic Cancer and Beyond

Summary: Rhenium-188 P2045, also known as BAY86-5284 or Tozaride, represents a distinctive advancement in radiopharmaceutical research targeting somatostatin receptors. This innovative 11-amino acid somatostatin peptide conjugate is radiolabelled with either rhenium-188 (¹⁸⁸Re) or technetium-99m (^99mTc). In June 2014, the United States Food and Drug Administration (FDA) granted Orphan Drug Designation to Rhenium-188 P2045 for the treatment of pancreatic cancer, recognising its potential importance in addressing a disease with limited therapeutic options. Prior investigations primarily revolved around its use in treating both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). However, with the emergence of orphan drug status, the drug’s clinical development has shifted decisively towards managing pancreatic cancer, a formidable illness frequently associated with grim prognoses. While the journey of Rhenium-188 P2045 in clinical trials has encountered various hurdles, the interest in its continued study speaks to its potential significance. This article explores the compound’s structure, mechanism of action, preclinical and clinical evidence, and prospective future directions, focusing on the pressing need for more effective treatments in pancreatic and other neuroendocrine tumours.

Keywords: Somatostatin receptors; Radiopharmaceuticals; Neuroendocrine tumours; Rhenium-188; Orphan Drug Designation; Pancreatic cancer.

Introduction to Rhenium-188 P2045

The use of radiopharmaceuticals has become increasingly significant in oncology, especially with the rise of personalised medicine. By incorporating radioactive isotopes into molecules that selectively target tumour cells, scientists can deliver potent radiation to malignant tissues while ideally sparing healthy cells. One such compound is Rhenium-188 P2045, also referred to as BAY86-5284 or Tozaride. This 11-amino acid peptide conjugate specifically targets somatostatin receptors, which are abundant in many types of tumours, including neuroendocrine tumours (NETs) and certain subtypes of lung cancer.

Rhenium-188 (¹⁸⁸Re) is a radionuclide that emits beta particles (β–) and has been explored for both diagnostic and therapeutic uses. Its properties, notably its relatively short half-life (approximately 17 hours) and the energy of its beta emissions make it suitable for targeted radionuclide therapy. By employing the ¹⁸⁸Re-labelled version of P2045, clinicians aim to destroy tumour cells through direct radiation, while the technetium-99m (^99mTc)-labelled analogue can be applied for diagnostic imaging to determine receptor status.

In June 2014, Rhenium-188 P2045 was granted an Orphan Drug Designation by the U.S. FDA for the treatment of pancreatic cancer. This status underscores the urgency and necessity of addressing diseases such as pancreatic cancer, which typically exhibit high morbidity and mortality. Although its first indications involved lung cancers, clinical programmes are pivoting towards pancreatic cancer due to the compound’s orphan status.

The story of Rhenium-188 P2045 demonstrates both the promise and the inherent complexity of drug development in oncology. A Phase I study in small cell lung cancer was completed in the mid-2000s, yet subsequent efforts to begin a new trial in 2014 were withdrawn. Nonetheless, the scientific and medical communities continue to watch this agent closely, hoping it can expand the arsenal of agents available for targeting malignancies with unmet clinical needs.

Background: The Role of Somatostatin Receptors in Cancer

Somatostatin receptors (SSTRs) are G protein-coupled receptors that govern a variety of physiological processes, including cell proliferation, hormone secretion, and angiogenesis. Somatostatin, the endogenous ligand for these receptors, operates as an inhibitory hormone in numerous organ systems. It restricts the release of growth hormone, insulin, glucagon, and other regulatory proteins.

In oncology, somatostatin receptors are of interest because many tumours overexpress these receptors. Neuroendocrine tumours, including carcinoid tumours and many pancreatic endocrine tumours, are known for increased SSTR expression. The presence of these receptors not only assists with diagnostic imaging—utilising agents like octreotide scans—but also provides therapeutic potential. If a tumour overexpresses SSTRs, that tumour cell population can be preferentially targeted by radiolabelled somatostatin analogues.

Pharmaceutical research has capitalised on this feature by modifying somatostatin analogues to achieve high affinity and specificity for these receptors while conjugating them to radioactive isotopes capable of delivering cytotoxic radiation. Octreotide-based agents have historically been the gold standard, yet novel peptides such as ¹⁸⁸Re-P2045 (BAY86-5284) have emerged as potential next-generation therapies.

The advantage of these molecules lies in their ability to exploit natural receptor-ligand interactions. By binding specifically to overexpressed receptors, radiopharmaceuticals deliver lethal doses of radiation directly to tumour sites. This specificity could reduce off-target effects, thereby improving the tolerability profile and quality of life for patients undergoing treatment.

¹⁸⁸Re-P2045 (BAY86-5284, Tozaride): Structure and Development

¹⁸⁸Re-P2045 is a proprietary compound formulated by conjugating an 11-amino acid somatostatin peptide to the radionuclide rhenium-188. This process involves engineering the peptide sequence to optimise receptor binding and enable stable chelation of the radioactive element. The conjugate is often referred to as Tozaride, although it has also been identified by the code name BAY86-5284 in some literature.

Key points in the development of ¹⁸⁸Re-P2045 include:

• Somatostatin peptide backbone: The scaffold ensures that the molecule retains high specificity and affinity for somatostatin receptors, particularly subtypes like SSTR2, which is frequently overexpressed in many neuroendocrine and other tumours.
• Rhenium-188 radiolabelling: ¹⁸⁸Re is chosen for therapeutic efficacy due to its beta-particle emissions. It is also advantageous in certain respects, as rhenium isotopes bear chemical similarities to technetium, a widely used radionuclide in nuclear medicine.
• Dual-labelling potential: The same peptide can be labelled with ^99mTc instead of ¹⁸⁸Re for diagnostic imaging, allowing clinicians to confirm receptor overexpression and estimate therapeutic uptake before administering the therapeutic agent.

Research into Rhenium-188 P2045 took shape in the early 2000s, spurred by promising data that linked effective receptor targeting with potential anticancer benefits. Early applications targeted lung cancer, given the frequent expression of somatostatin receptors in both small cell and non-small cell lung carcinoma. As data emerged regarding the prevalence and aggressiveness of pancreatic cancer, the compound’s therapeutic direction gradually realigned with the new orphan status it received in 2014.

Mechanism of Action

Rhenium-188 P2045 (BAY86-5284) exerts its antitumour activity via a targeted radiotherapy approach leveraging somatostatin receptor expression in malignant cells:

• Receptor Binding: The P2045 peptide sequence is designed to bind to SSTRs on the surface of target cells. This binding is highly specific and is mediated by the complementarity of the peptide’s structure to the receptor’s ligand-binding domain.
• Internalisation: Upon binding, receptor-ligand complexes are internalised into the cell through receptor-mediated endocytosis. The radiolabelled peptide, therefore, accumulates intracellularly, localising the radiation dose in tumour cells.
• Beta Emission: Rhenium-188 emits beta particles (β–) that travel short distances in tissue. These beta emissions cause direct DNA damage in the target cell as well as in nearby cells within a limited radius, contributing to the so-called “crossfire effect.”
• Cell Death and Tumour Control: The radiation damage leads to double-strand DNA breaks, triggering apoptosis or other pathways of cell death. Through repeated dosing, there is a possibility of reducing tumour burden, slowing progression, or potentially enhancing survival.

The effectiveness of Rhenium-188 P2045 hinges is not only based on receptor density and the avidity of the peptide for these receptors but also on the radiobiological properties of ¹⁸⁸Re. The chosen isotope’s half-life, emission energy, and availability (rhenium-188 can be sourced from tungsten-188/rhenium-188 generator systems) all influence how the therapy is administered and managed within the clinical setting.

Preclinical and Clinical Evaluations

Early research on Rhenium-188 P2045 focused on establishing proof of concept. Preclinical models, including in vitro cell culture studies and in vivo animal experiments, aimed to demonstrate the peptide’s affinity for somatostatin receptors, its stability under physiological conditions, and its therapeutic potential. These investigations showed promising tumour uptake and suggestive efficacy signals, providing the impetus for Phase I trials.

Phase I Clinical Trial in Small Cell Lung Cancer

The initial human evaluation of Rhenium-188 P2045 took place in patients with small cell lung cancer (SCLC). The trial spanned 2004-2005 and assessed safety, tolerability, pharmacokinetics, and biodistribution. Typically, a Phase I study also explores preliminary efficacy endpoints, although it is not powered to provide definitive results.

• Safety: Patients generally tolerated the radiolabelled peptide, with side effects mostly related to mild haematological suppression or local tissue reactions.
• Dosimetry: Imaging and blood tests were performed to measure radiation exposure to organs such as the kidneys, liver, and bone marrow, as well as overall clearance from the body.
• Receptor Targeting Confirmation: Imaging data confirmed the ability of ¹⁸⁸Re-P2045 to bind SSTR-positive tumours.

Withdrawn Study

A subsequent study aimed at exploring Rhenium-188 P2045 further was posted to the clinical trials database in anticipation of a January 2014 start. However, this trial was withdrawn, leaving significant gaps in the public dataset regarding expanded safety and efficacy results. The reasons for withdrawal could encompass sponsor decisions, regulatory hurdles, or changes in clinical development strategies.

In any case, interest in Rhenium-188 P2045 has persisted, not least because of its newly minted Orphan Drug Designation and the pressing need for better treatments in pancreatic cancer and other SSTR-expressing malignancies.

Orphan Drug Designation and Implications

In June 2014, the U.S. FDA granted Orphan Drug Designation to Rhenium-188 P2045 for the treatment of pancreatic cancer. This designation serves a specific purpose: to incentivise the development of drugs targeting conditions affecting fewer than 200,000 people in the United States. Pancreatic cancer, though not exceedingly rare, is still considered an area of high unmet medical need, as most patients face poor prognoses and limited therapeutic options.

Benefits of Orphan Drug Status

• Financial Incentives: Companies developing orphan drugs are often eligible for tax credits, grant funding, and marketing exclusivity for a certain period following approval.
• Regulatory Support: The FDA provides guidance to streamline the clinical development process for orphan drugs, including potential fee waivers and expedited review pathways.
• Increased Visibility: Public and investor awareness often grows when a compound earns orphan status, possibly facilitating partnerships or licensing deals to fund later-stage clinical trials.

Relevance to ¹⁸⁸Re-P2045

Earning this designation can significantly bolster the prospects for ¹⁸⁸Re-P2045 in the quest to transform the treatment landscape of pancreatic cancer. Given the aggressive nature of this disease, there is considerable motivation to pursue novel mechanisms that can work in tandem with—or offer an alternative to—traditional treatments such as surgery, chemotherapy, and external beam radiotherapy.

Orphan Drug Designation also implies that the compound’s sponsor may have the incentive to revisit or design new clinical trials specifically addressing the unique challenges of pancreatic cancer. These might range from dose-escalation studies evaluating the maximum tolerated dose in advanced pancreatic disease to combination trials in which ¹⁸⁸Re-P2045 could be paired with other emerging agents such as checkpoint inhibitors or chemotherapy.

Potential Applications in Pancreatic Cancer

While preliminary exploration focused on lung cancer, the clinical roadmap for ¹⁸⁸Re-P2045 now points more distinctly to pancreatic cancer, primarily due to its orphan drug status. Pancreatic cancer remains one of the deadliest malignancies worldwide, with a five-year survival rate commonly under 10%. Contributory factors include late diagnosis, rapid metastasis, and resistance to existing therapies.

Targeting Somatostatin Receptor-Expressing Pancreatic Tumours

Many pancreatic tumours, especially those of neuroendocrine origin, overexpress somatostatin receptors. This characteristic enables targeted strategies that exploit these receptors for both imaging and therapy. By employing ^99mTc-P2045 imaging, clinicians can locate tumours with high receptor density to determine whether a patient is a suitable candidate for Rhenium-188 P2045 therapy. Such a personalised approach maximises the likelihood of efficacy while minimising systemic toxicity.

Overcoming Treatment Resistance

Conventional treatments for advanced pancreatic cancer, such as gemcitabine-based chemotherapy, often yield only modest improvements in survival. The addition of targeted radiotherapy via somatostatin receptor ligands offers a different mechanism of action, potentially circumventing mechanisms of chemoresistance. Radiopharmaceuticals directly damage tumour DNA, contrasting with the metabolic or cell-cycle interference of chemotherapy.

Possible Combination Strategies

Combining Rhenium-188 P2045 with other modalities could enhance clinical outcomes. For instance, pairing it with immunotherapy drugs such as checkpoint inhibitors might heighten tumour immunogenicity, thereby improving immune system-mediated tumour control. Alternatively, scheduling ¹⁸⁸Re-P2045 around chemotherapy cycles could amplify tumour cell kill. The synergy between these regimens might lead to improved response rates and more robust survival benefits.

Challenges and Future Directions

The development of Rhenium-188 P2045, like many novel oncological therapies, faces challenges in manufacturing, regulatory approvals, and the complexities inherent in running large-scale clinical trials. Some key areas that require attention include:

• Supply and Distribution of Rhenium-188
  Although ¹⁸⁸Re can be derived from tungsten-188/rhenium-188 generator systems, ensuring a reliable supply on a global scale is logistically intricate. Institutions that wish to administer ¹⁸⁸Re-P2045 must have access to specialised nuclear pharmacy services.
• Safety and Dosimetry
  Thorough dosimetry studies are essential to prevent excessive radiation to healthy organs such as kidneys, liver, and bone marrow. Future trials need to continue mapping the pharmacokinetics of ¹⁸⁸Re-P2045 to identify optimal dosing regimens.
• Clinical Trial Design
  Designing robust trials involves selecting patient populations, establishing appropriate endpoints (e.g., overall survival, progression-free survival, or objective response rate), and accounting for potential combination therapies. The orphan drug status may simplify some regulatory aspects, but the small patient population still poses recruitment challenges.
• Resistance Mechanisms and Receptor Heterogeneity
  Tumours can develop resistance by downregulating somatostatin receptors or altering their expression profile. Heterogeneity within a single tumour population can result in partial treatment responses, prompting the need for strategies that address receptor variability.
• Future Indications
  Beyond pancreatic cancer and lung cancer, the overexpression of somatostatin receptors in various neuroendocrine tumours opens the door for potential expansion to other indications. Large-scale comparative trials or real-world evidence generation may identify additional subsets of patients who could benefit from ¹⁸⁸Re-P2045 therapy.

Given that the orphan designation was granted in 2014, the next steps for ¹⁸⁸Re-P2045 likely involve either the resumption of the withdrawn study or the initiation of an entirely new trial, possibly with improved design and a refined patient selection process. Technological innovations in molecular imaging could further refine the approach, ensuring that only those tumours most likely to respond receive therapy.

Conclusion

Rhenium-188 P2045 (BAY86-5284, Tozaride) has emerged as an intriguing radiopharmaceutical agent that capitalises on the ubiquitous role of somatostatin receptors in various malignancies. By conjugating a targeted peptide to a beta-emitting isotope, researchers aimed to establish a new avenue for delivering therapeutic radiation in a highly localised manner. Originally evaluated in small cell lung cancer, the compound’s clinical trajectory shifted once the U.S. FDA granted Orphan Drug Designation for pancreatic cancer in 2014.

The path towards integrating Rhenium-188 P2045 into routine clinical practice has been neither straightforward nor swift. Though a Phase I study demonstrated feasibility and initial safety, subsequent research faced setbacks, evidenced by a withdrawn clinical trial in 2014. Nevertheless, the potential benefits remain substantial. Pancreatic cancer, known for its late detection and dismal survival rates, stands to gain significantly from therapies that exploit receptor-specific mechanisms. If the ongoing scientific interest in ¹⁸⁸Re-P2045 translates to renewed clinical developments, it may provide a much-needed treatment alternative or adjunct for patients facing limited options.

Looking ahead, any further development of 188Re-P2045 hinges on thorough clinical investigation to ascertain efficacy, optimal dosing, and ideal combinations with other therapies. Researchers must confront barriers, including ensuring consistent supplies of rhenium-188, perfecting dosimetry, and managing potential resistance due to receptor heterogeneity. The expansion of novel imaging modalities and combination regimens also holds promise for moving this concept forward.

In short, Rhenium-188 P2045 represents a testament to the broader trend in oncology towards targeted therapy, guided by molecular markers such as somatostatin receptor overexpression. Should clinical research resume and confirm the early signals of efficacy, Rhenium-188 P2045 may indeed join the ranks of other peptide receptor radionuclide therapies, bringing renewed hope to those suffering from pancreatic cancer and potentially other somatostatin receptor-positive malignancies.

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