Clinical-stage oncology Fusion Pharmaceuticals, which focuses on the developing of the next-generation radiopharmaceuticals as precision medicines, confirmed significant progress in the development of FPI-2265 and shared update on FPI-1434 Phase 1 Cohort 2 data.  The company also shared an update about the production of the first clinical doses at the Company’s proprietary manufacturing facility.


“We begin 2024 with strong momentum, given a potential registration-enabling path for FPI-2265, encouraging results in our FPI-1434 program, including first signs of antitumor activity, and a fully operational Targeted Alpha Therapy (TAT) manufacturing facility that has already begun to produce clinical doses for our actinium-based PSMA lead program,” said John Valliant, Ph.D., Fusion Pharmaceuticals’ Chief Executive Officer.

Alpha (α-) emitting targeted therapies
Alpha (α-) emitting targeted therapies or TATs are being evaluated in a number of clinical trials as a potential next-generation theranostics with even higher efficacy due to their high linear energy and short range in human tissues. This short range of α particles makes them an interesting tool to irradiate single-cell lesions or treat solid tumors by minimizing unwanted irradiation of normal tissue surrounding the cancer cells, assuming a high specificity of the radiopharmaceutical and good stability of its chemical bonds. TATs are considered one of the most promising fields in novel targeted cancer therapy, with several early- and late-stage clinical trials for neuroendocrine tumors and metastatic prostate cancer already in progress, In addition, there is significant interest and investment in additional early-phase studies. As a result, ongoing studies helps increase the understanding the short- and long-term toxicity of TATs as well as help identify suitable therapeutic combination partners. [1][2][3]

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“We achieved alignment with the U.S. Food and Drug Administration (FDA) on a protocol and development plan for FPI-2265, providing our team with a potential path to registration and positioning FPI-2265 to be the first actinium-based PSMA targeting radioligand therapy to market, if approved. Given the significant and growing market for lutetium Lu 177 vipivotide tetraxetan (Pluvicto™; Novartis – formerly known as 177Lu-PSMA-617) we believe that FPI-2265 will address an important unmet need for patients who progress on or after lutetium-based therapy,” Valliant added. [4]

FPI-2265 Phase 2/3 Development Plan
Fusion Pharmaceuticals confirmed that it has aligned with the FDA on its submitted Phase 2/3 protocol for FPI-2265, a targeted alpha therapy (TAT) targeting prostate specific membrane antigen (PSMA) for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) with progressive disease. The updated development plan includes a Phase 2 dose optimization lead-in, expected to complete enrollment by the end of 2024, and a Phase 3 registrational trial expected to begin in 2025.

The Phase 2 portion of the protocol is designed to evaluate the safety and efficacy of FPI-2265 across three dosing regimens in approximately 60 patients with mCRPC with progressive disease after 177Lu-based PSMA radioligand therapy, such as PLUVICTO.

Based on literature and TATCIST data reported to date, 100 kBq/kg administered every 8 weeks is known to be a safe and active dose regimen.  In order to further optimize the benefit/risk ratio of FPI-2265, Fusion Pharmaceuticals  plans to explore alternate regimens with higher dosing frequency while keeping cumulative dose and total duration of treatment the same.

Additional regimens to be evaluated will include a dose of 50 kBq/kg every 4 weeks and 75 kBq/kg every 6 weeks. The primary endpoints are safety and the proportion of patients with ≥ 50% decline in PSA level with key secondary endpoints of objective response rate (ORR) and radiographic progression free survival (rPFS). The Phase 2 trial is expected to initiate in the second quarter of 2024 with enrollment completed by year-end. The Company will seek to hold an End of Phase 2 meeting with the FDA to determine the recommended Phase 3 dosing regimen based on analysis of the Phase 2 data.

“We believe evaluating dosing regimens that deliver the same total dose over the same duration of treatment in the Phase 2 portion of the study allows us to optimize our Phase 3 clinical trial dose in alignment with FDA guidance and determine the best potential regimen of FPI-2265,” noted Dmitri Bobilev, MD, Chief Medical Officer at Fusion Pharmaceuticals.

The Phase 3 portion of the trial is designed to be a registration-enabling global trial evaluating the efficacy and safety of FPI-2265 compared with standard of care in approximately 550 patients with mCRPC with progressive disease who have previously been treated with a 177Lu-based PSMA radiotherapy.

The primary endpoint will evaluate rPFS. Key secondary endpoints include PFS, ORR, OS, PSA50and duration of response. Fusion Pharmaceuticals plans to initiate the Phase 3 trial in 2025.

In February 2023, Fusion Pharmaceuticals acquired an IND for the ongoing Phase 2 clinical trial (the TATCIST trial) evaluating FPI-2265 (225Ac-PSMA I&T).

The TATCIST trial was designed to evaluate patients with mCRPC with progressive disease, including patients who are naïve to PSMA-targeted radiopharmaceuticals and those who have been pre-treated with 177Lu-based PSMA radiopharmaceutical therapy. Fusion intends to report data from approximately 25 to 30 patients in April 2024 and then prioritize enrollment in the new Phase 2/3 trial.

Fusion Pharmaceuticals is also pursuing the opportunity to potentially move the therapy candidate into earlier lines of treatment with combinations of FPI-2265 and olaparib. Fusion expects to initiate a combination trial in the first half of this year.

FPI-1434 Cohort 2 Data & Next Steps
Encouraging early findings from Cohort 2 in the ongoing FPI-1434 Phase 1 clinical trial showed that there were no dose limiting toxicities (DLTs)  observed to date in the 25 kBq/kg dose cohort. Two out of three patients completed the DLT period, and one pancreatic cancer patient discontinued treatment due to disease progression.

One heavily treated patient with Ewing sarcoma showed evidence of anti-tumor activity after a single 25 kBq/kg dose of FPI-1434. The second patient received four cycles of therapy and showed stable disease as best response. FPI-1434 was well tolerated, with no DLTs and transient Grade 1 or less thrombocytopenia at the 25 kBq/kg dose level.

Fusion Pharmaceuticals plans to complete and further evaluate results from Cohort 2 and hold a Safety Review Committee (SRC) meeting to evaluate the emerging data. Fusion plans to share more details on the data and the FPI-1434 development program in mid-2024.

Antibody-drug Conjugates
“We continue to believe alpha emitters represent the evolution of the toxin used in antibody-drug conjugates (ADCs) and hold the potential to improve the potency of naked antibodies. There is significant untapped potential to use the precision targeting of antibodies to deliver the potent payload of actinium directly to tumor cells. While early, we are encouraged by the results showing good safety and evidence of antitumor activity at low doses of FPI-1434,” Fusion Pharmaceuticals Bobilev said.

In June 2023, Fusion reported results from three patients at 15 kBq/kg in Cohort 1 of the cold/hot dosing regimen. In Cohort 1, cold/hot dosing was observed to be generally well tolerated with no treatment-related serious adverse events (SAEs) or dose DLTs. Pre-administration of cold antibody demonstrated improved tumor uptake while also reducing hematological toxicity observed in the hot only dosing arm. Two heavily pre-treated patients from the cold/hot dosing arm received three and five cycles of treatment, with both achieving durable stable disease as their best response.

Fusion Pharmaceuticals reported today that it has completed validation of its state-of-the-art good manufacturing practice (GMP) manufacturing facility and produced the first clinical dose of a TAT.

“The initiation of production at our own facility, and the diversification afforded by our external partnerships, positions us for execution on our multiple clinical programs,’ commented Fusion Pharmaceuticals CEO, John Valliant, Ph.D., said.

“We built Fusion on a foundation of end-to-end manufacturing expertise, including experience with global radiopharmaceutical logistics and distribution. We also now have one of the first in-house TAT manufacturing facilities with access to a generator technology that allows for convenient onsite production of actinium-225, providing us with additional capacity and flexibility in our manufacturing programs,” Valliant further noted.

Fusion Pharmaceuticals’ facility, which has clinical and commercial scale manufacturing capabilities, is designed to support the company’s growing pipeline of TATs and expected to be capable of producing up to 100,000 doses per year. Doses produced out of Fusion’s manufacturing facility are expected to support FPI-2265 manufacturing and are expected to be expanded to include Fusion’s other proprietary and partnered programs.

Clinical pipeline
Fusion Pharmaceuticals’ clinical pipeline includes:

  • FPI-2265 targeting prostate specific membrane antigen (PSMA) for metastatic castration resistant prostate cancer currently in a Phase 2 trial;
  • FPI-1434 targeting insulin-like growth factor 1 receptor currently in a Phase 1 clinical trial; and
  • FPI-2059, a small molecule targeting neurotensin receptor 1 (NTSR1), currently in a Phase 1 trial.

In addition to a robust proprietary pipeline, Fusion Pharmaceuticals has an established, ongoing, collaboration with AstraZeneca to jointly develop novel targeted alpha therapies (TATs) and combination programs between Fusion’s TATs and AstraZeneca’s DNA Damage Response Inhibitors (DDRis) and immuno-oncology agents.

In addition, the company received IND clearance for FPI-2068, the first novel TAT under the collaboration, which targets EGFR-cMET.

Fusion Pharmaceuticals has also entered into an ongoing collaboration with Merck & Co/MSD to evaluate FPI-1434 in combination with pembrolizumab (Keytruda®; Merck & Co/MSD) in patients with solid tumors expressing IGF-1R.

To support the growing pipeline of TAT’s, Fusion Pharmaceuticals signed strategic actinium supply agreements with Niowave, a domestic supplier of medical and industrial radioisotopes from uranium and radium, and leases a current Good Manufacturing Practice (GMP) compliant radiopharmaceutical manufacturing facility on the McMaster University campus in Hamilton, Ontario.

Clinical trials
Targeted Alpha Therapy With 225Actinium-Prostate Specific Membrane Antigen (PSMA)-I&T of Castration-resISTant Prostate Cancer (TATCIST) – ID NCT05219500
A Phase 1/​2 Study of [225Ac]-FPI-1434 Injection – ID NCT03746431
A Study of [225Ac]-FPI-2059 in Adult Participants With Solid Tumors – ID NCT05605522

Highlights of Prescribing Information
Lutetium Lu 177 vipivotide tetraxetan (Pluvicto™; Novartis)[Prescribing Information]
Pembrolizumab (Keytruda®; Merck & Co/MSD) [Prescribing Information]

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[2] Guerra Liberal FDC, O’Sullivan JM, McMahon SJ, Prise KM. Targeted Alpha Therapy: Current Clinical Applications. Cancer Biother Radiopharm. 2020 Aug;35(6):404-417. doi: 10.1089/cbr.2020.3576. Epub 2020 Jun 16. PMID: 32552031.
[3] Elgqvist J. Targeted alpha therapy: part I. Curr Radiopharm. 2011 Jul;4(3):176. doi: 10.2174/1874471011104030176. PMID: 22201706.
[4] Keam SJ. Lutetium Lu 177 Vipivotide Tetraxetan: First Approval. Mol Diagn Ther. 2022 Jul;26(4):467-475. doi: 10.1007/s40291-022-00594-2. Epub 2022 May 13. PMID: 35553387; PMCID: PMC9099330.

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