On June 26, 2023 RefleXion Medical, Inc., a therapeutic oncology company, reported that results of a prospective investigator-initiated clinical imaging study conducted on its X1 platform by City of Hope using positron emission tomography (PET) were presented on June 24 during an oral session at the Society of Nuclear Medicine and Medical Imaging (SNMMI) annual meeting in Chicago (Press release, RefleXion Medical, JUN 26, 2023, View Source [SID1234632917]). The study results serve as the foundation for evaluating the use of RefleXion’s SCINTIX biology-guided radiotherapy with a prostate-specific PET radiotracer for controlling external-beam radiotherapy delivery to prostate cancer tumor targets. City of Hope, one of the largest cancer research and treatment organizations in the U.S., is among the first in the nation to adopt this new radiotherapy technology that has the potential to change the way metastatic cancer patients are treated.

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Recently cleared by the U.S. Food and Drug Administration (FDA), SCINTIX technology is the first and only cancer therapy that uses each cancer’s unique biology to autonomously determine where to deliver radiotherapy, second-by-second, during the actual cancer treatment to indicated solid tumors of any stage. SCINTIX therapy uses signals produced by a PET radiotracer interacting with cancer cells to control delivery of external-beam radiotherapy to tumor targets.

The prostate-specific PET radiotracer used in the presented study – 18F-DCFPyL (PyL) – binds to prostate-specific membrane antigen (PSMA), a protein that is expressed in significantly elevated amounts by prostate cancer cells. Also recently approved by the FDA for diagnosing and staging prostate cancer, PyL can accurately and precisely pinpoint tumors in both the prostate and in other body areas where the cancer may have spread or metastasized.

"It is well established that PyL exquisitely detects tumors present in patients with prostate cancer, but targeting and treating those tumors can be challenging using existing radiotherapy approaches," said Jeffrey Wong, M.D., professor of the Department of Radiation Oncology and the Department of Immunology and Theranostics at City of Hope, and principal investigator of the RefleXion-supported PyL imaging study. "SCINTIX therapy could overcome these barriers, and our study results support continued exploration of leveraging PyL’s precision to expand SCINTIX therapy to patients with prostate cancer."

The prospective PyL imaging study established that tumors arising from prostate cancer could be visualized on the RefleXion X1 platform using signals from PyL consistent with PyL diagnostic imaging studies, and that SCINTIX treatment plans could be generated using these data. PSMA-directed SCINTIX treatment plans also met conventional radiotherapy organ dose constraints, suggesting the ability to spare nearby organs and other healthy tissue from potentially damaging radiation. SCINTIX therapy is currently cleared for use with 18F fludeoxyglucose (FDG), a common PET radiotracer, to treat primary and metastatic tumors in the lung and bone.

"We look forward to offering FDG-directed SCINTIX therapy to our patients in the next several weeks," said Terence Williams, M.D., Ph.D., professor and chair of City of Hope’s Department of Radiation Oncology. "As early collaborators in evaluating SCINTIX technology, it is gratifying to see research and clinical development efforts already advancing it toward another patient population in great need of improved radiotherapy approaches using the well-characterized benefits of PyL."

The presentation entitled "A Prospective Pilot Study of the RefleXion X1 PET-CT Subsystem Imaging Performance with [18F]-DCFPyL PSMA in Patients with Prostate Cancer" was part of oral session SS10 "Focus on Clinical Studies – New Insights."

On June 26, 2023 Blue Earth Diagnostics, a Bracco company and recognized leader in the development and commercialization of innovative PET radiopharmaceuticals, reported results of a post-hoc analysis assessing the impact of urinary activity on the interpretation of POSLUMA (flotufolastat F 18) injection (formerly known as 18F-rhPSMA-7.3) PET/CT in prostate cancer (Press release, Blue Earth Diagnostics, JUN 26, 2023, View Source [SID1234632916]). The analysis was based on data from Blue Earth Diagnostics’ prospective Phase 3 LIGHTHOUSE and SPOTLIGHT studies that evaluated the diagnostic performance and safety of POSLUMA in newly diagnosed and recurrent prostate cancer. The majority read results from 3 blinded readers assessing 712 evaluable POSLUMA scans showed that urinary activity did not influence disease assessment for the majority (96%, 682/712) of patients and that halo artifacts, that can potentially inhibit image assessment, occurred very rarely (0.3%, 2/712). The results as reported expanded on the initial data from a single reader that were detailed in the abstract. Recently approved by the U.S. FDA, POSLUMA is indicated for positron emission tomography (PET) of prostate-specific membrane antigen (PSMA) positive lesions in men with prostate cancer with suspected metastasis who are candidates for initial definitive therapy or with suspected recurrence based on elevated serum prostate-specific antigen (PSA) level. The results were reported at the Society of Nuclear Medicine and Molecular Imaging (SNMMI) Annual Meeting, held June 24 – 27, in Chicago, Ill.

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"The ability to gather actionable information from PSMA PET scans is important for physicians to make informed decisions about patient management for men with prostate cancer," Phillip Kuo, MD, Ph.D., Departments of Medical Imaging, Medicine, and Biomedical Engineering. "Activity in the urinary bladder area is a common feature of PSMA-PET radiopharmaceuticals. It can potentially obscure tumors and lymph nodes in the prostate region, which is the most common site of recurrence, and interfere with accurate image interpretation. The data presented here build on early clinical experience and suggest that, among this large dataset from two Phase 3 prospective trials, POSLUMA urinary activity is relatively low and rarely impacts disease assessment."

"We are pleased to share these results about our new FDA-approved product, POSLUMA, with the imaging community at SNMMI," said David E. Gauden, D.Phil., Chief Executive Officer of Blue Earth Diagnostics. "POSLUMA represents a new class of PSMA-targeted PET radiopharmaceuticals based on novel radiohybrid technology. It is engineered to advance clinical decision-making by providing beneficial information for treatment planning in men with prostate cancer, which can lead to changes in patient management. In preclinical and Phase 1 studies, POSLUMA demonstrated a high binding affinity for PSMA, with low urinary bladder activity, thus providing the potential for enhanced image evaluation in the prostate and regions near the ureters for patients with prostate cancer. We conducted this post-hoc analysis of PET scans from the Phase 3 LIGHTHOUSE and SPOTLIGHT studies to further investigate these earlier findings. We believe that POSLUMA’s diagnostic performance, high-affinity PSMA binding and low urinary activity characteristics make it a valuable diagnostic tool that is radiolabeled with 18F for high image quality and readily available patient access."

Results presented at SNMMI were based on 712 evaluable POSLUMA scans (348 newly diagnosed patients and 364 patients with recurrent prostate cancer from LIGHTHOUSE and SPOTLIGHT, respectively). Of the 718 eligible scans, 6 were excluded on the basis of cystectomy, renal failure or presence of a urinary catheter. Findings included quantitative analyses of activity in the urinary bladder, based on maximum and mean standardized uptake values (SUVmax and SUVmean, respectively). Qualitative analyses conducted by 3 blinded, independent PET readers examined the impact of any urinary activity on the ability to assess the prostate/prostate bed and pelvic/retroperitoneal lymph nodes using a 3-point scale.

The median bladder SUVmax and SUVmean for POSLUMA were 17.1 and 12.5, respectively. For the qualitative metrics, by majority read, it was possible to distinguish urinary activity from disease uptake in 96% (682/712) of patients. Halo artifacts impacting assessment around the ureters and bladder were only observed in 0.3% (2/712) of patients.

There were several limitations to the study, including that it was not designed as a head-to-head comparison with other PSMA-PET radiopharmaceuticals and that any comparisons with data from other radiopharmaceuticals reported in the literature should be made with caution. Another limitation was that reader agreement was not formally tested. It should also be noted that, per the Important Safety Information for POSLUMA, the interpretation of POSLUMA PET in patients with suspected prostate cancer recurrence may differ depending on imaging readers, particularly in the prostate/prostate bed region.

Results of the presentation, "Post-hoc analysis of the LIGHTHOUSE and SPOTLIGHT studies to assess the impact of urinary activity on interpretation of 18F-rhPSMA-7.3," were presented at SNMMI on June 27, 2023, by Phillip Kuo, MD, Ph.D., Departments of Medical Imaging, Medicine, and Biomedical Engineering, University of Arizona, Tucson, Ariz. Full session details and the abstract are available in the SNMMI 2023 online program here.

Blue Earth Diagnostics’ LIGHTHOUSE Phase 3 clinical trial (NC04186819) was a prospective, Phase 3, multi-center, single-arm, imaging study conducted in the United States and Europe to evaluate the safety and diagnostic performance of POSLUMA PET in men with newly diagnosed prostate cancer. Results have been presented at the 23rd Annual Scientific Meeting in Urologic Oncology (SUO) in December 20221 and at ASCO (Free ASCO Whitepaper) GU in February 2023.2 The SPOTLIGHT trial (NCT04186845) was a Phase 3, multi-center, single-arm imaging study conducted in the United States and Europe to evaluate the safety and diagnostic performance of POSLUMA PET imaging in men with suspected prostate cancer recurrence based on elevated PSA following prior therapy. Results from the SPOTLIGHT study were published online on April 26, 2023 in the Journal of Urology: DOI: 10.1097/JU.0000000000003493.3

About POSLUMA (flotufolastat F 18)

POSLUMA (flotufolastat F 18) injection (formerly referred to as 18F-rhPSMA-7.3) is an optimized, targeted radiohybrid diagnostic imaging agent indicated for positron emission tomography (PET) of prostate-specific membrane antigen (PSMA) positive lesions in men with prostate cancer with suspected metastasis who are candidates for initial definitive therapy or with suspected recurrence based on elevated serum prostate-specific antigen (PSA) level. Precision PET imaging with POSLUMA can help identify the location and extent of prostate cancer, providing clinically valuable information to guide patient management. POSLUMA represents a new class of high-affinity PSMA-targeted PET radiopharmaceuticals based on novel radiohybrid technology and is labeled with the radioisotope 18F to provide readily available patient access and leverage the high image quality of 18F-labeled PSMA PET imaging to facilitate effective detection of disease. POSLUMA was approved by the U.S. Food and Drug Administration in May 2023.

About Radiohybrid Prostate-Specific Membrane Antigen (rhPSMA)

Radiohybrid Prostate-Specific Membrane Antigen (rhPSMA) compounds consist of a radiohybrid ("rh") Prostate-Specific Membrane Antigen-targeted receptor ligand which attaches to and is internalized by prostate cancer cells, and they may be radiolabeled with imaging isotopes for PET imaging, or with therapeutic isotopes for therapeutic use – providing the potential for creating a true theranostic technology. Radiohybrid technology and rhPSMA originated from the Technical University of Munich, Germany. Blue Earth Diagnostics acquired exclusive, worldwide rights to rhPSMA diagnostic imaging technology from Scintomics GmbH in 2018, and therapeutic rights in 2020, and sublicensed the therapeutic application to its sister company Blue Earth Therapeutics. Blue Earth Diagnostics received U.S. Food and Drug Administration approval for its radiohybrid PET diagnostic imaging product for use in prostate cancer in 2023. rhPSMA compounds for potential therapeutic use are investigational and have not received regulatory approval.

Indication and Important Safety Information About POSLUMA

INDICATION

POSLUMA (flotufolastat F 18) injection is indicated for positron emission tomography (PET) of prostate-specific membrane antigen (PSMA) positive lesions in men with prostate cancer

with suspected metastasis who are candidates for initial definitive therapy
with suspected recurrence based on elevated serum prostate-specific antigen (PSA) level
IMPORTANT SAFETY INFORMATION

Image interpretation errors can occur with POSLUMA PET. A negative image does not rule out the presence of prostate cancer and a positive image does not confirm the presence of prostate cancer. The performance of POSLUMA for imaging metastatic pelvic lymph nodes in patients prior to initial definitive therapy seems to be affected by serum PSA levels and risk grouping. The performance of POSLUMA for imaging patients with biochemical evidence of recurrence of prostate cancer seems to be affected by serum PSA levels. Flotufolastat F 18 uptake is not specific for prostate cancer and may occur in other types of cancer, in non-malignant processes, and in normal tissues. Clinical correlation, which may include histopathological evaluation, is recommended.
Risk of Image Misinterpretation in Patients with Suspected Prostate Cancer Recurrence: The interpretation of POSLUMA PET may differ depending on imaging readers, particularly in the prostate/prostate bed region. Because of the associated risk of false positive interpretation, consider multidisciplinary consultation and histopathological confirmation when clinical decision-making hinges on flotufolastat F 18 uptake only in the prostate/prostate bed region or only on uptake interpreted as borderline.
POSLUMA use contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer. Advise patients to hydrate before and after administration and to void frequently after administration. Ensure safe handling to minimize radiation exposure to the patient and health care providers.
The adverse reactions reported in ≥0.4% of patients in clinical studies were diarrhea, blood pressure increase and injection site pain.
Drug Interactions: androgen deprivation therapy (ADT) and other therapies targeting the androgen pathway, such as androgen receptor antagonists, may result in changes in uptake of flotufolastat F 18 in prostate cancer. The effect of these therapies on performance of POSLUMA PET has not been established.
To report suspected adverse reactions to POSLUMA, call 1-844-POSLUMA (1-844-767-5862) or contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Full POSLUMA prescribing information is available at www.posluma.com/prescribing-information.pdf.

On June 26, 2023 Adicet Bio, Inc. (Nasdaq: ACET), a clinical stage biotechnology company discovering and developing allogeneic gamma delta T cell therapies for cancer, reported positive safety and efficacy data from the Company’s ongoing Phase 1 study of ADI-001 for the potential treatment of relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma (NHL) (Press release, Adicet Bio, JUN 26, 2023, View Source [SID1234632915]).

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"These data are exciting and beyond what one might expect to see given that patients enrolled in the study were heavily pre-treated," said Francesco Galimi, M.D., Ph.D., Senior Vice President and Chief Medical Officer of Adicet Bio. "Autologous CD19 CAR T therapies were studied on CAR T naïve patients with a median of 3 prior lines of therapy. In contrast, the ADI-001 Phase 1 trial enrolled patients with a median of 4 lines of prior therapy and, importantly, 50% had previously progressed on autologous CAR T therapy. Despite the advanced nature of the patients at baseline in the ADI-001 Phase 1 study, at our recommended Phase 2 dose (DL4) ADI-001 demonstrated an overall CR rate of 63%, a 6-month CR rate of 25%, and in patients that had progressed following autologous CD19 CAR T therapy, the CR rate of ADI-001 was 67% with a 6-month CR rate of 33%."

Added Galimi, "We plan to transition the ADI-001 program into a potential pivotal Phase 2 study in post-CAR T LBCL in the first half of 2024. In addition, we expect to provide a clinical update which will include efficacy, 6-month CR rate, and safety data, from additional post-CAR T LBCL patients in the second half of 2024."

"The autologous CD19 CAR T market is estimated to have an annual run rate in excess of $2.2 billion and is growing given recent approvals in the second line setting. Unfortunately, approximately 60-70% of these patients progress, which represents a significant unmet medical need," said Chen Schor, President and Chief Executive Officer of Adicet Bio. "In May we met with the FDA and discussed the design of our first potentially pivotal Phase 2 study with an accelerated approval pathway. We are very encouraged by these data and look forward to advancing ADI-001 into the next stage of clinical development and progressing our pipeline of novel gamma delta T cell product candidates in both hematologic malignancies and solid tumors."

Data highlights as of the May 4, 2023 data-cut date were as follows:

Of the 24 efficacy-evaluable patients, 3 received ADI-001 at dose level 1 (DL1) (30 million CAR+ cells), 3 received ADI-001 at dose level 2 (DL2) (100 million CAR+ cells), 6 received ADI-001 at dose level 3 (DL3) (300 million CAR+ cells), 4 received two infusions of ADI-001 at DL3 (two doses of 300 million CAR+ cells, one on day 1 and the second dose on day 7 following a single lymphodepletion), and 8 received ADI-001 at dose level 4 (DL4) (1 billion CAR+ cells).
Patients were heavily pretreated with a median of 4 prior lines of therapy (range 2-9), had relatively high tumor burden, and had a poor prognostic outlook based on their median International Prognostic Index (IPI) score. 50% of patients enrolled in the study had progressed on prior CAR T.
ADI-001 treatment demonstrated a 71% ORR and 63% CR rate in the study across all dose levels.
ADI-001 demonstrated an 83% ORR and 67% CR rate in heavily pre-treated patients (4 median prior lines of therapy) who had progressed on prior CAR T.
ADI-001 demonstrated a 6-month CR rate consistent with autologous CAR T when factoring number of prior lines of therapy and percent of patients enrolled in the study who progressed on prior CAR T.
Adicet selected the recommended Phase 2 dose (RP2D) as 1 billion CAR positive cells (DL4).
At the RP2D (DL4) (with 4 median prior lines of therapy, 38% post-CAR T) the 6-month CR rate was 25%. At this dose level, in patients who had progressed on prior CAR T, the CR rate was 67% and the 6-month CR rate was 33%.
The expansion and persistence of ADI-001 at the RP2D exceed values reported for approved autologous CD19 CAR T cell therapy. DL4 demonstrated a mean Cmax of 483 cells/ul with a mean time-to-peak at approximately day 9 and demonstrated persistence through day 28 with a mean concentration of 21 cells/ul.
ADI-001 was generally well-tolerated in the study and there were no occurrences of dose-limiting toxicities or graft vs host disease (GvHD). Of the 24 patients evaluable for safety, there was 1 report of Grade 3 or higher CRS and 1 report of Grade 3 or higher ICANS.
In May, the Company completed a Type B meeting with the FDA and expects to transition the ADI-001 program into a potentially pivotal Phase 2 study in post- CAR T LBCL in the first half of 2024.
Table 1 – Summary of Phase 1 ADI-001 Preliminary Efficacy Data as of the May 4, 2023 data-cut date:

Median No. of Prior Lines

Post-CAR T Patients

ORR (%)

CR Rate (%)

3-month

CR Rate (%)

6-month

CR Rate (%)

DL4 (RP2D)

4

3/8 (37.5%)

6/8 (75.0%)

5/8 (62.5%)

4/8 (50.0%)

2/8 (25.0%)

DL4

(RP2D)

Post CAR T

4

3/3 (100.0%)

3/3 (100.0%)

2/3 (67.7%)

1/3 (33.3%)

1/3 (33.3%)

All Doses

4

12/24 (50%)

17/24 (70.8%)

15/24 (62.5%)

9/24 (37.5%)

4/24 (16.7%)

Post CAR T

All Doses

4

12/12 (100.0%)

10/12 (83.3%)

8/12 (66.7%)

4/12 (33.3%)

2/12 (16.7%)

Table 2 – Summary of Phase 1 ADI-001 Safety Data in Efficacy Evaluable Patients as of the May 4, 2023 data-cut date*:

DL1(N=3)

DL2(N=3)

DL3(N=6)

DL3 X2(N=4)

DL4(N=8)

Total (N=24)

Any Grade

Gr>=3

Any Grade

Gr>=3

Any Grade

Gr>=3

Any Grade

Gr>=3

Any Grade

Gr>=3

Any Grade

Gr>=3

CRS

2 (66.7%)

0

0

0

1 (16.7%)

1 (16.7%)

4 (100.0%)

0

4 (50.0%)

0

11 (45.8%)

1 (4.2%)

ICANS

0

0

1 (33.3%)

0

0

0

1 (25.0%)

1 (25.0%)

1 (12.5%)

0

3 (12.5%)

1 (4.2%)

GvHD

0

0

0

0

0

0

0

0

0

0

0

0

DLT

0

0

0

0

0

0

0

0

0

0

0

0

Infection

1 (33.3%)

1 (33.3%)

2 (66.7%)

0

3 (50.0%)

2 (33.3%)

2 (50.0%)

1 (25.0%)

3 (37.5%)

2 (25.0%)

11 (45.8%)

6 (25.0%)

SAE-TEAE

1 (33.3%)

1 (33.3%)

2 (66.7%)

2 (66.7%)

4 (66.7%)

3 (50.0%)

2 (50.0%)

2 (50.0%)

3 (37.5%)

2 (25.0%)

12 (50.0%)

10 (41.7%)

Related SAE-TEAE

1 (33.3%)

0

1 (33.3%)

1 (33.3%)

3 (50.0%)

2 (33.3%)

2 (50.0%)

2 (50.0%)

3 (37.5%)

2 (25.0%)

10 (41.7%)

7 (29.2%)

*Safety assessment was performed using the Common Terminology Criteria for Adverse Events (v5) and the American Society for Transplantation and Cellular Therapy criteria.

Webcast/ Conference Call Information

Adicet will host a webcast presentation on Monday, June 26 at 4:30pm ET to discuss the most recent data-cut from its ongoing Phase 1 study evaluating the safety and tolerability of ADI-001 for the potential treatment of relapsed or refractory B-cell NHL.

The live webcast of the presentation can be accessed by registering under "Presentations & Events" in the investors section of the Company’s website at View Source Upon registration, all participants will receive a confirmation email with a unique passcode to provide access to the webcast event. To participate via telephone, please join by dialing 972-9349-2674 (domestic) or 1-646-876-9923 (international) and referencing the conference ID 97293492674. An archived replay will be available for 30 days following the presentation. The archived webcast will be available on the Company’s website beginning approximately two hours after the event.

About ADI-001

ADI-001 is an investigational allogeneic gamma delta CAR T cell therapy being developed as a potential treatment for relapsed or refractory B-cell NHL. ADI-001 targets malignant B-cells via an anti-CD20 CAR and via the gamma delta innate and T cell endogenous cytotoxicity receptors. Gamma delta T cells engineered with an anti-CD20 CAR have demonstrated potent anti-tumor activity in preclinical models, leading to long-term control of tumor growth. In April 2022, ADI-001 was granted Fast Track Designation by the FDA for the potential treatment of relapsed or refractory B-cell NHL.

About the GLEAN Study

The Phase 1 study is an open-label, multi-center study of ADI-001 enrolling adults diagnosed with B-cell malignancies who have either relapsed, or are refractory to, at least two prior regimens. The primary objectives of the study are to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of ADI-001, and to determine optimal dosing as a monotherapy. For more information about the clinical study design, please visit www.clinicaltrials.gov (NCT04735471).

On June 26, 2023 Pacific Biosciences of California, Inc. ("PacBio") (NASDAQ: PACB) reported that it has entered into a privately negotiated exchange agreement with a holder of PacBio’s outstanding 1.50% Convertible Senior Notes due 2028 (the "2028 Notes"), pursuant to which PacBio will issue $441 million principal amount of its 1.375% Convertible Senior Notes due 2030 (the "New Notes") in exchange for $441 million principal amount of the 2028 Notes (the "Exchange Transaction"), in a transaction exempt from registration under the Securities Act of 1933, as amended, and the rules and regulations thereunder (Press release, Pacific Biotech, JUN 26, 2023, View Source;301861431.html [SID1234632914]). The Exchange Transaction is expected to close on or about June 30, 2023, subject to customary closing conditions.

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"In 2021, we issued $900 million in convertible notes due in 2028, enabling us to scale the company for growth. By exchanging a portion of these notes, we have extended the duration of our debt, and with our plans to achieve positive cash flows during 2026, this further strengthens our financial position and gives us greater flexibility," said Christian Henry, President and Chief Executive Officer of PacBio. "This exchange agreement comes at an opportune time as we bring some of the most innovative sequencing solutions to the market."

The New Notes will have an initial conversion rate of 46.5116 shares of PacBio’s common stock ("common stock") per $1,000 principal amount of the New Notes (which is equal to an initial conversion price of approximately $21.50 per share of common stock), subject to customary anti-dilution and other adjustments. The Notes will mature on December 15, 2030, unless earlier repurchased, redeemed or converted. The Notes will pay interest semi-annually on each June 15 and December 15, commencing on December 15, 2023, at a rate of 1.375% per annum. Upon conversion, the Company will have the right to elect settlement in cash, shares of common stock or any combination thereof in its sole discretion.

In exchange for issuing the New Notes pursuant to the Exchange Transaction, PacBio will receive and cancel the exchanged 2028 Notes. Following the closing of the Exchange Transaction, $459 million in aggregate principal amount of 2028 Notes will remain outstanding with terms unchanged.

Additional information regarding this announcement may be found in a Current Report on Form 8-K that the Company intends to file today with the U.S. Securities and Exchange Commission.

Goldman Sachs & Co. LLC acted as exclusive financial advisor to PacBio in connection with the Exchange Transaction.

On June 26, 2023 Fusion Pharmaceuticals Inc. (Nasdaq: FUSN), a clinical-stage oncology company focused on developing next-generation radiopharmaceuticals as precision medicines, reported the presentation of interim data from the dose escalation portion of the Phase 1 trial of [225Ac]-FPI-1434 (FPI-1434) in patients with solid tumors expressing IGF-1R (Press release, , JUN 26, 2023, View Source [SID1234632913]). The data will be presented by Neeta Pandit-Taskar, M.D., of Memorial Sloan Kettering Cancer Center, tomorrow at the Society of Nuclear Medicine and Molecular Imaging (SNMMI) Annual Meeting and will include molecular imaging, safety and pharmacokinetics (PK) from two dosing regimens: one with FPI-1434 alone ("hot only"), and another in which a small dose of cold antibody (naked IGF-1R antibody without the isotope) is administered prior to each dose of FPI-1434 ("cold/hot"). The poster presentation is available via the SNMMI Annual Meeting mobile application.

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"Antibody drug conjugates (ADCs) have shown tremendous success recently, driven in part by the benefits of using more potent payloads. We believe that the high potency of alpha emitters in place of conventional chemical toxins represents the evolution of the ADC field and is a significant and underexploited opportunity. While much is known about optimal dosing levels and paradigms for small molecule radiopharmaceuticals against well-known targets like PSMA, there is comparatively less experience for antibody-based alpha therapies in solid tumors. Consequently, in the Phase 1 study of FPI-1434, we undertook a stepwise dose exploration, in patients with various cancer types expressing IGF-1R, that included three stages: (i) hot only regimen in a single ascending dose escalation; (ii) hot only regimen in a multiple ascending dose escalation; and (iii) cold/hot regimen in a multiple ascending dose escalation. Learnings from this multi-part study have taken us a step further towards unlocking the potential of antibody-based TATs as next-generation ADCs," said Chief Executive Officer John Valliant, Ph.D.

Dr. Valliant continued, "We are pleased to report data and key learnings from our first antibody targeted alpha therapy (TAT) program which showed pre-administration of cold antibody prior to administering radiolabeled FPI-1434 has the potential to significantly enhance the therapeutic index by driving more active drug to tumor sites with an improved safety profile compared to hot-only dosing. In addition, with pre-administration of cold antibody, only a fraction of the injected amount of radiation is needed to achieve comparable exposures to hot-only cohorts. Results show the pharmacokinetic profile of 15 kBq/kg in the cold/hot regimen is comparable to 40 kBq/kg hot only, with a safety profile that made it possible to deliver up to five cycles thus far. With encouraging safety, dosimetry, and PK results, as well as stable disease observed in two heavily pretreated patients despite a low dose, we are continuing evaluation of the cold/hot regimen at a higher dose level in Cohort 2. We expect to share those results around the end of 2023."

The Phase 1, multi-center, open-label clinical trial is designed to investigate the safety, tolerability and pharmacokinetics of FPI-1434 in patients with solid tumors expressing IGF-1R. The trial is also designed to establish the maximum tolerated dose for FPI-1434 and the recommended Phase 2 dose. As part of the precision medicine approach, prior to receiving the therapeutic injection of FPI-1434, patients are administered an indium-111 imaging analogue, [111In]-FPI-1547 (FPI-1547). The images collected are used to confirm the presence of tumor uptake and ensure that estimated radiation doses to organs and tissues are below protocol-specified safety limits.

Based on results from an imaging sub-study evaluating pre-administration of cold antibody prior to each dose of FPI-1547 that demonstrated a favorable gain in tumor lesion uptake versus normal tissue, the Company amended the Phase 1 trial protocol to evaluate both the hot only and cold/hot dosing regimens.

Cold/Hot Dosing Regimen
In the cold/hot arm, three patients were dosed in Cohort 1 at a dose of 15 kBq/kg following pre-administration of cold antibody. In Cohort 1, cold/hot dosing was observed to be safe with no treatment-related serious adverse events (SAEs) or dose limiting toxicities (DLTs). Absorbed dose to critical organs (kidney, liver and lungs) in this dosing regimen were less than 7% of defined limits, supporting continued dose escalation.

Pre-administration of cold antibody demonstrated improved tumor uptake while also reducing hematological toxicity observed in the hot only dosing arm. When normalized to 15 kBq/kg, the average lesion absorbed dose and dose/volume in the cold/hot arm were nearly double the level compared to hot only. Further, 15 kBq/kg in the cold/hot dosing arm shows comparable systemic exposure to approximately 40 kBq/kg of a hot only dose, but shows an improved hematological safety profile as measured by changes in platelet count.

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. The dose level from Cohort 1, while sufficient to demonstrate marked differences in tumor uptake and achieve stable disease, was expected to be sub-optimal with respect to efficacy.

Fusion is currently enrolling Cohort 2 in the cold/hot dosing regimen at 25 kBq/kg and expects to report data from this cohort around year-end 2023.

Hot Only Dosing Regimen
In the hot only multiple ascending arm, six patients were dosed across two cohorts. Dose-dependent decrease in blood counts, particularly thrombocytopenia, was identified as the most common type of adverse event related to FPI-1434, with Grade 4 thrombocytopenia observed at 75 kBq/kg and 55 kBq/kg. The Company has discontinued dosing in the hot only dosing arm and no longer plans to use this method of FPI-1434 administration.

"Given the known expression of IGF-1R on multiple cancers, Fusion believes in the opportunity for FPI-1434 to treat a broad array of cancer types," said Chief Medical Officer Dmitri Bobilev, M.D. "We believe that thrombocytopenia observed at higher dose levels in the hot only part of the trial, may result at least in part from direct effect of FPI-1434 on IGF-1R-expressing megakaryocytes and from Fc-mediated binding in normal tissues. The ability to use pre-administration of cold antibody to block the IGF-1R receptors on normal cells and non-target specific binding and deliver higher doses of radioactivity to tumor cells is highly encouraging. We look forward to sharing results from the second cohort."

Following the conclusion of the SNMMI Annual Meeting, the presentation can be found at View Source

Fusion Conference Call Information
Fusion will host a live conference call and webcast tomorrow beginning at 4:00 p.m. ET/3:00 p.m. CT to discuss the data presentation. To access the live call, please dial 1-877-870-4263 (U.S.), 1-855-669-9657 (Canada) or 1-412-317-0790 (international) and reference Fusion Pharmaceuticals. A webcast of the conference call will be available under "Events and Presentations" in the Investors & Media section of Fusion’s website at View Source The archived webcast will be available on Fusion’s website shortly after the conclusion of the call and will be available for 90 days following the event.

About FPI-1434
FPI-1434 is a radioimmunoconjugate designed to target and deliver alpha emitting medical isotopes to cancer cells expressing IGF-1R, a receptor that is overexpressed on many tumor types. FPI-1434 utilizes Fusion’s Fast-Clear linker to connect a human monoclonal antibody that targets IGF-1R with actinium-225, a powerful alpha-emitting isotope with desirable half-life and decay chain properties.