On April 10, 2021 Fusion Pharmaceuticals Inc. (Nasdaq: FUSN), a clinical-stage oncology company focused on developing next-generation radiopharmaceuticals as precision medicines, reported the presentation of preclinical data at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting (Press release, Fusion Pharmaceuticals, APR 10, 2021, View Source [SID1234577878]). The posters will be presented during the Preclinical Radiotherapeutics and Combination Immunotherapies sessions taking place today. The posters highlight the potential of Fusion’s targeted alpha therapies (TATs) to enable delivery of an alpha particle emitting isotope (actinium-225) as both monotherapies and combination therapies across multiple tumor types.

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"These data are the result of Fusion’s early investments in research to understand the power of combining our potent TATs with the latest generation of cancer therapies, such as checkpoint inhibitors and DNA damage response inhibitors (DDRis), and they reinforce our belief in the potential of our pipeline of TATs to redefine the utility of radiopharmaceuticals in the cancer treatment paradigm," said Fusion Chief Executive Officer John Valliant, Ph.D. "We believe we have an opportunity to advance clinical development of our product candidate FPI-1434 as monotherapy and in combination with these novel agents, leading to more treatment options for patients in earlier lines of therapy."

In one set of preclinical studies, highlighted in poster number LB130 titled, "Combination of IGF-1R Targeted Alpha Therapy with Olaparib Results in Synergistic Efficacy Against Colorectal and Lung Cancer Xenografts," results demonstrated that the delivery of alpha-particle radiation by FPI-1434 induced double-stranded DNA breaks and apoptosis in treated colorectal cancer tumor xenografts. Co-dosing with the PARP (poly ADP-ribose polymerase) inhibitor olaparib resulted in lower doses required for efficacy of FPI-1434 in lung and colorectal cancer tumor xenografts, supporting the potential clinical development of this combination.

In an additional set of preclinical studies, highlighted in poster number LB155 titled, "Combination of IGF-1R Targeted Alpha Therapy with Checkpoint Inhibitors Results in Synergistic Efficacy in Colorectal Cancer Syngeneic Model," data showed that treatment with IGF-1R TAT in combination with immune checkpoint inhibitors resulted in complete tumor eradication. Additionally, an increase in antigen-specific CD8 positive T cells and a strong "vaccine" effect were observed with the combination of IGF-1R TAT and immune checkpoint inhibitors, as noted by the prevention of tumor growth in animals that were reinoculated with the same tumor cells.

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.

On April 10, 2021 MEI Pharma, Inc. (NASDAQ: MEIP), a late-stage pharmaceutical company focused on advancing new therapies for cancer, reported preclinical data demonstrating that voruciclib, an orally administered cyclin-dependent kinase (CDK) inhibitor that is potent against CDK9, has single agent activity against multiple KRAS mutant cancer cell lines and synergistically inhibits growth of KRAS mutant cancers in combination with KRAS inhibitors (Press release, MEI Pharma, APR 10, 2021, View Source [SID1234577830]). The research is featured as an E-Poster Session presentation titled, "Voruciclib, a CDK9 inhibitor, downregulates MYC and inhibits proliferation of KRAS mutant cancers in preclinical models" at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021. Voruciclib is currently in a Phase 1b clinical trial as a monotherapy in patients with relapsed and/or refractory B-cell malignancies and acute myeloid leukemia (AML).

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To view the poster and a multimedia announcement with additional media and investor resources click here.

"Collectively, the data reported today offer the opportunity to expand our current development activities with voruciclib and support its potential as a therapeutic option for KRAS mutated cancers in combination with direct inhibitors of KRAS," said Daniel P. Gold, Ph.D., president and chief executive officer of MEI Pharma. "Beyond these data, we have ongoing efforts to explore other potential synergistic combinations in various KRAS mutated cancers as we evaluate opportunities to confirm these findings in a clinical setting."

KRAS mutated cancers are frequently associated with overexpression of MYC, a transcription factor regulating cell proliferation and growth. CDK9 is a known regulator of MYC transcription and a modulator of MYC protein phosphorylation. The data reported today in preclinical models demonstrates that voruciclib:

Results in a rapid decrease in the phosphorylation of proteins that promote MYC transcription
Rapidly decreases phosphorylation of MYC protein on Ser62, a site implicated in stabilizing MYC in KRAS mutant cancers
Possesses single agent activity against multiple KRAS mutant cancer cell lines both in vitro and in vivo
Synergistically inhibits KRAS G12C mutant cancer cell lines in combination with KRAS G12C inhibitors, both in vitro and in vivo
The full video presentation is available on our website here: View Source

About Voruciclib
Voruciclib is an orally administered CDK inhibitor differentiated by its potent in vitro inhibition of CDK9 in addition to CDK6, 4 and 1. CDK9 has important functions in cell cycle regulation, including the modulation of two therapeutic targets in cancer:

CDK9 is a transcriptional regulator of the myeloid leukemia cell differentiation protein ("MCL1"), a member of the family of anti-apoptotic proteins which, when elevated, may prevent the cell from undergoing cell death. Inhibition of CDK9 blocks the production of MCL1, which is an established resistance mechanism to the B-cell lymphoma ("BCL2") inhibitor venetoclax (marketed as Venclexta).
CDK9 is a transcriptional regulator of the MYC proto-oncogene protein ("MYC") which regulates cell proliferation and growth. Upregulation of MYC is implicated in many human cancers and is frequently associated with poor prognosis and unfavorable patient survival. CDK9, in addition to being a transcription factor for MYC, also decreases phosphorylation of MYC protein that is implicated in stabilizing MYC in KRAS mutant cancers. Targeting MYC directly has historically been difficult, but CDK9 is a promising approach to target this oncogene.
Voruciclib is currently being evaluated in a Phase 1b trial evaluating dose and schedule in patients with acute myeloid leukemia ("AML") and B-cell malignancies. Applications in solid tumors are also being explored, particularly in KRAS mutated cancers.

Investor and Analyst Video Webcast
MEI will host an investor and analyst video webcast event on Tuesday, April 13, 2021 at 8:00 AM Eastern Time reviewing data from the E-Poster Session presentation at AACR (Free AACR Whitepaper), in which MEI reported data demonstrating voruciclib downregulates MYC and synergizes with KRAS inhibitors to inhibit KRAS mutant cancers in preclinical models. The event will also include additional voruciclib data as well as an overview and update of MEI’s business.

You can access the live video webcast under the investor relations section of MEI’s website on the "Events and Presentation" page at: www.meipharma.com. A replay of the video webcast will be archived for at least 30 days after the conclusion of the live event.

On April 10, 2021 Freenome, a privately held biotechnology company that has pioneered a comprehensive multiomics platform for early cancer detection using a routine blood draw, reported results of an analysis revealing the potential to use its platform for patient stratification and monitoring (Press release, Freenome, APR 10, 2021, View Source [SID1234577863]). Plasma samples from patients with kidney (n=21), melanoma (n=14) or non-small cell lung cancer (n=91) revealed signatures of immune checkpoint inhibition treatment response found to be common across all three cancer types. Whole-genome cell-free DNA (cfDNA) sequencing identified 13 transcription factors and 269 genes that reveal a potential pathway of treatment resistance and a possible epithelial mesenchymal transition signature in responders. A subsequent longitudinal analysis on a subset of lung cancer patients also identified markers for treatment response.

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"These results show the promise of our multiomics platform, which combines signatures from both tumor- and non-tumor-derived sources," commented Mike Nolan, Chief Business Officer of Freenome. "A blood-based test that can predict and monitor treatment response would help address the clear need for improved biomarkers for cancer patients undergoing immune checkpoint inhibitor treatment, where responses are highly variable."

"This work further demonstrates the many applications of our multiomics platform, and highlights our commitment to understanding the full potential of cfDNA," commented C. Jimmy Lin, M.D., Ph.D., M.H.S., Chief Scientific Officer at Freenome. "Inferring nucleosome positioning through cfDNA is yet another way we can provide more insight to answer research questions and, ultimately, apply this to clinical questions that are integral to patient care."

Data were presented in a poster presentation at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting. The poster is available online at View Source

On April 10, 2021 Cardiff Oncology, Inc. (Nasdaq: CRDF), a clinical-stage biotechnology company developing onvansertib to treat cancers with the greatest medical need for new treatment options, including KRAS-mutated colorectal cancer, pancreatic cancer and castrate-resistant prostate cancer, in collaboration with scientists in the Center for Precision Cancer Medicine at the Massachusetts Institute of Technology (MIT), reported that new gene signature and mechanistic analyses related to its ongoing Phase 2 trial of onvansertib in metastatic castrate-resistant prostate cancer (mCRPC) were featured in a virtual oral poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 (Press release, Cardiff Oncology, APR 10, 2021, View Source [SID1234577879]).

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Analyses presented in the poster suggest that the androgen receptor signaling inhibitor (ARSi) abiraterone sensitizes certain prostate cancer cells to onvansertib by upregulating a set of mitosis related genes and disrupting mitotic spindle orientation. These results are consistent with previous findings showing that onvansertib and abiraterone synergize in an androgen receptor (AR)-independent manner in-vitro and in-vivo.

"The latest results from our collaborative studies with Cardiff Oncology provide important insight into the mechanisms of synergy between onvansertib and abiraterone in mCRPC," said Michael B. Yaffe, M.D., Ph.D., David H. Koch Professor of Science and Professor of Biology and Biological Engineering at the Massachusetts Institute of Technology. "Data showing a cellular mechanism for how these two compounds synergize in an AR-independent manner provide a strong scientific rationale for Cardiff Oncology’s ongoing Phase 2 trial and explain how the addition of onvansertib can improve clinical outcomes in patients showing initial abiraterone resistance. We have also identified a set of genes that appear to drive this mechanism of onvansertib-abiraterone synergy as well as predict patient response and archived clinical trial tissue from patients enrolled in the ongoing trial are being analyzed to confirm this hypothesis."

Mark Erlander, Ph.D., chief executive officer of Cardiff Oncology added, "The identification of a gene signature that appears to predict patient response to onvansertib-abiraterone combination therapy is encouraging, as is the finding that this signature is enriched in mCRPC patients with the known molecular basal tumor subtype. We look forward to continuing to work with our collaborators at MIT and Decipher Biosciences to validate this gene set as a predictive response biomarker. Validation of such a biomarker would be significant, as it would allow us to take a precision medicine approach to future trials by enabling the identification of patients most likely to benefit from therapy with onvansertib."

Highlights from the AACR (Free AACR Whitepaper) presentation include:

Inhibition of polo-like kinase 1 (PLK1) sensitizes CRPC cells to abiraterone, but not the ARSi enzalutamide, indicating that abiraterone and PLK1 inhibitors synergize in an AR-independent manner.
In vitro experiments and RNA sequencing analyses indicate that abiraterone’s AR-independent effects include the disruption of mitotic spindle orientation and the induction of a mitosis related gene signature.
Data suggest that the identified mitosis related gene signature may be predictive of patient response to onvansertib-abiraterone combination therapy, a hypothesis that is being further assessed in an ongoing Phase 2 trial evaluating the all-oral regimen of onvansertib, abiraterone and prednisone in mCRPC patients.
The identified mitosis related gene signature was found to be significantly enriched in the basal molecular subtype of prostate cancer.
The virtual poster, "The selective polo-like kinase (Plk1) inhibitor onvansertib and the antiandrogen abiraterone synergistically kill cancer cells through disruption of mitosis independently of androgen receptor signaling" by Patterson et al, is available for on-demand viewing on the AACR (Free AACR Whitepaper) Annual Meeting 2021 e-poster website and is also posted on the "Scientific Presentations" section of the Cardiff Oncology website at View Source

About the Phase 2 Trial of Onvansertib in Metastatic Castrate-Resistant Prostate Cancer

This trial is a Phase 2 open-label study of onvansertib in combination with abiraterone and prednisone, all administered orally, in patients with metastatic castration-resistant prostate cancer showing signs of early progressive disease (demonstrated by two rising prostate-specific antigen values separated by at least one week with no or minimal symptoms) while on Zytiga/prednisone therapy. The primary efficacy endpoint is the proportion of patients achieving disease control after 12 weeks of study treatment, as defined by a lack of prostate-specific antigen (PSA), radiographic, or symptomatic progression. The trial is being conducted by Beth Israel Deaconess Medical Center (BIDMC), Dana-Farber Cancer Institute (DFCI), and Massachusetts General Hospital Cancer Center (MGH). David Einstein, M.D., Genitourinary Oncology Program at BIDMC, is the principal investigator for the trial. For more information on the trial, please visit View Source

On April 10, 2021 Gilead Sciences reported that The PI3K inhibitors were once viewed as a blockbuster opportunity in blood cancer (Press release, Gilead Sciences, APR 10, 2021, View Source [SID1234577814]). But patient deaths in clinical trials for earlier-line use of Gilead Sciences’ first-to-market Zydelig dashed that hope. Now, in what could be viewed as a redemption of the drug class, Bayer’s Aliqopa has come up with a success safely.

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Adding Aliqopa to Roche’s Rituxan cut the risk of disease progression or death by 48% in patients with indolent non-Hodgkin’s lymphoma (iNHL) who relapsed after at least one prior therapy, according to data presented at the virtual American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting.

This showing makes Aliqopa the first PI3K inhibitor to demonstrate superior efficacy in combination with Rituxan with a manageable safety profile in patients with relapsed iNHL, Scott Fields, Bayer’s head of oncology development, said in a statement.

Bayer now plans to file the data to FDA and other drug regulators to potentially get Aliqopa into earlier, second-line iNHL, Barry Childs, Bayer’s global development lead for Aliqopa, said in an interview. The drug currently bears an accelerated approval in third-line follicular lymphoma (FL) based on tumor response data.

It also hopes the data, from the phase 3 Chronos-3 trial, could turn that conditional nod into a full one. The confirmatory trial Bayer has previously agreed with the FDA is actually the Chronos-4 study, which is testing Aliqopa in tandem with Rituxan and chemotherapy in relapsed iNHL. But Childs said the company will ask the FDA to consider using the current study instead, given that it’s also a randomized trial.

RELATED: Bayer gears up to take on Gilead in lymphoma with Aliqopa green light

For a second-line filing, Bayer intends to aim for a broader label for the whole iNHL population, though the FDA might pick apart each subset of disease, Childs and Fields cautioned during the interview.

Aliqopa’s benefits were shared across all prespecified iNHL subtypes in Chronos-3. For FL, the risk reduction amounted to 42%. The number was 52.5% for marginal zone lymphoma (MZL), 75.7% for small lymphocytic lymphoma (SLL) and 55.7% for Waldenstrom macroglobulinemia.

For the larger FL and MZL diseases, the subgroup analyses are powered to stand on their own, while the two smaller diseases aren’t statistically powered, according to Childs. That said, "there is consistent treatment effect," he added. "What we’re requesting of the FDA is that they will consider the treatment effect consistency to be part of their approval decision for the smaller subsets."

As for the perhaps more important data on Aliqopa’s ability to extend patient’s lives, Childs said the overall survival data were still immature after a median follow-up of 30 months as neither treatment arms has reached a median survival mark.

RELATED: Watch out, Gilead: TG Therapeutics wins FDA nod for potentially safer Zydelig rival

Gilead’s PI3K inhibitor Zydelig entered the U.S. market in 2014 for previously treated chronic lymphocytic leukemia, FL and SLL, bearing blockbuster hopes. However, the company was forced to cap several trials—including ones equivalent to Aliqopa’s Chronos-3 and Chronos-4—after reports of multiple deaths in its clinical programs in 2016. After that, the drug’s sales have never picked up, with just $72 million in 2020.

In Chronos-3, the Aliqopa regimen showed side effects that were generally consistent with the individual drugs, according to Bayer. Some of the frequent side effects such as hyperglycemia were transient and manageable, the company said.

There was however a relatively high discontinuation rate of 32% in the Aliqopa arm, versus 8% for solo Rituxan. The company is still exploring the exact reason, but Childs pointed to a higher rate of complete tumor clearance among Aliqopa patients, suggesting that some investigators may have chosen to discontinue patients especially during the pandemic because they were already in good remission. He also noted that the company took a very conservative protocol to discontinue patients who developed pneumonitis but only later realized that the side effect can be managed without taking patients off treatment.

RELATED: Bayer unveils first look at its post-Xarelto, post-Eylea life—and it’s better than expected

In terms of managing side effects, Childs pointed to Aliqopa’s intravenous administration—versus Zydelig and other PI3K inhibitors’ oral dosing—as an advantage as it can be given intermittently to allow normal tissues to recover between doses.

So far, Aliqopa still hasn’t earned a place in Bayer’s annual report, meaning that its 2020 sales were below the €262 million ($312 million) prostate cancer drug Xofigo raked in during the period. Verastem Oncology recently transferred its PI3K drug Copiktra to Secura Bio for $70 million upfront. That drug sold merely $9.3 million in the first half of 2020. TG Therapeutics just got a go-ahead for Ukoniq, and Incyte’s waiting in the wings with parsaclisib.

But as Bayer pharma chief Stefan Oelrich laid out at a recent investor event, the German company expects to see about €500 million in Aliqopa peak sales. With the Choronos-3 win, Bayer may now seek to move Aliqopa into earlier line of treatment and to markets beyond the U.S., Fields said.