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 Bolt Biotherapeutics, Inc. (Nasdaq: BOLT), a clinical-stage biotechnology company pioneering a new class of immuno-oncology agents that combine the targeting precision of antibodies with the power of both the innate and adaptive immune systems, reported that an online oral presentation with live Q&A and a Trial in Progress poster presentation for lead agent BDC-1001 are being presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 being held virtually from April 10-15th (Press release, Bolt Biotherapeutics, APR 10, 2021, View Source [SID1234618697]).

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The oral presentation explores immunosuppression mediated by various cells in the tumor microenvironment (TME), as well as the tumor-supportive nature of antigen presenting cells (APCs) in the TME in preclinical models. Reawakening these immunosuppressed APCs may result in a productive and durable anti-tumor immune response. Bolt is utilizing its Boltbody platform to create immune-stimulating antibody conjugates (ISACs), such as BDC-1001, that invoke this mechanism and provided complete tumor regression in preclinical tumor models.

"In murine models we have seen efficacy in a variety of tumors that are immunologically cold and well-established. Furthermore, consistent with our proposed mechanism of action for ISACs, we see evidence of increased myeloid and T cell infiltration in the tumor microenvironment mediated by BDC-1001 surrogate ISACs," said David Dornan, Ph.D., Chief Scientific Officer at Bolt Biotherapeutics. "We’re excited to share our rationale for selecting the linker-payload for BDC-1001 to optimize anti-tumor activity while minimizing the potential for the formation of anti-drug antibodies."

BDC-1001 is comprised of a tumor antigen-targeting monoclonal antibody (mAb), a trastuzumab biosimilar and an immune-stimulating agent (a TLR7/8 agonist) conjugated to each other with a non-cleavable linker. In a series of preclinical studies with BDC-1001, Bolt demonstrated the mechanism of action for their HER2-targeted ISAC. BDC-1001 surrogate was able to eliminate established, treatment-resistant tumors through the engagement of both innate and adaptive immunity. There were no adverse findings in toxicology studies of BDC-1001.

A Trial in Progress poster is also being presented by Manish R. Sharma, M.D. of START Midwest, a principal investigator in Bolt’s ongoing BDC-1001 Phase 1/2 trial. The poster details the design of the study: a four-part study with two dose-escalation parts and two dose-expansion parts. The study is evaluating BDC-1001 administered intravenously with or without an immune checkpoint inhibitor targeting PD-1 in up to 390 patients with HER2-expressing or HER2-amplified advanced or metastatic solid tumors. The dose escalation parts will evaluate sequential doses of BDC-1001 as a monotherapy or in combination with a PD-1 checkpoint inhibitor in a 3+3 design, with the ability to backfill up to an additional 12 patients in each dose cohort. The dose expansion parts will evaluate the recommended Phase 2 dose as monotherapy or in combination with a PD-1 checkpoint inhibitor in four cohorts of patients.

The primary objective of the dose escalation portion of the study is to assess safety as measured by the incidence of adverse events and serious adverse events; dose-limiting toxicities within the 3+3 design; and potential immune-related toxicities and determine the recommended phase 2 dose. Secondary objectives will evaluate pharmacokinetic parameters and pharmacodynamic biomarkers in tumor tissue and in peripheral blood associated with drug exposure. These exploratory studies will help reinforce the ISAC mechanism of action in humans and seek to identify biomarkers associated with BDC-1001 biological activity with or without an immune checkpoint inhibitor.

In January, Bolt presented a preliminary clinical update on the first 20 patients that showed early signs of clinical activity, including stable disease in several patients and a confirmed partial response by RECIST, and acceptable safety with all 20 patients completing their dose-limiting toxicity (DLT) evaluation period without DLTs or drug-related serious adverse events. Treatment-emergent adverse events deemed to be related to BDC-1001 have been mild or moderate in severity, including mild infusion-related reactions without interruption to dosing. Bolt expects to provide an update on the trial sometime in the second half of 2021.

About Bolt Biotherapeutics’ Immune Stimulating Antibody Conjugate (ISAC) Platform Technology
The Boltbody ISAC platform technology harnesses the ability of innate immune agonists to convert cold tumors into immunologically hot tumors, thereby illuminating tumors to the immune system and allowing them to be invaded by tumor killing cells. Boltbody ISACs have demonstrated the ability to eliminate tumors following systemic administration as monotherapy in preclinical models and have also led to the development of immunological memory, which is predicted to translate into more durable clinical responses for patients.

About the Ongoing BDC-1001 Phase 1/2 Study in Patients with HER2-Expressing Solid Tumors
The Phase 1/2, multi-center, open-label study is evaluating the safety, pharmacokinetics, pharmacodynamics and proof of mechanism of BDC-1001 in patients with HER2-expressing solid tumors. The first portion of the study includes a monotherapy dose-escalation phase in which cohorts of patients will receive ascending intravenous doses of BDC-1001 to determine the maximum tolerated dose and/or the recommended dose to advance into expansion cohorts and Phase 2 based on safety and tolerability. The second portion of the study is a dose expansion phase in which patients will receive BDC-1001 monotherapy to further evaluate the safety, tolerability and clinical antitumor activity of the recommended Phase 2 dose. Please refer to www.clinicaltrials.gov NCT04278144 for additional clinical trial information.

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.

On April 10, 2021 MacroGenics, Inc. (Nasdaq: MGNX), a biopharmaceutical company focused on developing and commercializing innovative monoclonal antibody-based therapeutics for the treatment of cancer, reported presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, taking place April 10-15, 2021 (Press release, MacroGenics, APR 10, 2021, View Source [SID1234577831]).

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"This year’s AACR (Free AACR Whitepaper) presentations highlight three antibody-based technologies upon which multiple molecules are being developed at MacroGenics," said Ezio Bonvini, M.D., Senior Vice President and Chief Scientific Officer of MacroGenics. "We are presenting pre-clinical data on MGC018, our clinical-stage, investigational antibody-drug conjugate (ADC) targeting B7-H3. At clinically relevant dose levels, MGC018 demonstrated potent antitumor activity in vivo in mouse patient-derived xenograft (PDX) models of squamous cell carcinoma of the head and neck (SCCHN). MGC018 is currently being investigated in a Phase 1 dose expansion study in advanced solid tumor cancers, including metastatic castration-resistant prostate cancer (mCRPC), non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC)."

"A second poster demonstrates that margetuximab, our Fc-engineered anti-HER2 mAb developed using our Fc Optimization platform, can upregulate checkpoint molecules on Natural Killer (NK) cells, CD8 T cells and tumor cells, potentially sensitizing them to immune checkpoint blockade. Consistent with this observation, PD-1 and LAG-3 blockade by tebotelimab, our investigational bispecific PD-1 × LAG-3 DART molecule, enhances margetuximab-mediated NK cell cytolytic activity in vitro," added Dr. Bonvini. "Finally, our third poster highlights pre-clinical data on IMGC936, an investigational ADAM9-directed ADC being developed in collaboration with ImmunoGen Inc. ADAM9 is highly expressed in a large number of solid tumors and our presentation shows that IMGC936 has activity against multiple solid tumor types in in vivo mouse PDX models. IMGC936 is currently being studied in a Phase 1 clinical trial evaluating safety and pharmacokinetics in cancer patients. Together, these results illustrate the drug development potential of all three technologies MacroGenics is deploying to identify and advance promising anti-cancer drug candidates."

Presentation details are as follows:

April 10, 2021, 8:30 AM – 11:59 PM
1555 – Enhanced HER2-dependent immune activation by margetuximab, an investigational Fc-engineered anti-HER2 mAb, supports combination with checkpoint blockade
Session PO.IM02.02 – Combination Immunotherapies

April 10, 2021, 8:30 AM – 11:59 PM
950 – Targeting B7-H3 in squamous cell carcinoma of the head and neck: Preclinical proof-of-concept with the investigational anti-B7-H3 antibody-drug conjugate, MGC018
Session PO.ET07.01 – Biological Therapeutic Agents

April 10, 2021, 8:30 AM – 11:59 PM
1841 – IMGC936, an investigational ADAM9-targeting antibody drug conjugate, is active against patient-derived ADAM9-expressing xenograft models
Session PO.IM02.10 – Therapeutic Antibodies, Including Engineered Antibodies

Posters of the above presentations may be accessed under "Events & Presentations" in the Investor Relations section of MacroGenics’ website at View Source

On April 10, 2021 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a late-stage targeted oncology company, reported initial preclinical results evaluating its investigational synthetic lethal PRMT5 inhibitor in methylthioadenosine phosphorylase (MTAP)-deleted cancer models (Press release, Mirati, APR 10, 2021, View Source [SID1234577848]). Mirati’s internally discovered PRMT5 compound is the first to specifically target the PRMT5/methylthioadenosine (MTA) complex. This approach is designed to leverage elevated levels of MTA in cancers exhibiting an MTAP deletion and to selectively kill cancer cells harboring this genetic alteration. The results were presented today during a late-breaking minisymposium at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting [Abstract # LB003].

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Preclinical results showed that the Mirati PRMT5 compound bound selectively to the PRMT5/MTA complex and demonstrated a greater than 100-fold selectivity for MTAP-deleted cells compared with cells that do not exhibit this genetic defect in both proliferation and mechanistic assays. This selectivity for the PRMT5/MTA complex and MTAP-deleted cancer cells allows for the selective targeting of cancer cells while sparing healthy cells, which are also dependent on PRMT5 for cell growth and survival. In addition, treatment of MTAP-deleted tumor xenograft-bearing mice with the Mirati PRMT5 compound resulted in halted tumor growth and near complete reduction of symmetric dimethylarginine (SDMA), a biomarker of PRMT5 activity, at well-tolerated dose levels.

"We are proud to have a potential first-in-class therapeutic agent to specifically target the PRMT5/MTA complex in MTAP-deleted cancer cells," said James Christensen, Ph.D., executive vice president and chief scientific officer, Mirati Therapeutics, Inc. "Based on discoveries made by Mirati scientists, we have designed a novel approach to specifically bind to and inhibit PRMT5 in complex with MTA. With this approach, we are able to target MTAP-deleted tumors, which should result in an improved therapeutic index relative to known PRMT5 and MAT2A inhibitors."

About PRMT5 Inhibition in MTAP-deleted Cancers

PRMT5 is an enzyme critical to the survival of both healthy and cancer cells and is partially inhibited by MTA, which accumulates in MTAP-deleted cancers. The MTAP deletion is present in approximately 10 percent of all cancers and is the most frequently observed gene deletion event (MTAP/CDKN2A) across several cancer types. Cancers with an MTAP deletion, such as pancreatic, lung, and bladder cancers, are associated with a poor prognosis, representing a significant unmet medical need.

Activated PRMT5 is crucial for the regulation of cellular processes essential for cell survival, including regulation of RNA splicing, gene expression and protein translation. In MTAP-deleted cancer cells, the inhibitory cofactor MTA accumulates and binds to PRMT5. Mirati’s PRMT5 compound selectively targets the PRMT5/MTA complex in MTAP-deleted cancer cells while sparing healthy cells. The Mirati PRMT5 compound is advancing toward an Investigational New Drug (IND) filing in the first half of 2022.