On January 17, 2023 PAVmed Inc. (Nasdaq: PAVM, PAVMZ) ("PAVmed"), a diversified commercial-stage medical technology company operating in the medical device, diagnostics, and digital health sectors, and its majority-owned subsidiaries Lucid Diagnostics Inc. (Nasdaq: LUCD) ("Lucid" or "Lucid Diagnostics"), a commercial-stage cancer prevention diagnostics company, and Veris Health Inc. ("Veris"), a private digital health company focused on enhanced personalized cancer care, reported a strategic business update, outlining near-term strategic priorities and resource reallocation (Press release, PAVmed, JAN 17, 2023, View Source [SID1234626324]). The companies will prioritize near-term Lucid and Veris Health commercialization efforts. They have implemented a workforce reduction of approximately 20 percent, product portfolio streamlining, and other cost-cutting measures which seek to lower quarterly cash burn by at least 25 percent.

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"PAVmed and Lucid Diagnostics Strategic Business Update Conference Call"

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"Over the past few quarters, we have engaged in a systematic effort to maximize our cash runway and protect our long-term shareholder interests, while executing on our strategic objectives in what remain challenging market conditions," said Lishan Aklog, M.D., PAVmed’s and Lucid’s Chairman and Chief Executive Officer. "We have decided to further extend this initiative by aggressively streamlining operations to focus substantially all our resources and near-term efforts on accelerating the commercialization of Lucid’s and Veris’ products, resulting in a meaningful reduction in our workforce and quarterly cash burn. We believe these groundbreaking commercial products, with their large market opportunities, are our most valuable assets and focusing on them provides our shareholders the greatest near and long-term value creation opportunity. Our leaner, more commercially focused posture puts us in the best position to realize this opportunity."

Lucid’s EsoGuard Esophageal DNA Test ("EsoGuard") utilizing its EsoCheck Cell Collection Device remains the first and only commercially available diagnostic test recommended by clinical practice guidelines to prevent esophageal cancer deaths through early precancer detection. EsoGuard targets a well-established population of approximately 30 million at-risk patients and an estimated $60 billion addressable market based on an effective Medicare payment rate of $1,938, which is consistent with our per-test gross margins targets. The volume of EsoGuard tests performed at Lucid’s dedicated CLIA-certified laboratory has grown steadily in recent quarters. The company began submitting claims to commercial insurers in late third quarter of 2022 and is starting to generate claims histories necessary to drive in-network commercial contract discussions. Out-of-network payments received to date have respected the Medicare rate.

Pursuant to this initiative, Lucid plans to:

continue to drive EsoGuard testing volume through ongoing engagement of sales personnel with primary care physicians, specialists and institutions, with an increasing focus on closing larger strategic accounts and new market development initiatives;
maintain current team of approximately forty sales professionals, having completed targeted layoffs and closed prior vacancies;
shift sales leadership attention from recruiting and hiring to ongoing engagement with large institutional and strategic accounts, while continuing to drive productivity of the current team;
maintain its team of nurse practitioners and other clinical personnel to support testing volume growth through existing Lucid Test Centers (LTC) in eleven states, and its burgeoning satellite LTC program, whereby Lucid personnel perform EsoCheck cell sampling procedures at prescribing physicians’ offices;
continue to invest in LucidDx Labs to assure EsoGuard testing capacity and drive quality improvements and cost efficiencies;
complete ongoing clinical utility studies to support in-network coverage;
delay completion of the EsoGuard BE-2 study to the second half of 2023; and
pause further development of the EsoCure Esophageal Ablation device.
The Veris Cancer Care Platform, which commercially launched last month, is a digital cancer care platform with symptom reporting, telehealth functions, and advanced data analytics, designed to improve personalized cancer care through remote patient monitoring (RPM). Veris’ software-as-a-service recurring-revenue business model allows oncology practices to leverage existing RPM codes, providing attractive margins to the oncology practice and to Veris. The company is concurrently developing an implantable physiological monitor, designed to be implanted alongside a chemotherapy port, which will interface with the Veris Cancer Care Platform. The implantable monitor will further enhance the clinical and commercial value of the platform by providing continuous RPM data independent of patient compliance. With several million US patients undergoing cancer treatment each year, the addressable market opportunity for Veris’ products is substantial. Importantly, commercial success is not predicated on securing third-party reimbursement, only on sales and product development execution.

Veris plans to:

continue to drive commercial adoption of the Veris Cancer Care Platform utilizing its existing sales personnel, and expand the commercial team only when commercial traction has been well-established;
delay development and regulatory submission of the implantable physiologic monitor to the second half of 2023; and
focus its workforce on near-term commercialization, having already eliminated certain technology positions focused on future data analytics, while retaining personnel directly involved in customer integration and technical support.

PAVmed plans to:

continue research and product development activities in support of Lucid commercialization, including next generation EsoGuard and EsoCheck products;
continue product development activities in support of Veris commercialization, namely its implantable physiologic monitor, as above;

continue its joint early-stage research and development project with Novosound Ltd. to explore applying its groundbreaking ultrasound technology to next-generation intravascular ultrasound imaging;
continue limited business development activities focused on high value, near-term accretive opportunities that are synergistic with existing commercial activity;

indefinitely pause or halt all other product development activities including CarpX, PortIO and NextFlo; and
pursue additional cost-cutting initiatives including not paying annual cash bonuses.

Conference Call

To access the conference call, listeners should dial 877-407-3982 toll-free in the U.S. or 201-493-6780 and ask to join the "PAVmed and Lucid Diagnostics Strategic Business Update Conference Call". The conference call will be available live at the investor relations section of PAVmed’s website at ir.pavmed.com and the investor relations section of Lucid Diagnostics’ website at ir.luciddx.com. Following the conclusion of the conference call, a replay will also be available for one week and can be accessed by dialing 844-512-2921 toll-free in the U.S. or 412-317-6671, followed by the PIN number 13735527.

On January 17, 2023 Natera, Inc. (NASDAQ: NTRA), a global leader in cell-free DNA testing, reported the publication of a new study in Nature Medicine, which demonstrates the ability of the SignateraTM molecular residual disease (MRD) test to identify patients with stage II-IV colorectal cancer (CRC) who are at an increased risk of recurrence and predict who is likely to benefit from adjuvant chemotherapy (ACT) (Press release, Natera, JAN 17, 2023, View Source [SID1234626323]). With this study, data supporting the clinical validity and utility of Signatera has now been published in 40 peer-reviewed publications.

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The paper describes results from the GALAXY arm of the ongoing CIRCULATE-Japan trial, which is one of the largest and most comprehensive prospective studies of MRD testing in resectable CRC. The data builds on results previously presented at the 2022 ASCO (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium (ASCO GI), now with median clinical follow-up extended to 16.74 months and DFS assessment at 18 months.

In the study, 1,039 patients with stage II-IV resectable CRC were monitored prospectively using the Signatera MRD test. Key takeaways include:

Post-surgical MRD status was predictive of chemotherapy benefit.
Patients who were MRD-positive four weeks after surgery (18%) derived significant benefit from ACT (adjusted HR 6.59, p-value <0.001).
MRD-negative patients (82%) did not see a significant benefit from ACT (p-value <0.167).
Post-surgical MRD status was the most significant prognostic risk factor for recurrence, in a multivariate analysis that accounted for all clinicopathological risk factors currently used for prognostication (HR 10.82, p-value <0.001).
Pre-surgical detection rate of 95.9% in patients with pathologic stage II-III disease and 93.1% in patients with stage II-IV disease.
Signatera dynamics are indicative of treatment response. Among the MRD-positive patients who were treated with ACT, those with ctDNA clearance had superior DFS compared to those without ctDNA clearance (adjusted HR 11, p-value <0.0001).
"Until now, oncologists did not have adequate tools to determine which colorectal cancer patients are likely to benefit from adjuvant systemic therapy," said the study’s principal investigator, Dr. Takayuki Yoshino, of the National Cancer Center Hospital East, Kashiwa, Chiba, Japan. "This study provides strong evidence that Signatera MRD-positive patients will benefit significantly from adjuvant therapy, while MRD-negative patients may be safely observed, regardless of clinical or pathological stage."

"This is a practice-changing study for the colorectal cancer community, demonstrating the predictive power of Signatera in the adjuvant setting," said Minetta Liu, M.D., chief medical officer of oncology at Natera. "We are proud to partner with the CIRCULATE consortium and look forward to making Signatera accessible to all colorectal cancer patients in the U.S., Japan and worldwide."

About Signatera

Signatera is a custom-built circulating tumor DNA (ctDNA) test for treatment monitoring and molecular residual disease (MRD) assessment in patients previously diagnosed with cancer. The test is available for both clinical and research use, and has been granted three Breakthrough Device Designations by the FDA for multiple cancer types and indications. The Signatera test is personalized and tumor-informed, providing each individual with a customized blood test tailored to fit the unique signature of clonal mutations found in that individual’s tumor. Signatera is intended to detect and quantify cancer left in the body, at levels down to a single tumor molecule in a tube of blood, to identify recurrence earlier and to help optimize treatment decisions.

On January 17, 2023 Eclipse Bioinnovations (Eclipsebio), a leading RNA genomics company developing and commercializing novel, data-driven technologies that interrogate RNA, reported its new research demonstrating the optimization of Eclipsebio’s industry-standard eCLIP technology to improve the study of RNA-binding protein interactomes, which promises to accelerate the study of human diseases caused by failed RNA processing (Press release, Eclipse Bioinnovations, JAN 17, 2023, View Source [SID1234626322]). The study, published in Nature Methods, was led by Eclipsebio’s Associate Director of Research Daniel Lorenz, Ph.D., and co-founder Gene Yeo, Ph.D.

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"Multiplexed transcriptome discovery of RNA-binding protein binding sites by antibody-barcode eCLIP"

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Enhanced cross-linking immunoprecipitation followed by high-throughput sequencing, or eCLIP, is a powerful technique to uncover RNA sequences where RNA-binding proteins (RBPs) bind, known as RBP interactomes. RBPs regulate RNA molecules, controlling the function and quantity of proteins expressed in a cell. RBP mutations have been associated with cancer, amyotrophic lateral sclerosis, and a number of other diseases.

"eCLIP is a powerful technique that scientists utilize to study disease samples with RBP mutations, and this optimized antibody-barcode eCLIP (ABC) technology will allow a faster and more efficient study of RBP interactomes to gain new insights into novel disease targets and therapeutics," said Eclipsebio CEO and cofounder Peter Chu, Ph.D. "ABC is designed to optimize the study of RNA-binding protein interactomes in clinically relevant samples, including disease tissues, where source materials are rare and often scarce."

In this published study, Eclipsebio and UC San Diego scientists developed the ABC methodology that bypasses electrophoresis and membrane transfer and allows the study of interactomes of more than one RBP in the same reaction tube, which will support small sample volumes and sizes.

"We proved that ABC methodology maintains a comparable sensibility and specificity to eCLIP while improving the number of RBP interactomes that can be studied in one reaction tube," explained Dr. Yeo. "We showed that a single ABC library obtained from one reaction tube generates similar data to ten separate eCLIP experiments."

During eCLIP, there is an immunoprecipitation (IP) step, where an antibody against the RBP of interest is used to "grab" the binding RNA. In ABC, the IP step allows using more than one antibody in the same reaction tube, where each antibody is tagged with a different DNA barcode. After the IP step, a multiplex reverse transcriptase (RT) reaction identifies to which one of the RBP antibodies the RNA sequences were bound since the DNA barcode used serves as a primer for the RT reaction.

Dr. Chu concluded, "The Eclipsebio team is committed to developing the leading technologies to accelerate the study of RNA regulation, and this study opens the door to even further scaling. By increasing the number of barcodes used in each reaction tube, more interactomes could be studied simultaneously. We look forward to supporting important RBP research with our current and future eCLIP products that will include the ABC technology."

The publication entitled, "Multiplexed transcriptome discovery of RNA-binding protein binding sites by antibody-barcode eCLIP," is available open access on Nature Methods.

About Eclipsebio’s RNA Genomics Platform and Products

Eclipsebio’s comprehensive RNA genomics platform is poised to build the world’s most detailed multi-dimensional RNA maps through transcriptome-wide views of RNA interactions with RNA binding proteins (RBP-eCLIP), RNA modifications such as m6A (m6A-eCLIP), alternative transcription start site and polyadenylation site usage (EndSeq), and microRNA-mRNA interactions (miR-eCLIP). Upcoming products in development are designed to profile translation (eRibo) and probe RNA structure

On January 17, 2023 Avacta Group plc (AIM: AVCT), a life sciences company developing innovative, targeted oncology drugs and powerful diagnostics reported that AVA6000 continues to show a very favourable safety profile in the fourth dose cohort of the ALS-6000-101 dose escalation phase 1 clinical trial (Press release, Avacta, JAN 17, 2023, View Source [SID1234626321]). Additionally, analysis of tumour biopsies obtained from six patients across several cohorts indicates that doxorubicin is being released within the tumour tissue, confirming the tumour targeting potential of the pre|CISION technology.

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AVA6000 continues to be well tolerated by patients in cohort 4, with a marked reduction in the incidence and severity of the typical toxicities associated with the standard doxorubicin chemotherapy administration. Typical toxicities include alopecia, myelosuppression, nausea, vomiting, mucositis, and cardiotoxicity. Importantly, even at the highest dosing levels in cohort 4, equivalent to more than double the normal dose of doxorubicin, the typical drug-related cardiotoxicity of doxorubicin was not observed.

A number of tumour biopsies obtained from patients in different cohorts have also been analysed in order to confirm the release of the active chemotherapy, doxorubicin, in the tumour tissue. This analysis shows that AVA6000 targets the release of doxorubicin to the tumour tissue at therapeutic levels which are much higher than the levels being detected in the bloodstream at the same timepoint.

Nineteen patients with a range of advanced and/or metastatic solid tumours enrolled across four cohorts, have been administered AVA6000 to date. On the basis of the very favourable safety profile of AVA6000 in the study to date, the Safety Data Monitoring Committee (SDMC) has recommended continuation to higher dose cohorts with the aim of identifying a maximum tolerated dose (MTD) necessary to inform the dosing levels for the phase 1b and future studies. The Company expects that it will complete these additional cohorts during the first half of 2023.

Dr Alastair Smith, Chief Executive Officer of Avacta Group plc commented: "We’re delighted with the very positive data emerging from the dose escalation study of our lead pre|CISION tumour targeted therapy AVA6000. The very significant reduction in the usual toxicities, plus the observed release of doxorubicin at significant levels in the tumour tissue, show that the pre|CISION platform has the potential to significantly improve the safety and tolerability of chemotherapies, and other drugs, by targeting their release to the tumour.

"This is extremely encouraging as we work towards realising our vision of "chemotherapy without side effects" to make a meaningful difference to cancer patients’ lives.

"We are now in a position to proceed beyond the fourth cohort in the dose escalation study to even higher doses than originally anticipated, which is an unexpected and very positive development. The data being generated in the ALS-6000-101 study are providing detailed insights into the pre|CISION platform, which add significant value to the technology and confirm the potential of the pre|CISION platform."

On January 17, 2023 Asher Biotherapeutics, Inc. (Asher Bio), a biotechnology company focused on developing therapies to precisely engage specific immune cells to fight cancer, reported that the first patient has been dosed with AB248 in a Phase 1 first-in-human study, AB248-101. AB248, a CD8-targeted interleukin-2 (IL-2), is Asher Bio’s lead compound and first to enter the clinic for the treatment of patients with solid tumors (Press release, Asher Biotherapeutics, JAN 17, 2023, View Source [SID1234626320]). The Phase 1a/1b study, which consists of a dose escalation and expansion stage, will evaluate AB248 as a monotherapy and in combination with KEYTRUDA (pembrolizumab), Merck’s anti-PD1 therapy, in patients with recurrent locally advanced or metastatic solid tumors, including melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC) and squamous cell carcinoma of the head and neck (SCCHN). As previously announced, Asher Bio is conducting this Phase 1a/1b trial under a clinical trial collaboration and supply agreement with Merck (known as MSD outside the United States and Canada).

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"We are delighted to begin clinical evaluation of AB248, our most advanced product candidate," said Craig Gibbs, Ph.D., Chief Executive Officer of Asher Bio. "This is a significant milestone for Asher Bio and our efforts to deliver a new class of therapies that address the limitations of existing immune-based medicines by specifically targeting them to, and activating, only the desired immune cell type, thereby avoiding pleiotropic effects that can both hinder efficacy and drive toxicity. I am grateful to our research team, which advanced AB248 from ideation through preclinical development in only three years, and I look forward to working with our clinical partners at sites across the United States to evaluate the potential of AB248 to deliver better outcomes – and restore hope, health and happiness – to patients with difficult-to-treat solid tumors."

High dose IL-2 (aldesleukin, Proleukin) was the first modern immunotherapy to show long lasting, durable, complete responses in a subset of cancer patients, leading to its approval for the treatment of patients with metastatic melanoma and RCC.1 More recently, high dose IL-2 also demonstrated similar responses in melanoma and RCC patients who previously failed checkpoint inhibitor immunotherapy.2 However high dose IL-2 has been associated with significant toxicities limiting its clinical use, and newer second-generation (not α) IL-2 medicines are generally limited by off-target effects that both suppress anti-tumor responses and drive toxicity. In order to overcome these challenges, Asher Bio developed an innovative cis-targeting approach to deliver IL-2 only to a specific immune cell subset. AB248 is an investigational cis-targeted immunotherapy that was engineered to selectively activate CD8+ T cells, which drive anti-tumor efficacy, while avoiding NK cells, which can act as a pharmacological sink and contribute to toxicity, as well as avoiding Tregs, which are immunosuppressive. Preclinical data were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022, where AB248 demonstrated an approximately 1000-fold preference for the activation of CD8+ T cells over NK cells and Tregs.

"We are very excited to enter the clinical evaluation of AB248 to assess its therapeutic potential in patients who failed prior standard of care treatments, and are very thankful to Dr. Costantine Albany and staff at Horizon Oncology, Lafayette IN for treating the first patient on January 10th, 2023, as well as Dr. David Spigel at Sarah Cannon Research Institute at Tennessee Oncology, Nashville and Dr. Elizabeth Buchbinder at the Dana Faber Cancer Institute and their respective staff for their collaboration as we start our Phase 1 study," said Andrea Pirzkall, M.D., Chief Medical Officer of Asher Bio. "Our research team designed AB248 to enable improved safety and efficacy by acting only on CD8+ T cells. Preclinical data showed AB248 to have a highly differentiated pharmacodynamic profile relative to other IL-2 therapeutics, suggestive of a potentially best-in-class IL-2 therapy. We expect to know from pharmacodynamic data whether treatment with AB248 is having its desired effect and hope to achieve proof-of-mechanism early in our development effort. We look forward to reporting initial clinical data in the second half of 2023."

About AB248 Phase 1 Trial

AB248-101 is an open-label Phase 1a/b study consisting of a dose escalation and expansion phase to investigate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of AB248 alone and in combination with pembrolizumab in subjects with locally advanced/metastatic solid tumors who failed prior therapies. The dose escalation phase will follow the Bayesian Optimal Interval (BOIN) design and enroll subjects at multiple dose levels and frequencies for the AB248 monotherapy portion and pembrolizumab combination.

Upon determining a recommended dosing regimen, the study will open indication specific expansion cohorts to further evaluate monotherapy AB248 and the combination of AB248 and KEYTRUDA in patients with melanoma, RCC and NSCLC after failure to prior therapies, as well as first-line SCCHN. Please refer to www.clincialtrials.gov (NCT05653882) for additional details related to this Phase 1a/1b clinical trial.

"I am excited to begin administering AB248 to patients as part of this clinical trial," said Elizabeth Buchbinder, M.D., Dana-Farber Cancer Center and investigator in the Phase 1a/1b clinical trial. "Although there has been significant progress made in the treatment of patients with locally advanced and metastatic solid tumors, many patients remain underserved by existing options, particularly once they have failed therapy with immune checkpoint inhibitors. I am encouraged by the preclinical data supporting AB248’s differentiated profile and look forward to working with Asher Bio and fellow clinical investigators to evaluate AB248 in this Phase 1a/1b clinical trial."

KEYTRUDA is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA

About AB248
AB248 is a novel CD8+ T cell selective IL-2, generated by fusing a reduced potency IL-2 mutein to an anti-CD8β antibody. It was specifically engineered to selectively and potently activate CD8+ T-cells, while avoiding natural killer (NK) cells, which can act as a pharmacological sink and contribute to toxicity, and regulatory T (Treg) cells, which are immunosuppressive. In preclinical studies, AB248 exhibited an approximately 1,000-fold preference for the activation of CD8+ T cells over NK cells and Tregs. In preclinical murine tumor studies, AB248 demonstrated potent anti-tumor activity both alone and in combination with PD-1 checkpoint blockade in a wide variety of murine tumor models.