On September 22, 2020 The Upstate Foundation reported that it has awarded grants to two Upstate Medical University researchers to support their work on pediatric cancer (Press release, SUNY Upstate, SEP 22, 2020, View Source [SID1234565486]).

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Following a competitive grant application and evaluation process overseen by Upstate’s Pediatric Research Advisory Committee, chaired by Leonard Weiner, MD, vice chair of academic affairs, the Foundation is providing funding of $25,000 each for projects proposed by Jeffrey Amack, PhD, associate professor of Cell and Developmental Biology, and Jason Horton, PhD,assistant professor of Orthopedic Surgery.

The grants, made possible through an anonymous estate gift to the Upstate Foundation, honor September as Pediatric Cancer Awarness Month.

"We are pleased to help fund these projects," said Eileen Pezzi, vice president for development at Upstate. "This generous and kind donor had an abiding interest in supporting both pediatric and adult oncology research. We’re proud to fulfill her wish and honor her memory in this way."

Amack’s research project, titled Regulation of cell proliferation by V-ATPase activity, seeks to better understand the role that the proton (H+) pump V-ATPase plays in controlling cell proliferation in multiple tumor types, including in several pediatric cancers.

Horton’s research initiative, entitled Treatment of tumor-associated osteolysis in Ewing sarcoma, will seek to determine if the antibiotic Mithramycin A (MithA) can mitigate tumor-associated osteolysis typical of the highly metastatic pediatric bone cancer, Ewing sarcoma.

"The funded projects were selected because they were exceedingly well-considered, well-structured, and quite feasible in terms of the results they seek to achieve," said Weiner. "Additionally, the advisory committee has had the pleasure of seeing Dr. Amack devise, manage, and execute a previous research project. These two new efforts fall squarely into each researcher’s respective areas of expertise and experience."

Those interested in learning more about these research projects are encouraged to contact Amack at [email protected] and Horton at [email protected]

Caption: From left: Jeffrey Amack, PhD, associate professor of cell and developmental biology, and Jason Horton, PhD, assistant professor of orthopedic surgery, have been awarded grants by the Upstate Foundation to further their work in pediatric cancer research.

On September 22, 2020 Sorrento Therapeutics, Inc. (Nasdaq: SRNE, "Sorrento") reported the public release of the results of its’ multicenter, open-label, Phase 1b Study to Evaluate Safety and MTD of Epidural Resiniferatoxin Injection for the Treatment of Intractable Cancer Pain, at the 14th Annual Pain Therapeutics Summit held virtually from September 21 to 22, 2020 (Press release, Sorrento Therapeutics, SEP 22, 2020, View Source [SID1234565485]). Data was presented by Srdjan Nedeljkovic, MD, Associate Professor of Anesthesia, Harvard Medical School/Brigham & Women’s Hospital.

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"We are extremely encouraged by the results of this initial study. Even in patients with high levels of pain, RTX given via an epidural injection has been found to reduce pain intensity without having any long-term adverse safety consequences," said Associate Professor of Anesthesia, Srdjan S. Nedeljkovic, M.D. from the Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital at Harvard Medical School. "The patient population had intractable pain that did not respond to other standard therapeutic approaches, including opioids. The addition of RTX to the management of patients with intractable advanced-stage cancer pain offers the prospect of reducing suffering and improving quality of life for this underserved patient population".

This multicenter, open-label study enrolled 17 adults with intractable moderate to severe cancer pain. Subjects were treated with a one-time epidural administration of RTX at escalating dose level cohorts, ranging from 0.4 µg to 25 µg in 3 ml saline, in seven cohorts. The first participant in each cohort served as the "Sentinel" subject. The first two dosing cohorts (0.4 µg and 1.0 µg) each included one subject. Subsequent cohorts proceeded with three subjects each (2, 4, 8, 15 and 25 µg).

Enrollment of dose escalation cohorts has completed, with 17 subjects receiving RTX. 65% were women and 35% were men. The median age was 58 years (range 28-82 years). The baseline numerical pain rating scale (NPRS) average score was a mean of 6.8 (standard deviation (S.D.) of 1.65), and the baseline NPRS worst score was a mean of 7.9 (S.D. of 1.26).

No dose-limiting toxicities were reported. Dose escalation was completed at 25 ug. The most frequently reported treatment-emergent adverse event was transient post-procedural pain that was described in 47.1% of subjects. Post-injection-associated pain was managed with traditional short-term pain medications on the day of RTX injection. Typically, the RTX-associated pain following injection subsided before the 8-hour post-injection assessment and resolved within 24 hours in all subjects. Transient and reversible adverse events reported in at least two RTX-treated subjects were nausea (17.6%), vomiting (17.6%), and headache (17.6%). A total of 15 serious adverse events (SAEs) were reported, but none were deemed by the investigator to be related to RTX treatment. Most adverse events were attributed to the underlying cancer diagnosis.

Clinical efficacy (CE) was assessed at three efficacy levels: CE30, CE50 and CE70, defined as a 30%, 50% and 70% decrease in pain, respectively, for three consecutive days from the original baseline NPRS score of ≥ 6/10.

A positive outcome was observed in the lowest dose of RTX administered (0.4 ug) at the CE30 efficacy point. A dose-response relationship was observed, with the majority of responders at the 15 ug and 25 ug dose levels. Of the 17 subjects, 11 achieved the CE30 prespecified efficacy end-point using NPRS scores. Day 90 results for all RTX doses pooled are shown below:

Percentage decrease in Pain Average Pain Worst Pain
> 30% reduction from Baseline 64.7 % 47.1 %
> 50% reduction from Baseline 35.3 % 29.4 %
> 70% reduction from Baseline 23.5 % 17.6 %
PK data revealed no detectable drug in plasma in 15 of the 17 subjects. Minimally detectable levels of RTX were seen in 2 of the 17 subjects, in each case only at the initial post-injection time point.

RTX administration was well-tolerated when given as a one-time epidural injection at doses up to 25 ug. Preliminary clinical pain improvement was observed in the dose-escalation phase. Based on the results, though the protocol allowed exploration of a 35 mcg dose for this indication, a dose beyond 25 mcg was not deemed necessary to qualify the safety and clinically meaningful efficacy of the drug. These preliminary data support further study of epidural RTX in a broader patient population with what would be considered moderate to severe pain associated with cancer in this orphan indication.

For access to the poster associated with the scientific presentation, please visit Sorrento Investor Relations Site

Sorrento intends to rapidly advance to larger scale trials and expects to submit a request to proceed with a multicenter, blinded, controlled Phase 3 trial to the FDA in the upcoming weeks.

About Resiniferatoxin (RTX)

A thousand times "hotter" than pure capsaicin (16 Billion Scoville units versus 16M), and with a high affinity for afferent pain nerves, resiniferatoxin binds to TRPV1 receptors and selectively ablates the nerve endings responsible for pain signals experienced by patients1. Delivered peripherally (into the joint space) the transient nerve ending ablation effect can have profound clinical benefits lasting for months to years (as shown in canine studies2).

RTX-001 was a multicenter, open-label dose escalation Phase 1b study to assess the safety and define the maximally tolerated dose of resiniferatoxin administered via the epidural route for the reduction of moderate to severe pain signal intensity associated with advanced cancer. The Phase 1b study was a dose-escalation protocol in which cohorts of patients received increasing doses of resiniferatoxin until the maximum tolerated dose was achieved. The primary objective of the study was to evaluate the safety of resiniferatoxin and identify the recommended Phase 3 dose. The secondary objective was to assess the preliminary efficacy of resiniferatoxin measured by assessing changes in the intensity of pain using the NPRS score, a widely used proprietary validated pain scale.

RTX is not approved for clinical use by regulatory authorities. Safety and efficacy have not been established.

On September 22, 2020 MacroGenics, Inc. (NASDAQ: MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, reported the publication of a manuscript in Blood, a journal of the American Society of Hematology (ASH) (Free ASH Whitepaper), which highlights interim results of an ongoing Phase 1/2 clinical trial of flotetuzumab in patients with acute myeloid leukemia (AML) (Press release, MacroGenics, SEP 22, 2020, View Source [SID1234565482]). Flotetuzumab (also known as MGD006) is an investigational, clinical-stage bispecific DART molecule that recognizes both CD123 on leukemic cells and CD3 on T cells, with the intended result of T cell mediated killing of leukemic blasts.

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As described in the article titled "Flotetuzumab as Salvage Immunotherapy for Refractory Acute Myeloid Leukemia," 88 AML patients were enrolled in the Phase 1/2 trial as of November 1, 2019, including 42 in dose escalation and 46 treated with flotetuzumab at the recommended Phase 2 dose (RP2D) of 500ng/kg/day. The majority (56%) had adverse risk by ELN 2017 criteria and 36% had secondary AML. Patients were heavily pretreated, with a median of three lines of prior therapy (range 1-9). Collectively, this group of patients represents a poor-prognosis population having few effective therapies and an otherwise limited life expectancy.

The most common treatment-related adverse event (TRAE) was infusion-related reaction/cytokine release syndrome (IRR/CRS), the majority reported as grade 1-2. Stepwise dosing during week 1, pre-treatment with dexamethasone, prompt use of tocilizumab and temporary dose reductions/interruptions successfully prevented severe IRR/CRS, resulting in acceptable tolerability.

As described in the publication, of 50 evaluable patients with relapsed or refractory AML, 30 patients entered the study with no prior response to induction therapy (primary induction failure AML or PIF AML) or having relapsed within six months of achieving an initial remission (early relapsed AML or ER AML), a combined population with poor prognosis and high unmet medical needs. This PIF/ER AML subset of patients showed a 16.7% (5/30) complete remission (CR) rate and a combined CR and complete remission with partial hematological recovery (CRh) rate of 26.7% (8/30) following flotetuzumab treatment. In contrast, only one of 20 patients with late relapsed AML achieved a CR following flotetuzumab treatment. PIF/ER patients who achieved CR/CRh showed median overall survival (OS) of 10.2 months (range 1.87-27.27), with 6- and 12-month survival rates of 75% (95% CI, 0.450-1.05) and 50% (95% CI, 0.154-0.846).

"The response to flotetuzumab in primary induction failure and early relapsed AML is consistent with our previously published data1 that an IFN-γ-related inflammatory gene expression signature in the AML bone marrow correlated with lack of response to induction chemotherapy but was associated with a greater likelihood to respond to flotetuzumab," said Sergio Rutella, M.D., Ph.D., FRCPath, John van Geest Cancer Research Centre, College of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom, and a co-author on the current paper. "AML is a highly heterogeneous disease. Our translational studies provided a strong mechanistic basis for studying flotetuzumab in these AML patients, who currently have few treatment options."

"The results recently published in Blood support our decision to conduct a pivotal study of flotetuzumab in the specific subset of AML patients who have previously experienced either a primary induction failure or an early relapse when treated with standard-of-care chemotherapy regimens. These individuals represent approximately 40-50% of all AML patients," said Scott Koenig, M.D., Ph.D., President and CEO of MacroGenics. "Moreover, the translational research provides a strong mechanistic basis for studying flotetuzumab in these AML patients, who currently have few treatment options. Our single arm clinical trial is ongoing as an expansion of the Phase 1/2 study, for which we plan to enroll a total of up to 200 patients. We plan to present interim results later this year."

1 "Immune Landscapes Predict Chemotherapy Resistance and Immunotherapy Response in Acute Myeloid Leukemia," Science Translational Medicine, 2020.

About Acute Myeloid Leukemia

AML is a hematological malignancy characterized by differentiation arrest and uncontrolled clonal proliferation of neoplastic precursors that prevent normal bone marrow hematopoiesis. Nearly 20,000 new cases of AML are diagnosed in the U.S. each year, with a median age of 69 years at diagnosis. Approximately 40-50% of newly diagnosed patients fail to achieve a complete remission with intensive induction therapy (primary induction failure) or experience disease recurrence after a short remission duration (<6 months; early relapsed). A very small number of these patients are expected to respond to salvage therapy. Although new targeted agents have been approved for the treatment of frontline or relapsed/refractory AML in recent years, approximately 50% of patients have no known targetable mutations. The discovery by the Rutella lab of an immunological gene signature in the AML tumor microenvironment forms the basis for a potential predictive biomarker for further clinical validation.

About Flotetuzumab

Flotetuzumab (also known as MGD006) is a clinical-stage bispecific DART molecule that recognizes both CD123 and CD3. CD123, the interleukin-3 receptor alpha chain, has been reported to be over-expressed on malignant cells in AML and other hematologic malignancies. The primary mechanism of action of flotetuzumab is believed to be its ability to redirect T lymphocytes to kill CD123-expressing cells. To achieve this, the DART molecule combines a portion of an antibody recognizing CD3, an activating molecule expressed by T cells, with an arm that recognizes CD123 on the target cells. Data from the Phase 1/2 clinical study of flotetuzumab in patients with primary induction failure / early relapse (PIF/ER) AML were presented in December 2019 at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting. MacroGenics is conducting a single-arm, registration-enabling clinical study to evaluate flotetuzumab in up to 200 patients with PIF/ER AML, with complete remission (CR) and CR with partial hematological recovery (CRh) as the primary endpoint. The study will be conducted as a continuation of the ongoing Phase 1/2 study (NCT02152956; to be updated). The FDA has granted orphan drug designation to flotetuzumab for the treatment of AML.

On September 22, 2020 ImmuPharma plc (LSE:IMM) (Euronext Growth Brussels: ALIMM), the specialist drug discovery and development company, reported on 2 September 2020 that following the placing, both Lind Global Macro Fund, LP ("Lind") and L1 Capital Global Master Opportunities Fund ("L1") had the right to require repayment of a portion of their convertible security issued pursuant to the convertible security deed dated 10 June 2020, details of which were announced by the Company on 11 June 2020 (Press release, ImmuPharma, SEP 22, 2020, https://www.immupharma.co.uk/repayment-convertible-security-lind-global-macro-fund-lp/ [SID1234565481]).

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The Company announces that Lind has requested repayment of part of its convertible security. The amount to be repaid in accordance with the terms of the convertible security deed is $1,068,762.50 leaving an amount outstanding under the Lind convertible security of $355,112.50.

L1 has not exercised its right to repayment.

Following the repayment the Company still expects to have sufficient cash resources to fund operations through the end of 2023.

On September 22, 2020 IMMUNOPRECISE ANTIBODIES LTD. (the "Company" or "IPA") (TSX VENTURE: IPA) (OTCQB: IPATF) (FSE:TQB2), a leader in full-service, therapeutic antibody discovery and development, reported that its subsidiary, IPA Europe, has made a substantial investment in its B-Cell Select platform at its research division in Oss, The Netherlands, enabled by investments in additional equipment to automate and significantly innovate their multi-species, target-interaction-based single B-cell selection technology and subsequent single cell cloning, thereby significantly accelerating the identification of comprehensive panels of diverse lead therapeutic antibodies (Press release, ImmunoPrecise Antibodies, SEP 22, 2020, View Source [SID1234565480]). The advanced B Cell Select platform seamlessly integrates into IPA’s optimization and antibody developability profiling workflow.

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"Our dedicated and motivated team members are driving the success our B Cell Select platform expansion. This powerful, multi-species platform is combined with direct, single B cell cloning and antibody binding profiling to rapidly identify highly diverse, clinically relevant antibodies to treat various diseases involving a broad variety of complex target antigens." stated Debby Kruijsen, General Manager of IPA Europe.

"Next to its suitability for a broad range of antibody sources, our advanced B Cell Select platform is also compatible with various target tools, including target-expressing cells, enabling us to select clones at an early stage of antibody discovery based on a functional read-out as well." says Ilse Roodink, Scientific Director of IPA-EU.

Interested in learning more? Our second-generation B Cell Select platform will be one of IPA’s showcased technologies presented at our webinar "High-Throughput Identification of Genetically Distinct, Target-Specific Antibodies", airing September 23rd at 11:00 EDT. Click here to register online.

About B Cell Select

ImmunoPrecise Antibodies’ B Cell Select platform enables the interrogation of a greater diversity of an antibody repertoire than otherwise possible. By interrogating isolated B-cells, IPA can analyze full organism repertoires with very little manipulation. This proprietary platform is species independent allowing for the generation of antibodies from samples not possible using other methods. B Cell Select can develop antibodies from any species (including humans) as well as from any tissue. As the platform explores the entire antibody repertoire, it can develop antibodies for anything that is possible in an animal’s immune repertoire including any protein class, complex therapeutic targets, post-translational modifications, and small molecules.

The B Cell Select platform enables the interrogation of 10 million blood cells to generate native monoclonal antibodies from immunized animals that specifically target an antigen. The B cell selection process takes place early in the antibody development process allowing for the rapid selection of top candidates, drastically increasing the success rate of antibody discovery. The platform also harnesses the power of the immune system to generate natural pairing of the antibodies produced by selected B cells. These deliverables in our discovery programs have less liabilities within the antibody sequences compared to unnatural pairs from in vitro screening that could potentially affect manufacturability of the antibodies.