On January 18, 2022 Moleculin Biotech, Inc., (Nasdaq: MBRX) ("Moleculin" or the "Company"), a clinical stage pharmaceutical company with a broad portfolio of drug candidates targeting highly resistant tumors and viruses, today reported that it has received an updated independent safety review of certain preliminary data for the first 30 patients in its three Phase 1 clinical trials with Annamycin targeting relapsed or refractory acute myeloid leukemia (AML) and the metastases of soft tissue sarcoma to the lungs (STS Lung), which concluded there was no evidence of cardiotoxicity (Press release, Moleculin, JAN 18, 2022, View Source [SID1234605545]). The review included analysis of ejection fraction, echo strain and certain troponin levels intended to assess potential for both acute and chronic heart damage. Additionally, the Company reported evidence that Annamycin may have a substantially lower incidence of alopecia (hair loss) than currently prescribed anthracyclines such as doxorubicin. Although 65%-92% of patients treated with doxorubicin typically experience hair loss, the incidence to date in patients treated with Annamycin is less than 10%1. Alopecia is considered an important factor in quality of life for many cancer patients.

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Two of the three clinical trials, as described more fully below, are ongoing and the data from those trials remain preliminary and are subject to change and future updates. The ongoing trials are both in the dose escalation phase (Phase 1) with the goal of determining the recommended Phase 2 dose (RP2D). In the course of this dose escalation, 19 of the 30 patients that have been reviewed to date have now been dosed above the lifetime maximum anthracycline limit currently set by the US Food and Drug Administration (FDA), further underscoring the potential for Annamycin to improve patient safety.

"Annamycin was designed to produce little to no cardiotoxicity, so we are pleased to see that this updated report continues to support that objective," commented Walter Klemp, Chairman and CEO of Moleculin. "This is a critical safety improvement in the field of anthracyclines since the risk of cardiotoxicity is the primary limitation in the use of currently prescribed anthracyclines. The apparent reduction in the incidence of hair loss is an added benefit that has the potential to significantly improve the quality of life for patients needing anthracycline therapy. We are also encouraged by the pace of recruitment for the STS Lung clinical trial and look forward to hopefully continuing the current pace of cohort updates. While the European AML trial has been slow in recruiting, we expect to announce an update regarding the next cohort in the first quarter of 2022."

1 Gonzalez et al. 2018; DOXORUBICIN HYDROCHLORIDE [package insert]. New York, NJ: Pfizer Injectables; 2019

An expert in assessing cardiotoxicity associated with chemotherapy at the Cleveland Clinic, the author of the independent review of Annamycin’s cardiac safety data added, "Although anthracyclines continue to be a cornerstone of chemotherapy for many cancer indications, their use has been limited due to the threat of both acute and chronic cardiotoxicity. The availability of an anthracycline that eliminated this risk would be a major advancement in patient safety."

Dr. Sant Chawla, Director of the Sarcoma Oncology Center, Director of the Cancer Center of Southern California, and a Principal Investigator in Moleculin’s STS Lung clinical trial concluded, "Patients often face difficult choices in an effort to balance the objectives of cancer therapy with quality of life. Having the ability to offer my patients a treatment alternative that substantially reduces the risk of alopecia would make Annamycin a valuable new alternative for patients who until now have had limited options."

Summary of Annamycin Clinical Trials

STS Lung Clinical Trial

The Phase 1b/2 study is an ongoing U.S. multi-center, open-label, single-arm study, which in its Phase 1b stage, will determine the maximum tolerated dose (MTD) or the recommended Phase 2 dose (RP2D) and safety of Annamycin. The Phase 2 portion of the study will explore the efficacy of Annamycin as a single agent for the treatment of subjects with STS with lung metastases for whom prior chemotherapy has failed, and for whom new chemotherapy is considered appropriate. A minimum of three subjects will be enrolled in each cohort of the Phase 1b portion of the study until an MTD is identified, after which there will be a recommendation for the RP2D based on an assessment of both safety and efficacy. Up to 25 subjects will be enrolled at the RP2D in Phase 2 to further evaluate efficacy. The Company has now opened enrollment in the fourth cohort of the Phase 1b portion of the study with dosing increased to 390 mg/m2. Three subjects minimum (6 maximum) for this and each subsequent dosing cohort will be enrolled until a maximum tolerated dose is identified. Therefore, up to 36 subjects may be enrolled in the Phase 1b portion of the study.

AML Europe Phase 1/2 Clinical Trial

The Phase 1/2 AML trial in Poland remains ongoing and is currently dosing patients at 240 mg/m2. Under the previous protocol transient elevated liver enzymes (AST and ALT) observed in two patients were initially deemed to be a dose limiting toxicity (DLT), however investigators believed this would inappropriately limit the potential for continued dose escalation. An amendment to the Annamycin clinical trial protocol was therefore undertaken, which allows for a change in the DLT criteria as it relates to transient grade 3 elevations and allows for the dosing of three additional patients in the 240 mg/m2 cohort. If no DLT (as defined by the new criteria) is experienced with these next three patients, the Company plans to escalate dosing in new cohorts by 30 mg/m2 instead of the 60 mg/m2 previously planned, and with a de-escalation of 15 mg/m2 at the DLT dose if future patients experience a DLT.

AML US Phase 1/2 Clinical Trial

The results from the Phase 1 portion of the Company’s U.S. Phase 1/2 clinical trial of Annamycin for the treatment of AML met its primary endpoint and demonstrated a clean safety profile with no evidence of cardiotoxicity when delivered to patients at or below the lifetime maximum anthracycline dose established by the FDA. The Company is awaiting data from its European AML trial prior to continuing with the Phase 2 portion of this trial.

About Annamycin

Annamycin is the Company’s next-generation anthracycline that has been shown in animal models to accumulate in the lungs at up to 30-fold the level of doxorubicin. Importantly, Annamycin has also demonstrated a lack of cardiotoxicity in multiple human clinical trials, including ongoing trials for the treatment of relapsed or refractory acute myeloid leukemia (AML) and soft tissue sarcoma (STS) lung metastases, and the Company believes that the use of Annamycin may not face the same usage limitations imposed on doxorubicin, one of the most common currently prescribed anthracyclines. Annamycin is currently in development for the treatment of AML and STS lung metastases and the Company believes it may have the potential to treat a number of additional indications.

Annamycin currently has Fast Track Status and Orphan Drug Designation from the U.S. Food and Drug Administration for the treatment of STS lung metastases, in addition to Orphan Drug Designation for the treatment of relapsed or refractory acute myeloid leukemia. For more information about the Phase 1b/2 study evaluating Annamycin for the treatment of STS lung metastases, please visit clinicaltrials.gov and reference identifier NCT04887298.

On January 18, 2022 Turning Point Therapeutics, Inc. (NASDAQ: TPTX), a precision oncology company developing next-generation therapies that target genetic drivers of cancer, reported updates and anticipated milestones across its 2022 strategic objectives (Press release, Turning Point Therapeutics, 18 18, 2022, View Source [SID1234605604]).

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"As we look to 2022, we are focused on continuing progress across our clinical stage pipeline and expanding our discovery engine," said Athena Countouriotis, M.D., president and CEO. "We are encouraged that all six cohorts in our registration enabling TRIDENT-1 study for our lead drug candidate repotrectinib continue to enroll at a strong pace and we look forward to providing topline BICR data from the ROS1-positive NSCLC cohorts in the second quarter of this year. With our strong balance sheet and organizational growth and leadership, we are well positioned to continue to make rapid progress across our entire portfolio."

The company’s key strategic priorities are:

1. ADVANCE REPOTRECTINIB PROGRAM

The company announced today that the Phase 2 registration enabling TRIDENT-1 study had strong progress across all cohorts for enrollment during the fourth quarter of 2021 with expansion cohort 4 (EXP-4 — ROS1-positive advanced NSCLC population pretreated with one prior TKI without chemotherapy) now fully enrolled with the targeted 60 patients. Enrollment across all six cohorts of the study remains open and continues to progress steadily. Enrollment in EXP-4 is ongoing to provide continued access to new patients.

Data from ROS1-positive TKI-naïve NSCLC patients in the Phase 1 portion of the TRIDENT-1 trial continue to demonstrate best-in-class potential. The duration of response (DOR) for 6 responder patients, among a total of 7 patients treated at or above the recommended Phase 2 dose, ranged from 5.6 to 42.2+ months with 3 patients who had DOR of greater than 30 months. DOR was calculated using blinded independent central review (BICR) assessments as of the data cut-off date of July 22, 2019 followed by physician assessments as of the data cut-off date of November 29, 2021. Duration of treatment for the 7 patients ranged from 10.9 to 45.8+ months with 4 out of 7 patients remaining on treatment for greater than 3 years as of the data cut-off date of November 29, 2021.

The company anticipates discussing with the U.S. Food and Drug Administration (FDA) topline BICR data from all of the ROS1-positive NSCLC cohorts from TRIDENT-1 at a pre-NDA meeting in the second quarter of 2022.The company plans on reporting the BICR results, including both objective response rate (ORR) and DOR, in the second quarter of 2022 prior to the pre-NDA meeting.

The company anticipates providing a clinical data update from the NTRK-positive advanced solid tumor cohorts from TRIDENT-1 in the second half of 2022.

2. ADVANCE OTHER PIPELINE PROGRAMS

ELZOVANTINIB (TPX-0022), MET/SRC/CSF1R INHIBITOR

Patient enrollment continues in the SHIELD-1 study at 40 mg QD to 40 mg BID in Phase 1 dose expansion and in parallel elzovantinib also is being studied at an intermediate dose level (60 mg QD to 60 mg BID) in Phase 1 dose escalation.
The company anticipates providing a clinical data update from the Phase 1 SHIELD-1 study in the second half of 2022.
The company anticipates initiating the Phase 2 portion of the SHIELD-1 study in the second half of 2022, pending FDA feedback on data from the intermediate dose level.

The company anticipates initiating the SHIELD-2 combination study of elzovantinib and aumolertinib in mid-2022, pending clearance of an investigational new drug (IND) application by the FDA.

Aumolertinib is EQRx, Inc.’s drug candidate targeting EGFR, and the combination of aumolertinib and elzovantinib will be studied in this Phase 1b/2 trial in patients with EGFR mutant MET-amplified advanced NSCLC who have progressed following treatment with osimertinib. The study will evaluate the safety, tolerability and preliminary efficacy of the combination regimen.
TPX-0046, RET INHIBITOR

The company continues to progress the dose-finding portion of the Phase 1/2 SWORD-1 study, where the company is evaluating multiple doses and schedules to further characterize the pharmacokinetics, safety, and efficacy profile before determining the RP2D.
TPX-0131, ALK INHIBITOR

The dose finding portion of the Phase 1/2 FORGE-1 study is ongoing. The company anticipates providing early interim data from initial patients treated in the dose-finding portion of the FORGE-1 study in the fourth quarter of 2022 or early 2023.
3. ADVANCE RESEARCH PROGRAMS

The company remains on track to nominate two development candidates in the second half of 2022. The company currently has four internal discovery programs targeting aberrant GTPase signaling known to drive genomically defined cancers with significant unmet medical need. The most advanced programs target KRAS G12D and the p21 activated kinase, or "PAK" family.

The company also plans on providing details on the other 2 GTPase signaling discovery programs during the second half of 2022.
FINANCIAL UPDATE

Based on its current operating plans, the company expects that its cash, cash equivalents and marketable securities of $975-985 million as of December 31, 2021 (unaudited), are sufficient to fund current operations into the second half of 2024.

On January 18, 2022 ADC Therapeutics SA (NYSE: ADCT), a commercial-stage biotechnology company improving the lives of those affected by cancer with its next-generation, targeted antibody drug conjugates (ADCs) for patients with hematologic malignancies and solid tumors, reported it has entered an exclusive license agreement with Mitsubishi Tanabe Pharma Corporation (MTPC) for the development and commercialization of ZYNLONTA (loncastuximab tesirine-lpyl) for all hematologic and solid tumor indications in Japan (Press release, ADC Therapeutics, JAN 18, 2022, View Source [SID1234605512]).

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Under the terms of the agreement, ADC Therapeutics will receive an upfront payment of $30 million and up to an additional $205 million in milestones if certain development and commercial events are achieved. ADC Therapeutics will also receive royalties ranging in percentage from the high teens to the low twenties based on net sales of the product in Japan. MTPC will conduct clinical studies of ZYNLONTA in Japan and will have the right to participate in any global clinical studies of the product by bearing a portion of the costs of the study.

In April 2021, the U.S. Food and Drug Administration (FDA) granted accelerated approval to ZYNLONTA as the first and only CD19-targeted ADC as a single-agent treatment for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy. A Marketing Authorization Application (MAA) for ZYNLONTA has been validated by the European Medicines Agency (EMA) and is under review by the EMA’s Committee for Medicinal Products for Human Use (CHMP). ZYNLONTA has also received Orphan Drug designation in Europe for DLBCL. In addition, Overland ADCT BioPharma, a joint venture formed by Overland Pharmaceuticals and ADC Therapeutics, is working to develop and commercialize ZYNLONTA in greater China and Singapore. Overland ADCT BioPharma is now conducting a pivotal Phase 2 clinical trial of ZYNLONTA in relapsed or refractory DLBCL in China, which is intended to support the anticipated registration of ZYNLONTA in China.

About ZYNLONTA (loncastuximab tesirine-lpyl)

ZYNLONTA is a CD19-directed antibody drug conjugate (ADC). Once bound to a CD19-expressing cell, ZYNLONTA is internalized by the cell, where enzymes release a pyrrolobenzodiazepine (PBD) payload. The potent payload binds to DNA minor groove with little distortion, remaining less visible to DNA repair mechanisms. This ultimately results in cell cycle arrest and tumor cell death.

The U.S. Food and Drug Administration (FDA) has approved ZYNLONTA (loncastuximab tesirine-lpyl) for the treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy, including DLBCL not otherwise specified, DLBCL arising from low-grade lymphoma and also high-grade B-cell lymphoma. The trial included a broad spectrum of heavily pre-treated patients (median three prior lines of therapy) with difficult-to-treat disease, including patients who did not respond to first-line therapy, patients refractory to all prior lines of therapy, patients with double/triple hit genetics and patients who had stem cell transplant and CAR-T therapy prior to their treatment with ZYNLONTA. This indication is approved by the FDA under accelerated approval based on overall response rate and continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

ZYNLONTA is also being evaluated as a therapeutic option in combination studies in other B-cell malignancies and earlier lines of therapy.

On January 19, 2022 CureLab Oncology,a clinical-stage biotech company, and the American Eurasian Cancer Alliance (AECA), reported to have partnered to expand research and to fast-track next-generation therapies for ovarian cancer in Eurasia (Press release, CureLab Oncology, JAN 18, 2022, View Source [SID1234605529]). The alliance aims to accelerate the clinical trials of CureLab Oncology’s Elenagen, an experimental DNA therapy, by leveraging the broad reach and influence of the AECA in the region.

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Since its inception in 2001, the AECA has implemented its vision of decreasing the burden of cancer in U.S. and Eurasian populations through strategic partnerships and programs that promote cancer research and enhance cancer control in the region. AECA’s reach extends across the Russian Federation, Central Asia (Kazakhstan, Uzbekistan, Kyrgyzstan, Tajikistan), Central Europe (Ukraine, Moldova, Belarus), the Baltics (Lithuania, Latvia, Estonia), and Caucasia (Armenia, Georgia, Azerbaijan).

In Belarus, for example, the AECA and CureLab Oncology have already teamed to help launch the International Gynecologic Cancer Society (IGCS) program within the country. CureLab’s ongoing clinical research studies of Elenagen therapy at the N.N. Alexandrov National Cancer Centre of Belarus have demonstrated encouraging preliminary results in triple-negative breast cancer and platinum-resistant ovarian cancer patients.

"We want to build on our program in Belarus and bring the fight against ovarian cancer to more countries in the region," said Alexander Shneider, Ph.D., CEO of CureLab Oncology. "The AECA’s commitment to strengthening global cancer research, promoting research training and education, and translating research into policy and programs will enable us to achieve that goal. Importantly, this is a two-way highway—if not a Möbius strip. An invention made by a team of American, Israeli, and Italian scientists came to Russia and Belarus for pre-clinical and early-stage clinical development, and now we are bringing it back to the United State for phase II clinical trials."

"For decades, AECA has been on the cutting edge of scientific and technological oncology advancements, and we’re thrilled to continue this important endeavor with CureLab Oncology," said Dr. Sophia Michaelson, executive director of the American Eurasian Cancer Alliance.

"Leveraging AECA’s strong partnerships throughout the Eurasian region has already helped to advance this experimental treatment agenda, and we are hopeful continued research will yield results that could be beneficial for the global cancer control community.

On January 18, 2022 ImmunityBio, Inc. (NASDAQ: IBRX), a clinical-stage immunotherapy company, reported its interim results (N=63) in its metastatic pancreatic cancer trial (QUILT 88) showing that the overall survival rate for patients doubled compared to historical survival rate of three months after two prior lines of therapy (Manax ASCO (Free ASCO Whitepaper) GI 2019) (Press release, ImmunityBio, JAN 18, 2022, View Source [SID1234605546]). The data of the Phase 2 trial studying a combination immunotherapy (Nant Cancer Vaccine) also show treatment-related serious adverse events were uncommon (8%) and no treatment-related deaths were reported. Based on these findings, ImmunityBio plans to meet with the FDA in 2022 to discuss the path for the approval of combination therapies for pancreatic cancer.

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The results were presented today at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal conference, which is being held virtually.

Pancreatic cancer is the fourth leading cause of cancer-related death in the United States and has one of the highest mortality rates of all major cancers, taking nearly 50,000 lives in the U.S. every year. Surgery and subsequent adjuvant chemotherapy are the preferred treatment options for pancreatic cancer today, but the five-year survival rate for late-stage cases is just 3%. For the majority of patients who present with more advanced disease, treatment typically consists of chemotherapy alone or supportive care for metastatic patients, and chemotherapy with or without radiation for those with locally advanced disease, leaving patients seeking new options.

"There are thousands of patients in advanced stages of this disease and there are few, if any, treatment options for them," said Patrick Soon-Shiong, M.D., Founder and Global Chief Scientific and Medical Officer of ImmunityBio, Inc. "Based on this encouraging data from our QUILT 88 trial, we are hopeful that our Nant Cancer Vaccine can potentially address this unmet need. What’s more, we designed this therapeutic candidate to be administered in an outpatient setting making it more accessible to future patients than traditional immune checkpoint inhibitors."

To date, 27% of third-line or greater patients (17/63) remain on study. The median overall survival in this highly advanced group of patients, who failed two to six prior lines of treatment, is 5.8 months (95% CI: 3.9, 6.9 months) exceeding the approximately three-month historical median overall survival. Of the 63 patients, 30 (48%) had progressed after two prior lines of therapy. Median overall survival in this group was 6.3 months (95% CI: 5.0, 9.8 months), more than doubling the historical overall survival. On the strength of this early data and significant unmet medical need, the company has expanded enrollment in the third-line or greater cohort.

QUILT 88 is an open-label study to evaluate the safety and efficacy of the Nant Cancer Vaccine, comprising ImmunityBio’s IL-15 receptor agonist Anktiva (N-803), its off-the-shelf targeted natural killer cells (PD-L1 t-haNK), and aldoxorubicin, an albumin-modulated agent, plus low-dose chemotherapy. This combination Nant Cancer Vaccine is randomized against standard-of-care high-dose chemotherapy for first- and second-line treatment; the third-line or greater cohort, with an original target of 50 patients, is a single arm with the primary endpoint of overall survival.

QUILT-88 Study Details

This Phase 2, randomized, three-cohort, open-label study will evaluate the comparative efficacy and overall safety of standard-of-care chemotherapy versus low-dose chemotherapy in combination with PD-L1 t-haNK, Anktiva (N-803), and aldoxorubicin in subjects with locally advanced or metastatic pancreatic cancer (NCT04390399). Each treatment setting, as well as each first- and second-line or later maintenance treatment, will be evaluated independently as Cohorts A, B, and C, respectively, with Cohorts A and B having independent experimental and control arms. The study is expected to enroll 328 subjects across all three cohorts giving effect to the expanded enrollment of Cohort C (63 of 80 participants are currently enrolled in Cohort C, third-line or greater). The primary objective of Cohorts A and B is progression-free survival (PFS) per RECIST V1.1, and the objective of Cohort C is overall survival (OS). Secondary objectives include initial safety and additional efficacy measures, including overall response rate (ORR), complete response (CR) rate, durability of response (DoR), disease control rate (DCR), and overall survival (OS).

Currently, three trial sites have been activated: Hoag Memorial Hospital Presbyterian in Orange County, Calif., The Chan Soon-Shiong Institute for Medicine in Los Angeles County, Calif., and Avera McKennan Hospital and University Health Center in Sioux Falls, South Dakota, which serves patients in the tri-state area (Iowa, Nebraska and South Dakota).