On September 18, 2023 Moleculin Biotech, Inc., (Nasdaq: MBRX) ("Moleculin" or the "Company"), a clinical stage pharmaceutical company with a growing pipeline, including Phase 2 clinical programs, for hard-to-treat tumors and viruses, reported it has received a new independent assessment for the absence of cardiotoxicity in subjects treated with Annamycin (Press release, Moleculin, SEP 18, 2023, View Source [SID1234635207]). Data from the following subjects were made available to an expert in chemotherapy who is affiliated with a leading cancer research institute in assessing cardiotoxicity. After review of this data, the independent expert concluded that there was no evidence of cardiotoxicity:

● The first cohort of 3 subjects (190 mg/m2) of its Phase 1B/2 clinical trial evaluating Annamycin in combination with Cytarabine (also known as "Ara-C" and for which the combination of Annamycin and Ara-C is referred to as AnnAraC) for the treatment of subjects with AML as both first line therapy and for subjects who are refractory to or relapsed after induction therapy (MB106). clinicaltrialsregister.eu: EudraCT 2020-005493-10 or clinicaltrials.gov: NCT05319587;

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● Cohort 4a (360 mg/m2) in the Phase 1B portion of the Company’s ongoing U.S. Phase 1B/2 clinical trial evaluating Annamycin for the treatment of soft tissue sarcoma lung metastases (MB-107), comprised of 3 subjects. clinicaltrials.gov: NCT04887298; and

● 14 subjects in the Phase 2 expansion Recommended Phase 2 Dose (RP2D) (330 mg/m2) of the ongoing U.S. Phase 1B/2 MB-107 clinical trial.

● This brings the total reviewed by an independent expert to 62 subjects covering 4 separate clinical trials in the U.S. and in Europe.

The data made available included left ventricular ejection fraction (LVEF) as determined by echocardiograms, ECHO strain imaging, and Troponin levels. "ECHO strain imaging" is a method in echocardiography (medical ultrasound) for measuring regional or global deformation (contraction or beating) of the myocardium (heart muscle). By strain rate imaging, the simultaneous function of different regions can be displayed and measured. Cardiac health biomarkers such as blood Troponin levels are considered an indicator of potential long-term heart damage.

"We continue to be encouraged by the potential of Annamycin, especially with the reports from this expert covering 62 subjects. This additional independent report of additional datasets provides further validation in the absence of cardiotoxicity," commented Walter Klemp, Chairman and Chief Executive Officer of Moleculin. "Annamycin continues to establish itself as a non-cardiotoxic anthracycline, even in subjects who have received far more than the lifetime maximum cumulative anthracycline exposure established by the FDA. In fact, 53 of the 62 subjects evaluated have been taken over the lifetime maximum of 450 mg/m2 and one of them as high as 3420 mg/m2. Our growing body of positive data for Annamycin continues to bolster our confidence in our belief that Annamycin is truly a ‘next generation’ anthracycline, especially in light of the growing efficacy data that we have previously reported in the treatment of STS lung mets and AML. We remain focused on advancing our Annamycin development programs and ultimately, addressing the medical unmet needs of people with difficult to treat cancers and viruses."

Annamycin is the Company’s next-generation anthracycline that has been designed to be non-cardiotoxic (unlike currently prescribed anthracyclines) and has been shown in animal models to accumulate in the lungs at up to 30-fold the level of doxorubicin (a commonly prescribed anthracycline), as well as demonstrating the ability to avoid the multidrug resistance mechanisms that typically limit the efficacy of doxorubicin and other currently prescribed anthracyclines. Annamycin is currently in development for the treatment of STS lung metastases (STS lung mets) as well as both first line therapy and therapy for relapsed or refractory acute myeloid leukemia (AML), and the Company believes the drug may have the potential to treat additional indications.

On September 18, 2023 Ligand Pharmaceuticals Incorporated (NASDAQ: LGND) ("Ligand," the "Company" or "we") reported that it has entered into a merger agreement, pursuant to which its subsidiary, Pelican Technology Holdings, Inc., ("Pelican") has become a wholly owned subsidiary of Primrose Bio, Inc. ("Primrose Bio", formerly known as Primordial Genetics, Inc.) (Press release, Ligand, SEP 18, 2023, View Source [SID1234635208]). Primrose Bio is a stand-alone private company focused on synthetic biology. As part of the transaction, Ligand retains the existing commercial royalties related to the Pelican Expression Technology and will own 49.9% of Primrose Bio. Simultaneous with the merger, Ligand entered into a Purchase and Sale Agreement with Primrose Bio and contributed $15 million in exchange for a portion of the economic rights from two contracts previously entered into by Primordial Genetics and an economic interest in potential future revenues generated from PeliCRM197.

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Primrose Bio combines the Primordial Genetics’ Function Generator and Ligand’s Pelican Expression Technology platform (formerly known as Pfenex Expression Technology) to create a revolutionary way of enhancing biological productivity to enable the next generation of therapeutics. Function Generator is designed to systematically generate tens of millions of novel genes in an ultra-high-throughput fashion, to enable the discovery of enzymes and microbes with improved function. The Pelican Expression Technology is a robust and scalable production platform used in five approved medicines that is especially well-suited for large-scale protein production of complex proteins. These proprietary technologies have been leveraged to create Prima RNApols and PeliCRM197, two manufacturing and formulation solutions licensed to biopharma companies to develop mRNA therapeutics and conjugate vaccines, respectively.

"The acquisition of Pfenex in 2020 was a successful and accretive deal for Ligand that continues to pay dividends. After incubating Pfenex and its Pelican Expression Technology for three years, we now have five commercial royalties from the technology platform, and with today’s announcement, we retain a significant equity stake in an exciting new company pushing the frontiers of synthetic biology," said Todd Davis, CEO of Ligand. "With the spinout of Pelican, retention of economic rights to commercial royalties, and subsequent purchase of economic rights, we are delivering on our strategy to streamline the Company’s operations and focus on accretive high-margin businesses and royalties. We believe this will accelerate profitability and growth for our investors and add multiple new royalty ‘shots-on-goal’ for Ligand while realizing lower infrastructure costs within our efficient high growth business model."

About the Pelican – Primordial Genetics Transaction

Pelican, which holds the Pelican Expression Technology, related patents, employees and operating business, has merged into a subsidiary wholly owned by Primordial Genetics
As part of the transaction, Primordial Genetics has changed its name to "Primrose Bio, Inc."
Ligand owns 49.9% of the equity of Primrose Bio, Inc.
Ligand retains the existing royalty rights from the Pelican Expression Technology, including economic rights to Jazz’s RYLAZE, Merck’s VAXNEUVANCE and V116 vaccines, Alvogen’s Teriparatide, Serum Institute of India’s Pneumosil and MenFive vaccines, among others.
Simultaneous with the merger, Ligand entered into a Purchase and Sale Agreement with Primrose Bio and contributed $15 million in exchange for economic rights in future programs
As part of the Purchase and Sale Agreement, Ligand receives a portion of the economic rights from two contracts previously entered into by Primordial Genetics related to proprietary RNA polymerase enzymes (Prima RNApols) and an economic interest in future revenue generated from PeliCRM197.
Financial Guidance

Ligand is increasing adjusted EPS guidance and modifying revenue guidance. As a result of the divestiture and given the profile of the Pelican business, Ligand will have lower contract revenue than previously expected but increased adjusted earnings. In addition, Ligand is updating royalty revenue guidance based upon the latest product sales estimates. Ligand’s updated guidance is now revenue of $124 million to $126 million (previously $124 to $128 million) and adjusted diluted EPS of $5.10 to $5.25 (previously $4.85 to $5.00). Guidance for royalties is now $82 million to $84 million (previously $78 to $82 million). Sales of Captisol are expected to be $25 million (previously $24 million) and contract revenue is now expected to be $17 million (previously $22 million).

On September 18, 2023 Kinnate Biopharma Inc. (Nasdaq: KNTE) ("Kinnate" or "the Company"), a clinical-stage precision oncology company, reported pipeline updates and a reprioritization plan, as well as a workforce restructuring, based on a strategic review of its business (Press release, Kinnate Biopharma, SEP 18, 2023, View Source [SID1234635206]).

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The review encompassed various factors, including the Company’s cash runway, near-term pipeline value creation prospects, the evolving regulatory landscape for targeted therapies, commercial potential, development strategy, and other relevant considerations. As a result, the Company is prioritizing the exarafenib combination, KIN-8741, and discovery efforts around its CDK4 selective program. Additionally, Kinnate will pause development of KIN-7136 and explore strategic alternatives for exarafenib monotherapy and KIN-3248, as part of the reprioritization plan. Concurrently, the Company will implement a workforce restructuring to align with its refined focus.

Nima Farzan, chief executive officer of Kinnate Biopharma Inc., commented, "Today, we are taking hard but necessary steps to streamline our programs, team and operations in order to advance our research and deliver meaningful benefits to patients and shareholders alike. These decisions reflect the current financing environment, oncology regulatory landscape and development timelines. We believe that reprioritizing our programs is the most effective approach to unlock the full promise of our innovative therapies."

Farzan added, "The reprioritization plan unfortunately impacts our workforce. It is undoubtedly difficult to part with our valued and highly talented employees who have made substantial contributions to our company. I want to thank each one of them for their dedication to Kinnate and our mission."

Pipeline Updates and Reprioritization Plan

Investigational Exarafenib Combined with Binimetinib: Pan-RAF plus MEK Inhibitor

Dose exploration for the combination of exarafenib and binimetinib is currently underway in the KN-8701 clinical trial, with a primary focus on NRAS mutant melanoma. NRAS alterations are detected in approximately 20-25% of melanoma patients, and as of today, there are no approved targeted therapies available for this subgroup, highlighting a significant unmet medical need.

As of September 11, 2023, the data cutoff, 44 patients with NRAS mutant melanoma and BRAF-altered solid tumors were enrolled across 6 exarafenib plus binimetinib combination dose cohorts, including 24 patients who continue on therapy.

In the first 5 cohorts, among 20 efficacy-evaluable patients with NRAS mutant melanoma (including Q61 and non-Q61 mutations), 12 patients had radiographic tumor reductions.

Among 16 efficacy-evaluable patients with NRAS mutant melanoma who had not received prior RAF, MEK, or ERK inhibitors, 6 achieved confirmed and unconfirmed partial responses (PRs), resulting in a 38% overall response rate (ORR), with 5 additional patients experiencing stable disease (SD) as their best response, yielding a 69% disease control rate (DCR).

In a subgroup of 17 efficacy-evaluable patients with NRAS Q61 mutations, which represent up to 90% of all NRAS melanoma mutations, 7 achieved confirmed and unconfirmed PRs, leading to a 41% ORR, and 6 others had SD as their best response, resulting in a 76% DCR.

The combination of exarafenib and binimetinib demonstrated significant pathway inhibition, as evidenced by reductions in phosphorylated extracellular signal-regulated kinase (pERK) and DUSP6 RNA expression in paired tissue biopsies.

Additionally, substantial (>50%, up to 100%) reductions in circulating tumor DNA were observed in 70% of the combination-treated patients with NRAS mutant melanoma.

As of September 18, 2023, exarafenib plus binimetinib was generally well-tolerated in two dose cohorts and cleared by a dose review committee. Exploration of the two final dose pairs for the combination regimen is underway.
In the fourth quarter of 2023, the Company intends to select two doses for further development.

Investigational KIN-8741: c-MET Inhibitor

KIN-8741 is designed to be a highly selective c-MET inhibitor with broad mutational coverage, including acquired resistance mutations, in solid tumors driven by exon 14-altered and/or amplified c-MET. A primary focus for KIN-8741 is on non-small cell lung cancer, where the c-MET exon 14 alteration serves as the primary driver alteration.

Kinnate expects to file an IND application for KIN-8741 with the U.S. Food and Drug Administration (FDA) in the fourth quarter of 2023.

Investigational Exarafenib Monotherapy: Pan-RAF Inhibitor

Enrollment in the exarafenib monotherapy dose expansion phase of KN-8701 has been completed. As of September 11, 2023, the data cutoff, a total of 107 patients were enrolled in the monotherapy arm, with 71 patients receiving the expansion dose of 300 mg twice daily (bid). Among these patients, 3 achieved a PR and 26 demonstrated SD as their best response.

As of the data cutoff, 26 patients with Class II-driven solid tumors were enrolled across both the dose escalation and dose expansion phases of KN-8701. Twenty-one of these patients received exarafenib as a monotherapy at 300 mg bid, with 7 patients continuing on therapy.

Out of 8 patients with Class II fusion-driven solid tumors who received exarafenib at 300 mg bid, 3 showed radiographic tumor reductions, 2 of the 6 efficacy-evaluable patients achieved confirmed PRs, resulting in a 33% ORR, and the remaining 4 efficacy-evaluable patients achieved SD as their best response, yielding a 100% DCR.

Among 13 patients with Class II non-fusion driven solid tumors treated with exarafenib at 300 mg bid, 7 patients experienced radiographic tumor reductions and 6 patients experienced SD as their best response, yielding a DCR of 60%. In addition, 1 patient treated at the 200 mg bid dose experienced a confirmed PR.

Exarafenib, administered at a dose of 300 mg bid to a cohort of 71 patients, demonstrated a consistent safety profile in line with previous reporting. Treatment-related adverse events (TRAEs) were observed in 73% of patients, with 51% experiencing skin-related TRAEs, primarily comprising rash (28%), dermatitis acneiform (21%) and pruritis (11%). Reversible, asymptomatic liver enzyme elevations were observed, including Grade 3 elevations in alanine aminotransaminase (ALT; n=7 patients) and aspartate aminotransferase (n=6) and Grade 4 increased ALT (n=2). Other common TRAEs included Grade 1 and 2 asthenia and fatigue (13%), nausea (13% overall including 1 Grade 3 TRAE) and vomiting (8 overall including 1 Grade 3 TRAE).

Overall, exarafenib was well-tolerated, with low rates of drug-related treatment interruption (27%), dose reductions (4%), and treatment discontinuations (9%). The mean dose intensity was 91%, with a median of 100%.
These clinical data involving over 100 patients treated with exarafenib support its favorable safety and tolerability profile, which validates the successful execution of KN-8701. This profile is further supported by favorable pharmacokinetic/pharmacodynamic properties. Notably, the data showed higher response and disease control rates in patients with BRAF Class II fusion versus BRAF Class II non-fusion-driven cancers. However, limited anti-tumor activity was observed with exarafenib monotherapy across all patients with Class II alterations, which may be attributed to the significant heterogeneity of Class II alterations and the presence of other co-occurring mutations.

Considering these results and the Company’s assessment of clinical development timelines for Class II fusion-driven solid tumors, Kinnate will not proceed with further clinical development of exarafenib as a monotherapy agent and will explore strategic alternatives.

Investigational KIN-3248: FGFR Inhibitor

As of September 11, 2023, the data cutoff, a total of 54 patients were enrolled in the ongoing dose escalation trial for KIN-3248, spanning 6 different dose levels: 5 mg once daily (QD) (dose level; DL 1), 10 mg QD (DL 2), 20 mg QD (DL 3), 30 mg QD (DL 4), 40 mg QD (DL 5) and 50 mg QD (DL 6). This includes 31 patients who have not been previously treated with an FGFR 2/3 inhibitor and 23 patients previously treated with an FGFR2/3 inhibitor.

The predicted efficacious dose of 40 mg QD (DL 5) has been cleared, and further exploration is ongoing at the 50 mg QD dose (DL 6).

Two PRs were observed, with 1 confirmed PR in a patient with pancreatic cancer who had not received prior treatment with an FGFR2 inhibitor; treatment began at 20 mg QD and was then increased to 30 mg QD.

Seven patients are currently enrolled at doses of 40 mg QD or higher and have not yet reached their first scan.

A dose-response relationship was observed in pharmacodynamic markers, including decreased pERK levels and increased serum phosphate levels.

As of the data cut off, the maximum tolerated dose has not yet been determined. The safety and tolerability profile of KIN-3248 is consistent with other FGFR inhibitors in clinical development or currently approved.
Kinnate will explore strategic alternatives for the KIN-3248 program.

Investigational KIN-7136: MEK Inhibitor

KIN-7136 is designed to be a brain-penetrant MEK inhibitor. Kinnate previously announced that the FDA cleared the IND application for KIN-7136.

Based on the reprioritization plan, the Company will not initiate a clinical trial for KIN-7136 at this time.

CDK4 Program

Kinnate is exploring drug candidates (DC) for a potentially brain-penetrant, selective CDK4 inhibitor and expects to nominate a DC in the fourth quarter of 2023.

Corporate Update

Kinnate will implement a corporate restructuring by reducing the Company’s workforce by approximately 70%. The Company expects to have 28 remaining full-time employees. The Company is also taking related measures to reduce operating expenses. This includes separating from all employees of its wholly-owned subsidiary in China, Kinnjiu Biopharma.

As of June 30, 2023, Kinnate had approximately $204.3 million in cash, cash equivalents and investments, which is anticipated to fund operations into at least the second quarter of 2026.

On September 18, 2023 Kineta, Inc. (Nasdaq: KA), a clinical-stage biotechnology company focused on the development of novel immunotherapies in oncology that address cancer immune resistance, reported a research agreement with Fred Hutchinson Cancer Center to evaluate VISTA expression as a potential biomarker in cancer patients from Kineta’s ongoing Phase 1/2 clinical trial evaluating KVA12123, the company’s VISTA blocking immunotherapy, alone and in combination with pembrolizumab (Press release, Kineta, SEP 18, 2023, View Source;utm_medium=rss&utm_campaign=kineta-announces-new-research-agreement-to-evaluate-vista-biomarker-expression [SID1234635205]).

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The primary objective is to evaluate VISTA as a biomarker to guide patient selection and treatment optimization for VISTA-targeted therapies where no standardized scoring method currently exists. Similar to standards established for PD-L1 immune checkpoint, there is a need to quantify VISTA expression in the tumor microenvironment (TME) to properly guide patient selection.

"We are excited to work with the Fred Hutchinson Cancer Center and tap into their cancer pathology expertise as we advance the clinical development of KVA12123," said Thierry Guillaudeux, Ph.D., Chief Scientific Officer of Kineta. "VISTA expression has the potential to be a clinically relevant biomarker that we can use to inform our Phase 2 clinical study design with KVA12123 and ultimately predict positive anti-tumor responses to treatment."

VISTA is a negative immune checkpoint that suppresses T cell function in a variety of solid tumors. High VISTA expression in tumor correlates with poor survival in cancer patients and has been associated with a lack of response to other immune checkpoint inhibitors. Blocking VISTA induces an efficient polyfunctional immune response to address immunosuppression and drives anti-tumor responses.

KVA12123 is a fully human engineered IgG1 monoclonal antibody that was designed to bind to VISTA through a unique epitope at both physiologic and acidic pH levels. KVA12123 may be an effective immunotherapy for many types of cancer including NSCLC (lung), colorectal, renal cell carcinoma, head and neck, and ovarian. Initial clinical data from Kineta’s ongoing Phase 1/2 study of KVA12123 in advanced solid tumors is anticipated by end of 2023.

On September 18, 2023 KayoThera, Inc. ("KayoThera"), an early-stage therapeutics company developing first-in-class, oral, small molecule inhibitors of the retinoid pathway, reported that it has selected KAYO-1609 as its first drug development candidate (Press release, KayoThera, SEP 18, 2023, View Source [SID1234635204]). KAYO-1609 has demonstrated a differentiated safety profile across a variety of species with ideal drug-like properties. Preclinical studies in multiple models of cancer support the potential of KAYO-1609 in the treatment of genetically-defined cancers based on the molecule’s mechanism of action. With the nomination of KAYO-1609 as the development candidate, KayoThera is well-positioned for IND-enabling studies, clinical planning, and partnering activities.

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Retinoid signaling is known to both inhibit helper CD4 T cells that mediate tumor cell destruction, and cause maturation of regulatory T cells that dampen the immune system’s response to cancer. Retinoid signaling further forces differentiation of monocytes into tumor-associated macrophages that can promote tumor growth and metastasis. Collectively, these activities reduce the immune system’s ability to detect and eliminate malignant cells. Inhibition of the amplified retinoid signaling found in unique tumor types could potentially restore or enhance the anti-tumor immune activity, enabling a unique approach to cancer immunotherapy in patients with few therapeutic options.

"Despite its known roles in blunting the body’s anti-tumor immune defense, previous efforts to develop retinoid signaling antagonists have failed due to unacceptable toxicity in preclinical development," said Mark Esposito, Ph.D., vice president of R&D, and co-founder of KayoThera. "The discoveries on which KayoThera was founded enable the development of orally available, small molecule inhibitors of this important signaling pathway that have very favorable safety profiles. The preclinical safety and efficacy data generated to date in studies of KAYO-1609 are exceptionally promising, and we intend to move as rapidly as possible toward initiating human clinical trials of this novel molecule in genetically-defined cancers."

KAYO-1609 has demonstrated excellent safety and tolerability, with no dose-limiting toxicities observed in studies across five different species. Preclinical studies also have identified a dose-responsive biomarker for target engagement that is expected to facilitate the IND-enabling studies. KayoThera expects to initiate IND-enabling studies of KAYO-1609 in the third quarter of 2023 and anticipates filing an IND application with the FDA by the end of 2024. Following acceptance of the IND, the company plans to initiate a human clinical trial of KAYO-1609 in patients with genetically-defined cancers that are most likely to demonstrate clinical benefit based on the mechanism of action of KAYO-1609.

"The selection of KAYO-1609 as our lead oncology development candidate is the most recent demonstration of the significant progress, we have made over the past few months to position KayoThera for success," said Kendall Mohler Ph.D., chief development officer and board member of KayoThera. "In May we announced the expansion of our pipeline into the cardiometabolic disease space, with a focus on Type 2 diabetes and in July we strengthened our financial position with multiple grants and the expansion of our Series A financing. Taken together, we now have the financial resources to advance exciting and differentiated candidates in cancer and Type 2 diabetes, diseases with significant unmet clinical need that are associated with significant mortality and morbidity. We are committed to developing retinoid signaling pathway inhibitors as novel therapeutic modalities that can improve outcomes for patients living with these and other serious diseases."