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."

On September 18, 2023 ImmunoGen, Inc., (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported that in connection with the previously announced appointment of Ms. Lauren White as ImmunoGen’s Senior Vice President and Chief Financial Officer, the compensation committee of the Company’s Board of Directors (the "Compensation Committee") approved grants of non-qualified stock options to purchase 295,975 shares of its common stock and restricted stock units ("RSUs") covering 51,625 shares of its common stock under the Inducement Plan to Ms. White (Press release, ImmunoGen, SEP 18, 2023, View Source [SID1234635203]).

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The Inducement Plan is used exclusively for the grant of equity awards to individuals who were not previously employees of ImmunoGen (or following a bona fide period of non-employment), as an inducement material to such individual’s entering into employment with ImmunoGen, pursuant to Rule 5635(c)(4) of the Nasdaq Listing Rules.

The options have an exercise price of $15.71 per share, which is equal to the closing price of ImmunoGen’s common stock on the Nasdaq Global Select Market on September 18, 2023. Each option will vest as to 25% of the shares underlying such option on the first anniversary of the grant date and as to an additional 6.25% of the shares underlying the option quarterly thereafter, subject to Ms. White’s continued employment on each vesting date. Each RSU will vest as to 25% of the shares underlying the RSU award on the first anniversary of the grant date and as to an additional 25% of the shares underlying the RSU award annually thereafter, subject to Ms. White’s continued employment on each vesting date. Each option and RSU is subject to the terms and conditions of the Inducement Plan and the terms and conditions of a stock option agreement and an RSU agreement covering the respective grants.

On September 18, 2023 Galera Therapeutics, Inc. (Nasdaq: GRTX), a clinical-stage biopharmaceutical company focused on developing and commercializing a pipeline of novel, proprietary therapeutics that have the potential to transform radiotherapy in cancer, reported that a Type A Meeting has been scheduled for September 28, 2023 with the U.S. Food and Drug Administration (FDA) regarding the Complete Response Letter (CRL) received for the Company’s New Drug Application (NDA) for avasopasem manganese (avasopasem) (Press release, Galera Therapeutics, SEP 18, 2023, View Source [SID1234635202]). The FDA is expected to issue written meeting minutes approximately 30 days following the meeting.

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"We look forward to further understanding the FDA’s review of our NDA for avasopasem and the data from our two randomized placebo-controlled clinical trials," said Mel Sorensen, M.D., Galera’s President and CEO. "We believe in avasopasem’s potential to bring meaningful benefit to patients with head and neck cancer suffering from severe oral mucositis. With clarity on the perspective of the FDA reviewers from the meeting and subsequent minutes, we hope to identify necessary steps to bring avasopasem to these patients."

The Company intends to gain an understanding from the FDA of its evaluation of avasopasem for radiotherapy-induced severe oral mucositis (SOM) in patients with head and neck cancer undergoing standard-of-care treatment and next steps to support an NDA resubmission. The Type A Meeting is the highest priority classification of meeting that the FDA grants to NDA sponsors.