On April 17, 2023 Nektar Therapeutics (Nasdaq: NKTR) reported a strategic reprioritization and cost restructuring plan that includes a new pipeline focus on immunology, as well as several cost reduction initiatives, which the company expects will significantly reduce future operating expenses and extend its cash runway into the middle of 2026 (Press release, Nektar Therapeutics, APR 17, 2023, View Source [SID1234630165]).

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Key elements of the new plan include:

● Prioritize REZPEG development: Nektar intends to work with Eli Lilly to ensure the continuation of REZPEG development whether it is under the existing Eli Lilly agreement or Nektar regains the rights to REZPEG. The Phase 1b data for REZPEG in atopic dermatitis previously presented at the EADV meeting in September 2022 showed that a dose-dependent improvement was observed in key efficacy measures of mean change in EASI, EASI-75, vIGA-AD scores, and Itch NRS ≥4-point improvement rates over placebo with 12 weeks of treatment. These improvements were observed for an additional 36 weeks following the 12-week treatment period. These proof-of-concept data show REZPEG’s ability to stimulate Tregs to target an immune system imbalance resulting in an improvement of disease activity in patients. The Phase 1b data were recently highlighted in a talk by Eric Lawrence Simpson, MD, FAAD at the 2023 American Academy of Dermatology (AAD) Annual Meeting on March 17, 2023 in the scientific session covering atopic dermatitis, as a potential future remittive therapy.

● Continue development of lead oncology asset, NKTR-255, while seeking a strategic development partner: As part of the strategic reprioritization, Nektar will continue its Phase 2 study of NKTR-255 in combination with cell therapies and the Phase 2 JAVELIN Bladder Medley Study with partner Merck KGaA while it explores strategic partnership options for NKTR-255. NKTR-255 is an investigational IL-15 receptor agonist designed to boost antitumor immunity by increasing the proliferation and survival of natural killer and memory CD8+ T cells and may have broad potential applicability across oncology indications.

● Continue core research programs in immunology: Nektar will continue to advance two preclinical pipeline candidates in auto-immune diseases including a new PEG-Colony Stimulating Factor (CSF1) program and a separate TNFR2 agonist antibody being developed in collaboration with Biolojic Design. The company plans to file an IND for at least one of these programs in 2024.

● Implement a cost restructuring plan: As part of the strategic reprioritization, Nektar also plans to reduce its San Francisco-based workforce by approximately 60%. Once the cost restructuring plan has been fully completed, the company is expected to have approximately 55 employees based in San Francisco. The company anticipates that its Huntsville manufacturing facility, which supports several large pharmaceutical partners, will continue to operate with its current staff. The restructuring also includes actions to reduce additional operating costs and is expected to be substantially completed by June 2023.

"Following a comprehensive review of our portfolio, we have made the decision to prioritize the advancement of our immunology programs," said Howard W. Robin, President and CEO of Nektar. "We intend to work with Eli Lilly either to continue REZPEG’s development in the clinic under our existing agreement or to regain the rights to REZPEG for Nektar. We believe the strong data generated for this asset demonstrates its potential as a remittive therapy in atopic dermatitis and sets the stage to move quickly into a Phase 2b study. REZPEG would be positioned as a novel potential therapeutic in a significant, growing biologic treatment landscape."

"The strategic initiative we announced today is intended to further streamline our operations and to extend considerably our cash runway into the middle of 2026," continued Robin. "Although the actions we are taking today are difficult, we are incredibly grateful for the contributions of the employees departing Nektar."

Nektar had cash, cash equivalents, and marketable securities of approximately $456 million as of March 31, 2023. These significant reductions in the company’s operating expenses, including personnel-related costs and external expenses, are expected to extend the company’s cash runway into the middle of 2026. Projected annual savings from the headcount reduction will be fully realized in 2024 and represent an annual savings of approximately $30 million. Nektar expects non-recurring cash payments of approximately $8 million, primarily in the second quarter of 2023 associated principally with the workforce reduction.

Executive Management Changes

As part of this initiative, Nektar also announced several changes to its executive team:

● Dr. Brian Kotzin, Nektar’s Chief Medical Officer, will be stepping down from his full-time role but will continue to serve in an ongoing role as a strategic advisor to the company. Dr. Mary Tagliaferri, current Chief Development Officer, will assume the role of Chief Medical Officer.

● Jillian Thomsen will be stepping down from her role as Chief Financial Officer (CFO) and will depart the company in June following a transition period. The company has appointed Sandra Gardiner to the role of acting CFO. Sandra is a skilled business and finance executive with over 30 years of financial and accounting experience. She is a partner at FLG Partners, a leading CFO services firm in Silicon Valley.

● Kevin Brodbeck, Nektar’s SVP of Technical Operations, will depart the company in June following a transition period. Ken Franke, current VP of Biologics Development & Manufacturing will assume Kevin’s responsibilities.

The company thanks its departing executives for their contributions to Nektar.

Conference Call Details to Announce First Quarter 2023 Financial Results:

Nektar will announce its financial results for the first quarter 2023 on Tuesday, May 9, 2023, after the close of U.S.-based financial markets. Howard W. Robin, President and Chief Executive Officer, will host a conference call to review the results beginning at 5:00 p.m. Eastern Time/2:00 p.m. Pacific Time.

The press release and live audio-only webcast of the conference call can be accessed through a link that is posted on the Home Page and Investors section of the Nektar website: View Source The web broadcast of the conference call will be available for replay through June 4, 2023.

To access the conference call, please pre-register at Nektar Earnings Call Registration. All registrants will receive dial-in information and a PIN allowing them to access the live call.

On April 17, 2023 Myricx Pharma (‘Myricx’), an oncology drug discovery company focused on developing precision medicines based on its N-myristoyltransferase (NMT) platform has unveiled its antibody drug conjugate (ADC) programme, presenting promising in vivo data at the American Association for Cancer Research (AACR) (Free AACR Whitepaper)’s Annual Meeting, AACR (Free AACR Whitepaper) 2023, April 14-19, Florida (Press release, Myricx Pharma, APR 17, 2023, View Source [SID1234630164]).

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NMT inhibitors (NMTi) have previously been shown to inhibit viability and growth of haematological cancers. Myricx’s novel highly potent NMTi are selectively cytotoxic in multiple cancer cell lines as well as exhibiting tumour regression in in vivo models of both haematological and solid cancers. Myricx has also developed a transcriptional signature which predicts cancer cell sensitivity to NMTi with high confidence.

Myricx’s advanced chemistry offers the potential for the development of NMTi as a novel payload on a wide range of existing linker and antibody ADC technologies. A unique feature of NMTi-ADCs is that they contain two targeting mechanisms: a monoclonal antibody (mAb) that targets the payload to antigen positive cancer cells; and selectivity for specific cancers with high intrinsic sensitivity to NMTi. Myricx has data elucidating the mechanism of this sensitivity.

Myricx’s most advanced ADC, MYX2449, is a selective and ultrapotent NMTi conjugated via a cleavable linker to trastuzumab (HER2+ mAb). Positive in vitro and in vivo data presented at AACR (Free AACR Whitepaper)2 demonstrate MYX2449 cytotoxic potency in selective cancer cell lines, anti-tumour efficacy in both high and low HER2 expressing cancers, with tolerability >10 times its efficacious dose in in vivo models.

As a proof of concept (PoC) for its NMTi-ADC approach, Myricx tested MYX2449 trastuzumab-NMTi ADC in in vivo models of gastric cancer (GC) and breast cancer (BC), as many of these cancers express HER2 and also express the NMTi sensitivity signature. MYX2449 delivered differentiated activity and improved efficacy compared to the gold standard ADC trastuzumab-deruxtecan in a GC model with excellent tumour shrinkage at 5mpk in the xenograft and excellent cyno tolerability at the highest dose, 20mpk. Similar efficacy was obtained in a BC xenograft model.

Encouraged by these positive PoC results, Myricx is now exploring a range of ADCs in further hard-to-treat solid cancers that express both the NMTi sensitivity signature and ADC-compatible antigens.

Myricx CEO Dr Robin Carr who presented the ADC-NMTi poster at AACR (Free AACR Whitepaper) said "NMT inhibitors represent a novel class of ADC payloads that can be exploited as targeted therapies in cancer. Based on our positive PoC data we believe that ADC-NMTi offer huge potential for selective cancer cell killing via its unique mechanism of action."

Myricx is a start-up from two of London’s leading biomedical research organizations, Imperial College London and the Francis Crick Institute. Myricx scientists and founding collaborators were the first to identify that inhibition of NMT is highly effective in the treatment of MYC-driven cancer models acting through the unfolded protein response (UPR). UPR stress is a known vulnerability of cancer and Myricx is now using its discoveries to build a proprietary pipeline of targeted cancer therapies. The company is developing NMTi as small molecule drugs as well as novel selective cytotoxic payloads for ADCs.

In addition to the poster on its lead ADC programme, scientists from Myricx’s collaborators presented two posters on Myricx’s small molecule programmes and NMT biology, including in vivo reprogramming of tumour-associated macrophages to an anticancer phenotype by modulating NMT activity1 and how deregulation of MYC-family proteins sensitizes cancers to NMT inhibition, resulting in the identification of NMTi sensitivity and mechanism.3

Professor Ed Tate, Myricx co-founder and lead author of the posters presented by the Imperial College London/Francis Crick Institute teams said "NMT is a hot emerging drug target in cancer and Myricx has developed high-quality proprietary chemical inhibitors of NMT that have led to breakthrough discoveries and unlocked an unexpected and unique mechanism of cancer cell killing, specific to cancers with vulnerabilities associated with the unfolded protein response. Furthermore, we have recently shown that NMTi has the potential to drive anti-tumour innate immune responses, including the reprogramming of tumour-associated macrophages in the tumour microenvironment.

"These discoveries alongside the massive potential of NMTi as a selective ADC payload pave the way for novel and highly efficacious treatments for patients."

1. Poster number: 439: From foe to friend: In vivo reprogramming of tumour-associated macrophages to an anti-cancer phenotype by modulating N-myristoyltransferase activity – presented by @Wouter Kallemeijn, Francis Crick Institute/Imperial College London
New Drug Targets 16 April 1:30 PM Section 16 board 3

2. Poster number: 2635: N-Myristoyltransferase (NMT) inhibitors as novel potent payloads for antibody drug conjugates – presented by our CEO @Robin Carr
Antibody Technologies session 17 April, 1:30 PM Section 13 board 3

3. Poster number: 4871: Dysregulation of MYC-family proteins sensitizes cancers to NMT inhibition: identification of NMTi sensitivity and mechanism – presented by @James Zhang, ICR/Imperial College London
Anticancer Approaches Targeting Signal Transduction Pathways 18 April 1:30 PM Section 13 board 14

On April 17, 2023 Kura Oncology, Inc. (Nasdaq: KURA), a clinical-stage biopharmaceutical company committed to realizing the promise of precision medicines for the treatment of cancer, reported preclinical data supporting the potential use of farnesyl transferase inhibitors (FTIs) to treat various types of solid tumors in combination with targeted therapies, including KRASG12C inhibitors and anti-angiogenic tyrosine kinase inhibitors (TKIs) (Press release, Kura Oncology, APR 17, 2023, View Source [SID1234630163]). These data were featured in two poster presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting on Sunday, April 16 in Orlando. Copies of the posters are available on Kura’s website at www.kuraoncology.com/pipeline/publications.

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New preclinical data in the poster titled, ‘Tipifarnib synergizes with a TKI in clear cell renal cell carcinoma models,’ demonstrates the synergistic activity of tipifarnib and axitinib, a TKI approved to treat advanced renal cell carcinoma (RCC), in cell- and patient-derived RCC xenograft models. These data support the potential to administer an FTI in combination with a TKI for the treatment of RCC, and studies are ongoing to further evaluate the mechanistic basis of the synergy observed with the combination.

In addition, new findings were presented in the poster titled, ‘Combination of tipifarnib with KRASG12C inhibitors to prevent adaptive resistance,’ evaluating the effects of tipifarnib in combination with adagrasib and sotorasib in cell line and xenograft models of KRASG12C mutant non-small cell lung cancer (NSCLC). These data reveal that the addition of tipifarnib leads to significant tumor regression in xenograft models and suppresses mTOR signaling reactivation relative to treatment with the KRASG12C inhibitors alone. These results support further preclinical studies to determine the mechanism of action for the combination.

"Although targeted therapies have demonstrated meaningful clinical activity, including objective responses, across a range of solid tumors, over time adaptive resistance almost invariably emerges, limiting the ability of the targeted therapies to drive sustained clinical benefit. Yesterday, we presented encouraging preclinical data that highlight the potential for FTIs to prevent or delay emergence of resistance to certain classes of targeted therapies," said Troy Wilson, Ph.D., J.D., President and Chief Executive Officer of Kura Oncology. "We believe these promising preclinical data strongly support our rationale to combine KO-2806 with KRASG12C mutant inhibitors and TKIs in NSCLC and RCC, respectively."

In parallel to the clinical evaluation of tipifarnib, the Company is advancing KO-2806, a potent inhibitor of farnesyl transferase that was designed to improve upon potency, pharmacokinetic and physicochemical properties of earlier FTI drug candidates. The Company expects to initiate the Phase 1 first-in-human study (FIT-001) later this year to assess safety, tolerability and preliminary antitumor activity of KO-2806 as a monotherapy and in combination with other targeted therapies in adult patients with advanced solid tumors. Following completion of the dose escalation as a monotherapy, Kura plans to evaluate KO-2806 in dose escalation combination cohorts in advanced solid tumors.

On April 17, 2023 Kinnate Biopharma Inc. (Nasdaq: KNTE) (Kinnate), a clinical-stage precision oncology company, reported the addition of two new internally developed next generation development candidates to its targeted oncology pipeline – a brain penetrant mitogen-activated protein kinase (MEK) inhibitor and a highly selective mesenchymal-epithelial transition factor gene (c-MET) inhibitor (Press release, Kinnate Biopharma, APR 17, 2023, View Source [SID1234630162]).

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The company also announced that it had approximately $231 million of cash, cash equivalents and investments as of March 31, 2023, which is anticipated to fund planned operations into early 2025.

"We are proud of our growing portfolio of precision oncology programs comprised of highly selective therapeutics with optimized drug properties designed to address broad alteration coverage, resistance mechanisms and now brain penetrance," said Robert Kania, Ph.D., senior vice president, drug discovery, Kinnate Biopharma Inc. "The addition of Kinnate’s next generation MEK and c-MET research programs to our development pipeline illustrates the productivity of our capability-based discovery engine, which is delivering on our goal of bringing forward one new IND a year. Targeted therapies have tremendous potential to help patients, but only about ten percent of patients with advanced or metastatic cancer are eligible for currently approved targeted therapies. We look forward to continued progress powered by our Kinnate Discovery Engine and the impact we can have on the lives of those battling cancer."

In-House Brain-Penetrant MEK Inhibitor Designed for Optimal Control in Potential Commercial Opportunities

KIN-7136 is designed to be a next generation brain-penetrant MEK inhibitor for investigation in advanced adult solid tumors, primarily non-small cell lung cancer (NSCLC), that are MAPK pathway-driven, including those with brain metastases.

Kinnate expects to enter the clinic with KIN-7136 in the second half of 2023, pending U.S. Food and Drug Administration (FDA) clearance on its investigational new drug (IND) application. The goal of the Phase 1 clinical trial will be to establish safety and tolerability, and generate understanding of the pharmacokinetics, pharmacodynamics and early clinical activity of KIN-7136 as a monotherapy.

In parallel, the company intends to evaluate KIN-7136 combined with exarafenib, Kinnate’s investigational pan-RAF inhibitor. Kinnate plans to prioritize exploring the KIN-7136 and exarafenib combination in BRAF Class I patients with NSCLC that have been previously treated with a RAF inhibitor and patients with NRAS mutant melanoma. This approach enables access to a potentially broader patient population to be evaluated with exarafenib, including those with brain metastases. KIN-7136 may serve as part of the company’s long-term RAF combination strategy.

Today, the company separately provided a preliminary update on the combination arm of the ongoing Phase 1 KN-8701 clinical trial evaluating exarafenib with binimetinib, a first generation MEK inhibitor with minimal brain penetrant properties, in patients primarily with NRAS mutant melanoma.

In-House, Highly Selective c-MET Inhibitor Designed for Broad Mutational Coverage

Research has shown that acquired resistance to approved and in-development c-MET inhibitors limits clinical benefit. Up to 35% of patients treated with approved c-MET inhibitors develop on-target resistance mutations, leaving them with limited treatment options and a poor prognosis. In patients with NSCLC, about 3-4% of patients present with actionable MET exon 14 alterations.

KIN-8741 is designed to be a highly selective c-MET inhibitor with broad mutational coverage, including acquired resistance mutations, across a variety of solid tumors in which c-MET is overexpressed, such as NSCLC.

Kinnate expects to enter the clinic with KIN-8741 in the first half of 2024, pending FDA clearance on its IND application.

CDK12 Program Update

The company will deprioritize development for its CDK12 program and evaluate strategic alternatives as it deepens focus on its two clinical-stage assets and advances development of its MEK and c-MET programs.

Virtual Investor Webcast Information

Kinnate will host a webcast today, April 17, 2023, at 5:30 p.m. ET. Investors and the general public are invited to listen to a live webcast of the session through the "Investors and Media" section on Kinnate.com or by dialing the U.S. toll free number +1-888-256-1007 and entering confirmation code: 7465233. An archived edition of the session will be available following the event.

On April 17, 2023 Kinnate Biopharma Inc. (Nasdaq: KNTE) (Kinnate), a clinical-stage precision oncology company, reported positive monotherapy dose escalation data for its investigational, highly selective and potent pan-RAF inhibitor, exarafenib, from Part A1 of its ongoing global Phase 1 KN-8701 clinical trial (Press release, Kinnate Biopharma, APR 17, 2023, View Source [SID1234630161]). These results will be featured in an oral presentation today at 3:35 p.m. ET during the Clinical Trials Mini Symposium Session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2023 Annual Meeting. (Abstract #CT032)

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The company today also provided details around its monotherapy dose expansion strategy (Part B) and a preliminary update on the combination arm (Part A2) evaluating exarafenib with binimetinib, a MEK inhibitor, in patients with BRAF-altered solid tumors and/or who have NRAS mutant melanoma.

Kinnate will host a virtual investor webcast today at 5:30 p.m. ET to discuss these updates, along with the expansion of its early development pipeline announced separately.

"The exarafenib dose escalation data provide striking proof of concept for a monotherapy pan-RAF inhibitor," said Alexander Spira, MD, PhD, FACP, co-director, Virginia Cancer Specialists Research Institute. "For the first time, a pan-RAF inhibitor has shown both promising tolerability as a single agent and has achieved compelling breadth of activity with durable responses in targetable mutations. Responses in patients with BRAF Class II or NRAS alterations is meaningful because no approved targeted therapy is available today, and physicians are left with limited treatment options for advanced cancers, which means patients often have poor survival outcomes. I look forward to the further study of exarafenib’s therapeutic potential to address these patients who are currently medically underserved."

Key Exarafenib Monotherapy Data Presented at AACR (Free AACR Whitepaper) 2023

The data at AACR (Free AACR Whitepaper) were based on a February 28, 2023 data cutoff. Sixty patients with a median of three prior therapies had been enrolled into six monotherapy dose escalation cohorts: 25 mg bid (dose level; DL 1), 50 mg bid (DL 2), 100 mg bid (DL 3), 200 mg bid (DL 4), 300 mg bid (DL 5) and 400 mg bid (DL 6). Treated patients included those with solid tumors driven by BRAF Class I (41.7%), Class II (13.3%) and Class III (30%) alterations or melanoma with NRAS mutations (15%). BRAF and NRAS alterations were identified by local laboratories either in tumor or plasma. As of the data cutoff, all 60 patients enrolled were part of the safety analysis population, of which 49 patients were efficacy evaluable.1

Favorable Tolerability Profile; Only 3% (n=2/60) of Patients Discontinued Therapy Due to Treatment-Related Adverse Events

The maximum tolerated dose (MTD) was determined to be 300 mg bid (n=29). At therapeutically relevant exposures, there was no cutaneous (skin) evidence of paradoxical activation. Dose limiting toxicities observed at the highest dose level (400 mg bid) were Grade 3 acneiform rash (n=1) and Grade 3 macular rash (n=1).

Treatment-related adverse events (TRAEs) reported by investigators at any Grade occurred in 73.3% (n=44) of patients, with 18.3% of TRAEs reported as Grade 3 or higher (n=11). There were no Grade 5 TRAEs reported as of the data cutoff.

The most common TRAEs of any Grade were skin related (21.7%; n=13), with 3.3% (n=2) of patients having skin events that were Grade 3 or greater.

Grade 2 gastrointestinal (GI) TRAEs occurred in 3.3% of patients (n=2). No Grade 3 GI TRAEs were observed.

Reversible, asymptomatic increased alanine transaminase and/or increased aspartate aminotransferase TRAEs were reported at Grade 3 (n=4; 6.7%) and Grade 4 (n=1; 1.7%).

In all patients (n=60) treated with exarafenib, the overall relative mean dose intensity was 97% and was 95% in patients treated at 300 mg bid (n=29). The median for both patient sets was 100%.2
Dose Dependent and Steady State Unbound Exposures with Exarafenib Treatment

Pharmacokinetic analyses demonstrated dose-dependent increases in exarafenib exposure (Cmax; peak plasma concentration and area under the curve) with increasing dose.

Exarafenib had a half-life of eight hours in patients, which is a longer duration range than the predicted half-life preclinically, supporting a bid dosing strategy.

At 300 mg bid, exarafenib delivered high target coverage in patients. Unbound exposures exceeded the IC50 values across BRAF and NRAS cell lines by two-to-ten-fold, while remaining below the wild type cells IC50. We believe multiple fold target coverage is ultimately necessary for meaningful outcomes in these patient subtypes.

Treatment with exarafenib also led to significant reductions in circulating tumor DNA across BRAF and NRAS-altered tumor types.
Promising Early Efficacy, Including RECIST Responses in Priority BRAF Class II and NRAS Subtypes

In total, 6 patients achieved a partial response (PR) with exarafenib monotherapy treatment during dose escalation, including five confirmed PRs as evaluated by Response Evaluation Criteria in Solid Tumors (RECIST). For responders, the average tumor reduction was 61% and treatment duration was 7 months. Four of the 6 responders continue exarafenib therapy.

Treatment with exarafenib at 300 mg bid, the MTD, in patients with BRAF Class II or NRAS alterations led to a 30% (3 of 10) overall response rate (ORR).

The ORR in patients with BRAF Class II alterations was 33% (1 of 3) at 300 mg bid, which included a patient with non-small cell lung cancer (NSCLC) harboring a BRAF Class II fusion.

In addition, 71% (5 of 7) of patients with BRAF Class II alterations achieved an objective tumor reduction. In all treated patients with Class II alterations, the disease control rate was 86% (6 of 7).

The ORR in patients with NRAS alterations was 29% (2 of 7) at 300 mg bid and included patients with NRAS mutant melanoma and a patient with colorectal cancer harboring an NRAS alteration co-occurring with a BRAF Class III alteration.

The two additional subtypes with confirmed PRs included RAF inhibitor naïve patients with BRAF Class I (V600E) papillary thyroid cancer and squamous cell carcinoma. One unconfirmed PR was reported in a RAF pretreated patient with BRAF Class I melanoma.

Twenty-two patients achieved stable disease (SD) across dose levels, including 10 patients with objective tumor shrinkage (up to 20%), showing encouraging breadth of activity and prolonged disease control in a broad range of alterations and tumor types.
1Efficacy evaluable set includes all participants with documented BRAF (or melanoma with NRAS) genomic alterations (as specified for each study Part) who received at least 1 dose of exarafenib and have >= 1 measurable lesion at baseline for disease response assessment and at least 1 post-baseline efficacy assessment per RECIST Version 1.1 criteria. Response assessments performed by each respective clinical trial site (local, investigator-assessed radiology). Disease control rate is defined as the percent of participants who achieved a complete response, PR or SD as their best overall response in accordance with RECIST v1.1.

2Overall relative dose intensity based on assigned dose will use the full course of dose received (including intrapatient dose escalation or de-escalation) divided by the total planned dose as per the originally assigned.

Exarafenib Monotherapy Dose Expansion Strategy Optimized for Probability of Success

The expansion cohorts of the KN-8701 clinical trial opened year-end 2022 and are currently enrolling patients at the 300 mg bid dose.

Kinnate refined its dose expansion strategy to include greater enrichment of more sensitive tumor and alteration types based on the emerging profile and clinical signals observed during dose escalation.

The priority cohorts will enroll patients with BRAF Class II alterations, including BRAF fusions, across solid tumors, primarily melanoma and NSCLC. These cohorts are expected to enroll approximately 55 patients.

The company expects to provide initial monotherapy dose expansion data in the first half of 2024.

Exarafenib + Binimetinib Dose Escalation Ongoing; Early Clinical Activity Observed

Key combination updates as of March 31, 2023 include:

Enrolled 12 patients primarily with NRAS mutant melanoma into 3 combination dose cohorts: (1) exarafenib 100 mg bid and binimetinib 45 mg bid, (2) exarafenib 100 mg bid and binimetinib 15 mg bid, and (3) exarafenib 200 mg bid and binimetinib 15 mg bid.

Enrollment continues at exarafenib 200 mg bid dose and binimetinib 15 mg bid, with safety evaluation ongoing.

Two of the 7 efficacy evaluable patients achieved RECIST PRs, including an unconfirmed PR in a patient with NRAS mutant melanoma and a confirmed PR in a patient with BRAF Class II pancreatic cancer. One additional patient with NRAS mutant melanoma experienced a 25% reduction in their target lesions. Patients who responded continue combination therapy.

Kinnate will prioritize development of the exarafenib combination in patients with NRAS mutant melanoma. The trial will also enroll RAF pre-treated patients with a BRAF Class I alteration.

The company expects to provide an update in the second half of 2023 on the combination dose that will be taken into dose expansion.
"With the selection of the maximum tolerated dose for exarafenib, we initiated monotherapy dose expansion with enrollment ongoing in patients with a meaningful unmet medical need and where we believe we have the highest probability of success with a single-agent pan-RAF, including in patients with advanced lung cancer and melanoma that harbor a BRAF Class II alteration," said Richard Williams, MBBS, PhD, chief medical officer, Kinnate Biopharma Inc. "In addition, with a well-tolerated monotherapy profile, compelling PK/PD and responses as the backbone, we continue to pursue priority pan-RAF combination approaches, such as with a MEK inhibitor in NRAS mutant melanoma, where a combination may offer additive benefit to patients."

Nima Farzan, Kinnate Biopharma Inc. chief executive officer, commented, "Kinnate was formed just five years ago, and in that time, we have evolved from a start up to a global, precision oncology company with two programs in the clinic and a growing pipeline of targeted therapy candidates developed by our own scientists. Today, we are proud to share the first clinical data from the company on exarafenib, showing early efficacy both as a monotherapy and as a combination regimen in BRAF and NRAS-altered cancers. This potential best-in-class pan-RAF inhibitor anchors our growing pipeline and positions the company for future growth."

Today’s AACR (Free AACR Whitepaper) presentation is available on the company’s website at Kinnate.com.

Virtual Investor Webcast Information

Kinnate will host a webcast today, Monday, April 17, 2023, at 5:30 p.m. ET. Investors and the general public are invited to listen to a live webcast of the session through the "Investors and Media" section on Kinnate.com or by dialing the U.S. toll free number +1-888-256-1007 and entering confirmation code: 7465233. An archived edition of the session will be available following the event.

About Exarafenib

Exarafenib is an orally administered, potent and selective investigational small molecule pan-RAF inhibitor. Unlike currently available treatments that target only Class I BRAF kinase mutations, exarafenib is designed to target BRAF Class II and Class III alterations, where it has the potential to be a first-line targeted therapy, in addition to covering BRAF Class I alterations, and as a potential treatment for NRAS mutation-positive melanoma.

KN-8701 Clinical Trial Background

KN-8701 is an ongoing, global Phase 1 clinical trial (NCT04913285) evaluating exarafenib in patients with advanced solid tumors harboring BRAF Class I, II and III alterations, and/or who have NRAS mutant melanoma. KN-8701 contains a two-part dose escalation: Part A1 is evaluating exarafenib as a monotherapy across BRAF alterations and tumor types, and Part A2 is evaluating exarafenib in combination with binimetinib, a MEK inhibitor. Part B, dose expansion, is evaluating exarafenib at the recommended dose and schedule in patients with BRAF-altered cancers including lung cancer, melanoma and other solid tumors.