On June 22, 2022 National Brain Tumor Society reported that the U.S. Food and Drug Administration (FDA) granted accelerated approval to a new treatment combination that will now be available as an option for certain brain tumor patients (Press release, National Brain Tumor Society, JUN 22, 2022, View Source [SID1234616328]).

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The FDA approved the combination of two oral drugs called dabrafenib (brand name: Tafinlar) and trametinib (brand name: Mekinist) for the treatment of advanced tumors that have a mutation called "BRAF V600E." The approval includes use in both adult and pediatric (older than 6 years of age) high- and low-grade glioma patients with this mutation whose tumors progressed after prior treatment.

The approval is based on the results from a number of clinical trials, which included adult and pediatric high-grade and low-grade glioma patients. Data pooled from across these trials showed that the Tafinlar-Mekinist combination successfully shrank a significant percentage of these patients’ tumors. Using a measure called "Overall Response Rate (ORR)," trials found that 33% of high-grade glioma patients responded to the combination, while 50% of low-grade glioma patients saw tumor shrinkage benefits. For the pediatric glioma patients, 25% responded to the treatment.

The BRAF V600E mutation is estimated to be prevalent in 5-15% of all low-grade gliomas (15-20% of pediatric low-grade gliomas), including 60-80% of pleomorphic xanthoastrocytomas (PXA), 20-70% of gangliogliomas, and 10% of pilocytic astrocytomas. The mutation has been identified less frequently in high-grade gliomas, including approximately 3% of glioblastomas.

"This approval will offer a much-needed new treatment option for hundreds of glioma patients with a BRAF V600E mutation," said David Arons, chief executive officer, National Brain Tumor Society. "This is very positive news for the brain tumor community and offers hope that current research and drug development efforts are beginning to yield meaningful breakthroughs for patients that currently have too few options. We thank Novartis for including both adult and pediatric glioma patients in these trials, as well as the researchers and clinicians involved, and most importantly the patients and their families that participated in the studies."

The most common side effects seen in adult patients were fever, fatigue, nausea, rash, chills, headache, hemorrhage, cough, vomiting, constipation, diarrhea, muscle and joint pain, and edema.

The most common side effects seen in pediatric patients included fever, rash, vomiting, fatigue, dry skin, cough, diarrhea, dermatitis acneiform, headache, abdominal pain, nausea, hemorrhage, and constipation.

Because the approval for this treatment was granted through the FDA’s accelerated approval pathway, the sponsor of the clinical trial, Novartis, will be required to complete confirmatory trials to verify the effectiveness of these drugs to date. According to reports, the company may already have additional evidence of effectiveness in pediatric low-grade glioma patients, including in children as young as one. Based on data presented recently at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting, the Tafinlar-Mekinist combination resulted in 47% ORR versus chemotherapy (11%) and reduced the risk of progression or death by 69%. Additionally, in a separate, small subset of this trial, pediatric high-grade glioma patients treated with Tafinlar-Mekinist showed an ORR of 56.1% and generally consistent safety results.

Further buoying these results were data also presented at ASCO (Free ASCO Whitepaper) 2022 from Day One Bio of their own BRAF-targeting drug, tovorafenib (DAY101), which also showed effectiveness in relapsed pediatric low-grade glioma. We await additional future results from trials of tovorafenib (DAY101).

"Given this latest approval, and the recent data from ASCO (Free ASCO Whitepaper), NBTS strongly urges that neuro-surgical and oncology providers treating glioma patients secure for patients a test that can identify their BRAF V600E status as part of robust molecular biomarker testing informed by the 2021 World Health Organization’s reclassification of CNS tumors as a routine step that could determine which patients could benefit from these drugs," added Arons.

On June 22, 2022 The Cancer Research Institute (CRI), a nonprofit organization dedicated to the discovery and development of powerful immunotherapies for all types of cancer, reported the newest cohort of scientists chosen for the CRI Lloyd J. Old STAR Program (Scientists Taking Risks) (Press release, Cancer Research Institute, JUN 22, 2022, View Source [SID1234616171]). Each STAR will receive a grant of $1.25 million payable over five years to carry out high-risk/high-reward research that has the potential to produce transformative leaps forward in tumor immunology. This long-term funding provides a degree of flexibility and freedom for CRI STARs to explore new and disruptive avenues of cancer research.

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"The competitive CRI Lloyd J. Old STAR program supports gifted, mid-career scientists working at the intersection of immunology, technology, and bioinformatics to identify specific molecular and genetic factors that influence patient responses to immunotherapy, discovering answers to the field’s key scientific questions to potentially effect a sea change in how cancer patients are diagnosed and treated," said Jill O’Donnell-Tormey, Ph.D., CEO and director of scientific affairs at the Cancer Research Institute, which now actively supports twenty-two STARs throughout the U.S. and Europe.

The announcement comes during the tenth annual Cancer Immunotherapy Month celebrations in June of scientists who are driving new and lifesaving advances in the immunological treatment and prevention of cancer. This year’s Cancer Research Institute Lloyd J. Old STARs include:

Iliyan D. Iliev, Ph.D., of Weill Cornell Medicine, who is breaking new ground in efforts to understand the role fungi play in cancer development and immunotherapy, characterizing how different fungal strains promote or inhibit cancer growth through interaction of their metabolites and toxins with the immune system, and determining how the presence of fungi within the tumor microenvironment and blood influences – and may even predict – patient responses to treatment with immunotherapy
Philip J. Kranzusch, Ph.D., of the Dana-Farber Cancer Institute and Harvard Medical School, who has discovered and is exploring thousands of previously uncharacterized signaling enzymes from the cGAS family involved in immune cell responses to threats, using biochemistry and structural biology to uncover the functions of these enzymes and their related cellular pathways in order to define at the molecular level how they are activated, potentially leading to new, more effective therapeutic strategies
Kole T. Roybal, Ph.D., of the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center and Gladstone-UCSF Institute of Genomic Immunology, who has developed a synthetic biology approach to modifying immune cell receptor and signaling gene programs to create "smart cell" therapeutics with enhanced abilities to target tumors more precisely and more safely than current cell therapies, which have so far proven largely ineffective against solid tumors despite their successes in treating cancers of the blood
Brian Ruffell, Ph.D., of the H. Lee Moffitt Cancer Center and Research Institute, who aims to improve patient responses to immunotherapy by using CRISPR-Cas9 genetic screens to define specific molecular pathways involved in suppression of dendritic cells – key orchestrators of the immune response to cancer and other threats – in order to identify and validate targets of immunotherapy for preclinical development
Ansuman T. Satpathy, M.D., Ph.D., of Stanford University School of Medicine, Stanford Cancer Institute, and Gladstone-UCSF Institute of Genomic Immunology, who is using new genetic analysis technologies capable of scanning and profiling the entire genome of immune cells to understand how transcription and expression of specific genes affects immune cell behavior or leads to dysfunctions in specific cellular pathways that contribute to T cell exhaustion, and is developing and using tools from functional genomics and mass spectrometry to study fundamental properties of the immune system in search of new regulators of anti-tumor immune responses
Matthew H. Spitzer, Ph.D., of the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center and Gladstone-UCSF Institute of Genomic Immunology, who is using cutting-edge experimental and computational technologies to explore the role of immune cells circulating outside tumors – rather than those within the tumor microenvironment – in conferring long-term protection against cancer and infection, leading potentially to the identification of therapeutic targets involved in tumor-mediated immune suppression throughout the body.
The Cancer Research Institute named this program in honor of Lloyd J. Old, M.D., the "Father of Modern Tumor Immunology," who served as CRI’s founding scientific and medical director from 1971 to 2011. A mentor to generations of immunologists and tumor immunologists who flourished under his guidance and went on to make significant contributions to the field, Dr. Old embodies the ideals of the STAR program, through which CRI identifies and funds high-impact scientists whose outstanding work has distinguished them as today’s visionaries in cancer immunology.

The following members of CRI’s Scientific Advisory Council leadership comprise the CRI Lloyd J. Old STAR Program Selection Committee:

Carl F. Nathan, M.D., (Committee Chair), R.A. Rees Pritchett Professor of Microbiology and Chair, Department of Microbiology and Immunology, Weill Cornell Medicine
James P. Allison, Ph.D., Regental Professor and Chair of Immunology; Olga and Keith Wiess Distinguished University Chair for Cancer Research; Executive Director of the Immunotherapy Platform; Deputy Director for Applied Research of Genitourinary Cancers; Director of the Parker Institute for Cancer Immunotherapy, University of Texas MD Anderson Cancer Center; and 2018 Nobel Laureate
Glenn Dranoff, M.D., Global Head of Immuno-Oncology, Novartis Institutes for Biomedical Research
Kunle Odunsi, M.D., Ph.D., FRCOG, FACOG, Director, University of Chicago Medicine Comprehensive Cancer Center; Dean of Oncology and Professor of Obstetrics and Gynecology, Division of Biological Sciences, University of Chicago
Ellen Puré, Ph.D., Professor of Pharmacology; Grace Lansing Lambert Professor of Biomedical Science and Chair, University of Pennsylvania School of Veterinary Medicine; Director, Penn Vet Cancer Center; and Member, Abramson Cancer Center, University of Pennsylvania
Robert D. Schreiber, Ph.D., Andrew M. and Jane M. Bursky Distinguished Professor, Pathology and Immunology; Interim Chief, Division of Immunobiology; Director, Center for Human Immunology and Immunotherapy Programs; Co-Leader, Tumor Immunology Program, Siteman Cancer Center, Washington University School of Medicine
E. John Wherry, Ph.D., Chair, Department of Systems Pharmacology & Translational Therapeutics; Richard and Barbara Schiffrin President’s Distinguished Professor; Director, Institute for Immunology; Co-Program Leader, Immunobiology Program, Abramson Cancer Center, and Co-Director, Parker Institute for Cancer Immunotherapy, University of Pennsylvania
Jedd D. Wolchok, M.D., Ph.D., Lloyd J. Old/Virginia and Daniel K. Ludwig Chair in Clinical Investigation; Chief, Immuno-Oncology Service, Human Oncology and Pathogenesis Program; Director, Parker Institute for Cancer Immunotherapy at MSK; and Associate Director, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center.
Applications to the next CRI Lloyd J. Old STAR Program funding round are due January 15, 2023. To learn more about the program, including eligibility and application instructions, go to cancerresearch.org/star.

On June 22, 2022 Echosens, a high-technology company offering liver diagnostic solutions, and Novo Nordisk A/S, a leading global healthcare company, reported a partnership to advance early diagnosis of non-alcoholic steatohepatitis (NASH) and increase awareness of the disease among patients, healthcare providers and other stakeholders (Press release, Novo Nordisk, JUN 22, 2022, View Source [SID1234616187]).

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NASH is a chronic metabolic liver disease that affects more than 115 million people worldwide1. The condition is caused by build-up of fat and inflammation in the liver. This causes progressive damage to the liver and can lead to end-stage liver disease and death.

NASH is a ‘silent’ disease due to lack of symptoms in the early stages and, as a result, it is estimated that nine out of 10 people living with NASH go undiagnosed2. To significantly increase early diagnosis, broadly accepted non-invasive tests for diagnosing people living with NASH are needed, as confirmatory diagnosis currently relies on an invasive procedure known as a liver biopsy.

Echosens and Novo Nordisk will collaborate to support additional clinical validation, generation of real-world evidence and adoption of non-invasive diagnostic tests for NASH and work together to increase awareness of the disease and the importance of early diagnosis and management. The companies have a shared ambition of doubling diagnostic rates for people living with advanced to severe NASH by 2025.

"NASH is the more severe form of non-alcoholic fatty liver disease (NAFLD). It has few non-specific or no symptoms in its early stage, leading to inappropriate referrals to secondary care and patients often remaining undiagnosed until irreversible complications occur," said Dominique Legros, CEO at Echosens. "There is a pressing need for a broader adoption of our non-invasive liver tests to improve the diagnosis of people living with NASH, and we are proud to partner with Novo Nordisk to combine our strengths and shared mission to empower medical professionals with improved ways to assess, diagnose and manage the condition."

NASH is more common in people living with obesity (82% of people with NASH are living with obesity) and conditions related to obesity, such as type 2 diabetes (44% of people with NASH are living with type 2 diabetes)3. The low diagnosis rate for NASH is partly caused by a lack of awareness of the condition and associated risk factors among at-risk patients, healthcare providers, payers and policymakers.

"At Novo Nordisk we are committed to driving change in NASH, to develop new treatment options and advance care for this serious, chronic disease. An important step towards realizing that ambition is to ensure that we can identify the people in need of care," said Camilla Sylvest, executive vice president for Commercial Strategy & Corporate Affairs at Novo Nordisk. "But we cannot solve this challenge alone and through our partnership with Echosens, we hope to leverage our complementary skills to meet the needs of patients, healthcare providers and other stakeholders striving to address this ‘silent’ epidemic."

About NASH

Non-alcoholic steatohepatitis (NASH) is the most severe form of non-alcoholic fatty liver disease (NAFLD). It is a progressive metabolic liver disease characterised by fat accumulation and inflammation in the liver, which can lead to scarring, or fibrosis, and eventually end-stage liver disease and death. The risk of progression to advanced liver disease, including liver cancer, is higher in people with NASH than in the general population, and NASH is predicted to be the leading cause of liver transplantation by 2030. Moreover, NASH increases the risk of developing cardiovascular disease. Currently, no treatment is globally approved for the treatment of NASH, and people with NASH are left with very few management options.

On June 22, 2022 Castle Biosciences, Inc. (Nasdaq: CSTL), a company improving health through innovative tests that guide patient care, reported new data demonstrating the clinical value of the Company’s tests for skin cancer in guiding more informed disease management decisions (Press release, Castle Biosciences, JUN 22, 2022, View Source [SID1234616188]). Data on each of Castle’s skin cancer tests, as outlined below, was shared during the recent Society of Dermatology Physician Assistants (SDPA) Annual Summer Dermatology Conference 2022 .

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DecisionDx-Melanoma

While patients with thin cutaneous melanoma (CM) tumors (T1, ≤1mm) are typically deemed low risk by traditional staging alone, studies have shown that up to 15%1-3 of these patients will go on to experience disease recurrence. As such, there is an opportunity to use DecisionDx-Melanoma to identify which patients with thin CM tumors may have aggressive tumor biology and thus could benefit from increased surveillance through advanced imaging or adjuvant therapy.

"The data in this study reinforced what we find in clinical practice: some patients initially thought to be low risk by traditional, clinicopathologic staging methods can have more aggressive tumor biology, and their melanoma may come back, even after their primary tumor has been removed," said lead study author Abel Jarell, M.D., dermatologist and dermatopathologist at Northeast Dermatology Associates in Portsmouth, New Hampshire. "DecisionDx-Melanoma can help identify these high-risk patients who may warrant a need for more intense treatment and surveillance to reduce their likelihood of recurrence and potentially improve the overall outcome of their disease."

Patients with T1 CM (classified according to the American Joint Committee on Cancer Eighth Edition (AJCC8) staging framework) from three previously published studies were combined for analysis (N=979). The results of the analysis was shared in a poster titled, "The 31-gene expression profile test stratifies the risk of recurrence in patients with T1 cutaneous melanoma: Results of a pooled analysis of 979 patients." The poster, which is available here, highlights the ability of DecisionDx-Melanoma to stratify patients with thin CM tumors according to their risk of recurrence.

Study highlights:

In the study, patients with thin tumors who received a DecisionDx-Melanoma high-risk Class 2B result had lower 3-year recurrence-free survival than patients with a low-risk Class 1A result (75.9% vs. 97.7%) and an 8-fold higher recurrence rate (22.5% vs. 2.7%, p<0.001).
Moreover, nearly one in four patients in the cohort who received a DecisionDx-Melanoma high-risk Class 2B result experienced melanoma recurrence, with a median 11-month time to recurrence.
A high-risk Class 2B test result was a significant predictor of disease recurrence (HR=4.49, p=0.001), similar to a positive sentinel lymph node (SLN) (HR=4.46, p<0.001). As a positive SLN is evidence that a patient’s melanoma has spread, these patients are candidates for advanced imaging and potentially, adjuvant therapies. These data suggest that patients receiving a DecisionDx-Melanoma Class 2B result could benefit from similar, more intense treatment aligned to their elevated risk of recurrence.
DecisionDx-SCC

The rise of squamous cell carcinoma (SCC) diagnoses is an emerging problem in the U.S. that is complicated by broad clinicopathological staging criteria and treatment guidelines for the disease. Castle’s DecisionDx-SCC test was designed to address this unmet medical need for patients with SCC and one or more high-risk factors. The test provides clinically actionable information about a patient’s biologic risk of metastasis, independent of clinicopathologic factors and traditional staging systems, which can help guide more informed and risk-appropriate treatment decisions within established guidelines.

The poster, titled "Study of 400 dermatologic clinicians corroborates the clinical impact of the prognostic 40-gene expression profile (40-GEP) test in patients with high-risk cutaneous squamous cell carcinoma (SCC)," shares the impact of DecisionDx-SCC test results on clinicians’ management of invasive SCC. The poster is available here.

"The study showed that many clinicians would consider de-escalating treatment plan decisions and potentially forgoing interventions for some patients if their DecisionDx-SCC test results indicated a low biological risk of metastasis," said Robert Cook, Ph.D., senior vice president of research and development at Castle Biosciences. "DecisionDx-SCC test results, when considered on their own and in the context of other clinicopathologic staging systems, can lead to risk-aligned treatment plan changes, either de-intensified or intensified, based on a patient’s individual metastatic risk. We were pleased that the survey responses supported this."

Study highlights:

The majority of clinicians (approximately 80%) indicated they would recommend ordering DecisionDx-SCC for patients with SCC lesions on high-risk locations when also considering the size of the lesion.
Previous studies4,5 have found that DecisionDx-SCC test results (low, moderate or high biological risk results) led to risk-aligned decreases or increases in clinician-directed treatment plans.
The survey results supported this, with the majority of clinicians who recommend the use of interventions for patients with high-risk SCC indicating they would consider forgoing certain treatments (64% for radiologic nodal imaging, 68% for SLN biopsy and 66% for adjuvant radiation therapy) for at least some patients who received a DecisionDx-SCC Class 1 test result (low biologic risk of metastasis).
Intention to further reduce recommendations for radiologic nodal imaging or SLN biopsy with a Class 1 test result was seen in those clinicians who were already using DecisionDx-SCC in their clinical practice (72% and 75%, respectively), accentuating the impact of the test among users.
MyPath Melanoma and DecisionDx DiffDx-Melanoma

MyPath Melanoma and DecisionDx DiffDx-Melanoma are Castle’s diagnostic tests designed to provide objective, highly accurate results to aid in the diagnosis of suspicious melanocytic lesions with ambiguous histopathology. The tests can provide clinically actionable information to help guide and potentially increase confidence in a diagnosis, if any uncertainty or discordance exists, to help clinicians deliver more informed patient management plans and provide their patients with more appropriate and individualized care.

The poster, titled "The current 23- and 35-gene expression profile (GEP) ancillary diagnostic testing workflow for difficult-to-diagnose melanocytic lesions increases the rate of actionable results to 99%," highlights how the current laboratory workflow for Castle’s two diagnostic tests can leverage the strengths of both individual tests to report accurate and clinically actionable results. The poster can be viewed here.

Study highlights:

In the current laboratory workflow, clinical samples are processed first through MyPath Melanoma, and if a technical failure or intermediate result is received, processed next through DecisionDx DiffDx-Melanoma.
In the study, the test workflow demonstrated a high rate of accuracy in the performance cohort, with 96.0% sensitivity and 87.8% specificity.
Based on the analysis of Castle test results reported over a six-month period (June 3-Dec. 3, 2021), the current workflow substantially improved the reporting of clinically actionable results from a historic rate of ~77% with MyPath Melanoma alone to over 99% when both tests were run in a combined workflow.
About DecisionDx-Melanoma

DecisionDx-Melanoma is a gene expression profile test that uses an individual patient’s tumor biology to predict individual risk of cutaneous melanoma (CM) metastasis or recurrence, as well as the risk of sentinel lymph node positivity, independent of traditional staging factors, and has been studied in more than 6,300 patient samples. Using tissue from the primary melanoma, the test measures the expression of 31 genes. Additionally, Castle has an ongoing collaboration with the National Cancer Institute (NCI) to link DecisionDx-Melanoma testing data with data from the Surveillance, Epidemiology and End Results (SEER) Program’s registries on CM cases. This collaboration has resulted in Castle’s analysis of 5,226 samples (clinically tested through December 31, 2018) in a study to evaluate melanoma-specific survival and overall survival; in this study, patients tested with DecisionDx-Melanoma had better survival rates than untested patients, and the data suggested that DecisionDx-Melanoma can accurately risk-stratify for disease progression to aid in risk-aligned treatment plans for improved patient outcomes and survival. The test has been validated in four archival risk of recurrence studies of 901 patients and six prospective risk of recurrence studies including more than 1,600 patients. Additionally, impact on patient management plans for one of every two patients tested has been shown in five multi-center/single-center studies including more than 800 patients. The consistent performance and accuracy demonstrated in these studies provides confidence in disease management plans that incorporate DecisionDx-Melanoma test results. To predict risk of recurrence and likelihood of sentinel lymph node positivity, the Company utilizes its proprietary algorithms, i31-ROR and i31-SLNB, to produce an Integrated Test Result. Through March 31, 2022, DecisionDx-Melanoma has been ordered 97,288 times for patients with cutaneous melanoma.

About DecisionDx-SCC

DecisionDx-SCC is a 40-gene expression profile test that uses an individual patient’s tumor biology to predict individual risk of cutaneous squamous cell carcinoma metastasis for patients with one or more risk factors. The test result, in which patients are stratified into a Class 1 (low), 2A (moderate) or 2B (high) risk category, predicts individual metastatic risk to inform risk-appropriate management.

Peer-reviewed publications have demonstrated that DecisionDx-SCC is an independent predictor of metastatic risk and that integrating DecisionDx-SCC with current prognostic methods can add positive predictive value to clinician decisions regarding staging and management.

About MyPath Melanoma and DecisionDx DiffDx-Melanoma

MyPath Melanoma and DecisionDx DiffDx-Melanoma are two gene expression profile tests designed to provide a highly accurate, objective result to aid dermatopathologists and dermatologists in characterizing difficult-to-diagnose melanocytic lesions. Of the approximately two million suspicious pigmented lesions biopsied annually in the U.S., Castle estimates that approximately 300,000 of those cannot be confidently classified as either benign or malignant through traditional histopathology methods. For these cases, the treatment plan can also be uncertain. Obtaining highly accurate, objective ancillary testing can mean the difference between a path of overtreatment or the risk of undertreatment. Interpreted in the context of other clinical, laboratory and histopathologic information, MyPath Melanoma and DecisionDx DiffDx-Melanoma are designed to reduce uncertainty and provide confidence for dermatopathologists and help dermatologists deliver more informed patient management plans.

On June 22, 2022, Applied Therapeutics, Inc. (the "Company") reported that entered into an underwriting agreement (the "Underwriting Agreement") with SVB Securities LLC (the "Underwriter"), relating to the issuance and sale pursuant to an underwritten public offering (the "Offering") of 20,000,000 shares (the "Shares") of its common stock, par value $0.0001 per share (the "Common Stock"), 10,000,000 pre-funded warrants to purchase Common Stock in lieu of Shares (the "Pre-Funded Warrants") at an exercise price of $0.0001 per share, and accompanying warrants to purchase up to 30,000,000 shares of its Common Stock (the "Common Warrants" and together with the Pre-Funded Warrants, the "Warrants") at an exercise price of $1.00 per share (the Shares and Warrants together, the "Securities") (Filing, 8-K, Applied Therapeutics, JUN 22, 2022, View Source [SID1234616309]). Each share of Common Stock and accompanying Common Warrant was sold at a public offering price of $1.00, less underwriting discounts and commissions, and each Pre-Funded Warrant and accompanying Common Warrant was sold at a public offering price of $0.9999, less underwriting discounts and commissions, as described in the prospectus supplement, dated June 22, 2022, filed with the Securities and Exchange Commission on June 24, 2022. The Pre-Funded Warrants and the Common Warrants are immediately exercisable and will expire five years from the date of issuance. Holders may not exercise any Pre-Funded Warrants or Common Warrants that would cause the aggregate number of shares of Common Stock beneficially owned by the holder to exceed 9.99% of the Company’s outstanding Common Stock immediately after exercise. Holders of the Warrants (together with affiliates) who immediately prior to the issue date beneficially own more than 9.99% of outstanding Common Stock may not exercise any portion of their Pre-Funded Warrants or Common Warrants if the holder (together with affiliates) would beneficially own more than 19.99% of the Company’s outstanding Common Stock after exercise. The Warrants are subject to adjustment in the event of certain stock dividends and distributions, stock splits, stock combinations, reclassifications or similar events affecting the Common Stock and also upon any distributions for no consideration of assets to the Company’s stockholders. In the event of certain corporate transactions, the holders of the Warrants will be entitled to receive, upon exercise of the Warrants, the kind and amount of securities, cash or other property that the holders would have received had they exercised the Warrants immediately prior to such transaction. The Warrants do not entitle the holders thereof to any voting rights or any of the other rights or privileges to which holders of Common Stock are entitled. The Company intends to use the net proceeds from this Offering for general corporate purposes. General corporate purposes may include research and development costs, including the conduct of clinical trials and process development and manufacturing of the Company’s product candidates, expansion of the Company’s research and development capabilities, working capital and capital expenditures. Entities affiliated with Alexandria Venture Investments, LLC, which, as of March 31, 2022, owned 13.1% of the Company’s outstanding Common Stock, purchased 3,500,000 shares and 1,500,000 Pre-Funded Warrants in the Offering.

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The Offering closed on June 27, 2022.