On March 21, 2023 Vaccinex, Inc. (Nasdaq: VCNX), a clinical-stage biotechnology company pioneering a differentiated approach to treating cancer and neurodegenerative disease through the inhibition of SEMA4D, reported the initiation of a single-arm open label, Phase Ib/2 study to evaluate pepinemab in combination with avelumab as second line combination immunotherapy for patients with metastatic pancreatic adenocarcinoma (PDAC), NCT05102721 (Press release, Vaccinex, MAR 21, 2023, View Source [SID1234629112]).

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The principal goal of this proof-of-concept study is to investigate the safety and efficacy of the combination of pepinemab and the PD-L1 immune checkpoint inhibitor (ICI), avelumab, in patients with PDAC, with particular attention to changes in the tumor microenvironment.

"We are very pleased to be working with Dr. David Linehan and his team at the University of Rochester Cancer Center and Wilmot Cancer Institute to conduct this important proof-of-concept study evaluating pepinemab and avelumab in PDAC. The team received a grant from the Gateway Discovery Award to support the trial concept," said Maurice Zauderer, CEO of Vaccinex. "Metastatic pancreatic adenocarcinoma is the third leading cause of cancer-related deaths. The profoundly immunosuppressive tumor microenvironment (TME) in PDAC remains a significant barrier to effective cytotoxic and immune based therapies. Low response rates to current chemotherapy regimens are evidenced by a 5-year survival rate of only 5-10%, underscoring the significant need for new treatment options. We believe that pepinemab has demonstrated a favorable safety profile when used in combination with the immune checkpoint inhibitor (ICI) avelumab1, and the combination may represent a novel treatment option for patients with this devastating disease."

Dr. Zauderer continued, "The hypothesis for evaluating pepinemab in combination with ICIs in PDAC is supported by a robust body of preclinical studies and human clinical data. These data suggest that treatment with the semaphorin 4D (SEMA4D) blocking antibody, pepinemab, may reverse immunosuppression to promote the infiltration and activation of dendritic cells and CD8+ cells into the TME, rendering "cold" tumors "hot" and leading to enhanced efficacy of ICIs such as avelumab."

Dr. Luis Ruffolo, MD, University of Rochester Medical Center, will be presenting details of these PDAC studies at SSO 2023, International Conference on Surgical Cancer Care in Boston, MA on March 23.

Potential Mechanism of Action for pepinemab in combination with ICIs in PDAC

Tumors that are characterized by a high level of immunosuppressive myeloid cells may be potential candidates for treatment with pepinemab. The tumor microenvironment (TME) of PDAC is characterized

by dense fibrotic tissue and abundance of highly suppressive myeloid cells that creates an immunologically "cold" setting with a minimal adaptive T-cell response that limit the efficacy of immune therapies.

In PDAC, both SEMA4D and PD-1 are expressed on CD8+T cells in the TME. Myeloid cells within the TME express a high level of SEMA4D receptors and signaling through this pathway induces their suppressive activity. This suggests that blocking SEMA4D may represent a novel immunotherapeutic strategy for PDAC. In preclinical oncogene driven PDAC tumor models, treatment with Sema4D blocking antibody in combination with immune checkpoint blockade and standard of care chemotherapy increased penetration of effector T cells and improved response to treatment.

These observations in PDAC are consistent with a large body of preclinical and clinical data showing that pepinemab promotes infiltration and activation of dendritic cells and CD8+ T-cells and reverses immunosuppression within the tumor microenvironment.

About the Phase 1b/2 Study in Patients with PDAC

The single-arm, open label Phase 1b/2 study was designed to evaluate the use of pepinemab, a humanized IgG4 monoclonal antibody that inhibits SEMA4D, in combination with the anti-PD-L1 immune checkpoint inhibitor (ICI), avelumab, as second line treatment for patients with metastatic pancreatic adenocarcinoma who have received first line treatment with either 5-floururacil (5-FU) or gemcitabine.

The trial was designed at the ASCO (Free ASCO Whitepaper)-AACR Clinical Trial workshop to integrate evaluation of safety and efficacy. The study will be conducted in two segments utilizing a Simon two-stage design. The Phase 1b stage is intended to establish the tolerability (defined as the maximally tolerated dose) of the combination. Phase 2 begins after 16 subjects are enrolled at the recommended Phase2 dose and successful completion of futility evaluation in Phase 1b. The Phase 2 expansion stage is intended to assess the efficacy of the combination therapy. Efficacy, defined as objective response rate, will be assessed by RECIST1.1 criteria and iRECIST. When combined with the 16 patients from the Phase 1b segment, the overall study cohort will have an evaluable sample of 40 patients. Robust correlative analysis of TME and genomic profiling of tumor biopsies will be conducted to ascertain mechanisms of treatment response and failure.

Vaccinex has global commercial and development rights to pepinemab. The Company is the sponsor of the study which is being primarily funded by a grant from the Gateway Discovery Award (administered by the Conquer Cancer Foundation/ASCO). Pepinemab is being provided by Vaccinex and avelumabis being provided by Merck KGaA, Darmstadt, Germany and Pfizer, Inc. Additional information about the study is available at: clinicaltrials.gov.

Avelumab is co-developed and co-commercialized by Merck KGaA, Darmstadt, Germany and Pfizer Inc

1. Shafique MR, Fisher TL, Evans EE, Leonard JE, et al. Clin Cancer Res. 2021 Jul 1;27(13):3630-3640. doi: 10.1158/1078-0432.CCR-20-4792.

On March 21, 2023 ReCode Therapeutics, a genetic medicines company using superior delivery to power the next wave of mRNA and gene correction therapeutics, reported that David Lockhart, Ph.D., President and Chief Scientific Officer of ReCode Therapeutics, will participate in a panel discussion titled "Novel LNPs Targeting Diverse Tissues" at 10:00 a.m. ET on Tuesday, March 28, 2023 at the virtual BMO Biopharma Spotlight Series: Novel Technologies for the Delivery of Genetic Medicines (Press release, ReCode Therapeutics, MAR 21, 2023, View Source;utm_medium=rss&utm_campaign=recode-therapeutics-to-present-at-bmo-biopharma-spotlight-series-novel-technologies-for-the-delivery-of-genetic-medicines [SID1234629111]).

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On March 21, 2023 MonTa Biosciences reported that it will be presenting very strong data on our immuno oncology technology with our drug candidate MBS8 at the annual meeting of AACR (Free AACR Whitepaper) in Orlando, Florida (Press release, MonTa Biosciences, MAR 21, 2023, View Source [SID1234629108]). Come to learn more about our technology and have a talk on April 17, where MonTas CEO, Simon S Jensen will present these very encouraging data on cancer immunotherapy.

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On March 21, 2023 X4 Pharmaceuticals Inc. (Nasdaq: XFOR), a leader in the discovery and development of novel small-molecule therapeutics to benefit people with diseases of the immune system, reported financial results for the fourth quarter and full year ended December 31, 2022 and highlighted key 2022 events and expected upcoming milestones (Press release, X4 Pharmaceuticals, MAR 21, 2023, View Source [SID1234629106]).

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"We could not be more pleased with the progress we made in 2022 advancing our investigational therapy, mavorixafor, towards commercialization," said Paula Ragan, Ph.D., President and Chief Executive Officer of X4 Pharmaceuticals. "Our clinical trial data continue to speak for themselves, demonstrating mavorixafor’s ability to elevate circulating levels of neutrophils, lymphocytes, and monocytes in people with immune system dysfunction. Following the positive results from our 4WHIM clinical trial in late 2022, we continue to expect presentation of additional Phase 3 data in the second quarter of 2023 and the submission of our first New Drug Application (NDA) in the U.S. early in the second half of the year. We are now enrolling patients in our Phase 2 trial in people with certain chronic neutropenic (CN) disorders and anticipate announcing clinical data from this trial along with clarity on the potential regulatory path forward for mavorixafor in CN disorders in the second or third quarter of 2023."

2022 Highlights & Key Anticipated Upcoming Milestones

Positive Clinical Results: With a tightened focus on advancing mavorixafor in chronic neutropenia indications, X4 announced successful conclusion of and positive data from key clinical programs in 2022:
•Pivotal, Phase 3 4WHIM trial: In late November, the company announced that its Phase 3 clinical trial evaluating oral mavorixafor in people with WHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome met its primary endpoint and first key secondary endpoint, with mavorixafor achieving statistically significant and clinically relevant longer times above threshold levels for both absolute neutrophil and absolute lymphocyte counts versus placebo and demonstrating good tolerability in the trial.
◦Additional data from the 4WHIM trial are expected to be presented at medical conferences in the second quarter of 2023.

Exhibit 99.1
◦The company is now preparing to meet with U.S. regulatory authorities to discuss next steps in advancing mavorixafor towards an NDA submission, which is still anticipated early in the second half of 2023.
◦To the best of the company’s knowledge, mavorixafor is the first and only oral therapy in development to demonstrate durable improvements in severe chronic neutropenia and lymphopenia, the hallmarks of WHIM syndrome, a rare primary immunodeficiency for which there are no approved treatments.
•Phase 1b Chronic Neutropenia Trial: In September 2022, X4 presented positive data from a Phase 1b clinical trial demonstrating the ability of one dose of oral mavorixafor to increase and normalize absolute neutrophil counts (ANC) in people with idiopathic, cyclic, or congenital chronic neutropenia as monotherapy or administered concurrently with injectable granulocyte colony-stimulating factor (G-CSF).
◦The company continues to believe that these results suggest an expanded future market opportunity for mavorixafor that could include up to 50,000 diagnosed patients in the U.S. with certain forms of chronic neutropenia.
◦The Phase 1b trial has now been amended and expanded into a Phase 2 clinical trial to assess the long-term durability, safety, and tolerability of oral mavorixafor in a larger population with idiopathic, cyclic, or congenital chronic neutropenia.
◦Participants are currently being enrolled in the Phase 2 CN trial and X4 anticipates announcing clinical data and clarity on the scope and timing of the expected Phase 3 clinical program for mavorixafor in chronic neutropenia in the second or third quarter of 2023.

Greater Insight into Mavorixafor Market Potential: Throughout 2022, X4 presented results from both its clinical and research programs, further supporting the commercial potential of mavorixafor in a variety of chronic neutropenia indications, including WHIM syndrome, at multiple, prominent medical conferences.
•Conferences included: the American Academy of Allergy Asthma & Immunology (AAAAI) Annual Meeting, the Clinical Immunology Society (CIS) Annual Meeting, the European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress, the North American Immuno-Hematology Clinical Education & Research (NICER) Symposium, the European Society for Immunodeficiencies (ESID), the National Organization for Rare Diseases (NORD) fall Summit, and the Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper).
•These presentations not only highlighted new insights into the genotype and phenotype of people with WHIM syndrome, helping to identify additional patients and educate treating physicians, but also spotlighted new understandings into and confirmation of mavorixafor’s ability to mobilize mature, functional white blood cells from the bone marrow into the blood, and helped elucidate the unmet medical needs and the size of the U.S. population living with severe chronic neutropenia.

Strong Balance Sheet to Support Drive to Commercialization: Despite continued challenging market conditions, during 2022, X4 successfully completed two large financings, raising aggregate gross proceeds of approximately $120 million and has subsequently re-negotiated its loan facility agreement:
•In July 2022, X4 completed a private investment in public equity (PIPE) financing, receiving aggregate gross proceeds of approximately $55 million.
•In December 2022, the company completed a public offering that yielded gross proceeds of approximately $65.0 million before deducting underwriting discounts and estimated offering expenses and any proceeds from the exercise of the warrants to be issued in the offering.

Exhibit 99.1
•On January 6, 2023, X4 entered into a Second Amended and Restated Loan and Security Agreement with Hercules Capital that amended and restated all previous loan and security agreements, and that included the extension of the interest-only payment period through the third quarter of 2024 and an agreement to further extend the interest-only period to the first quarter of 2026 if certain milestones are achieved.
•In addition, the covenant under the Hercules agreement requiring that the company maintain cash in an aggregate amount greater than $30.0 million was lowered to $20.0 million, subject to certain terms and conditions.

Fourth Quarter and Full Year 2022 Financial Results
•Cash, Cash Equivalents & Restricted Cash: X4 had $123.0 million in cash, cash equivalents, and restricted cash as of December 31, 2022. X4 believes that it has sufficient funds to support company operations into the second quarter of 2024.
•Research and Development (R&D) Expenses were $19.0 million and $61.1 million for the fourth quarter and full year ended December 31, 2022, respectively, as compared to $12.2 million and $50.6 million for the comparable periods in 2021. R&D expenses included $0.5 million and $2.5 million of certain non-cash expenses for the fourth quarter and full year ended December 31, 2022, respectively.
•Selling, General and Administrative Expenses (SG&A) were $6.6 million and $27.0 million for the fourth quarter and full year ended December 31, 2022, respectively, as compared to $7.1 million and $24.7 million for the comparable periods in 2021. SG&A expenses included $0.6 million and $2.7 million of certain non-cash expenses for the fourth quarter and full year ended December 31, 2022, respectively.
•Net Loss: X4 reported a net loss of $29.1 million and $93.9 million for the fourth quarter and full year ended December 31, 2022, respectively, as compared to $30.2 million and $88.7 million for the comparable periods in 2021. Net loss included $1.1 million and $5.2 million of stock-based compensation expenses for the fourth quarter and full year ended December 31, 2022, respectively. Net loss included $1.6 million and $6.2 million of stock-based compensation expenses for the fourth quarter and full year ended December 31, 2021, respectively. Net loss for the fourth quarter and full year ended December 31, 2021 included a non-cash goodwill impairment charge of $9.8 million. There was no goodwill impairment charge in 2022.
Conference Call and Webcast
X4 will host a conference call and webcast today at 9:00 am ET to discuss these financial results and business highlights. The conference call can be accessed by dialing 1-855-327-6837 within the United States or 1-631-576-4098 internationally, followed by the conference ID: 10020997. The live webcast can be accessed on the investor relations section of X4 Pharmaceuticals’ website at www.x4pharma.com. Following the completion of the call, a webcast replay of the conference call will be available on the company website.

On March 21, 2023 Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE), a biopharmaceutical company focused on the development and commercialization of novel therapies for rare and ultra-rare diseases, reported the grant of non-qualified stock options to purchase an aggregate of 7,130 shares of common stock of the company and 5,885 restricted stock units of the company’s common stock to ten newly hired non-executive officers of the company (Press release, Ultragenyx Pharmaceutical, MAR 21, 2023, View Source [SID1234629105]). The awards were approved by the compensation committee of the company’s board of directors and granted under the Ultragenyx Employment Inducement Plan, with a grant date of March 16, 2023, as an inducement material to the new employees entering into employment with Ultragenyx in accordance with Nasdaq Listing Rule 5635(c)(4).

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The restricted stock units vest over four years, with 25% of the underlying shares vesting on each anniversary of the grant date, subject to the employee being continuously employed by the company as of such vesting dates. The stock options vest over four years, with 25% of the shares underlying the option vesting on the first anniversary of the grant date and the remainder vesting with respect to 1/48th of the shares underlying the options on each monthly anniversary thereafter, subject to the employee being continuously employed by the company as of such vesting dates. The stock options have a ten-year term and an exercise price of $40.22 per share, equal to the per share closing price of Ultragenyx’s common stock on March 16, 2023.