On December 22, 2021 Dovetail Genomics, the industry leader in advanced proximity ligation genomic solutions, reported details of a new study, led by University of Michigan researchers and published in Nature, which showed for the first time that inhibiting the SWI/SNF chromatin remodeling complex prevents several oncogenes from being expressed and slows prostate cancer growth in cell and animal models (Press release, Dovetail Genomics, DEC 22, 2021, View Source [SID1234597627]). These findings were made possible, in part, by Hi-C technology developed by Dovetail Genomics, with the company’s proximity ligation HiChIP MNase Kit providing essential information about 3D chromatin architecture, illuminating the effect the PROTAC had on chromatin remodeling. In addition, Dovetail scientists Mital Bhakta and Jay Ghurye contributed to the paper.

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"This is a revolutionary finding," said Arul Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology and senior author on the paper. "By controlling chromatin structure in prostate cancer cells, we shut down several oncogenic pathways at once. This could offer new hope for patients, particularly those with resistant disease."

Chromatin is the combination of DNA, RNA and proteins that tightly package genetic material in the nucleus. Cells have evolved complex mechanisms, including the SWI/SNF complex, to open up chromatin and allow gene expression.

In the study, the research team designed a proteolysis targeting chimera (PROTAC), a small molecule compound, that degrades SMARCA2 and SMARCA4, essential SWI/SNF components. This degradation had a ripple effect. Inhibiting SWI/SNF kept chromatin closed to cancer-driving transcription factors, which could not reach gene enhancers, muting well-known oncogenes, such as AR (androgen receptor), FOXA1, ERG and MYC.

This work highlights potential therapeutic targets to defeat enhancer-addicted prostate and possibly other cancers. Equally important, PROTAC synergized with the androgen receptor antagonists, which are often used to treat prostate cancer, making them more effective.

"Dovetail has always put an acute focus on cancer research, understanding that proximity ligation takes oncology studies to the next level," said Todd Dickinson, CEO of Dovetail Genomics. "We were thrilled to partner with Dr. Chinnaiyan on this study, helping to identify a critical advance in cancer data and research."

The full article can be found here: View Source

On December 22, 2021 Emendo Biotherapeutics, a next-generation CRISPR biotech expanding the reach of gene editing therapeutics, and Seattle Children’s Research Institute reported a research collaboration to investigate how hematopoietic stem cells (HSCs) extracted from patients with severe congenital neutropenia (SCN) respond to priming treatments ahead of administering a CRISPR-based therapeutic (Press release, Seattle Children Hospital, DEC 22, 2021, View Source [SID1234597626]).

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ELANE-related SCN, also known as SCN1, is a rare, autosomal dominant disease in which a mutation occurs in one allele of the ELANE gene, thereby preventing HSCs from differentiating into white blood cells, specifically neutrophils, which leaves the patient highly susceptible to recurrent bacterial infections, osteoporosis, developmental delays and abnormalities.

"Patients with SCN often suffer from reduced quality of life due to the lack of improvements in the standard of care," said Dr. David Rawlings, Division Chief of Immunology at Seattle Children’s Hospital and Director of the Center for Immunity and Immunotherapies at Seattle Children’s Research Institute. "These children are immunocompromised, and, as a result, we feel a great sense of urgency to ensure we’re exploring all possible avenues towards a solution."

"Seattle Children’s collaboration with Emendo, utilizing its unique approach to edit only the mutated allele with CRISPR, will enable us to address the unmet needs of SCN at the very core," added Rawlings, who also serves as a professor of pediatrics and adjunct professor in the Department of Immunology at the University of Washington School of Medicine. "We’re excited about this opportunity, and look forward to continuing the collaboration beyond this initial study."

Editing the mutated ELANE gene with CRISPR first requires overcoming a technological hurdle: Only the mutated allele must be targeted, while the healthy allele remains intact. Emendo engineered its roster of next-generation CRISPR nucleases to be biologically active and so specific that they can differentiate between two alleles of the same gene. EMD-101, Emendo’s lead therapeutic candidate for SCN, was specifically engineered to target the mutant ELANE allele.

HSCs have been widely studied as a treatment for sickle cell anemia and cancer, as well as a potential therapy to treat organ and tissue damage. However, HSCs require initial priming prior to stem cell transplantation, which is typically done by administering G-CSF (granulocyte colony stimulating factor). Yet, the same drug is also a short-term treatment for SCN patients.

To better understand how SCN patients would respond to a priming dose of G-CSF and plerixafor, Emendo will evaluate the mobilization of HSCs excised from a small group of patients with SCN, which would be gene-edited later. Concurrently, Seattle Children’s will evaluate the composition of the HSCs obtained from the same patients. Prior mouse studies conducted by Emendo have shown that human cells edited to excise the disease-causing ELANE allele sufficiently engrafted and replaced existing diseased cells, restoring proper neutrophil differentiation.

"By combining our allele-specific genome editing technology with Seattle Children’s renowned expertise in SCN — spearheaded by Dr. Rawlings — we are laying the foundation for future clinical trials that could lead to potential therapies to treat the disease," said David Baram, Ph.D., CEO of Emendo. "Our portfolio of engineered nucleases tailored to any gene or allele gives us the unique opportunity to tackle the inherent challenges of SCN. Through this collaboration we’ll be able to provide stronger evidence and further proof points for the capabilities of our technology."

Based on the outcome of the research, a protocol for a clinical trial could be developed with an expected initiation in late 2022, pending regulatory approval. Seattle Children’s has certain preferred rights to serve as a clinical trial site.

On December 22, 2021 CEL-SCI Corporation (NYSE American: CVM) reported financial results for the fiscal year ended September 30, 2021, as well as key clinical and corporate developments (Press release, Cel-Sci, DEC 22, 2021, View Source [SID1234597625]).

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Clinical and Corporate Developments included:

On October 22, 2021, CEL-SCI announced it completed the commercial scale expansion of its dedicated current Good Manufacturing Practice (cGMP) facility in which it manufactures its immunotherapy Multikine (Leukocyte Interleukin, Injection)*. The construction, which began in 2020, was designed to ensure it will be compliant with all requirements of the U.S. Food and Drug Administration’s (FDA) and European cGMP regulations as the facility’s production capacity has been doubled to meet anticipated market demand for Multikine once it receives regulatory approval.
On June 28, 2021, CEL-SCI announced top line results from its 9.5 year global pivotal Phase 3 study for Multikine in head and neck cancer. The Phase 3 results showed a long-term 5-year overall survival (OS) benefit in the treatment arm receiving Multikine treatment regimen followed by surgery and radiation. This survival benefit was statistically significant (two-sided p=0.0236, HR=0.68), robust and durable, with no safety issues, something not commonly seen with cancer drugs. In fact, the survival benefit increased over time and at 5-years the overall survival benefit reached an absolute 14.1% advantage for the Multikine treated arm over control (n=380, total study patients treated with surgery plus radiation): the Multikine treatment arm showed 62.7% overall survival versus the control arm which showed only 48.6% overall survival.
The OS benefit of 14.1% at 5 years for this treatment arm exceeded the 10% OS benefit set out for the study population in the protocol. The results from the Phase 3 cancer study proved that Multikine met all of protocol required benefits stated in the study protocol in patients in the treatment arm receiving surgery and radiation as their standard therapies.
Based on the results of this pivotal Phase 3 study, CEL-SCI intends to file a Biologic License Application with the FDA for approval of the Multikine treatment regimen in advanced primary squamous cell carcinoma of the head and neck patients scheduled to receive surgery and radiation as their primary treatments. CEL-SCI’s trial was conducted in over 20 countries in which marketing clearance applications may also be filed subsequent to FDA filing and/or approval.
CEL-SCI raised net proceeds of approximately $54.1 million during fiscal 2021 through the sale of common stock and the exercise of warrants and options. As of September 30, 2021, CEL-SCI had $42.2 million in cash, cash equivalents and U.S. Treasury Bills.
"Having conducted and completed the largest ever study in head and neck cancer, we are filing for regulatory approval with confidence that Multikine extends life in this severely unmet medical need. Our team has delivered and continues to work hard at preparing our BLA filing, validating and preparing our manufacturing facility for commercial production and publishing our data in peer reviewed journals. With a solid cash runway, we are optimistic about the future and the potential for Multikine to improve the lives of head and neck cancer patients and their families," stated CEL-SCI CEO, Geert Kersten.

CEL-SCI reported a net loss of $36.4 million in fiscal year 2021 versus a net loss of $30.3 million in fiscal year 2020. The increase in net loss was predominantly due to an increase in research and development expenses by approximately $5.3 million, or 30%, and an increase in general and administrative expenses by approximately $1.4 million, or 12%, compared to the year ended September 30, 2020. With the conclusion of the Phase 3 study, the expenditures for fiscal 2022 are expected to be lower.

On December 22, 2021 DURECT Corporation (Nasdaq: DRRX) reported a licensing agreement granting Innocoll Biotherapeutics plc, a specialty pharmaceutical company and portfolio business of Gurnet Point Capital, exclusive development and commercialization rights to POSIMIR (bupivacaine solution) for infiltration use, DURECT’s FDA-approved non-opioid, sustained-release local analgesic for the treatment of post-surgical pain in adults following arthroscopic subacromial decompression surgery, in the United States (Press release, DURECT, DEC 22, 2021, https://investors.durect.com/news-releases/news-release-details/durect-and-innocoll-announce-136-million-us-licensing-agreement [SID1234597622]).

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"We are excited to license the U.S. development and commercialization rights for POSIMIR to Innocoll, whose dedicated hospital sales and marketing organization is deeply committed to providing non-opioid analgesia products to patients in the post-surgical setting," said James E. Brown, President and Chief Executive Officer of DURECT Corporation. "Completing this POSIMIR deal is another important step in the continued transformation of DURECT as we continue to focus on larsucosterol, our lead epigenetic regulator, which is in late-stage clinical development for alcohol-associated hepatitis."

"We believe that POSIMIR has the potential to become a cornerstone of multi-modal post-operative pain management as well as an important contributor to the on-going efforts to provide safe and effective alternatives to opioid-based medications following surgery," added Louis Pascarella, Chief Executive Officer of Innocoll. "Innocoll is now the only company with two bupivacaine-based, sustained-release, non-opioid products, that are FDA approved and indicated for relief of post-surgical pain in specified surgical procedures. We are currently on track to launch POSIMIR in the second quarter of 2022, subject to commercial supply timelines."

Terms of the Collaboration

Under the terms of the agreement, Innocoll will make near-term payments to DURECT of $6 million, consisting of a $4 million license fee and a $2 million payment upon first commercial sale, with the potential for up to an additional $130 million in commercial, regulatory and intellectual property milestone payments as well as tiered, low to mid double-digit royalties on net product sales in the United States.

Innocoll has been granted the exclusive right to develop and commercialize POSIMIR in the United States. Innocoll has also been granted the right to conduct additional development activities to expand the approved indications for POSIMIR, and DURECT’s contract manufacturing supply agreement for POSIMIR has been assigned to Innocoll. DURECT retains all commercial rights to POSIMIR throughout the rest of the world.

Conference Call

DURECT will host a conference call today to discuss the license agreement with Innocoll:

View Source

The conference call will also be available by webcast on DURECT’s homepage at www.durect.com under the "Investors" tab. If you are unable to participate during the webcast, the call will be archived on DURECT’s website under "Event Calendar" in the "Investors" section.

On December 22, 2021 Agenus (NASDAQ: AGEN), an immuno-oncology company with an extensive pipeline of checkpoint antibodies, adjuvants, and vaccines designed to activate immune response to cancers and infections, reported the publication of results in the Journal of Clinical Oncology (JCO) from a global Phase 2 clinical study of balstilimab (Bal) plus zalifrelimab (Zal) in second-line (2L) recurrent/metastatic cervical cancer patients who had relapsed after treatment with platinum-based therapy (Press release, Agenus, DEC 22, 2021, View Source [SID1234597621]).

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"We’re excited to present this data from the largest study conducted to date, assessing the benefit from combined PD-1 and CTLA-4 inhibition in this patient population," said Steven O’Day, MD, Chief Medical Officer of Agenus. "The combination data with Bal (anti-PD-1) and Zal (anti-CTLA-4) in recurrent/metastatic cervical cancer represents a meaningful improvement over currently available therapies while demonstrating a well-tolerated safety profile. We are committed to pursuing the benefit of combination therapies with first-generation antibodies like Zal as well as with our next-generation candidates which include our Fc-enhanced anti-CTLA-4 antibody AGEN1181."

The trial showed that in the 125 evaluable patients treated with Bal/Zal, ORR was 25.6%; among PD-L1+ patients, the ORR was 32.8%. The Phase 2 trial was conducted in patients with recurrent/metastatic cervical cancer who had relapsed after prior platinum-based therapy, a population disproportionately represented by younger women, who have limited effective treatment options. Complete and partial responses were achieved by 8.0% and 17.6% of all patients respectively. The disease control rate in the trial was 52.0%. Responses achieved in patients were highly durable, with a median duration of response not yet reached (NR) following 21-month median follow-up (95% CI: 9.7 months to NR). Median overall survival was 12.8 months, with 69.2% and 53.3% of patients remaining alive at 6 and 12 months, respectively. Responses were observed across tumor histologies in the trial.

"With durable responses and a well-tolerated safety profile, the combined inhibition of PD-1 and CTLA-4 is a much-needed option for patients in this setting," said David O’Malley, MD, lead study investigator; Professor and Director of the Division of Gynecologic Oncology, The Ohio State University – James Cancer Center.

The Bal/Zal combination continued to show no unexpected toxicities and no new safety signals were identified. TRAEs leading to discontinuations occurred in 7.7% of patients.

About Cervical Cancer
Cervical cancer is a malignancy that originates in the cervix, the lower part of the uterus. It is the fourth most common cancer diagnosed among women globally, with nearly 14,500 patients expected to be diagnosed in the U.S. alone in 2021. Cervical cancer disproportionately affects younger women and is most frequently diagnosed between the ages of 35 to 44 in the U.S., with the average age at diagnosis being 50. Despite preventable measures such as HPV vaccination and early pap-smear that exist for prevention and early detection of disease, over 50% of cervical cancer cases in the U.S are only detected after the disease has spread. In patients whose disease has spread to distant parts of the body, 5-year survival rate in the U.S. is estimated to be 17%. Nearly 4,300 women are expected to die from cervical cancer in the U.S. in 2021.

About Balstilimab
Balstilimab is a novel, fully human monoclonal immunoglobulin G4 (IgG4) designed to block PD-1 (programmed cell death protein 1) from interacting with its ligands PD-L1 and PD-L2. PD-1 is a negative regulator of immune activation that is considered a foundational target within the immuno-oncology market.

About Zalifrelimab
Zalifrelimab is a novel, fully human monoclonal immunoglobulin G1 (IgG1) designed to block CTLA-4 (cytotoxic T-lymphocyte associated antigen 4) from interacting with its ligands CD80 and CD86. CTLA-4 is a negative regulator of immune activation that is considered a foundational target within the immuno-oncology market.