On June 25, 2020 Simcha Therapeutics, a biotechnology company developing first-in-class biologic drugs that modulate powerful cytokine pathways, launched today with $25 million in Series A financing and a mission to harness the precision and power of the immune system through the use of directed evolution (Press release, Simcha Therapeutics, JUN 25, 2020, View Source [SID1234561473]).

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Simcha’s lead program involves a customized variant of interleukin-18 (IL-18), a cytokine with potent antitumor effects, developed in the lab of Scientific Founder Aaron Ring, M.D., Ph.D., Assistant Professor of Immunobiology at the Yale School of Medicine. The biology and preclinical profile of this molecule, which Simcha expects to advance to the clinic in the first half of 2021, is described in detail in a scientific paper published today in the journal Nature.

Cytokine therapies heralded the immuno-oncology revolution more than 30 years ago with the discovery that interleukin-2 (IL-2) could promote rare, but dramatic, responses in melanoma and kidney cancer patients. However, they have not lived up to their promise as a class due to substantial toxicities and limited efficacy. Simcha was founded to overcome those obstacles by using directed evolution to engineer a new generation of cytokines with improved properties relative to those of their native variants. Simcha’s molecules are purpose-built to control immune cell activation, differentiation and proliferation — and to reverse the immunosuppressive tumor microenvironment that is a barrier to effective eradication of the cancer.

"Cytokines represent a compelling therapeutic class because they tap into pathways that are hard-wired into immune cells. The challenge is that nature didn’t design them to be anti-cancer therapies; they’re signaling molecules, so their activity can be hard to specifically direct," Dr. Ring said. "At Simcha, we set out to improve on nature’s design by engineering custom-built proteins that can precisely activate and expand populations of crucial immune responders, such as natural killer (NK) cells and T cells. Too many cancer patients do not respond to the immunotherapies available today. We’re hopeful that our approach will provide new options and potential benefits to these patients."

Evading a "Decoy" Receptor

Simcha’s lead asset, ST-067, activates the IL-18 receptor, triggering potent inflammatory signaling in antitumor immune cells of both the adaptive and innate branches of the immune system.

Early efforts by leading pharmaceutical companies to develop IL-18 into a drug failed. Dr. Ring’s lab broke new ground by identifying the reason for that failure: The tumor microenvironment is teeming with a "decoy" called IL-18BP, which binds IL-18 and blocks it from activating its receptor. When infused as a drug, IL-18 is drawn to the decoy and fails to reach its true target. As described in the Nature paper, the decoy receptor is a "major barrier to IL-18 immunotherapy."

To overcome that barrier, Dr. Ring’s lab used directed evolution to create a version of the cytokine that would evade the decoy and bind only to the true IL-18 receptor. This was a difficult task, since IL-18 normally binds its decoy 10,000 times tighter than it does to the IL-18 receptor. The designer version of IL-18 made in Ring’s lab has dramatic alterations in its receptor binding properties, biasing binding towards the IL-18 receptor and away from the decoy by more than one million-fold. This "decoy-resistant" property enables the custom-built cytokine to work effectively in the immunosuppressive tumor microenvironment.

Potent Single-agent Antitumor Effects

When Ring’s lab tested the decoy-resistant IL-18 and compared it to natural IL-18 in mice, they found that — just as in human patients — natural IL-18 had little to no antitumor activity. By contrast, the decoy-resistant IL-18 had potent single-agent activity that inhibited tumor growth and even produced complete tumor regression in many animals, including in tumor types that are refractory to checkpoint inhibitors.

Ring’s lab also examined the effect of decoy-resistant IL-18 on the tumor microenvironment. A key finding: The engineered IL-18 acted on a crucial population of "stem-like" T cells within tumors, increasing their numbers over tenfold and skewing their development toward a highly active effector phenotype, as opposed to an exhausted or dysfunctional state. In checkpoint-resistant tumors, the engineered IL-18 also acted on innate NK cells, increasing their numbers and maturation to promote antitumor activity.

"The mechanism of action of decoy-resistant IL-18 is unique and distinct from immunotherapeutic agents that are being developed for other pathways. For this reason, we are hopeful it could be effective in tumors that have not otherwise responded to immune-based treatments, as well as enhance the activity of standard cancer immunotherapies," said Dr. Ring.

Founder’s Strong Record in IO Drug Discovery

Dr. Ring has a strong track record in immuno-oncology drug discovery. He co-invented the first described CD122-biased IL-2 variant, originally detailed in Nature in 2012, which is now advancing through preclinical studies at Medicenna Therapeutics. He also developed a high-affinity SIRPα antagonist, featured in Science in 2013, that is now in clinical development at ALX Oncology as ALX-148. For these and other discoveries, Ring was named to Forbes ‘30 under 30’ list of rising stars in health care in 2016 and has been honored with an NIH Director’s Early Independence Award and recognition as a Pew-Stewart Scholar in Cancer Research.

Simcha plans to build out a full executive team as the company prepares to move ST-067 into the clinic next year.

The company’s investors include WuXi AppTec’s Corporate Venture Fund, Sequoia Capital China and Connecticut Innovations.

On June 25, 2020 Fusion Pharmaceuticals Inc. (NASDAQ: FUSN), a clinical-stage oncology company focused on developing next-generation radiopharmaceuticals as precision medicines, reported the pricing of its initial public offering of 12,500,000 common shares at a public offering price of $17.00 per share (Press release, Fusion Pharmaceuticals, JUN 25, 2020, View Source [SID1234561490]). All of the shares are being offered by Fusion. The gross proceeds of the offering, before deducting underwriting discounts and commissions and other offering expenses payable by Fusion, are expected to be $212.5 million. In addition, Fusion has granted the underwriters a 30-day option to purchase up to an additional 1,875,000 common shares at the initial public offering price.

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The shares are expected to begin trading on the Nasdaq Global Market on June 26, 2020 under the ticker symbol "FUSN." The offering is expected to close on June 30, 2020, subject to the satisfaction of customary closing conditions.

Morgan Stanley, Jefferies, and Cowen, are acting as joint book-running managers for the offering. Wedbush PacGrow is acting as lead manager for the offering.

A registration statement relating to these securities became effective on June 25, 2020. The offering will be made only by means of a prospectus. Copies of the final prospectus, when available, may be obtained Morgan Stanley & Co. LLC, Attention: Prospectus Department, 180 Varick Street, Second Floor, New York, New York 10014; or Jefferies LLC, Attention: Equity Syndicate Prospectus Department, 520 Madison Avenue, 2nd Floor, New York, NY 10022, by telephone: (877) 547–6340 or by email at [email protected]; or Cowen and Company, LLC, c/o Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, New York 11717, Attn: Prospectus Department, by telephone at (833) 297-2926, or by email at [email protected].

Fusion obtained a receipt for a final base PREP prospectus filed with the securities commissions or similar securities regulatory authorities in each of the provinces of Canada, other than Québec, on June 25, 2020. A copy of the Canadian supplemented PREP prospectus containing pricing information and other important information relating to Fusion’s common shares may, when available, be obtained from Morgan Stanley Canada Limited and Jefferies Securities, Inc., care of the Morgan Stanley and Jefferies contact details referred to above. Prospective Canadian investors should clearly indicate in their request that they are a Canadian prospective investor and are requesting a copy of the Canadian supplemented PREP prospectus. When available, a copy of the Canadian supplemented PREP prospectus will be available on the SEDAR website at www.sedar.com under Fusion’s profile.

On June 25, 2020 Simcha Therapeutics, a biotechnology company developing first-in-class biologic drugs to modulate powerful cytokine pathways, reported that this week shared data at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting highlighting the potent effects on natural killer cells and stem-like CD8+ cells of its lead asset, a customized variant of IL-18 purpose-built to reverse the immunosuppressive tumor microenvironment (Press release, Simcha Therapeutics, JUN 25, 2020, View Source [SID1234561474]).

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An oral presentation given by Yale researcher Ting Zhou, Ph.D., detailed findings that the IL-18 variant, which was engineered to avoid the "decoy" receptors that abound in the tumor microenvironment, promotes a strong response by natural killer cells against "cold" tumors – those that are no longer expressing significant MHC Class 1 antigens. NK cells quickly become exhausted and lose efficacy when confronted with tumor cells deficient in MHC Class 1. Those tumors are thus refractory to traditional checkpoint inhibition immunotherapy. The decoy-resistant IL-18 (DR-18) engineered in the lab of Simcha’s founder, Aaron Ring, M.D., Ph.D., showed an ability to rescue those exhausted NK cells and thereby stimulate strong anti-tumor activity in multiple animal models.

Single cell RNA sequencing and flow cytometry revealed that DR-18 promoted functional maturation of highly proliferative NK cells. These newly matured cells retained polyfunctional capacity to produce effector molecules that play a critical role in orchestrating both innate and adaptive immune responses, including IFN-γ, Gzmb, and TRAIL. Ablation of NK cells or neutralization of IFN-γ reversed these effects.

"These results highlight the potential of our tailored cytokine to overcome the immunosuppressive tumor microenvironment and elicit a strong therapeutic response by NK cells, even in cold tumors," said Dr. Ring. "The single-agent activity of this decoy-resistant IL-18 is compelling, and we are optimistic that it could bring new hope to patients who no longer respond to checkpoint inhibitors. We look forward to bringing this investigational therapy to the clinic in the first half of 2021."

Dr. Zhou also presented a poster at AACR (Free AACR Whitepaper) demonstrating that DR-18 acts on a crucial population of "stem-like" T cells within tumors, increasing their numbers over tenfold and skewing their development toward a highly active effector phenotype, as opposed to an exhausted or dysfunctional state. These results highlight DR-18’s ability to remodel the intratumoral ecosystem to encourage the proliferation of potent anti-tumor effector cells.

"These results make clear that the IL-18 pathway is a powerful target for immunotherapeutic intervention — as long as that intervention avoids the decoy receptors in the tumor microenvironment," Dr. Ring said. "We’re delighted to be able to share these data with the scientific community at AACR (Free AACR Whitepaper)."

The human variant of the DR-18 is designated ST-067 in Simcha’s pipeline. Simcha is moving through IND-enabling studies and expects to initiate a Phase 1 trial in people with cancer refractory to checkpoint inhibitors in the first half of 2021.

On June 25, 2020 Aethlon Medical, Inc. (Nasdaq: AEMD), a medical device technology company focused on developing products to diagnose and treat life and organ threatening diseases, reported financial results for its fiscal year ended March 31, 2020 and provided an update on recent developments (Press release, Aethlon Medical, JUN 25, 2020, View Source [SID1234561491]).

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Company Updates

Aethlon Medical, Inc. (Company or Aethlon) is continuing the development of its proprietary Hemopurifier, which is a first in class therapeutic device designed for the single use depletion of cancer-promoting exosomes and circulating viruses. The Hemopurifier has previously been designated a Breakthrough Device by the FDA for the treatment of glycosylated viruses, including Ebola and other hemorrhagic fever viruses, and in late 2018 was additionally designated as a Breakthrough Device "…for the treatment of individuals with advanced or metastatic cancer who are either unresponsive to or intolerant of standard of care therapy, and with cancer types in which exosomes have been shown to participate in the development or severity of the disease…".

Aethlon is currently preparing for the initiation of clinical trials in patients with advanced and metastatic cancers. The Company is initially focused on the treatment of solid tumors, including head and neck cancer, gastrointestinal cancers and other cancers. Under an Investigational Device Exemption (IDE) application approved by FDA in October 2019 the Company is initiating an Early Feasibility Study (EFS – the device equivalent of a phase 1 study) in patients with advanced and/or metastatic head and neck cancer at the UPMC Hillman Cancer Center in Pittsburgh, PA. The EFS will enroll 10-12 subjects and will investigate the combination of the Hemopurifier with standard of care pembrolizumab (Keytruda) in the front line setting.

On June 17, 2020, the FDA approved a supplement to the Company’s existing IDE for the use of the Hemopurifier in life threatening viral infections, to allow for the treatment of patients with SARS-CoV-2/COVID-19 infection. This will allow for up to 40 of these patients to be treated under a New Feasibility Study protocol at up to 20 clinical sites in the U.S.

In other news, the Company announced that Thomas L. Taccini has joined the Aethlon management team as Vice President, Manufacturing and Product Development. Mr. Taccini has over 35 years of experience in leading teams in engineering, product development, project management, quality systems and regulatory affairs for multiple different classes of medical devices.

Financial Results for the Fiscal Year Ended March 31, 2020

The Company recorded government contract revenue of $650,187 in the fiscal year ended March 31, 2020. This revenue resulted from work performed under the Company’s Phase 2 Melanoma Cancer Contract with the National Institutes of Health, or NIH. The Company recorded government contract revenue of $229,625 in the fiscal year ended March 31, 2019.

Operating expenses for the fiscal year ended March 31, 2020 were approximately $6.58 million, compared to $6.23 million for the fiscal year ended March 31, 2019. This increase of approximately $350,000, or 6%, in the fiscal year ended March 31, 2020 was due to increases in professional fees of $537,000 and in general and administrative expense of $595,000, which were partially offset by a decrease of $781,000 in payroll and related expenses.

The $537,000 increase in our professional fees in the fiscal year ended March 21, 2020 was primarily due to a $694,000 increase in our legal fees and a $111,000 increase in our accounting fees, which were partially offset by decreases of $245,000 in consulting fees. The increase in legal and accounting fees related to increased activity in our registration statement filings and in intellectual property actions, among other matters.

The $595,000 increase in general and administrative expenses in the fiscal year ended March 21, 2020 was primarily due to the combination of a $316,000 increase in our clinical trial expenses, a $198,000 increase in subcontracting and other costs related to our government contracts, and an increase of $87,000 in laboratory supplies.

The $781,000 decrease in payroll and related expenses in the fiscal year ended March 21, 2020 was due to a combination of a decrease in our stock-based compensation of $475,000 and a decrease of $306,000 in cash-based compensation, primarily due to the termination of consulting and severance payments to our former chief executive officer and former president.

Other expense in the fiscal year ended March 21, 2020 consisted of a non-cash loss on debt extinguishment, interest expense and a gain on share for warrant exchanges, and in the fiscal year ended March 21, 2019, consisted of interest expense only. Other expense for the fiscal year ended March 21, 2020 was approximately $450,000, compared to other expense of approximately $220,000 for the fiscal year ended March 21, 2019.

As a result of the changes in revenues and expenses noted above, our net loss before noncontrolling interests increased to approximately $6,380,000 for the fiscal year ended March 31, 2020, from $6,220,000 for the fiscal year ended March 31, 2019.

At March 31, 2020, we had a cash balance of approximately $9.6 million.

In June 2020, we raised additional cash through the sale of 2,685,600 shares of common stock under our ATM facility at an average price of $2.70 per share of net proceeds. The aggregate net proceeds to us were approximately $7.3 million.

The unaudited condensed consolidated balance sheet for March 31, 2020 and the unaudited condensed consolidated statements of operations for the fiscal years ended March 31, 2020 and 2019 follow at the end of this release.

Conference Call

The Company will hold a conference call today, Thursday, June 25, 2020 at 4:30 p.m. Eastern Time to review financial results and recent corporate developments. Following management’s formal remarks, there will be a question and answer session.

Interested parties can register for the conference by navigating to View Source Please note that registered participants will receive their dial in number upon registration.

Interested parties without internet access or unable to pre-register may dial in by calling:

All callers should ask for the Aethlon Medical, Inc. conference call.

A replay of the call will be available approximately one hour after the end of the call through July 2, 2020. The replay can be accessed via Aethlon Medical’s website or by dialing 1-877-344-7529 (domestic) or 1-412-317-0088 (international) or Canada Toll Free at 1-855-669-9658. The replay conference ID number is 10145174.

On June 25, 2020 BerGenBio ASA (OSE:BGBIO), a clinical-stage biopharmaceutical company developing novel, selective AXL kinase inhibitors for severe unmet medical need, reported positive clinical and translational data from Cohort B, stage 1 of in the phase II trial (BGBC008) (Press release, BerGenBio, JUN 25, 2020, View Source [SID1234561475]). This cohort of the trial is evaluating bemcentinib in combination with MSD’s Keytruda (pembrolizumab) in previously treated non-small cell lung cancer (NSCLC) patients with confirmed progression on prior immune checkpoint therapy. The trial is recruiting the second stage of the cohort.

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The data was presented today by Professor Hani Gabra M.D. Ph.D., Chief Medical Officer of BerGenBio ASA, at the Next Gen Immuno-Oncology Congress, a virtual event, see: View Source The presentation will be available on the Company website in the Presentations section www.bergenbio.com/investors/presentations/

BerGenBio announced on 15th January 2020 that stage 1 of this trial cohort had met its primary end point of overall response rate and criteria were met for expansion of this cohort to a second stage.

The Company reports that Cohort B, stage 1 included 12 evaluable patients for cAXL, BerGenBio’s proprietary composite-AXL (cAXL) immunohistochemistry biomarker. Seven of these 12 patients were scored cAXL positive, six of these seven patients reported clinical benefit, including1 PR and 1 PRi (unconfirmed) and 2.5 fold improvement in mPFS. Further, an update was presented for Overall Survival data from cohort A, where cAX-postive patients reported 12-month OS of 79% and mOS of 17.3 months (data still maturing), whereas cAXL-negative 60% and 12.4months respectively and in-line with historic controls.

The BGBC008 trial (ClinicalTrials.gov Identifier: NCT03184571) is conducted in three cohorts evaluating the safety and benefit of bemcentinib and Keytruda combination in refractory NSCLC patients. Cohort A (fully recruited, patients that are refractory to first line chemotherapy), Cohort B (enrolling second line patients who have received single agent checkpoint inhibitor in the first line) and Cohort C (that enrols second line patients refractory to the first line treatment of checkpoint inhibitor in combination with chemotherapy), cohorts B2 and C are actively recruiting patients. The study is being sponsored by BerGenBio in collaboration with MSD, a tradename of Merck & Co., Inc., Kenilworth, New Jersey, USA, who continue to supply Keytruda for use in the study under a collaboration agreement signed in March 2017.

Richard Godfrey, Chief Executive Officer of BerGenBio, said: "This interim clinical and translational data adds further confidence to the potential patient benefit of selective AXL inhibition with bemcentinib, to reverse resistance to immune checkpoint inhibitors in selected cAXL-positive patients who have relapsed on immunotherapy. This would be a highly desirable alternative to the second-line chemotherapy standard-of-care. Top line data from expansion cohorts B2 and cohort C should be available towards the end of 2020."

About AXL

AXL kinase is a cell membrane receptor and an essential mediator of the biological mechanisms underlying life-threatening diseases. In cancer, AXL suppresses the body’s immune response to tumours and drives cancer treatment failure across many indications. AXL expression defines a very poor prognosis subgroup in most cancers. AXL inhibitors, therefore, have potential high value at the centre of cancer combination therapy, addressing significant unmet medical needs and multiple high-value market opportunities. Research has also shown that AXL mediates other aggressive diseases.

About Bemcentinib

Bemcentinib (formerly known as BGB324), is a potentially first-in-class selective AXL inhibitor in a broad phase II clinical development programme. Ongoing clinical trials are investigating bemcentinib in multiple solid and haematological tumours, in combination with current and emerging therapies (including immunotherapies, targeted therapies and chemotherapy), and as a single agent. Bemcentinib targets and binds to the intracellular catalytic kinase domain of AXL receptor tyrosine kinase and inhibits its activity. Increase in AXL function has been linked to key mechanisms of drug resistance and immune escape by tumour cells, leading to aggressive metastatic cancers.