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CDX-1140 Demonstrates Clinical and Biological Activity in Patients with Advanced Solid Tumors in Phase 1 Dose Escalation Study

On November 8, 2019 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported data from the Company’s ongoing CD40 agonist program at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 34th Annual Meeting (Press release, Celldex Therapeutics, NOV 8, 2019, View Source [SID1234550802]). CD40, expressed on dendritic cells and other antigen presenting cells, is an important target for immunotherapy, as it plays a critical role in the activation of innate and adaptive immune responses. CDX-1140 is a fully human agonist anti-CD40 monoclonal antibody that was specifically designed to balance good systemic exposure and safety with potent biological activity, a profile which differentiates CDX-1140 from other CD40-activating antibodies for systemic therapy.

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CDX-1140 is currently in a Phase 1 dose escalation study. The study includes both monotherapy and combination cohorts with CDX-301, Celldex’s dendritic cell growth factor, designed to increase the number of dendritic cells which are critical to initiating antitumor immunity and are a key target for CDX-1140. Celldex intends to add additional combination cohorts with mechanisms that the Company believes could be complementary or synergistic with CDX-1140 and has prioritized a combination with KEYTRUDA (pembrolizumab).

"CDX-1140 has exceeded the hurdles we defined for Phase 1 monotherapy development and has potential to be a best in class CD40 agonist," said Diane C. Young, MD, Senior Vice President and Chief Medical Officer. "Based on the clinical activity observed in patients with head and neck squamous cell carcinoma in the monotherapy arm of the study, we have added an expansion cohort of 15 patients to further explore this potential. Dose escalation in the combination arm with CDX-301 is ongoing, but data observed to date suggest that CDX-301 is capable of further enhancing this effect and support our plans to explore CDX-1140’s potential in combination with other mechanisms of action that could be complementary or synergistic. We are particularly excited about the newly added combination cohort of CDX-1140 with pembrolizumab as it joins two key immune mechanisms—the enhancement of the immune system with CDX-1140 and the releasing of the brake on the immune system with pembrolizumab," concluded Dr. Young.

"At 1.5 mg/kg, CDX-1140 has achieved one of the highest systemic dose levels in the CD40 agonist class and is associated with manageable immune-related adverse events that are consistent with approved, effective therapies like checkpoint inhibitors," said Rachel Sanborn, MD, Co-director of the Thoracic Oncology Program and Director of the Phase 1 Trials Program at Providence Cancer Institute and a lead investigator in this study. "Reaching higher dose levels increases the likelihood of effectively activating dendritic cells and macrophages within the tumor, which may be an important contributing factor in driving meaningful clinical activity, such as we are observing in these checkpoint refractory patients. I am very enthusiastic about CDX-1140’s potential and look forward to future data updates from the study," concluded Dr. Sanborn.

Study Highlights

Promising clinical activity emerging with CDX-1140 monotherapy and combination with CDX-301 (n=38 patients with pre- and post-scans; n=7 patients awaiting assessment; enrollment ongoing). Patients were heavily pretreated (median of 4 prior therapies) and per protocol were required to have received all standard of care treatments prior to study entry.

Two patients with radiographic evidence of tumor necrosis among 5 patients with recurrent/refractory HNSCC, including prior checkpoint inhibition therapy, treated with CDX-1140 monotherapy doses of 0.72mg/kg or higher
Patient one: dramatic shrinkage of a large, protruding neck mass on physical exam after two doses of CDX-1140 at 1.5 mg/kg, evidence of tumor necrosis/cavitation on CT scan, patient reported decreased tumor pain
Patient two: cavitation of greater than 50% of lung metastases on CT scan after one dose of CDX-1140 at 3 mg/kg
A patient with gastroesophageal carcinoma with RECIST response after two cycles of CDX-1140 at 0.36 mg/kg plus CDX-301
41% shrinkage of liver and lymph node target lesions, including near complete resolution of the liver lesion
Response duration of four months
Six patients with stable disease: n=4 CDX-1140 monotherapy; n=2 CDX-1140/CDX-301 combination; duration 1.8 months to 5.4 months; one patient with immune unconfirmed progressive disease (iUPD) noted on first scan who has since continued treatment without confirmation of progressive disease for 10+ months at CDX-1140 at 0.09 mg/kg plus CDX-301
CDX-1140 monotherapy and combination with CDX-301 has been generally well tolerated to date

CDX-1140 monotherapy dose escalation completed to 3.0 mg/kg, with maximum tolerated dose and recommended Phase 2 dose determined to be 1.5 mg/kg
Mostly grade 1 or grade 2 drug related adverse events
Mostly low grade, transient changes in serum liver transaminases
2 of 6 patients with pneumonitis at CDX-1140 3.0 mg/kg exceeding MTD
No dose limiting toxicities to date in the CDX-301 combination cohorts up to 0.72 mg/kg CDX-1140; CDX-1140 at 1.5 mg/kg plus CDX-301 cohort currently ongoing
Potent pharmacological effects associated with immune activation observed

Transient induction of inflammatory cytokines and chemokines associated with dendritic cell and T cell activation at higher dose levels
Similar activation observed with each cycle of therapy
Peripheral blood immune cells have upregulated immune activation markers
CDX-301 markedly increases the number of dendritic cells and is associated with higher IL-12p40 induction; IL-12 is a key molecule for inducing anti-tumor T cell responses
Future development:
Based on the clinical activity observed in HNSCC, Celldex is actively enrolling up to an additional 15 patients with HNSCC at 1.5 mg/kg CDX-1140 monotherapy. Dose escalation of CDX-1140 in combination with CDX-301 is nearing completion with patients currently enrolling to the 1.5 mg/kg CDX-1140 cohort. In addition, Celldex has amended the ongoing Phase 1 study to evaluate CDX-1140 in combination with KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy under a clinical trial collaboration agreement with Merck (known as MSD outside of the U.S. and Canada). The cohort is designed to characterize the safety, pharmacodynamics and activity of CDX-1140 in combination with pembrolizumab in patients refractory to PD1/PDL1 treatment. Celldex expects this cohort will open to enrollment in Q1 2020.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA.

Cytokinetics Announces Pricing of Public Offering of Convertible Senior Notes

On November 8, 2019 Cytokinetics, Incorporated (Nasdaq: CYTK) reported that it has agreed to sell an aggregate of $120.0 million principal amount of its 4.00% convertible senior notes due 2026, or the notes, in an underwritten public offering (Press release, Cytokinetics, NOV 8, 2019, View Source [SID1234550801]). Cytokinetics has granted the underwriters a 30-day option to purchase up to an additional $18.0 million aggregate principal amount of the notes in connection with the offering, solely to cover over-allotments. The aggregate principal amount of the offering was increased from the previously announced offering size of $100.0 million. The offering is expected to close on November 13, 2019, subject to customary closing conditions.

Cytokinetics intends to use the net proceeds from the proposed offering to fund (i) the continued development of and commercial readiness activities associated with omecamtiv mecarbil, (ii) the continued clinical development of CK-274 and related compounds in indications associated with hypertrophic cardiomyopathies and related diseases associated with diastolic dysfunction and cardiac fibrosis, including heart failure with preserved ejection fraction, (iii) the continued clinical development of reldesemtiv in patients with amyotrophic lateral sclerosis and spinal muscular atrophy, including potential Phase 3 clinical trials and other commercial readiness activities, and (iv) working capital and other general corporate purposes, including tenant improvement of the new facility Cytokinetics plans to move into in 2021, capital expenditures, debt service or retirement of debt, including existing debt outstanding under Cytokinetics’ loan and security agreement. Cytokinetics also intends to use a portion of the net proceeds from the proposed offering to pay the cost of the capped call transaction described below.

The notes will be senior unsecured obligations of Cytokinetics and will bear interest at a fixed rate of 4.00% per year, payable semi-annually in arrears on May 15 and November 15 of each year, commencing on May 15, 2020. The notes will mature on November 15, 2026, unless earlier converted, redeemed or repurchased. Prior to the close of business on the business day immediately preceding July 15, 2026, the notes will be convertible at the option of the holders only upon the satisfaction of certain conditions. Thereafter, the notes will be convertible at the option of the holders at any time until the close of business on the scheduled trading day immediately before the maturity date. Upon conversion, Cytokinetics will pay or deliver, as the case may be, cash, shares of its common stock or a combination of cash and shares of its common stock, at its election. The initial conversion rate will be 94.7811 shares per $1,000 principal amount of notes (equivalent to an initial conversion price of approximately $10.55 per share), subject to adjustment upon the occurrence of specified events.

Cytokinetics may not redeem the notes prior to November 20, 2023. Cytokinetics has the right, at its election, to redeem all, or any portion, of the notes, at any time and from time to time, on a redemption date occurring on or after November 20, 2023 and, in the case of any partial redemption, on or before the 60th scheduled trading day before the maturity date, for cash, but only if the last reported sale price per share of Cytokinetics’ common stock exceeds 130% of the conversion price then in effect for a specified period of time ending on the trading day immediately before the date the notice of redemption is sent, at a redemption price equal to 100% of the principal amount of the notes to be redeemed, plus accrued and unpaid interest to, but excluding, the redemption date.

Morgan Stanley & Co. LLC and Mizuho Securities are acting as joint book-runners for the offering. JMP Securities is acting as lead manager, and H.C. Wainwright & Co. is acting as co-manager for the offering.

In connection with the pricing of the notes, Cytokinetics has entered into a privately negotiated capped call transaction (together with any additional capped call transactions entered into in connection with the exercise by the underwriters of their over-allotment option as described below, the capped call transactions), with one of the underwriters in the offering or its affiliate, or the capped call counterparty. The capped call transactions will cover, subject to customary adjustments, the number of shares of Cytokinetics’ common stock that will initially underlie the notes. The capped call transactions are generally expected to reduce the potential dilution of Cytokinetics’s common stock and/or offset any cash payments Cytokinetics is required to make in excess of the principal amount of converted notes, as the case may be, as a result of any conversion of the notes, with such reduction and/or offset subject to a cap based on the cap price. The cap price of the capped call transactions will initially be approximately $14.07 per share, which represents a premium of approximately 70% over the per share closing price of Cytokinetics’s common stock of $8.275 per share on November 7, 2019, and is subject to certain adjustments under the terms of the capped call transactions. If the underwriters in this offering exercise their over-allotment option, Cytokinetics expects to use a portion of the net proceeds from the sale of the additional notes to enter into an additional capped call transaction with the capped call counterparty.

In connection with establishing its initial hedge of the capped call transactions, the capped call counterparty or its affiliates have advised Cytokinetics that it or its affiliates expect to purchase Cytokinetics’ common stock and/or enter into various derivative transactions with respect to Cytokinetics’ common stock concurrently with, or shortly after, the pricing of the notes, including with certain investors in the notes. This activity could increase (or reduce the size of any decrease in) the market price of Cytokinetics’ common stock or the notes at that time.

In addition, the capped call counterparty or its affiliates may modify its hedge positions by entering into or unwinding various derivatives with respect to Cytokinetics’ common stock and/or purchasing or selling Cytokinetics’ common stock or other securities of Cytokinetics in secondary market transactions following the pricing of the notes and prior to the maturity of the notes (and are likely to do so on each exercise date of the capped call transaction, which are expected to occur during the 60 trading day period beginning on the 61st scheduled trading day prior to the maturity date of the notes, or following any termination of any portion of the capped call transaction in connection with any repurchase, redemption or early conversion of the notes). This activity could also cause or avoid an increase or decrease in the market price of Cytokinetics’ common stock or the notes, which could affect noteholders’ ability to convert the notes and, to the extent the activity occurs during any observation period related to a conversion of the notes, affect the amount and value of the consideration that noteholders will receive upon conversion of the notes.

An automatic shelf registration statement relating to the notes was previously filed with the Securities and Exchange Commission, or SEC, and became immediately effective on November 6, 2019. The offering will be conducted by means of a prospectus supplement and accompanying prospectus. The final prospectus supplement and the accompanying prospectus relating to and describing the terms of the proposed offering will be filed with the SEC and, when filed, will be available on the SEC’s website at www.sec.gov. Copies of the final prospectus supplement and the accompanying prospectus related to the offering may also be obtained by contacting: Morgan Stanley & Co. LLC, Attention: Prospectus Department, 180 Varick Street, 2nd Floor, New York, New York 10014; or Mizuho Securities USA LLC, Attn: Equity Capital Markets, 320 Park Avenue, 12th Floor, New York, NY 10022-6815, by telephone (212) 205-7600, or by email: [email protected].

This press release shall not constitute an offer to sell or the solicitation of an offer to buy the notes, nor shall there be any sale of the notes in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

Oncolytics Biotech® Announces AWARE-1 Data Presented at the 34th Annual Meeting of the Society for Immunotherapy of Cancer

On November 8, 2019 Oncolytics Biotech Inc. (NASDAQ:ONCY) (TSX:ONC), currently developing pelareorep, an intravenously delivered immuno-oncolytic virus, reported at the annual meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper), highlighting data from the AWARE-1 study in early breast cancer (Press release, Oncolytics Biotech, NOV 8, 2019, View Source [SID1234550800]). The 34th Annual SITC (Free SITC Whitepaper) Meeting is being held November 6-10, 2019 at the Gaylord National Hotel & Convention Center in National Harbor, Maryland.

"This is the first-time our biomarker data from AWARE-1 has been presented at a major academic conference," said Dr. Rita Laeufle, Chief Medical Officer of Oncolytics Biotech. "The primary objective of this study is to evaluate changes in the immune environment of patients diagnosed with early stage breast cancer using our biomarker of T cell clonality measured by CelTIL score. This measures a change or expansion of infiltrating immune cells and importantly, an increase in CelTIL is known to correlate with a positive patient outcome. This initial data shows replication of pelareorep occurs exclusively in tumor tissue and there is an increase in CelTIL through the expansion of existing T cells, and most importantly, through the creation of new T cell clones. We continue to show that pelareorep changes the immunogenetic environment within the tumor, and the results of this early stage breast cancer study support our use of this biomarker and its value in predicting tumor response in our upcoming BRACELET-1 study in hormone receptor positive metastatic breast cancer."

The next patient cohort to report from AWARE-1 focuses on patients receiving pelareorep and the standard of care, without Tecentriq. This cohort will allow for the comparison of patients treated with standard of care plus pelareorep, to patients receiving the standard of care, plus pelareorep, plus Tecentriq. This will be the first data from AWARE-1 to confirm the impact pelareorep has on enhancing the anti-tumor T cell response both on its own, and in combination with a checkpoint inhibitor.

The poster, "A window-of-opportunity Study of pelareorep in Early Breast Cancer (AWARE-1)", was authored by AWARE-1 principal investigator, Aleix Prat, et al, and presented by Dr. Patricia Villagrasa, Scientific Director at SOLTI Innovative Breast Cancer Research. The AWARE-1 study continues to screen and enroll patients and we expect to provide interim data before the end of the year and final results in the first half of 2020.

SITC Presentation Details

Title: A window-of-opportunity Study of pelareorep in Early Breast Cancer (AWARE-1)
Abstract ID: P373
Poster Presentation – Friday, Nov. 8, 7:00 am – 8:00 pm
Location: Poster Hall (Prince George AB)
About AWARE-1

AWARE-1 is an open label window-of-opportunity study in early stage breast cancer that will enroll 38 patients into five cohorts:

Cohort 1 (n=10), HR+ / HER2- (pelareorep + letrozole)
Cohort 2 (n=10), HR+ / HER2- (pelareorep + letrozole + atezolizumab)
Cohort 3 (n=6), TNBC (pelareorep + atezolizumab)
Cohort 4 (n=6), HR+ / HER2+ (pelareorep + trastuzumab + atezolizumab)
Cohort 5 (n=6), HR- / HER2+ (pelareorep + trastuzumab + atezolizumab)
The study combines the standard of care by breast cancer subtype with pelareorep and atezolizumab. Patients are biopsied on day one followed immediately by treatment, then again on day three, and a final biopsy after three weeks, on the day of their mastectomy. Data generated from this study is intended to confirm that the virus is acting as a novel immunotherapy and to provide comprehensive biomarker data by breast cancer sub-type. The primary endpoint of the study is overall CelTIL (a measurement of cellularity and tumor-infiltrating lymphocytes). Secondary endpoints for the study include CelTIL by breast cancer subtype, safety and tumor, and blood-based biomarkers.

The study is being coordinated by Dr. Aleix Prat, Head of Medical Oncology at the Hospital Clínic of Barcelona, Associate Professor of the University of Barcelona and the Head of the Translational Genomics and Targeted Therapeutics in Solid Tumors Group at August Pi i Sunyer Biomedical Research Institute (IDIBAPS) and member of Oncolytics’ Scientific Advisory Board.

About Breast Cancer

Breast cancer is the most common cancer in women worldwide, with over two million new cases diagnosed in 2018, representing about 25 percent of all cancers in women. Incidence rates vary widely across the world, from 27 per 100,000 in Middle Africa and Eastern Asia to 85 per 100,000 in Northern America. It is the fifth most common cause of death from cancer in women globally, with an estimated 522,000 deaths.

Breast cancer starts when cells in the breast begin to grow out of control. These cells usually form a tumor that can often be seen on an x-ray or felt as a lump. The malignant tumor (cancer) is getting worse when the cells grow into (invade) surrounding tissues or spread (metastasize) to distant areas of the body.

About Pelareorep

Pelareorep is a non-pathogenic, proprietary isolate of the unmodified reovirus: a first-in-class intravenously delivered immuno-oncolytic virus for the treatment of solid tumors and hematological malignancies. The compound induces selective tumor lysis and promotes an inflamed tumor phenotype through innate and adaptive immune responses to treat a variety of cancers and has been demonstrated to be able to escape neutralizing antibodies found in patients.

Iovance Biotherapeutics Announces Updated Phase 2 Clinical Data from the Lifileucel Metastatic Melanoma Trial at the Society for Immunotherapy of Cancer 34th Annual Meeting

On November 8, 2019 Iovance Biotherapeutics, Inc. (NASDAQ: IOVA), a late-stage biotechnology company developing novel T cell-based cancer immunotherapies, reported that new data from Cohort 2 of the ongoing Phase 2 lifileucel metastatic melanoma study (C-144-01) were presented Friday, Nov. 8, 2019, at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 34th Annual Meeting in National Harbor, Maryland (Abstract P865) (Press release, Iovance Biotherapeutics, NOV 8, 2019, View Source [SID1234550799]).

Highlights from the poster presentation include:

An objective response rate (ORR) of 35 percent as assessed by IRC as compared to 36 percent as assessed by investigator
Median DOR was not reached as assessed by either IRC (range: 1.6+ to 21.2+ months) or investigator (range: 2.2 to 21.2+ months) at 11.3 months median follow up. In addition, based on the most recent data cut from the study, median DOR was not reached as assessed by investigator at 12.8 months of median study follow-up.
An overall concordance rate of 89.4 percent between investigator assessment and IRC assessment (n=66)
"We are pleased to see continued evidence of durability with lifileucel therapy as patients are evaluated with longer term follow-up," commented Maria Fardis, Ph.D., MBA, president and chief executive officer of Iovance Biotherapeutics. "In addition, concordance between IRC assessment and investigator reported results is highly favorable in this metastatic disease setting as compared with the published literature. These results continue to show that lifileucel offers a potential therapeutic option for the metastatic melanoma patients enrolled in this study. We continue to enroll patients in the pivotal cohort of the study, Cohort 4, which is expected to serve as the basis for an expected Biologics License Application (BLA) submission for lifileucel in late 2020."

Cohort 2 in the ongoing C-144-01 study includes consecutively dosed post-PD-1 patients with Stage IIIC/IV unresectable melanoma who also have received BRAF/MEK therapy if clinically indicated. In this study, patients had experienced a mean of 3.3 lines of prior therapy including anti-PD1 blocking antibody, and the patients had a high baseline tumor burden. The adverse event profile of lifileucel treatment in the C-144-01 study continued to be consistent with the underlying advanced disease and the profile of the lymphodepletion and IL-2 regimens.

Affimed Announces Pricing of Public Offering of Common Shares

On November 8, 2019 Affimed N.V. ("Affimed" or the "Company") (Nasdaq: AFMD), a clinical stage biopharmaceutical company committed to giving patients back their innate ability to fight cancer, reported the pricing of its previously announced public offering of 12,000,000 of its common shares at a public offering price of $2.50 per common share (Press release, Affimed, NOV 8, 2019, View Source [SID1234550798]). In addition, Affimed has granted the underwriters a 30-day option to purchase up to an additional 1,800,000 common shares at the public offering price less underwriting discounts. After deducting the underwriting discounts, the net proceeds of the public offering are expected to be approximately $28.2 million. The offering is expected to close on or about November 13, 2019, subject to customary closing conditions.

Jefferies LLC and SVB Leerink LLC are acting as joint book-running managers and SunTrust Robinson Humphrey, Inc. and Laidlaw & Company (UK) Ltd. as co-managers of the offering. A shelf registration statement relating to these securities filed with the Securities and Exchange Commission (the "SEC") was declared effective by the SEC on November 7, 2018. The offering will be made only by means of a prospectus and prospectus supplement. A preliminary prospectus supplement and accompanying prospectus related to the offering have been filed with the SEC and are available at the SEC’s website located at www.sec.gov. A final prospectus supplement and accompanying prospectus will be filed with the SEC. Copies of the final prospectus supplement and accompanying prospectus related to the offering may be obtained by contacting Jefferies LLC, Attention: Equity Syndicate Prospectus Department, 520 Madison Avenue, 2nd Floor, New York, NY 10022, or by telephone at (877) 821-7388, or by email at [email protected], or SVB Leerink LLC, Attention: Syndicate Department, One Federal Street, 37th Floor, Boston, MA 02110, by telephone at (800) 808-7525, ext. 6132, or by email at [email protected].

This press release shall not constitute an offer to sell or a solicitation of an offer to buy, nor shall there be any sale of, these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.