On September 20, 2018 Exicure, Inc. (OTCQB:XCUR), the pioneer in gene regulatory and immunotherapeutic drugs utilizing three-dimensional spherical nucleic acid (SNA) constructs, reported that Phase 1 results for AST-008, an SNA consisting of toll-like receptor 9 (TLR9) agonists designed for immuno-oncology applications (Press release, Exicure, SEP 20, 2018, View Source [SID1234529502]).

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"Phase 1 results for AST-008 demonstrated our desired highly potent immune system activation without serious adverse events or dose limiting toxicity. We believe this molecule could lead to better combination therapies for patients with cancer and, to that end, we expect to initiate a Phase 1b/2 trial in patients before year end," said Dr. David Giljohann, Chief Executive Officer of Exicure. "These data support the potential of our SNA platform for immuno-oncology and set the stage for ongoing development of the SNA platform into indications well beyond cancer."

Exicure’s Phase 1 Trial Results

The Phase 1 trial of AST-008 was a single ascending subcutaneous dose trial comprised of 16 healthy volunteers. AST-008 was shown to be safe and tolerable in all subjects, with no serious adverse events and no dose limiting toxicity. AST-008 was well tolerated and all AST-008-related adverse events were of short duration, reversible and consistent with TLR9 activation.

In addition to the principle safety and tolerability endpoint, the trial screened for levels of select cytokines and markers of immune cell activation. AST-008 was shown to elicit high levels of certain cytokines as well as activate important effector cells of the immune system including T cells and natural killer cells, the main drivers of anti-tumor response.

For the four subjects receiving the trial’s top dose of about 20 µg/kg of AST-008, initial analyses suggest that the average fold-increase above baseline for these cytokines is approximately as follows: IFN-gamma: 3 fold; IL-6: 57 fold; IL-12: 2 fold; IP-10: 32 fold; and MCP-1: 4 fold. At this dose, AST-008 also elicited 9.5 fold and 3.5 fold increases in the fraction of activated T cells and natural killer cells, respectively, compared to baseline.

Exicure’s Planned Phase 1b/2 Patient Trial

Exicure intends to begin an open-label Phase 1b/2 trial of intra-tumorally dosed AST-008 in combination with a checkpoint inhibitor before year end. The trial will begin with an AST-008 dose finding Phase 1b stage, followed by a Phase 2 expansion stage. In the Phase 1b, Exicure will enroll patients with superficial injectable tumors and will prioritize those with Merkel cell carcinoma, cutaneous squamous cell carcinoma, melanoma, and squamous cell carcinoma of the head and neck. Preliminary data from the Phase 1b stage are expected in late 2019.

Historical TLR9 Agonist Healthy Volunteer Data

In 2015, Mologen AG published results (European Journal of Cancer, 2015, volume 51, supplement 1, page S12) from a healthy volunteer trial. In a single cohort, 13 subjects each received one 60 mg dose (equivalent to 923 µg/kg for a 65 kg subject) of lefitolimod subcutaneously. On average, across the cohort, there was a 7 fold-increase in IP-10 expression above baseline. No cell activation data were reported. Lefitolimod is currently in a Phase 3 clinical trial.

In 2004, Coley Pharmaceutical Group (now Pfizer, Inc.) published results (Journal of Immunotherapy, 2004, Volume 27, pages 460–471) from a single ascending dose healthy volunteer trial. In that trial, their TLR9 agonist, PF-03512676, was administered subcutaneously to six subjects per dose level. For the 20 µg/kg dose level, the average fold-increase above baseline for these cytokines is as follows: IFN-gamma: no change from baseline; IL-6: 8 fold; IL-12: no change from baseline; IP-10: 9 fold; and MCP-1: 3 fold.

On September 20, 2018 Y-mAbs Therapeutics, Inc. (the "Company" or "Y-mAbs") (Nasdaq:YMAB) a late-stage clinical biopharmaceutical company focused on the development and commercialization of novel, antibody-based therapeutic products for the treatment of cancer, reported the pricing of its initial public offering of 6,000,000 shares of common stock at a public offering price of $16.00 per share, for gross proceeds of $96 million, before underwriting discounts and commissions and estimated offering expenses payable by the Company (Press release, Y-mAbs Therapeutics, SEP 20, 2018, View Source [SID1234529522]). All shares are being offered by the Company.

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In addition, the Company has granted the underwriters a 30-day option to purchase up to an additional 900,000 shares of common stock from the Company at the initial public offering price, less underwriting discounts and commissions.

The Company’s common stock is expected to begin trading on the Nasdaq Global Select Market under the ticker symbol "YMAB" on Friday, September 21, 2018. The offering is expected to close on Tuesday, September 25, 2018, subject to customary closing conditions.

BofA Merrill Lynch and Cowen are acting as joint book-running managers for the offering. Canaccord Genuity is acting as lead manager for the offering and BTIG is acting as co-manager for the offering.

A registration statement relating to the securities being sold in the offering was declared effective by the Securities and Exchange Commission (the "SEC") on September 20, 2018. The offering is being made only by means of a prospectus. Copies of the final prospectus relating to this offering may be obtained, when available, by contacting BofA Merrill Lynch, NC1-004-03-43, 200 North College Street, 3rd Floor, Charlotte, NC 28255-0001, Attn: Prospectus Department or by email at [email protected]; or Cowen and Company, LLC, c/o Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, NY 11717, Attention: Prospectus Department, or by phone at (631) 274-2806.

Additionally, when available, copies of these documents may be obtained for free by accessing the EDGAR database on the SEC’s website at www.sec.gov.

This press release shall not constitute an offer to sell or the solicitation of an offer to buy these securities, 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 the registration or qualification under the securities laws of any such state or jurisdiction.

On September 20, 2018 Pierre Fabre reported that the European Commission (EC) has granted marketing authorisation for the combination of BRAFTOVI (encorafenib) and MEKTOVI (binimetinib) for the treatment of adult patients with unresectable or metastatic melanoma with a BRAFV600 mutation, as detected by a validated test (Press release, Pierre Fabre, SEP 20, 2018, View Source [SID1234529504]).1,2 The EC decision is applicable to all 28 European Union (EU) member states plus Liechtenstein, Iceland and Norway.

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"We are extremely pleased that European patients with advanced BRAF-mutant melanoma will now have the combination of BRAFTOVI and MEKTOVI as a new treatment option", said Frédéric Duchesne, President & CEO of the Pierre Fabre Pharmaceuticals Division. "All of us at Pierre Fabre are driven to make a real difference for patients. Bringing more than 30 years of oncology experience and our heritage in dermatology to our partnership with Array BioPharma, we have been able to harness our expertise in order to help men and women living with this devastating disease. Today’s news inspires us to continue pursuing new innovations that will benefit patients".

The EC decision, which follows the positive opinion by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) in July, is based on results from the Phase 3 COLUMBUS trial.3 This trial demonstrated that the combination of BRAFTOVI 450 mg once daily and MEKTOVI 45 mg twice daily significantly improved median progression-free survival (PFS), compared with vemurafenib alone 960 mg twice daily (14.9 months versus 7.3 months, respectively: hazard ratio [HR] 0.54, 95% confidence interval [CI], 0.41–0.71; two-sided p<0.0001).3 Data published in The Lancet Oncology4 in September 2018 demonstrated that treatment with BRAFTOVI and MEKTOVI achieved a median overall survival (OS) of 33.6 months, compared with 16.9 months for patients treated with vemurafenib as a monotherapy (HR 0.61, 95% CI, 0.47–0.79; p<0.0001) in the planned analysis of OS in the COLUMBUS trial4. The most common adverse reactions (≥25%) occurring in patients treated with BRAFTOVI administered with MEKTOVI at the recommended dose (n=274 based on two Phase II trials and COLUMBUS) were fatigue, nausea, diarrhoea, vomiting, retinal detachment, abdominal pain, arthralgia, increased blood creatine kinase and myalgia.1,2 In the COLUMBUS trial, adverse events leading to discontinuation that were suspected to be related to the study treatment occurred in 6% of patients.3,4

"The European Commission’s approval is an important advance in improving the prognosis of patients with advanced BRAF-mutant melanoma", said Professor Reinhard Dummer, University of Zürich, Vice-Chairman of the Department of Dermatology in the University Hospital of Zürich, Switzerland, and investigator of the COLUMBUS study. "Physicians and patients will now have BRAFTOVI and MEKTOVI as an effective and well-tolerated treatment combination option, which has been shown to delay disease progression and potentially prolong patients’ lives".

Important safety information and recommendations for the use of BRAFTOVI and MEKTOVI are detailed in the Summary of Product Characteristics (SmPC), published in the European public assessment report (EPAR) and available in all official EU languages.
See full SmPC at: View Source

On 27 June 2018, Pierre Fabre’s partner Array BioPharma, which has exclusive rights for these medicines in the United States (US), announced that the combination of BRAFTOVI and MEKTOVI was approved by the US Food and Drug Administration (FDA) for the treatment of unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test.5,6 BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma.

About BRAF-mutant Metastatic Melanoma
Melanoma develops when unrepaired DNA damage to skin cells triggers mutations that may lead them to multiply and form malignant tumours. Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates.7,8 There are a variety of gene mutations that can lead to metastatic melanoma. The most common genetic mutation in metastatic melanoma is BRAF. There are more than 100,000 new cases of melanoma diagnosed in Europe each year,9 approximately half of which have BRAF mutations, a key target in the treatment of metastatic melanoma.10–11

About BRAFTOVI (encorafenib) and MEKTOVI (binimetinib)
BRAFTOVI (encorafenib) is an oral small-molecule BRAF kinase inhibitor and MEKTOVI (binimetinib) is an oral small-molecule MEK inhibitor that targets key enzymes in the MAPK signalling pathway (RAS-RAF-MEK-ERK). Inappropriate activation of proteins in this pathway has been shown to occur in many cancers, including melanoma, colorectal cancer, non-small-cell lung cancer, thyroid and others.

Pierre Fabre has exclusive rights to develop and commercialise BRAFTOVI and MEKTOVI worldwide, except in the US and Canada, where Array BioPharma retains exclusive rights; Israel, where Medison has exclusive rights; and in Japan and South Korea, where Ono Pharmaceutical has exclusive rights to commercialise both products.

BRAFTOVI + MEKTOVI Abbreviated EU Prescribing Information
▼These medicinal products are subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 of SmPC for how to report adverse reactions.

Name of the medicinal products: BRAFTOVI (encorafenib) 75 mg hard capsules and 50 mg hard capsules. MEKTOVI (binimetinib) 15 mg film-coated tablets.

Clinical particulars:
Therapeutic indications: Encorafenib in combination with binimetinib is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

Posology and method of administration: Encorafenib treatment in combination with binimetinib should be initiated and supervised under the responsibility of a physician experienced in the use of anticancer medicinal products. Posology: The recommended dose of encorafenib is 450 mg (six 75 mg capsules) once daily, when used in combination with binimetinib. The recommended dose of binimetinib is 45 mg (three 15 mg tablets) twice daily corresponding to a total daily dose of 90 mg approximately 12 hours apart. Dose modification: The management of adverse reactions may require dose reduction, temporary interruption or treatment discontinuation (for complete information, please refer to SmPC 4.2 section). Method of administration: For oral use. The capsules of encorafenib are to be swallowed whole with water. They may be taken with or without food. The concomitant administration of encorafenib with grapefruit juice should be avoided. The tablets of binimitinib are to be swallowed whole with water. They may be taken with or without food.

Contraindications: Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 of the BRAFTOVI and MEKTOVI SmPc.

Special warnings and precautions for use: Encorafenib and binimetinib have to be given in combination. Before taking encorafenib in combination with binimetinib, patients must have BRAFV600 mutation confirmed by a validated test. For complete information on the following special warnings and precautions for use: Patients who have progressed on a BRAF inhibitor, patients with brain metastases. Left ventricular dysfunction, Haemorrhage, ocular toxicities. QT Prolongation, New primary malignancies, Cutaneous and non-cutaneous malignancies, Liver laboratory abnormalities, Hepatic impairment, Renal impairment, CK elevation and rhabdomyolysis, Hypertension, Venous thromboembolism (VTE), Pneumonitis/Interstitial lung disease, Lactose intolerance, please refer to BRAFTOVI and MEKTOVI SmPC 4.4 section.

Interaction with other medicinal products and other forms of interaction: Encorafenib is primarily metabolised by CYP3A4. Therefore, concomitant administration of encorafenib with strong CYP3A4 inhibitors should be avoided. Agents that are CYP3A4 substrates (inhibitor and inducer) should be co-administered with caution. Binimetinib is primarily metabolised through UGT1A1 mediated glucuronidation. Therefore, inducers and inhibitors of UGT1A1 should be co-administered with caution. For complete information, please refer to SmPC, 4.5 section.

Undesirable effects: Summary of safety profile: At the recommended dose (n=274) in patients with metastatic melanoma, the most common adverse reactions (≥ 25%) occurring in patients treated with encorafenib administered with binimetinib were fatigue, nausea, diarrhea, vomiting, retinal detachment, abdominal pain, arthralgia, blood CK increased and myalgia. For complete information, please refer to BRAFTOVI and MEKTOVI SmPC 4.8 section.

For complete information please refer to the full SmPC which can be found at: View Source

About COLUMBUS
The COLUMBUS trial (NCT01909453) is a two-part, international, randomised, open-label, Phase 3 trial evaluating the efficacy and safety of BRAFTOVI (encorafenib) in combination with MEKTOVI (binimetinib) compared with vemurafenib and encorafenib monotherapy in 921 patients with locally advanced, unresectable or metastatic melanoma with BRAFV600 mutation.12 The primary endpoint of the trial was median progression-free survival (PFS); all secondary efficacy analyses, including the prospectively planned analysis overall survival (OS), are descriptive in nature. More than 200 sites across North America, Europe, South America, Africa, Asia and Australia participated in the COLUMBUS trial.

The EC decision is based on results from the Phase 3 COLUMBUS trial, which demonstrated that the combination improved median PFS, compared with vemurafenib alone (14.9 months versus 7.3 months, respectively: HR 0.54, 95% CI, 0.41–0.71; p<0.001).1–3 As presented at ASCO (Free ASCO Whitepaper) in June 2018, treatment with BRAFTOVI and MEKTOVI achieved a median OS of 33.6 months, compared with 16.9 months for patients treated with vemurafenib as a monotherapy (HR 0.61, 95% CI, 0.47–0.79; p<0.0001) in the planned analysis of OS in the COLUMBUS trial.1–2,4 Adverse events leading to discontinuation that were suspected to be related to the study treatment occurred in 6% of patients.3,4 The most common Grade 3–4 adverse events, seen in more than 5% of patients, were: increased gamma-glutamyltransferase (9%), increased creatine phosphokinase (7%) and hypertension (6%).3,4

On September 20, 2018 Portola Pharmaceuticals, Inc. (Nasdaq: PTLA) reported the appointment of industry veteran Scott Garland as president and chief executive officer, effective October 8, 2018 (Press release, Portola Pharmaceuticals, SEP 20, 2018, View Source;p=irol-newsroomArticle&ID=2368241 [SID1234529523]). Mr. Garland brings to his new role more than two decades of broad executive leadership experience, including a strong track record driving multiple billion dollar product launches. He will also serve on the Company’s Board of Directors.

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Mr. Garland joins Portola from Relypsa, Inc., where he was president and previously chief commercial officer. During his tenure, Mr. Garland was responsible for the integration and growth of the U.S. operations after Relypsa was acquired by Vifor Pharma Group in 2016.

Prior to Relypsa, Mr. Garland was executive vice president and chief commercial officer of Exelixis, Inc., where he led global commercial operations and directed sales, marketing and market access in the United States. Previously, Mr. Garland spent close to a decade at Genentech leading full scale commercial franchises for two multi-billion dollar therapies – Avastin (bevacizumab) and Rituxan (rituximab). He started his career at Merck as a sales representative and then went on to serve at Amgen in various sales and marketing roles, including market development, to support the launch of Aranesp (darbepoetin alfa).

Hollings C. Renton, Chairman of the Board, said: "Scott is an exceptional choice to lead Portola through this exciting period of commercial evolution. His leadership and operational experience in hematology, oncology and hospital-based products aligns with our portfolio, and I am confident he will help realize the full potential of the Company’s life-changing medicines, drive long-term growth to maximize shareholder value and develop a best-in-class culture that will allow us to continue to attract and retain top industry talent. We look forward to introducing Scott during our third quarter conference call in early November."

Mr. Garland said: "This is a rare opportunity to join a company with two FDA-approved medicines, a promising compound in development and a financial position to support long-term growth. I am excited to partner with such a committed Board and leadership team to build on the Company’s current pace of innovation and focus on execution to deliver potentially life-saving therapies to patients."

Mr. Garland holds an M.B.A. from the Fuqua School of Business at Duke University and a Bachelor of Science degree in biological sciences from California Polytechnic State University, San Luis Obispo. He has been a member of the Board of Directors of Karyopharm Therapeutics since 2014.

On September 26, 2018 NANOBIOTIX (Euronext: NANO – ISIN: FR0011341205), a late clinical-stage nanomedicine company pioneering new approaches to the treatment of cancer, reported it will present an update on and data from its NBTXR3 development program at the International Conference on Immunotherapy Radiotherapy Combinations that will take place from September 20 to 22, 2018 in Paris, France (Press release, Nanobiotix, SEP 20, 2018, View Source [SID1234529669]).

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Follow-up of Phase I/II in advanced Head and Neck cancers in elderly and frail patients ineligible for cisplatin or
intolerant to cetuximab In the Phase I part of this trial, which is conducted to determinate the recommended dose, 18 patients have been injected with NBTXR3. Follow-up of patients that received highest doses of NBTXR3 (15% and 22% dose levels) shows that every patient alive at the 12-month cut-off date was still alive after 23 months or more. At 26 months, one of the patients treated at the 15% dose level had died.

These data suggest the potential of NBTXR3 to impact survival for this advanced cancer patient population.
Immuno biomarker study in randomized phase II/III soft tissue sarcoma clinical trial Immunohistochemistry analyses revealed that, compared to radiation therapy alone (29 patients), NBTXR3 activated by radiation therapy (23 patients) increased the density of CD8+ T cell lymphocyte, and decreased FOXP3+ (Treg) into the tumors, while macrophage number remained relatively constant. These data indicate that NBTXR3 activated by radiation therapy could modulate the antitumor immune response.

In vivo investigation of NBTXR3 mode of action inducing distant immune response on CT26 tumoral model
Depletion experiment of CD8+ T cells (NBTXR3+3x4Gy+anti-CD8) induces a partial loss of tumor growth control of
treated tumors, and a complete abolition of the abscopal effect (distal tumors). This result indicates that the abscopal effect was driven by CD8+ T cells. Interestingly, depletion of CD4+ T cells (NBTXR3+3x4Gy+anti-CD4) increases the efficacy of NBTXR3 + radiation therapy at both sites (treated and distal tumors). As anti-CD4 treatment lead to Treg depletion (known to have a protumoral role), Treg depletion might have improved NBTXR3 radiation therapy treatment. These observations continue to support the rationale for the use of NBTXR3 activated by radiation therapy to seek to transform tumors