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ISA Pharmaceuticals Announces Start of Phase 2 Combination Trial of ISA101b and Regeneron’s Cemiplimab in Oropharyngeal Cancer

On January 21, 2019 ISA Pharmaceuticals B.V., a clinical-stage company dedicated to the development of rationally designed immunotherapeutics, reported randomization of the first patient in a Phase 2 combination trial of its lead compound ISA101b and Regeneron´s (NASDAQ: REGN) anti-PD-1 antibody cemiplimab (REGN2810) (Press release, ISA Pharmaceuticals, JAN 21, 2019, View Source [SID1234532797]).

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This double blind, placebo-controlled, randomized, phase 2 study (NCT03669718) will enroll approximately 164 patients with HPV16-positive oropharyngeal cancer (OPC), who have failed first-line chemotherapy. Patients will be randomly allocated on a 1:1 basis to the combination of cemiplimab/ISA101b or cemiplimab/placebo. In both study arms, patients will receive treatment in cycles of 3 weeks for up to 24 months. The primary efficacy objective of this trial is to assess whether the addition of ISA101b to cemiplimab will elicit a higher Overall Response Rate (ORR, as per RECIST 1.1 criteria) compared to cemiplimab plus placebo. Secondary endpoints include Progression Free Survival (PFS), Overall Survival (OS), as well as safety and tolerability of cemiplimab plus ISA101b (as compared to cemiplimab plus placebo). The study will be conducted at approximately 50 investigative sites in the USA and Europe.

ISA Pharmaceuticals´ lead compound ISA101 is a clinical-stage SLP immunotherapy targeting HPV16-induced diseases such as cervical cancer and head–and-neck cancer. It induces specific immune responses to the oncogenic E6 and E7 antigens of HPV16. Cemiplimab, also known as REGN2810, is currently under review by EMA and was approved by the U.S. Food and Drug Administration in September 2018 under the brand name Libtayo as monotherapy for patients with advanced cutaneous squamous cell carcinoma. Regeneron, in collaboration with Sanofi, is developing cemiplimab both alone and in combination with other therapies for the treatment of various cancers.

"We are excited about this new clinical trial with ISA101b and cemiplimab," said Dr. Leon Hooftman, CMO of ISA Pharmaceuticals. "ISA101b has already demonstrated very promising results when combined with nivolumab in a previous study in advanced HPV16-positive cancers. Particularly in patients with relapsed head-and-neck cancer the percentage of patients with a meaningful tumor response appeared to be twice as high as achieved with nivolumab alone. The objective of the current randomized trial is to confirm such clinical benefit of ISA101b in a controlled setting."

"In our collaboration with Regeneron that was announced in December 2017, this is the first of two indications in which we jointly aim to develop novel combination immunotherapies for cervical cancer and head-and-neck cancer," said Gerben Moolhuizen, CEO of ISA Pharmaceuticals. "I am very proud of the efforts of the joint team that allowed us to advance quickly to this stage. We look forward to the first read-out from the trial, which is expected in the second half of 2020."

Oropharyngeal cancer, a subtype of head-and-neck cancer, affects tissues of the throat (oropharynx), e.g. the base of the tongue, the tonsils, the soft palate, and the walls of the pharynx. Oropharyngeal cancers can be divided into two types: HPV-positive, which are related to human papillomavirus infection, and HPV-negative cancers, which are usually linked to alcohol or tobacco use.

BerGenBio announces start of phase I trial evaluating ADCT-601, a novel anti-AXL ADC, in patients with advanced solid tumours

On January 21, 2019 BerGenBio ASA (OSE:BGBIO), reported that the first patient has been dosed in a phase I clinical trial evaluating the safety, tolerability, pharmacokinetics and anti-tumour efficacy of ADCT-601, an AXL-targeting antibody drug conjugate (ADC), in patients with advanced solid tumours (Press release, BerGenBio, JAN 21, 2019, View Source [SID1234532796]).

ADCT-601 is composed of a humanised monoclonal antibody against human AXL (BGB601) discovered by BerGenBio, conjugated to a pyrrolobenzodiazepine (PBD) dimer toxin. BGB601 was out-licensed for ADC development to ADC Therapeutics SA (ADCT). In preclinical studies, ADCT-601 has demonstrated potent and specific anti-tumour activity in multiple in vivo models and was stable and well tolerated, as reported by ADCT at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) annual congress in 2018.

The open-label, multi-centre, single arm phase I trial will enrol approximately 75 patients with selected tumour types and will be managed and sponsored by license partner ADC Therapeutics. For more information see View Source (accessing trial identifier NCT03700294).

Richard Godfrey, Chief Executive Officer of BerGenBio, commented: "We congratulate ADC Therapeutics on reaching this important milestone. We are pleased to now see three of our AXL-targeting modalities in clinical development with the potential to address large patient populations. Our focus remains on completing our ongoing oncology phase II programme with bemcentinib, a first-in-class highly selective oral AXL inhibitor, and start randomised, potentially pivotal trials later this year. In the meantime, we look forward to providing updates on the development of BGB149, a therapeutic AXL antibody, and ADCT-601, an anti-AXL ADC, as they progress through phase I testing."

END

About ADCT-601
BerGenBio out-licensed two novel and proprietary anti-AXL monoclonal antibodies invented by the Company to ADC Therapeutics SA (ADCT) for the development of an antibody drug conjugate (ADC).

ADCT-601 is composed of BGB601, a humanised monoclonal antibody that binds to human AXL, conjugated using GlycoConnect technology to a linker with a pyrrolobenzodiazepine (PBD) dimer toxin. Once bound to an AXL-expressing cell, ADCT-601 is internalised into the cell where enzymes release the PBD-based warhead. The PBD-based warhead has the ability to form highly cytotoxic DNA interstrand cross-links, blocking cell division and ultimately killing the cancer cell. ADCT-601 is currently undergoing Phase I clinical testing (NCT03700294).

Under the license, a series of development, regulatory and sales-based milestones are due to BerGenBio from ADCT upon the achievement of certain specified events. The first milestone payment is triggered during the phase I clinical study.

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 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.

US FDA Approves ONTRUZANT® (trastuzumab-dttb), Samsung Bioepis’ First Oncology Medicine in the United States

On January 20, 2019 Samsung Bioepis Co., Ltd. reported that the U.S. Food and Drug Administration (FDA) has approved ONTRUZANT (trastuzumab-dttb), a biosimilar referencing HERCEPTIN 1 (trastuzumab), across all eligible indications, namely adjuvant treatment of HER2-overexpressing breast cancer, metastatic breast cancer and metastatic gastric cancer or gastroesophageal junction adenocarcinoma in patients who have not received prior treatment for metastatic disease (Press release, Samsung Bioepis, JAN 20, 2019, View Source [SID1234532794]). Please see Boxed Warnings and Important Safety Information for ONTRUZANT below.

ONTRUZANT is Samsung Bioepis’ first oncology biosimilar to receive FDA approval, and will be marketed and distributed in the United States (US) by Merck, which is known as MSD outside of the US and Canada.

"For many cancer patients in the US, battling cancer has not only been a health issue, but a considerable financial burden brought on by cancer treatment. Biosimilars are intended to be lower cost, high-quality treatment options that have the potential to alleviate such burden. We sincerely hope our trastuzumab biosimilar will do exactly that," said Sang-Jin Pak, Senior Vice President and Head of Commercial Division, Samsung Bioepis. "At Samsung Bioepis, we will continue to demonstrate our enduring commitment to biosimilars by further strengthening our pipeline and widening the availability of approved treatments for cancer patients across the US."

ONTRUZANT was also approved by the European Commission (EC) in November 2017, and has since been launched in a growing number of European countries.

About ONTRUZANT (trastuzumab-dttb)
ONTRUZANT is indicated for adjuvant treatment of HER2-overexpressing node-positive or node-negative (ER/PR-negative or with one high-risk feature*) breast cancer:

As part of a treatment regimen containing doxorubicin, cyclophosphamide and either paclitaxel or docetaxel
With docetaxel and carboplatin
As a single agent following multi-modality anthracycline-based therapy
Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product.
* High-risk is defined as ER/PR positive with one of the following features: tumor size >2 cm, age <35 years, or tumor grade 2 or 3.
ONTRUZANT is indicated:

In combination with paclitaxel for the first line treatment of HER2-overexpressing metastatic breast cancer
As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease
Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product.
ONTRUZANT is indicated, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, who have not received prior treatment for metastatic disease.
Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product

Select Important Safety Information

Cardiomyopathy

ONTRUZANT administration can result in sub-clinical and clinical cardiac failure manifesting as congestive heart failure and decreased left ventricular ejection fraction with greatest risk when administered concurrently with anthracyclines. Evaluate cardiac function prior to and during treatment. Discontinue ONTRUZANT for cardiomyopathy.
Infusion Reactions; Pulmonary Toxicity

Administration can result in serious and fatal infusion reactions and pulmonary toxicity. Symptoms usually occur during or within 24 hours of administration. Discontinue ONTRUZANT for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome.
Embryo-Fetal Toxicity

Exposure to ONTRUZANT during pregnancy can result in oligohydramnios in some cases complicated by pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these risks and the need for effective contraception
Exacerbation of Chemotherapy-Induced Neutropenia

In randomized, controlled clinical trials, the per-patient incidences of NCI-CTC Grade 3-4 neutropenia and of febrile neutropenia were higher in patients receiving trastuzumab products in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received trastuzumab and those who did not
Most Common Adverse Reactions

The most common adverse reactions for trastuzumab products in breast cancer were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia
The most common adverse reactions for trastuzumab products in metastatic gastric cancer were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia
These are not all of the risks associated with ONTRUZANT. For additional information on ONTRUZANT indications, as well as Important Safety Information related to its use, including Boxed WARNINGS, please see the ONTRUZANT Prescribing Information HERE

Precision BioSciences Enters Into Private Convertible Note Financing

On January 16, 2019 Precision BioSciences ("Precision" or the "Company"), a genome editing company dedicated to improving life (DTIL) through its proprietary ARCUS genome editing platform, reported that it has entered into an agreement for the issuance and sale of convertible promissory notes in a private placement transaction in the aggregate principal amount of approximately $40 million, which will bring the Company’s total capital generated in the last year to over $150 million and total funding since inception to over $300 million (Press release, Precision Biosciences, JAN 16, 2019, View Source [SID1234534181]). Contributors to this financing were largely first-time investors in the Company.

Investors in Precision now include ArrowMark Partners, Franklin Templeton, Cowen Healthcare Investments, venBio, F-Prime, RA Capital Management, Brace Pharma Capital, Pontifax AgTech, OCV Partners, DSAM, Adage Capital Management, Cormorant Asset Management, Gilead Sciences, Laurion Capital Management, Vivo Capital, Lilly Asia Ventures, Alexandria Venture Investments, Ridgeback Capital, Ditch Plains Capital Management, Agent Capital, entities affiliated with Leerink Partners, Amgen Ventures, Osage University Partners, DUMAC and the Longevity Fund.

Entry into a Material Definitive Agreement

On January 19, 2019 On January 19, 2019, Shanghai Cellular Biopharmaceutical Group Ltd. ("CBMG Shanghai"), a controlled entity of Cellular Biomedicine Group, Inc. (the "Company"), reported that it has entered into a credit agreement (the "Credit Agreement") with China Merchants Bank, Shanghai Branch (the "Merchants Bank") (Filing, 8-K, Cellular Biomedicine Group, JAN 19, 2019, View Source [SID1234532905]). Pursuant to the Credit Agreement, the Merchants Bank agreed to extend credit of up to RMB 100 million (approximately $14.7 million) to CBMG Shanghai via revolving and/or one-time credit lines. The types of credit available under the Credit Agreement, include, but not limited to, working capital loans, trade financing, commercial draft acceptance, letters of guarantee and derivative transactions. The credit period under the Credit Agreement runs until December 30, 2019. As of the date of this Current Report on Form 8-K, no amounts had been drawn down under the Credit Agreement.

Pursuant to the Credit Agreement, CBMG Shanghai will enter into a supplemental agreement with the Merchants Bank prior to the applicable drawdown that will set forth the terms of each borrowing thereunder (except for working capital loans), including principal, interest rate, term of loan and use of borrowing proceeds. With regard to working capital loans to be provided pursuant to the Credit Agreement, CBMG Shanghai shall submit a withdrawal application that includes the principal amount needed, purposes of the loan and a proposed quarterly interest rate and term of the loan for the Merchants Bank’s review and approval. The terms approved by the bank will govern such working capital loans. The bank has the right to adjust the interest rate for working capital loans from time to time based on changes in national policy, changes in interest rate published by the People’s Bank of China, credit market conditions and the bank’s credit policies. Upon CBMG Shanghai’s non-compliance with the agreed use of loan proceeds, the interest rate for the amount of loan proceeds improperly used will be the original rate plus 100% starting on the first day of such use. If CBMG Shanghai fails to pay a working capital loan on time, an extra 50% interest will be charged on the outstanding balances starting on the first day of such default.

Under the Credit Agreement, CBMG Shanghai has the obligation to notify the Merchants Bank prior to certain corporate actions and assist the bank in taking measures to ensure repayment of the loans provided under the Credit Agreement upon occurrence of such events. Such corporation actions include: (i) major financial losses and assets losses, (ii) loans to or guarantees for third parties or mortgages on its properties, (iii) revocation or cancellation of business license or applications for bankruptcy, (iv) major operational or financial crises of its controlling shareholder or other related entities that affect its business operations, (v) related party transactions that involve 10% or more of CBMG Shanghai’s net assets and (vi) legal proceeding that have material adverse effects on its operations or financial condition. Pursuant to the Credit Agreement, CBMG Shanghai cannot enter into a merger, an acquisition or a joint venture, transfer its equity interest or consummate a reorganization or share ownership restructuring without prior written consent of the Merchants Bank. The Credit Agreement also contains a covenant requiring that CBMG Shanghai maintain or improve its existing operations and preserve or increase the value of its existing assets.

Events of default under the Credit Agreement include, among other matters, CBMG Shanghai’s failure to perform its obligations thereunder, untrue or inaccurate representations, use of loan proceeds for purposes that are inconsistent with the Credit Agreement or related agreements. Additionally, a default under any other loan agreement of CBMG Shanghai that is not cured within three months of such default shall be deemed an event of default under the Credit Agreement. Upon the occurrence of an event of default, the Merchant Bank has the right to reduce the credit available under the Credit Agreement, suspend the use of the remaining credit by CBMG Shanghai and declare all outstanding balance to become immediately due and payable.

Pursuant to a pledge agreement which became enforceable upon execution of the Credit Agreement, Cellular Biomedicine Group Ltd. (HK), a wholly owned subsidiary of the Company ("CBMG HK"), provided a guarantee of CBMG Shanghai’s obligations under the Credit Agreement. In connection with such guarantee, CBMG HK deposited $17,000,000 into its account at the Merchants Bank for a 12-month period starting January 7, 2019 and also granted the Merchants Bank a security interest in the cash deposited.