On January 7, 2019 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported that the Safety Review Committee (SRC) has endorsed dose escalation in the ongoing ADP-A2AFP (AFP) study in patients with hepatocellular carcinoma (liver cancer) to the second dose cohort (Press release, Adaptimmune, JAN 7, 2019, View Source;p=RssLanding&cat=news&id=2382311 [SID1234532522]). The SRC has also endorsed moving to the expansion phase of the ADP-A2M10 (MAGE-A10) lung cancer study.

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Across both studies, most adverse events have been consistent with those typically experienced by cancer patients undergoing cytotoxic chemotherapy or other cancer immunotherapies with no evidence of alloreactivity or toxicity related to off-target binding.

In the ADP-A2AFP study, two patients have received 100 million transduced SPEAR T-cells targeting AFP in the first dose cohort, and there was no evidence of hepatotoxicity. The SRC endorsed dose escalation after evaluating the first two patients and taking into consideration the benefit:risk profile observed across programs in Cohort 1.

In the ADP-A2M10 lung cancer study, ten patients have been treated in the first three cohorts (up to six billion transduced cells), and the expansion phase will allow for doses of up to ten billion transduced cells (range 1.2 to 10 billion).

"We are pleased that the SRC has endorsed moving to the expansion phase of the ADP-A2M10 lung cancer study. Additionally, our ADP-A2AFP study has progressed to the next dose level of 1 billion transduced cells. Importantly, we did not observe liver toxicity in the two patients treated at a dose of 100 million transduced cells. In our other studies, we continue to enroll in the expansion phases and, as we previously have said, we are on track to report our next clinical data by May this year," said Rafael Amado, Adaptimmune’s President of Research & Development.

Overview of ADP-A2AFP (AFP) Study Design

This is a first-in-human, open-label study utilizing a modified 3+3 design in up to 36 patients with escalating target doses of 100 million (Cohort 1), 1 billion (Cohort 2), and 1.2‑6 billion (Cohort 3) transduced SPEAR T-cells to evaluate safety, including dose limiting toxicities (DLTs) followed by an expansion phase with doses of up to 10 billion SPEAR T-cells
This trial is being conducted in patients with hepatocellular carcinoma
There was a 21-day stagger between patients in Cohort 1, with this stagger dropping to 7 days in Cohorts 2, and 3 in the absence of DLTs. There is no pre-determined stagger in the expansion phase
Cohorts 1-3 were intended to enroll 3 patients each with an expansion to 6 patients if DLTs were observed
The expansion phase can enroll up to 30 patients
The lymphodepletion regimen is fludarabine (flu) (20mg/m2/day) and cyclophosphamide (cy) (500 mg/m2/day) for 3 days
Efficacy is assessed by overall response rate, time to response, duration of response, progression-free survival, and overall survival at weeks 4, 8, and 16, month 6, and then every 3 months until confirmation of disease progression
Overview of ADP-A2M10 (MAGE-A10) Lung Cancer Study Design

This is a first-in-human, open-label study utilizing a modified 3+3 design in up to 28 patients with escalating target doses of 100 million (Cohort 1), 1 billion (Cohort 2), and 1.2‑6 billion (Cohort 3) transduced SPEAR T-cells to evaluate safety, including DLTs followed by an expansion phase with doses of up to 10 billion SPEAR T-cells
This trial is being conducted in patients with non-small cell lung cancer (NSCLC)
There was a 21-day stagger between patients in Cohort 1, with this stagger dropping to 7 days in Cohorts 2, and 3 in the absence of DLTs. There is no pre-determined stagger in the expansion phase
Cohorts 1-3 were intended to enroll 3 patients each with an expansion to 6 patients if DLTs were observed
The expansion phase can enroll up to 10 patients
The lymphodepletion regimen is cyclophosphamide (1800 mg/m2/day) for 2 days in Cohort 1, fludarabine (flu) (30mg/m2/day) and cyclophosphamide (cy) (600 mg/m2/day) for 3 days in Cohort 2, and Cy (600 mg/m2/d) x 3 days + Flu (30 mg/m2/d) X 4 days in Cohort 3
Efficacy is assessed by response rate, duration of response, progression-free survival, and overall survival at weeks 4, 8, and 12, month 6, and then every 3 months (for 2 years) and then every 6 months until confirmation of disease progression

On January 7, 2019 OncoSec Medical Incorporated (OncoSec) (NASDAQ:ONCS), a company developing novel cancer immunotherapies, reported it has established a collaboration with the GOG Foundation, Inc., (GOG Foundation), to conduct a registration-enabled study of TAVO (tavokinogene telseplasmid) in women with recurrent/persistent cervical cancer (OMS-150) (Press release, OncoSec Medical, JAN 7, 2019, View Source [SID1234532538]).

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In June, 2018, KEYTRUDA (pembrolizumab) received accelerated approval from the FDA for the treatment of advanced cervical cancer with disease progression during or after chemotherapy based on data from a single-arm 98 patient study that showed a 14% overall response rate (ORR). Previous data in other advanced solid tumors demonstrate that TAVO combined with KEYTRUDA can induce objective responses in patients who do not respond to anti-PD-1 antibody monotherapy.

In this registration-directed clinical trial, OncoSec and GOG will evaluate the combination of TAVO and commercially available KEYTRUDA with the goal of achieving a clinically meaningful response rate greater than what has already been demonstrated with KEYTRUDA alone (14%). OncoSec and the GOG Foundation plan to enroll approximately 80 to 100 patients, who qualify for standard of care treatment with KEYTRUDA, in this single-arm study with TAVO. The trial will be open to patients with surface or subcutaneous lesions that are accessible via TAVO’s current delivery system. Patient enrollment is expected to begin in the first half of 2019. Importantly, should a clinically meaningful increase be observed in patients receiving the TAVO beyond that which they receive from KEYTRUDA alone, OncoSec plans to seek accelerated approval of TAVO in this patient population.

"KEYTRUDA is only the second drug in 30 years to be approved for the treatment of cervical cancer and, though it represents significant progress, the number of patients who can benefit is limited. Our goal is to improve upon the 14% KEYTRUDA response rate with the addition of TAVO," said Daniel J. O’Connor, President and Chief Executive Officer of OncoSec. "We believe that TAVO, our proprietary intratumoral plasmid-based IL-12, is an excellent complement for expanding the clinical benefit of anti-PD-1 therapies, especially for those patients that are resistant to anti-PD-1 therapies. Given that KEYTRUDA is already approved and reimbursed for this indication, this study fits perfectly with our strategy of identifying opportunities to conduct small, relatively low-cost single-arm clinical studies that have the potential to offer a rapid path to drug approval and commercialization."

The study will be conducted within GOG Foundation’s network under OncoSec’s investigational new drug (IND) application for TAVO. The GOG Foundation is a world-renowned non-profit organization with the purpose of conducting clinical research for the prevention and treatment of all gynecologic cancers, such as ovarian cancer, cervical cancer, endometrial cancer, vulvar cancer, and vaginal cancer. Its members make up a multi-disciplinary group, consisting of gynecologic oncologists, medical oncologists, pathologists, radiation oncologists, nurses, statisticians, and basic scientists.

"Conducting research that can lead to promising new therapies for women facing cervical cancer and other gynecological malignancies is central to our mission, and this collaboration is an exciting opportunity to bring our esteemed network and expertise in quality scientific research to the table," said Larry J. Copeland, MD, GOG Foundation President. "We’re grateful to play a role in this trial and look forward to advancing this therapy through the clinic."

On January 7, 2019 Evotec AG (Frankfurt Stock Exchange: EVT, MDAX/TecDAX, ISIN: DE0005664809) reported an additional investment of approximately $ 6 m towards Exscientia’s latest funding round (Series B). Exscientia, the world-leading Artificial Intelligence (AI)-driven drug discovery company, has raised $ 26 m in a Series B financing round (Press release, Evotec, JAN 7, 2019, View Source;announcements/press-releases/p/evotec-invests-in-financing-round-of-exscientia-5767 [SID1234532554]). Celgene Corporation and GT Healthcare Capital Partners joined as new investors and Evotec, previously the only large external investor, fully participated in this round.

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The company will use the proceeds of this financing round to grow its "full stack" AI drug discovery capability and to expand its pipeline, with a target of establishing an expansive portfolio of projects, both in-house and with partners.

"Exscientia and Evotec have been partners since early 2016 to advance novel small molecules and bispecific small molecules in immuno-oncology. The excellent progress of this partnership, and the great recent industry validations of our initial investment, are the basis of the expanded and deepened corporate relationship and investment," said Dr Werner Lanthaler, Chief Executive Officer of Evotec.

Professor Andrew Hopkins, CEO and founder of Exscientia, commented: "This Series B marks a milestone in our development and enables us to drive the next phase of strong business growth. Over the past 12 months, we have substantially expanded our operations and capabilities to become a full stack AI drug discovery company. Furthermore, our unique Centaur Chemist platform allows us to move rapidly from idea generation to new drug molecules ready for IND and clinical development. With this new funding, Exscientia is positioned to become the dominant player in AI drug discovery, driving radical change in R&D productivity."

Dr Craig Johnstone, Chief Operating Officer of Evotec added: "We are very pleased to continue to participate in the growth of Exscientia. This investment is another indicator of our commitment to the development of cutting-edge technologies, including the application of machine learning and artificial intelligence to improve predictive power in drug discovery science."

Exscientia has made considerable progress during 2018 and anticipates its first IND-ready programmes, driven by AI, in the next 12 months.

On January 7, 2019 Agios Pharmaceuticals, Inc. (NASDAQ: AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported its key 2019 initiatives in conjunction with its presentation at the 37th Annual J.P. Morgan Healthcare Conference in San Francisco (Press release, Agios Pharmaceuticals, JAN 7, 2019, View Source [SID1234532570]). The company will webcast its presentation today at 9:30 a.m. PT (12:30 p.m. ET) at investor.agios.com.

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"During 2018, just ten years after the founding of Agios, we achieved approval of our second internally discovered oncology medicine, launched a robust registrational program in PK deficiency and successfully opened the company’s seventh IND," said David Schenkein, M.D., chief executive officer at Agios. "Our validated research platform and proven drug development strategy are poised to help drive future growth across our oncology and rare genetic disease portfolios. Our priorities for 2019 include expanding the reach of our IDH inhibitors into the frontline AML and solid tumor settings, completing enrollment in two pivotal studies of mitapivat and exploring the utility of PKR activators in other hemolytic anemias, and furthering clinical development for AG-270 in MTAP deleted tumors and AG-636 in lymphoma."

The company plans to achieve the following milestones in 2019.

Cancer:

Potential FDA approval of the supplemental new drug application (sNDA) for single agent TIBSOVO (ivosidenib) for the treatment of patients with newly diagnosed AML with an IDH1 mutation who are not eligible for standard therapy.

Submit a sNDA to the FDA for TIBSOVO for second line or later IDH1m cholangiocarcinoma by year-end.

Initiate a registration-enabling Phase 3 study of vorasidenib (AG-881) in low-grade glioma with an IDH1 mutation by year-end.

Determine recommended dose of AG-270, a first-in-class methionine adenosyltransferase 2a (MAT2A) inhibitor, in methylthioadenosine phosphorylase (MTAP)-deleted tumors and initiate expansion arms, including a single agent arm in a variety of MTAP deleted cancers and a combination arm in a solid tumor in the first half of 2019.

Initiate a Phase 1 dose-escalation trial of AG-636, an inhibitor of the metabolic enzyme dihydroorotate dehydrogenase (DHODH), in lymphoma in the first half of 2019.

Rare Genetic Diseases:

Complete enrollment in two global pivotal trials for mitapivat in adults with PK deficiency by year-end 2019:

ACTIVATE-T: A single arm trial of approximately 20 regularly transfused patients

ACTIVATE: A 1:1 randomized, placebo-controlled trial of 80 patients who do not receive regular transfusions

Achieve proof-of-concept for mitapivat in thalassemia in the second half of 2019.

The company highlighted select data presentations expected in 2019.

Updated data from the ongoing Phase 1 combination trial of TIBSOVO with azacitidine in patients with newly diagnosed AML with an IDH1 mutation in the first half of 2019.

Data from the perioperative ‘window’ trial with TIBSOVO and AG-881 in IDHm low-grade glioma in the first half of 2019.

Topline data from the Phase 3 ClarIDHy study of TIBSOVO in IDH1m advanced cholangiocarcinoma to be reported in the first half and full data to be presented in the second half of 2019.

Data from the dose-escalation portion of the ongoing Phase 1 study of AG-270 in patients with MTAP-deleted tumors in the second half of 2019.

The company also provided an update on the following 2018 milestones achieved in December:

Submitted an sNDA to the FDA for TIBSOVO for the treatment of patients with newly diagnosed AML with an IDH1 mutation who are not eligible for standard therapy.

Submitted a Marketing Authorization Application to the European Medicines Agency for TIBSOVO for the treatment of adult patients with R/R AML with an IDH1 mutation.

Initiated a Phase 2 proof-of-concept trial of mitapivat in thalassemia.

2018 Year-End Cash and Guidance

Agios ended 2018 with approximately $805 million of cash, cash equivalents and marketable securities. The company expects that its cash, cash equivalents and marketable securities as of December 31, 2018, together with anticipated product and royalty revenue, anticipated interest income, and anticipated expense reimbursements under our collaboration agreements, but excluding any additional program-specific milestone payments, will enable the company to fund its anticipated operating expenses and capital expenditure requirements through at least the end of 2020.

Presentation at 37th Annual J.P. Morgan Healthcare Conference

Agios will webcast its corporate presentation from the 37th Annual J.P. Morgan Healthcare Conference in San Francisco on Monday, January 7, 2019 at 9:30 a.m. PT (12:30 p.m. ET). A live webcast of the presentation can be accessed under "Events & Presentations" in the Investors section of the company’s website at agios.com. A replay of the webcast will be archived on the Agios website for at least two weeks following the presentation

On January 7, 2019 Coherus BioSciences, Inc. (the "Company") reported that it has entered into a credit agreement (the "Agreement") with affiliates of Healthcare Royalty Partners (together, the "Lenders") (Press release, Coherus Biosciences, JAN 7, 2019, View Source [SID1234532628]). The Agreement consists of a six-year term loan facility for an aggregate principal amount of $75,000,000 (the "Borrowings"). The obligations of the Company under the loan documents are guaranteed by the Company’s material domestic U.S. subsidiaries (the "Guarantors").

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The Borrowings under the Agreement bear interest through maturity at 7.00% per annum plus LIBOR (customarily defined). If the consolidated net sales (customarily defined) for UDENYCA, the Company’s pegfilgrastim (Neulasta) biosimilar, for the fiscal year ending December 31, 2019, are in excess of $250,000,000, then the interest rate will be reduced as of January 1, 2020 to 6.75% per annum plus LIBOR. Interest is payable quarterly in arrears.

Principal payments on the Borrowings are required to be paid in equal quarterly installments beginning on the four year anniversary of the Closing Date (or, if consolidated net sales of UDENYCA in the fiscal year ending December 31, 2021 are less than $375,000,000, beginning on the three year anniversary of the Closing Date), with the outstanding balance to be repaid on January 7, 2025 (the "Maturity Date").

The Company is also required to make mandatory prepayments of the Borrowings under the Agreement, subject to specified exceptions, with the proceeds of asset sales, extraordinary receipts, debt issuances and specified other events including the occurrence of a change in control.

If all or any of the Borrowings are prepaid or required to be prepaid under the Agreement, then the Company shall pay, in addition to such prepayment, a prepayment premium (the "Prepayment Premium") equal to (i) with respect to any prepayment paid or required to be paid on or prior to the three year anniversary of the Closing Date, 5.00% of the Borrowings prepaid or required to be prepaid, plus all required interest payments that would have been due on the Borrowings prepaid or required to be prepaid through and including the three year anniversary of the Closing Date, (ii) with respect to any prepayment paid or required to be paid after the three year anniversary of the Closing Date but on or prior to the four year anniversary of the Closing Date, 5.00% of the Borrowings prepaid or required to be prepaid, (iii) with respect to any prepayment paid or required to be paid after the four year anniversary of the Closing Date but on or prior to the five year anniversary of the Closing Date, 2.50% of the Borrowings prepaid or required to be prepaid, and (iv) with respect to any prepayment paid or required to be prepaid thereafter, 1.25% of the Borrowings prepaid or required to be prepaid.

In connection with the Agreement, the Company paid a closing fee to the Lenders of $1,125,000. Upon the prepayment or repayment of the Borrowings (or upon the date such prepayment or repayment is required to be paid), the Company is required to pay an additional exit fee in an amount equal to 4.00% of the total principal amount of the Borrowings.

The obligations under the Agreement are secured by a lien on substantially all of the Company’s and the Guarantors’ tangible and intangible property, including intellectual property. The Agreement contains certain affirmative covenants, negative covenants and events of default, including, covenants and restrictions that among other things, restrict the ability of the Company and its subsidiaries to, incur liens, incur additional indebtedness, make loans and investments, engage in mergers and acquisitions, in asset sales, and declare dividends or redeem or repurchase capital stock. Additionally, the consolidated net sales for UDENYCA must not be lower than $70,000,000 for the fiscal year ending December 31, 2019, (b) $125,000,000 for the fiscal year ending December 31, 2020, and (c) $150,000,000 for each fiscal year thereafter. A failure to comply with these covenants could permit the Lenders under the Agreement to declare the Borrowings, together with accrued interest and fees, to be immediately due and payable.