On March 13, 2020 Major venture capitalist firm Flagship Pioneering has brought together two of its sister biotech companies to create a new, singly focused effort (Press release, Torque Therapeutics, MAR 13, 2020, View Source,autoimmune%20disorders%20and%20infectious%20diseases [SID1234573748]).

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Torque Therapeutics and Cogen Immune Medicine now become Repertoire Immune Medicines, a combined biotech looking to tap into the curative powers of our immune system to prevent, treat and cure cancer, autoimmune disorders and infectious diseases.

Torque CEO John Cox, an ex-Biogen exec who also shepherded its spinoff Bioverativ through its $11.6 billion acquisition by Sanofi, becomes the new company’s chief.

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Torque has been working on what it calls "deep-primed adoptive cell transfer" treatments it believes can surmount the hurdles that limit the use of cell therapy in cancer. These include getting past the microenvironment around a tumor that quashes the immune system and shuts down T-cell function.

The company "deep-primes" T cells to target multiple tumor antigens and puts cytokine and immunomodulators on their surfaces to call forth an immune response in the tumor microenvironment, the company says. Its first program, TRQ-1501, primes T cells to carry IL-15, a cytokine that promotes the proliferation of natural killer cells.

This will continue under the new biotech but will combine the work of Cogen, which also tapped the power of a patient’s immune system to fight disease. Now, it’s working on technologies for its so-called DECODE discovery and DEPLOY product platforms that "allow in-depth characterization of the immune synapse and the ability to rationally design, and clinically develop, multi-clonal immune medicines."

Repertoire has three discovery technologies that are at the heart of its immune synapse deciphering platform:

MCR, cell-based reporter assays to experimentally quantify MHC-specific peptide display and de-orphan TCR clonotypes across virtually unlimited peptide-MHC libraries;
‍CIPHER, MHC multimer-based assays to detect and measure TCR clonotypes, peptide-MHC reactivity and phenotypes on a single-cell level;
CAPTAN, internally developed deep-learning computational tools to classify platform hits and leverage large data sets to predict TCR reactivity beyond what is currently possible.
It said in a statement it is currently working on clinical trials "using autologous T cells primed against cancer antigens and tethered to IL-15." Specifically, Repertoire is testing its first dose escalation safety trial with TRQ15-01, using its PRIME platform to prepare the patient’s T cells and its TETHER platform to link an IL-15 nanogel immune modulator to the T cells.

"Repertoire is pioneering a new class of therapies based on high throughput, high content interrogation of the intrinsic ability of T cells to prevent, or cure diseases," said Noubar Afeyan, Ph.D., CEO of Flagship Pioneering and co-founder and chairman of Repertoire Immune Medicines.

He added: "Our products will be designed to leverage the highly evolved, potent and clinically-validated mechanism of the natural immune synapse to provide immune security to patients. With these ambitious goals in mind, we are pleased to have a proven leader, John Cox, as CEO to realize our shared vision to dramatically improve outcomes for those in need or at risk."

On March 13, 2020 X4 Pharmaceuticals, Inc., a Delaware corporation ("X4") and its qualified subsidiaries, including without limitation X4 Therapeutics, Inc. (together with X4, the "Borrower") entered into a First Amendment to the Amended and Restated Loan and Security Agreement dated June 27, 2019 (collectively the "Amended Loan Agreement") with Hercules Capital, Inc., and Hercules Capital Funding Trust 2019-1 (collectively the "Lender" or "Hercules"), which provides for aggregate maximum borrowings of up to $50.0 million (Filing, 8-K, X4 Pharmaceuticals, MAR 13, 2020, View Source [SID1234555647]).

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The Amended Loan Agreement consists of (i) a term loan of $25.0 million (including the $20.0 million previously outstanding under the Amended and Restated Loan and Security Agreement dated June 27, 2019) and an additional $5.0 million drawn at the closing of the first amendment on March 13, 2020 (the "Closing Date") (the "Tranche 1 Term Loan Advance"), (ii) subject to the achievement of certain performance milestones and other conditions, a right of the Borrower to request that the Lender make additional term loan advances in an aggregate amount of up to $7.5 million through June 30, 2021 the ("Tranche 2 Term Loan Advance"), (iii) subject to the achievement of certain performance milestones and conditions, a right of the Borrower to request that the Lender make additional term loan advances in an aggregate amount of up to $7.5 million through June 30, 2022 ( "Tranche 3 Term Loan Advance") and (iv) subject to the Lender’s investment committee’s sole discretion, a right of the Borrower to request that the Lender make additional term loan advances in an aggregate amount of up to $10.0 million through December 31, 2022 ("Tranche 4 Term Loan Advance").

Borrowings under the Amended Loan Agreement bear interest at a variable rate equal to a per annum rate of interest equal to the greater of either (i) 3.75% plus the prime rate as reported in The Wall Street Journal, and (ii) 8.75%. In an event of default, as defined in the Amended Loan Agreement, and until such event is no longer continuing, the interest rate applicable to borrowings under the Amended Loan Agreement would be increased by 4.0%.

Borrowings under the Amended Loan Agreement are repayable in monthly interest-only payments through January 1, 2022, and in equal monthly payments of principal and accrued interest from February 1, 2022 until the maturity date of the loan, which is July 1, 2023. X4 may prepay all, but not less than all, of the outstanding borrowings, subject to a prepayment premium of up to 2.0%, 1.0% or 0.5% of the principal amount outstanding as of the date of repayment, in each case depending on when such repayment is made. In addition, the Amended Loan Agreement provides for payments by the Borrower to Hercules of (i) $795,000 payable upon the earlier of November 1, 2021 or the repayment in full of all obligations under the Amended Loan Agreement, and (ii) 4.0% of the aggregate principal amount of all Term Loan Advances drawn under the Amended Loan Agreement (which payment amount would be $2.0 million if X4 borrowed the aggregate maximum principal amount of $50.0 million), payable upon the earlier of the maturity of the Amended Loan Agreement or the repayment in full of all obligations under the Amended Loan Agreement.

Borrowings under the Amended Loan Agreement are collateralized by substantially all of the Borrower’s personal property and other assets except for their intellectual property (but including rights to payment and proceeds from the sale, licensing or disposition of the intellectual property). Under the Amended Loan Agreement, the Borrower has agreed to affirmative and negative covenants to which the Borrower will remain subject until maturity or repayment of the loan in full. The covenants include, without limitation:

(a) Effective immediately upon the date the outstanding principal amount of the advances under the Amended Loan Agreement exceeds $25.0 million, Borrower at all times thereafter shall maintain cash in an account or accounts of Borrower in which Hercules has a first priority security interest, in an aggregate amount greater than or equal to the greater of (i) $30.0 million or (ii) 6 multiplied by a metric based on prior months’ cash expenditures ("RML"); provided, however, that from and after Borrower’s achievement of certain performance milestones, the required level shall be reduced to the greater of (x) $20.0 million, or (y) 3 multiplied by the current RML; and provided further, that subject to the achievement of certain milestones, this covenant shall be extinguished.

(b) Restrictions on the Borrowers’ ability to incur additional indebtedness, pay dividends, encumber its intellectual property, or engage in certain fundamental business transactions, such as mergers or acquisitions of other businesses, with certain exceptions.

The Borrower’s obligations under the Amended Loan Agreement are subject to acceleration upon occurrence of specified events of default, including payment default, insolvency and a material adverse change in the Borrower’s business, operations or financial or other condition.

In addition, under the Amended Loan Agreement, Hercules has the right to participate, in a cumulative amount of up to $3.0 million in the aggregate, of which $1.0 million has already been exercised as of the Closing Date, and subject to exceptions as provided in the Amended Loan Agreement, in any future offering of X4’s equity securities for cash that is solely for financing purposes and is broadly marketed to multiple investors.

The foregoing description of the Amended Loan Agreement does not purport to be complete and is qualified in its entirety by reference to the Amended Loan Agreement, which is attached hereto as Exhibit 10.1 and is incorporated herein by reference.

On March 13, 2020 Moleculin Biotech Presented the Corporate Presentation (Presentation, Moleculin, MAR 13, 2020, View Source [SID1234555607]).

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On March 13, 2020 Hutchison China MediTech reported SANET-ep trial (clinicaltrials.gov identifier NCT02588170) demonstrated that surufatinib significantly improves progression-free survival ("PFS") in patients with advanced extrapancreatic (non-pancreatic) neuroendocrine tumors compared to placebo, with a median PFS of 9.2 months versus 3.8 months, respectively (hazard ratio = 0.334, 95% CI 0.223 to 0.499, p<0.0001) (Press release, Hutchison China MediTech, MAR 13, 2020, https://www.chi-med.com/enets-2020/ [SID1234555570]). This presented analysis evaluated the safety profile and adverse events of special interest ("AESI") of surufatinib from SANET-ep data. 93.8% of patients in the surufatinib group and 73.5% of patients in the placebo group had at least one treatment-emergent AESI.

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The analysis concluded that AESIs of Grade 3 or higher hypertension and proteinuria occurred more frequently with surufatinib than with placebo, with the most common (at least 3% of patients) grade 3 or greater AESIs being hypertension (40.3% with surufatinib vs. 16.2% with placebo), proteinuria (23.3% vs. 0) and hemorrhage (3.1% vs. 2.9%). It also concluded that AESIs leading to treatment discontinuation were uncommon, with AESIs leading to dose discontinuation in at least 1% of patients being proteinuria (3.9% with surufatinib vs. 0 with placebo), hemorrhage (1.6% vs 1.5%), and hepatic failure (0.8% vs 1.5%). Surufatinib has a manageable safety profile in patients with advanced extra-pancreatic neuroendocrine tumors.

Title: Safety Profile and Adverse Events of Special Interest for Surufatinib in Chinese Patients with Advanced Extra-Pancreatic Neuroendocrine Tumors: Analysis of the Phase 3 SANET-ep Trial

Authors: Jie Li, Jianming Xu, Zhiwei Zhou, Chunmei Bai, Yihebali Chi, Zhiping Li, Nong Xu, Enxiao Li, Tianshu Liu, Yuxian Bai, Sha Guan, Lin Shen

Abstract: #2914

Introduction The previously reported SANET-ep trial (NCT02588170) demonstrated surufatinib significantly improves progression-free survival (PFS) in patients (pts) with advanced extrapancreatic neuroendocrine tumors (epNETs) compared to placebo; median PFS (9.2 vs. 3.8 months; HR = 0.334, 95% CI 0.223 to 0.499, p<0.0001).

Aims The present analysis evaluates the safety profile and adverse events of special interest (AESIs) of surufatinib from SANET-ep data.

Patients and Methods Pts were randomized (2:1) to receive surufatinib (300 mg once daily continuously) or placebo. Treatment-related AESIs and time-to-first occurrence of AESIs were summarized. Predefined AESIs included hepatic failure (HF), proteinuria (P), hypertension (HTN), haemorrhage (H), and acute renal failure (ARF), which were searched with narrow MedDRA Standardized MedDRA Query (SMQ).

Results A total of 121/129 (93.8%) pts in the surufatinib group and 50/68 (73.5%) in the placebo group had ≥ 1 treatment-emergent AESI; the mean relative dose intensity was 86.42% and 96.78%, respectively. The most commonly reported (>10% of pts) AESIs were P (84.5% vs 57.4%), HTN (68.2% vs 30.9%), and H (55.8% vs 27.9%). The most common (≥3% of pts) grade ≥3 AESIs were HTN (40.3% vs 16.2%), P (23.3% vs 0) and H (3.1% vs 2.9%); the median time-to-onset of these events in the surufatinib group was 13.5, 28, and 32 days, respectively. AESIs (≥1% of pts) leading to dose discontinuation were P (3.9% vs 0), H (1.6% vs 1.5%), and HF (0.8% vs 1.5%).

Conclusions The AESIs of Grade ≥ 3 HTN and P occurred more frequently with surufatinib; however, AESIs leading to treatment discontinuation were uncommon. Surufatinib has a manageable safety profile in pts with advanced epNETs.

Keywords extra-pancreatic, neuroendocrine tumors, safety

On March 13, 2020 RefleXion Medical, a therapeutic oncology company pioneering the use of biology-guided radiotherapy (BgRT)* to treat all stages of cancer reported it has received marketing clearance from the U.S. Food & Drug Administration (FDA) for stereotactic body radiotherapy (SBRT), stereotactic radiosurgery (SRS) and intensity modulated radiotherapy (IMRT) for its RefleXion X1 machine (Press release, RefleXion Medical, MAR 13, 2020, View Source [SID1234555559]).

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"We are at the forefront of an enormous change in expanding the use of radiotherapy from a treatment solely for early-stage cancer patients to an entirely new group of patients who need it most, those with advanced stage cancer," said Todd Powell, CEO and president of RefleXion. "This initial marketing clearance of our RefleXion X1 machine is a steppingstone on the path to our goal of providing BgRT as a novel treatment modality that will expand the overall radiotherapy market significantly.

"We have been preparing for commercial operations in the brand new factory we opened last year and expect to begin machine shipments within the next quarter," continued Powell.

The RefleXion X1 is the only machine that combines high quality computed tomography (CT) imaging, known as fan-beam CT, with a linear accelerator to reduce motion artifacts that can inhibit accurate targeting of the radiation dose to a patient’s tumor. Its groundbreaking design rotates up to 60 times faster than other linear accelerators and modulates dose delivery from 100 points per beam station. These combined improvements may reduce the side effects of radiotherapy by allowing radiation oncologists to better localize the tumor, reduce patient setup errors and precisely deliver dose to complex tumor targets while avoiding nearby normal structures.

"Transitioning this company from a research effort to what is, as of today, a commercial entity has been a thrilling 10-year journey," said Sam Mazin, Ph.D., founder and CTO of RefleXion. "Along the way, RefleXion has become an organization supported by dedicated and brilliant people in every corner, including our clinical partners. We will celebrate this milestone and then quickly turn our sights to bringing our biology-guided radiotherapy to market."

BgRT, a novel treatment modality under development, uses the biological signature of a tumor to characterize its movement and to deliver a precisely tracked therapeutic radiation dose to the tumor. The RefleXion X1 machine with BgRT is designed to overcome the technical limitations that currently restrict radiotherapy to one or two tumors. Once developed, RefleXion will scale BgRT to treat all visible tumors, even those that move rapidly due to involuntary processes such as breathing or digestion, in the same treatment session.