On January 28, 2020 Legend Biotech reported that, according to the terms and conditions of an agreement with Janssen Biotech, Inc. (Janssen), the fourth milestone payment has been achieved relating to the U.S. clinical development of the B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) therapy, LCAR-B38M (JNJ-68284528 (JNJ-4528)) (Press release, Legend Biotech, JAN 28, 2020, View Source [SID1234555395]).

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"We are pleased to have achieved this milestone, the fourth under the LCAR-B38M collaboration with Janssen," said Yuan Xu, PhD, CEO of Legend Biotech. "JNJ-4528 continues to advance in the clinic and we congratulate the Legend and Janssen teams on continued progress towards bringing this therapy to patients."

In December 2017, Legend and Janssen entered into a worldwide collaboration and license agreement to develop, manufacture and commercialize LCAR-B38M (JNJ-4528) in multiple myeloma. JNJ-4528 identifies the investigational product candidate being studied globally, except in China where the investigational product candidate (with identical CAR) isidentified as LCAR-B38M. Under the agreement, Legend received an upfront payment of $350 million from Janssen, and is entitled to receive additional payments upon achievement of specified development, production performance, regulatory and sales milestones. The companies have entered into a 50/50 cost-sharing/profit-split arrangement, except in Greater China, where Legend and Janssen have a 70/30 cost-sharing/profit-split arrangement. In December 2018, the first clinical milestone in the U.S. was achieved, resulting in a milestone payment from Janssen in 2019. Legend received the second and third milestone payments from Janssen in July 2019.

About CAR-T and BCMA CAR-T cells are an innovative approach to eradicating cancer cells by harnessing the power of a patient’s own immune system. BCMA is a protein that is highly expressed on myeloma cells. By targeting BCMA, CAR-T therapies may have the potential to redefine the treatment paradigm for multiple myeloma.

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excessive proliferation of plasma cells.

Although treatment may result in remission, unfortunately, patients will most likely relapse as there is currently no cure. Refractory multiple myeloma is when a patient’s disease is non-responsive or progresses within 60 days of their last therapy. Relapsed myeloma is when the disease has returned after a period of initial, partial or complete remission and does not meet the definition of being refractory. While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms that can include bone problems, low blood counts, calcium elevation, kidney problems or infections. Patients who relapse after treatment with standard therapies, including protease inhibitors and immunomodulatory agents, have poor prognoses and few treatment options available. In 2020, the American Cancer Society projects that 32,270 new cases of multiple myeloma and 12,830 deaths will occur in the United States.

On January 28, 2020 Mogrify Ltd (Mogrify), a UK company aiming to transform the development of cell therapies, reported that it has secured $1.1M of additional funding from SBRI Healthcare, the NHS England funded initiative championed by the Academic Health Science Network (AHSN), to assess its regenerative cartilage therapy, for the treatment of cartilage defects, osteoarthritis and other musculoskeletal conditions, before entering clinical trials (Press release, Mogrify, JAN 28, 2020, View Source [SID1234553998]). This grant follows on from the Phase I funding announced in 2019, which enabled Mogrify to identify the transcription factors and culture conditions required to convert various cell types into healthy mature chondrocytes, using Mogrify’s data-driven direct cellular conversion technology.

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The Mogrify platform (Rackham et al., Nature Genetics, 2016) takes a systematic big-data approach to identify, from next-generation sequencing and gene-regulatory networks, the conversion factors needed to produce cells that exhibit safety, efficacy and scalable manufacturing profiles suitable for development as regenerative cell therapies. The cellular conversions developed by Mogrify will allow both the scalable production of chondrocytes in vitro for use in autologous and allogeneic chondrocyte implantation for cartilage defects, and an in vivo reprograming therapy to reverse the pathophysiology of osteoarthritis. The Phase II funding from SBRI will be used to progress these cell conversions through pre-clinical safety and efficacy studies in vivo.

Dr. Karin Schmitt, CBO, Mogrify, said: "We select projects strategically based on both commercial and scientific considerations and are delighted with the progress of this collaboration with Dr. Wael Kafienah’s laboratory at the University of Bristol. The continued support for our lead musculoskeletal asset from SBRI Healthcare has not only allowed us to reach this phase but will enable us to carry the chondrocyte conversions through to the next stage."

Pierre-Louis Joffrin, Corporate Development Executive, Mogrify, said: "Osteoarthritis is the most common joint disorder and with current treatments focused only on addressing the symptoms, there is a huge unmet medical need. Through this additional funding from the NHS England initiative, we will be able to take the project through the efficacy and safety studies necessary to see it make a difference to patients as we now start planning for the clinical stages of the development."

On January 28, 2020, Biogen Inc. (the "Company") reported that it has entered into a Credit Agreement with Bank of America, N.A., as Administrative Agent, Swing Line Lender and the L/C Issuer, and the lenders party thereto (the "Credit Agreement") (Filing, 8-K, Biogen, JAN 28, 2020, View Source [SID1234553768]). The Credit Agreement provides for a $1.0 billion five-year unsecured, revolving credit facility (the "Revolving Credit Facility"). The Revolving Credit Facility includes borrowing capacity in the form of letters of credit of up to $25.0 million.

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Borrowings under the Revolving Credit Facility are available for working capital, capital expenditures, acquisitions and other lawful corporate purposes. No proceeds from the Revolving Credit Facility were drawn down as of the closing date of the Credit Agreement.

Revolving loans under the Credit Agreement (other than swing line loans) will bear interest at rate per annum equal to a Eurocurrency Rate – for dollars, euros, sterling and yen, the London Interbank Offered Rate ("LIBOR") or for any other currency approved pursuant to the terms of the Credit Agreement, at the rate designated at the time of such approval, in each case subject to a floor of 0.00% per annum, plus an applicable margin ranging from 0.750% to 1.375% depending on the ratings of the Company’s non-credit enhanced, senior unsecured long-term debt, as determined by either Standard & Poor’s or Moody’s (the "Debt Ratings") or, at the Company’s option, a Base Rate equal to the higher of (i) the Bank of America prime rate, (ii) the Federal Funds Rate plus 0.50% and (iii) a daily rate equal to one month LIBOR plus 1.00%, subject to a floor of 0.00% per annum (the "Base Rate"), plus an applicable margin ranging from 0.000% to 0.375% based on the Company’s Debt Ratings. Swing line loans will bear interest at the Base Rate plus the applicable margin for Base Rate loans.

In addition to paying interest on any outstanding principal under the Revolving Credit Facility, the Company will pay (i) a commitment fee in respect of the unutilized commitments thereunder and (ii) customary letter of credit fees and agency fees. The commitment fees range from 0.050% to 0.175% per annum based on the Company’s Debt Ratings.

The Revolving Credit Facility will terminate and all amounts outstanding thereunder are due and payable five years after the closing date, subject to certain extension options as set forth in the Credit Agreement. Under the Revolving Credit Facility, voluntary prepayments are permitted, in whole or in part, in minimum amounts without premium or penalty, other than customary breakage costs with respect to Eurocurrency borrowings. The Revolving Credit Facility requires quarterly interest payments or, in the case of Eurocurrency borrowings, at the end of the interest period therefor, with the principal due on the maturity date.

The Credit Agreement contains customary representations and warranties, affirmative and negative covenants and events of default. The Credit Agreement also includes a financial covenant requiring the Company to maintain, measured as of the end of each fiscal quarter, a maximum consolidated leverage ratio of 3.5 to 1.0 (which may be temporarily increased to 4.0 to 1.0 upon the election of the Company as a result of a material acquisition, subject to customary limitations).

A copy of the Credit Agreement is attached hereto as Exhibit 10.1 and is incorporated herein by reference. The description of the Credit Agreement is a summary only and is qualified in its entirety by the terms of the Credit Agreement.

On January 28, 2020 University of California reported that Using genetically engineered human pluripotent stem cells, University of California San Diego School of Medicine researchers created a new type of cancer model to study in vivo how glioblastoma, the most common and aggressive form of brain cancer, develops and changes over time (Press release, University of California at Los Angeles, JAN 28, 2020, View Source;scc012820.php [SID1234553647]).

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"We have developed stem cell models that are CRISPR-engineered to have tumor-associated driver mutations in glioblastoma, which harbor essentially all features of patient-derived tumors, including extrachromosomal DNA amplification," said co-senior author Frank B. Funari, PhD, professor in the Department of Pathology at UC San Diego School of Medicine and head of the Laboratory of Tumor Biology in the San Diego branch of the Ludwig Institute for Cancer Research.

"These models, or avatars as we call them, enable us to study human tumor development over long periods in vivo, which has not been feasible with patient-derived tissue samples which already harbor other genetic changes."

Reporting in the January 28, 2020 issue of Nature Communications, researchers used CRISPR editing to make precise mutations in an otherwise "normal" genome to create the genetic conditions that enable tumor development. The resulting avatars are unique in that they behave like a grade 4 glioma — a fast-growing type of tumor that starts in the glial cells of the brain — in their level of pathology, transcriptome signatures, engineered genetic alterations and evolution of genetic mutations, such as the emergence of extrachromosomal DNA and chromosomal rearrangements.

"The addition of single-cell RNA sequencing and computational tools enabled efficient analysis of big data to truly evaluate the surprising intra-tumor heterogeneity present in our avatars which replicates what is seen in patients samples," said co-senior author Gene W. Yeo, PhD, professor in the Department of Cellular and Molecular Medicine and the Institute for Genomic Medicine at UC San Diego and faculty member in the Sanford Consortium for Regenerative Medicine.

Existing mouse models work for testing drugs for specific mutations, but do not account for the diverse ways that tumors can develop. Human tissue samples do not allow for standardization in testing. This new avatar modeling system, said the authors, provides a platform for standardized studies on tumor biology and evolution.

"We can now test which mutations predicted by cancer genome projects are truly tumor-driving, and how they become invasive," said Yeo. "More importantly, these cancer avatars provide systematic, well-controlled opportunities for drug discovery."

Glioblastoma is highly malignant. Standard treatment is aggressive: surgery, followed by chemotherapy and radiation. Yet most tumors recur within six months. The two-year survival rate is 30 percent.

This avatar mimics the intra-tumor heterogeneity observed in people, making it a good option for detailed examination of tumor evolution and searching for therapeutic vulnerabilities based on driver genetics, said Furnari.

"Next steps include screening drugs, testing other mutations in adult and pediatric brain tumors as well as to evaluate if these approaches can model tumors in other tissues, such as the pancreas and lung," said Furnari.

On January 28, 2020 Sysmex Group Company reported that Pathologist Dr. Vincente Peg of the Vall d´Hebron University Hospital (Barcelona Spain) and colleagues have presented a correlation between the clearance of circulating tumor DNA (ctDNA) in HER2-positive or triple-negative breast cancer patients undergoing neoadjuvant treatment with a clinical/pathologic complete response at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Advances in Liquid Biopsies conference held in Miami, Florida (USA), January 13-16, 2020 (Press release, Sysmex Inostics, JAN 28, 2020, View Source [SID1234553637]). The researchers utilized both a SureSeq NGS cancer gene enrichment panel (Oxford Gene Technology, a Sysmex Group Company) for identifying lead mutations from breast cancer FFPE tissue, and Sysmex Inostics’ SafeSEQ personalized liquid biopsy platform for patient-specific longitudinal analysis of plasma ctDNA.

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Neoadjuvant therapy to reduce tumor size prior to surgical resection is common in the treatment of early stage breast cancer. However, there exists an unmet clinical need to distinguish those patients with residual disease after Neoadjuvant Therapy (NAT) from those who achieved complete response in order to better understand which patients are appropriately suited for surgery. Researchers from Vall d´Hebron deployed SureSeq NGS testing to identify driver mutations in breast cancer biopsy tissue of 29 patients with early stage disease. The mutations detected with SureSeq were subsequently followed in the plasma of patients with the SafeSEQ ultrasensitive personalized ctDNA platform to complement radiographic assessment and provide more detailed information on an individual’s response to NAT.

Of 29 Stage II and Stage III triple-negative and HER2-positive breast cancer patients examined in the study, 20 (69%) had TP53 or PIK3CA tissue mutations identified by SureSeq with 17 out of 20 (85%) patients having detectable mutations with SafeSEQ in plasma samples prior to initiation of NAT. Longitudinal plasma analysis conducted at treatment mid-point and post-treatment immediately prior to surgery demonstrated the absence of ctDNA following NAT was observed in all patients (12/12) showing a complete clinical response. However, ctDNA was detected in 3 out of 5 (60%) of patients who did not achieve complete clinical response suggesting that ctDNA testing – alongside of imaging – is an important clinical parameter to consider when determining complete response to neoadjuvant treatment.

"This study addresses the unmet need to de-escalate surgery in patients with no sign of disease." Dr. Vicente Peg commented. "How can we avoid surgically removing something that is just not there? Circulating tumor DNA by itself is able to detect 85% of patients that achieve pathologic complete response; however, when combined with imaging we can identify 100% of patients. These findings are an important first step to showing that we can accurately identify those patients who may avoid unnecessary surgery."

Reference:
Ciriaco, N., Zamora, E. and Peg, V. et al. AACR (Free AACR Whitepaper) Advances in Liquid Biopsy Conference 2020 Poster session B January 15, 2020. Clearance of ctDNA in triple-negative and HER2-positive breast cancer patients during neoadjuvant treatment is correlated with pathological complete responses, Poster B63.