ACTIP bulletin no. 72

ACTIP bulletin no. 72, July – October 2017

Next ACTIP meeting

Hosted by Clean Cells, BE Vaccines and Valneva in Nantes, France
30 November–1 December 2017
The meetings are for ACTIP members and individually invited guests.
More information can be obtained via
actip-secretariat@telefonica.net

In this issue
Webinars
Communications
Biomanufactoring news
Vaccine News
Business News
European Commission News
Regulatory News
Clinical Trials News
Research News
Stem Cell News
Agenda

Webinars

Addressing the Challenges of Therapeutic Vector Development

The dynamic landscape of molecular biology has bolstered gene-therapy endeavours, underscoring their true therapeutic potential in recent years. The webinar will address factors that are critical for viral vector development from the analytical scale to larger clinical-scale manufacturing modalities. Drawing attention to these parameters will ultimately lead to better downstream transductions for gene expression and knockdowns or genome editing.
Tuesday, November 7, 2017, 5:00 pm CET.
To register: http://www.workcast.com/register?cpak=5090457994558337

Communications

Shortlist announced for the European Biotech SME Awards 2017

Nightingale Health, NovaBiotics, Carbios, Numaferm and Iden Biotechnology were shortlisted out of 25 biotech SMEs to compete for the Most Innovative European Biotech SME Awards 2017. On 22 November, the finalists will take part in a pitch session followed by an awards ceremony at the European Parliament in Brussels.
See: http://www.europabio.org/cross-sector/publications/europabio-announces-finalists-most-innovative-european-biotech-sme-awards

Survey report: state of the bioprocessing and biomanufacturing industry 2017

The results from the second annual ‘state of the industry’ survey are now available. The survey was conducted to gauge views about the current state of the bioprocessing and biomanufacturing market and to identify the issues that matter. Key topics include bioprocessing challenges, investment and capacity, cell lines, disposable technologies, biological products and more.
For more information: https://www.biopharma-reporter.com/Library/Survey-Report-State-of-the-global-biomanufacturing-and-bioprocessing-industry-2017?utm_source=BPR_SurveyReport&utm_medium=email&utm_campaign=23Oct17
Source: BioPharmaReporter 23 Oct, 2017.

Biomanufacturing News

Protein A resin for mAb capture

GE Healthcare has launched a Protein A resin it says can improve monoclonal antibody purification capacity by up to 40% compared to its current offering. The firm launched MabSelect PrismA and believes the improved efficiency of the resin will make it the preferred option among its biopharma costumers in the capture of monoclonal antibodies. MabSelect PrimA uses a new Protein A ligand and a new agarose bead, which have been optimized to achieve very high dynamic binding capacities.
Source: http://www.biopharma-reporter.com, Sept 26, 2017.

EU distribution: BioCat on board the Vmax Express

SGI-DNA has selected BioCat to distribute its protein expression platform Vmax Express, which it says is more rapid than traditional expression systems. Under the agreement, BioCAT will manage the promotion, marketing, sales and support of the Vmax Expres cells and media for the European market, offering the reactions for €197 to clients.
Source: http://www.biopharma-reporter.com, Sept 20, 2017.

GE launches new cell therapy thawing technology

GE Healthcare has launched a thawing technology for cell therapies it says removes the risks and inconsistencies of standard water baths. Water bath thawing is the most common method for thawing cell therapies, however potential inconsistencies arise due to subjective determination of the taw endpoint and risk of water contamination. GE Healthcare has launched the VIA Thaw CB1000, an automated platform for the dry thawing of cryo-bags which overcomes these problems.
Source: http://www.biopharma-reporter.com, Sept 6, 2017.

CHO platforms are unsustainable for biopharma’s future, says Dyadic

Industry is feeling the low yield and high cost limitations of the CHO cell line and must look to alternatives (e.g. fungi, algae, insect cells) to make next-generation biological products, says fungal-based protein expression firm Dyadic International. “Industry is starting to experience the limitations of CHO expression yields for the next wave of biologics, bi-specific and tri-specific antibodies. The already low yields and high costs of producing biologics with CHO appear to make CHO unsustainable and commercially unaffordable for producing these complex molecules” according to the CEO of Dyadic International.
Source: http://www.biopharma-reporter.com, Aug 25, 2017.

Modular single-use facilities rebalance Biopharma’s capacity scales

Modular facilities and single-use systems are fast becoming a standard part of the bioproduction infrastructure as industry looks to mitigate future capacity constraints. Single use technology has come of age and is no longer touted as a straight-up replacement of large-scale manufacturing. It is now considered as a complementary and compatible option supported by cost-effective and quick to build facilities giving biopharma greater efficiency and flexibility in managing its capacity utilisation.
Source: http://www.biopharma-reporter.com, Aug 2, 2017.

Horizon cell line sequence released in bid to up bioproduction efficiency

Horizon Discovery released the sequence which will allow researchers to both screen for the genes associated with a desired phenotype and modify a genome sequence based on its knock-out CHO K1 cell line in a bid to drive innovation in bioproduction.
Source: http://www.biopharma-reporter.com, Aug 2, 2017.

ABEC breaks the 2,000L ‘plastic ceiling’ with 4,900L single-use bioreactor

ABEC says its latest offering has twice the working volume of the 2,000L bioreactor systems generally deemed to be the upper limit in single-use bioprocessing. The ability to redefine the process economics of single-use and to provide a much larger process window within a single-use bioreactor is driving “significant” demand for larger systems. As well as the reduction in costs of goods based on a drop in consumables, facility and operation costs using larger systems.
Source: http://www.biopharma-reporter.com, July 12, 2017.

Vaccine News

Bavarian Nordic wins up-to-$539M BARDA contract for Smallpox Vaccine

Bavarian Nordic has won an up-to-$539 M contract from the Biomedical Advanced Research and Development Authority (BARDA) to supply its freeze-dried Imvamune® smallpox vaccine for the U.S. Strategic National Stockpile. The contract consists of an initial $100 M base award toward manufacturing and storage of Imvamune® vaccine bulk and represents the third bulk contract inked between the company and BARDA. The two earlier bulk contracts total a combined $233 M.
The contract includes two initial options: Up to $299 M toward the filling and freeze-drying of Imvamune® produced under the three bulk awards and up to $140 M toward clinical development, regulatory commitments, and portions of the establishment and validation of fill/finish activities.
Source: www.genengnews.com/gen-news-highlights, Sept 28, 2017.

Gates foundation invests up to $40 M in Immunocore to develop TCR-based therapies

The Bill & Melinda Gates Foundation is investing up to $40 M in Immunocore to support development of the company’s soluble TCR (T-cell receptor)-based ImmTAV® (immune mobilizing monoclonal TCRs against virus) and ImmTAB® (immune mobilizing monoclonal TCRs against bacteria) therapeutics for infectious diseases that represent global health challenges. The organizations will focus on the development of ImmTav and ImmTAB molecules for treating tuberculosis (TB) and human immunodeficiency virus (HIV), which have the potential to reduce treatment timelines and improve patient outcomes.
The investment in Immunocore is being made as part of The Gates Foundation’s program-related investments (PRI) strategy, which aims to stimulate private sector–driven innovation and attract external capital to global health and development initiatives that could improve the lives of vulnerable populations.
Source: www.genengnews.com/gen-news-highlights, Sept 18, 2017.

Human flu vaccine triggers broad immune responses against multiple strains

An influenza vaccine trial in human volunteers has generated results that could help scientists develop a universal influenza vaccine that offers broad protection against yearly shifting viral strains. In the small-scale Phase I study, a group 2 subtype H7N9 vaccine generated high levels of memory B cells that recognized the conserved stem region of both group 1 and group 2 influenza virus hemagglutinin (HA) proteins.
These data suggest that a group 2–based stem immunogen could prove more effective than a group 1 immunogen at eliciting broad cross-group protection in humans. The work was published in Science Immunology.
Source: www.genengnews.com/gen-news-highlights, July 14, 2017.

Sanofi shells out $650m for non-egg based vaccine maker Protein Sciences

Sanofi will add the recombinant protein-based influenza vaccine Flublok to its products, along with a manufacturing facility in Pearl River, New York. The deal worth $650 M, plus a further $100 M upon achievement of certain milestones sees Sanofi increase its presence in the recombinant vaccine space, adding protein sciences insect virus-based expression technology and its commercial vaccine Flublok, which is the only recombinant protein-based influenza vaccine approved by the US FDA.
Source: http://www.biopharma-reporter.com, July 11, 2017.

Vaccine manufacturing deviation reports up by 19% in 2016, US FDA

An increase of quality, process control and specification issues contributed to a rise in reported vaccine manufacturing deviations last year a US FDA report finds. For the report see: https://www.fda.gov/downloads/BiologicsBloodVaccines/SafetyAvailability/ReportaProblem/BiologicalProductDeviations/UCM564872.pdf
Source: http://www.biopharma-reporter.com, July 5, 2017.

Cell-based flu vaccine hits commercial scale

Rather than rely on poultry and the eggs for the manufacture of yearly flu vaccines, the World Health Organization and FDA have encouraged vaccine manufacturers to look to other manufacturing technologies, such as use of a cell-based production model. Seqirus announced that it has successfully used such a model for the large-scale production of the flu vaccine using a cell-derived H3N2 candidate vaccine virus that was originally procured from the National Influenza Center in Singapore.
This development is especially timely, considering the Government Accountability Organization just released a report in May 2017 asserting that the U.S. government only has one “dependable manufacturer for producing egg-based vaccine for rapid pandemic mitigation.” Disease affecting poultry and their eggs, such as the avian flu, can drastically reduce the ability of a manufacturer to produce an adequate quantity of vaccine in the face of a pandemic threat.
Source: www.genengnews.com/gen-news-highlights, June 22, 2017.

Business News

Amgen delaying U.S. launch of Humira biosimilar in settlement with AbbVie

Amgen has agreed to delay the U.S. launch of its FDA-approved biosimilar version of AbbVie’s Humira® (adalimumab) until 2023, under a settlement the companies announced today that ends their patent dispute over the multi-indication blockbuster drug.
Amgen’s Humira near-copy Amjevita™ (adalimumab-atto) was the fourth biosimilar authorized for sale in the U.S. when it won FDA approval in September 2016. Six months later in March 2017, Amgen won EC approval for the biosimilar, which will be marketed in Europe as Amgevita™ (biosimilar adalimumab). However, the patent dispute with AbbVie has effectively kept the drug from reaching both markets.
The settlement calls for AbbVie to grant Amgen a nonexclusive license to AbbVie’s Humira-related intellectual property. That license will begin October 16, 2018, in most European countries and January 31, 2023, in the U.S.
The companies said they agreed to license periods on a country-by-country basis for worldwide use and sale of Amgen’s Humira biosimilar, though their separate announcements did not furnish details on the dates and nations. Also undisclosed were precise terms of the settlement, though AbbVie stated that it will receive royalties from Amgen. AbbVie also said that all litigation pending between the parties will be dismissed, and that Amgen has acknowledged the validity of AbbVie’s intellectual property related to Humira.
Source: www.genengnews.com/gen-news-highlights, Sept 28, 2017.

MilliporeSigma opens Chinese bioprocessing centre to showcase tech

MilliporeSigma has opened a biopharma process development and technology centre in China. The site in Shanghai will offer biopharma customers access to MilliporeSigma’s range of end-to-end process development capabilities and services, including cell line development, upstream and downstream process development and non-GMP clinical production.
Source: http://www.biopharma-reporter.com, Sept 27, 2017.

ChromaTan to develop continuous purification tech with $2.5M US FDA grant

ChromaTan will develop an integrated and continuous downstream purification platform through provisions in the 21st Century Cures Act to support manufacturing initiatives. The $2.5 M grant will be used to develop the Continuous Countercurrent Tangential Chromatography (CCTC) platform at ChromaTan’s laboratory in West Philadelphia.
Source: http://www.biopharma-reporter.com, Sept 20, 2017.

Catalent to acquire Cook Pharmica for $950M

Catalent agreed to acquire Cook Pharmica for $950 M, in a deal that would continue the consolidation of contract development and manufacturing organizations (CDMOs) to which biopharmas have increasingly outsourced operations, and bolster the buyer’s biologics capabilities. The acquisition would join Cook Pharmica’s drug substance and drug product manufacturing and related services with Catalent’s development, delivery, and supply operations creating a combined company that, the buyer says, would strengthen its position in biologics development and analytical services, manufacturing, and finished product supply.
Source: www.genengnews.com/gen-news-highlights, Sept 19, 2017.

The Japanese patent office intends to grant BioInvent’s important patent relating to the immune-oncology antibody BI-1206

BioInvent International AB announced that the Japanese patent office has decided that the company’s first patent application relating to the immune-oncology antibody BI-1206 now can proceed to grant. The patent will be granted once all remaining administrative actions, such as payment of fees, have been completed by BioInvent. This patent is important since it covers the use of the company’s drug candidate BI-1206, and similarCD32b antibodies, in combination with a CD19 or CD20 antibody, such as rituximab, in the treatment of cancer or inflammatory diseases in certain groups of patients. This will be the third patent granted in this patent family, after the patents granted in Australia and by the European Patent Office. There are also corresponding patent applications pending in other countries.
Source: BioInvent press release, Sept 12, 2017.

Merck to acquire Rigontec, expanding cancer immunotherapy franchise

Merck & Co. has agreed to acquire Rigontec for up to €464 M, in a deal that will expand the cancer immunotherapy franchise of the Keytruda® (pembrolizumab) developer with a three-year-old Bonn University spinout whose technology targets the retinoic acid-inducible gene I (RIG-I) pathway. Rigontec says its proprietary agonists are designed to activate RIG-I in order to induce both immediate and long-term antitumor immunity. The technology, Rigontec says, can be used for developing bifunctional RNA molecules for the treatment of infectious and inflammatory diseases in addition to cancer.
Source: www.genengnews.com/gen-news-highlights, Sept 6, 2017.

Thermo Fisher completes $7.2 B Patheon acquisition

Thermo Fisher has entered the contract development and manufacturing (CDMO) space through the acquisition of Patheon. The $7.2 B deal first announced in May 2017, was completed and sees Thermo Fischer add small and large molecule contract manufacturing capacity, a network of production plants and 9000 staff to its business.
Source: http://www.biopharma-reporter.com, Aug 30, 2017.

CSL adding scalable stem cell gene therapy tech in $91m Calimmune buy

CSL Behring will launch itself into the stem cell gene therapy through the acquisition of Calimmune, adding the hematopoietic stem cell gene therapy preclinical candidate Cal-H for the treatment of sickle cell disease and β-thalassemia. In addition the Select+ and Cytegrity platform manufacturing technologies will be acquired.
Source: http://www.biopharma-reporter.com, Aug 30, 2017.

MilliporeSigma to buy Natrix Separations with an eye on single use

MilliporeSigma has agreed to buy chromatography membrane supplier Natrix Separations to expand its vaccine and mAb production tech offering. The acquisition was prompted by Natrix’s chromatography membrane platform which is ideal for biomanufacturing processes employing single-use technologies.
Source: http://www.biopharma-reporter.com, Aug 29, 2017.

Cancer cell therapy developer Kite Pharma finds $11.9 B buyer in Gilead

Gilead Sciences has agreed to acquire Kite Pharma for approximately $11.9 B, the companies said, in a deal that combines the chimeric antigen receptor T-cell (CAR-T) pipeline of Kite, a leading cancer immunotherapy developer, with the buyer’s specialty drug portfolio, including hepatitis treatments beset by declining sales.
Kite and rival Novartis are seeking the first FDA approval of a CAR-T therapy. In May, the U.S. regulator accepted for priority review the company’s Biologics License Application for lead CAR-T therapy axicabtagene ciloleucel (formerly KTE-C19) for treating relapsed or refractory aggressive non-Hodgkin lymphoma in patients who are ineligible for autologous stem cell transplant. The FDA has set a November 29, 2017, Prescription Drug User Fee Act target action date.
In July 2017, Kite submitted the first CAR-T application in Europe, a marketing authorization application to the European Medicines Agency seeking approval of axicabtagene ciloleucel for patients with relapsed/refractory diffuse large B-cell lymphoma, transformed follicular lymphoma, and primary mediastinal B-cell lymphoma who are ineligible for autologous stem cell transplant. Kite expects to win European approval next year.
Source: www.genengnews.com/gen-news-highlights, Aug 28, 2017.

VistaGen’s cell production methods receive US patent boost

VistaGen Therapeutics has received a notice of allowance for a stem cell production patent, which the firm says could be used in autoimmune disorder and cancer treatments. The US Patent and Trademark Office (USPTO) issued VistaStem a subsidiary of VistaGen the notice for patent no. 14/359,517, which covers methods for producing hematopoietic precursor stem cells usually found in red blood marrow.
Source: http://www.biopharma-reporter.com, Aug 22, 2017.

Vendors optimistic for future despite slowdown in growth

Bioprocessing suppliers have recently expressed optimism in the sector despite a slowdown in growth, and one expert believes this will drive investment in new tech and markets.
Source: http://www.biopharma-reporter.com, Aug 18, 2017.

Sanofi and Regeneron end ten-year mAb collaboration

“One of the most productive arrangements in the history of the biotechnology industry” will end, says Regeneron on its monoclonal antibody collaboration with Sanofi. The collaboration brought regulatory success to a number of products for the partners, including high cholesterol treatment Praluenet (alirocumab), eczema drug Duplixent (dupilumab), and rheiumatoid arthritis niologic Kevzara (sarilumab). The collaboration will be ending in accordance with its terms without any extension on December 31st 2017.
Source: http://www.biopharma-reporter.com, Aug 16, 2017.

Roche offsetting biosimilar competition with 16 breakthrough therapies

Roche is confident its biologics pipeline and plan to reformulate some of its top selling monoclonal antibodies can offset sales erosion resulting from biosimilar competition. Pharmaceutical sales for Roche’s second quarter stood at CHF 9.6 B, with its top three products Mabthera/Rituxan, Herceptin and Avastin, contribution a total of CHF 5.3 B. All three were up 4-5% compared to last year. But the three monoclonal antibodies are beginning to face competition in Europe and the US, e.g. the US FDA recommended the approval of Amgens Avastin and Mylan’s Herceptin biosimilar, while the EC approved Truxima Celltrion’s version of Mabthera.
Source: http://www.biopharma-reporter.com, July 28, 2017.

Mitsubishi Tanabe to pay $1.1 B for Parkinson’s drug formulator Neuroderm

Mitsubishi Tanabe Pharma has agreed to pay $1.1 B to acquire Parkinson’s disease focused formulation and drug-device developer Neuroderm Ltd. Neuroderm’s lead product candidate ND0612 is a liquid formulation combining levodopa and carbidopa. The production, which is in Phase III trials in the US is designed for continuous administration using specially developed belt worn pump. The firm has a second Parkinson’s disease drug ND0701 (apomorphine) in development, as well as a transdermal CNS disease medication called ND0801 (nicotide and opipramol).
Source: http://www.in-pharmatechnologist.com, July 25, 2017.

Sanofi to buy insect cell vaccines company protein sciences for up to $750 M

Sanofi is looking to bolster its recombinant-based influenza vaccine portfolio through the acquisition of Protein Sciences for $650 M upfront and potentially up to another $100 M in milestones. The transaction, which has been approved by the Protein Sciences board and the majority of its shareholders, is expected to close during Q3 2017, subject to regulatory clearance.
Protein Sciences notes that its Flublok® Quadrivalent influenza vaccine is the only recombinant protein-based flu vaccine approved by the FDA. The vaccine, which is manufactured using a 100% egg-free cell culture system, was cleared by the U.S. regulator for use in adults, in October last year.
Source: www.genengnews.com/gen-news-highlights, July 11, 2016.

European Commission News

Telling the story of European Biotechnology

The European Research Council (ERC) announced its 2018 grant competitions with a total budget of around €1.86 B, most of which earmarked for early- to mid-career researchers. In addition, the ERC is reintroducing Synergy Grants, the funding scheme for groups of two to four scientists who jointly address ambitious research problems. See:
https://erc.europa.eu/news/nearly-€2-billion-investment-top-european-researchers-erc-plan-201.
Source: EuropaBio newsletter 29 July-4 Aug, 2017.

EU to probe if drug firms’ pre-submission meetings sway EMA approval decisions

Drug firms’ pre-submission meetings with the EMA may influence agency approval decisions according to European Ombudsman Emily O’ Reilly who has launched an investigation. The Ombudsman called on the EMA to provide details of the pre-submission process and how it is managed.
Source: http://www.in-pharmatechnologist.com, July 19, 2017.

Congratulations are in order for 64 SMEs! H2020 to invest €97 M

The EC will fund a further €97 M to the 64 small and medium-sized companies selected under Phase 2 of the Horizon 2020 SME Instrument. The investment will allow companies from 16 countries to continue working on 57 innovation projects, in addition to benefiting from 12 days of business coaching.
See: http://ec.europa.eu/research/index.cfm?pg=newsalert&year=2017&na=na-170717
Source: EuropaBio newsletter 15-21 July 2017.

Top 10 European biopharma clusters

A provocative study published in Science and Public Policy contends that Europe lacks the cutting-edge science long seen in the U.S., and increasingly published in Asia. The co-authors based their conclusion on research showing that European investigators published almost twice as many research papers of minimal impact papers, while their U.S. counterparts generated at least twice as many very-highly cited scientific papers, resulting in more Nobel prizes. The only exceptions, where European researchers came close to Americans, were in clinical medicine and physics, which the co-authors dismissed as more multinational and collaborative.
The conclusion may come as something of a surprise to industry watchers, who would note that Europe has many of the essentials needed for biopharma success. These include top-flight academic research, significant public research funding, a growing number of small- and medium-sized biotechs nurtured by regional biotech clusters, and a heritage of pharmaceutical giants stretching back to 1668, when Merck KGaA was founded in Darmstadt, Germany.
And Europe is close to developing a new and costly essential toward expanding biopharma in this century: The EC was to hold a summit meeting at which member nations were to commit themselves toward launching by 2020 the European Open Science Cloud a virtual environment to store, share, and reuse data across disciplines and borders to benefit Europe’s 1.7 M researchers and 70 M science and technology professionals. By year’s end, member nations will be presented with an implementation plan or “roadmap” and details of funding; total costs have been estimated at €6.7 B.
This year’s European Cluster Ranking includes all of the countries that appeared on last year’s Top 10 List, but with several changes in the rankings, notably at the top. The GEN’s annual European nations cluster ranking is based on these five criteria: public research funding, venture capital funding, patents, number of biotech companies, jobs. The ranking is: 1) United Kingdom; 2) Germany; 3) France; 4) The Netherlands; 5) Spain; 6) Switzerland; 7) Sweden; 8) Belgium; 9) Denmark; 10) Italy.
Source: www.genengnews.com/gen-news-highlights, June 19, 2017.

Regulatory News

Roche’s OCREVUS (ocrelizumab) approved in Switzerland for primary progressive and relapsing forms of multiple sclerosis

Roche announced that the Swiss agency for the authorisation and supervision of therapeutic products (Swissmedic) has granted authorisation of OCREVUS® (ocrelizumab) for the treatment of adult patients with active relapsing forms of multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS). MS, which affects almost 15,000 people in Switzerland, is the leading cause of non-traumatic disability in young adults and often results in serious and permanent disabilities.
Source: Roche Media Release, Sept 28, 2017.

US FDA red light for Janssen’s arthritis mAb

The US FDA has rejected Janssen Biotech’s application for Sirukumab, a monoclonal antibody (mAb) designed to treat severely active rheumatoid arthritis (RA). Sirukumab a fully human monoclonal IgG1 kappa antibody is designed to selectively inhibit circulating, naturally occurring IL-6, believed to contribute to autoimmune conditions like the systemic inflammatory condition RA. The US FDA requires additional clinical data in order to reassess the firm’s Biologics License Application.
Source: http://www.biopharma-reporter.com, Sept 26, 2017.

Roche receives EU approval of TECENTRIQ® (atezolizumab) in a specific type of metastatic lung cancer and two types of metastatic bladder cancer

Roche announced that the EC has granted a marketing authorisation for TECENTRIQ (atezolizumab) as a monotherapy for the treatment of people with locally advanced or metastatic non-small cell lung cancer after they have been previously treated with chemotherapy.
The EC has also granted marketing authorisation for TECENTRIQ as a monotherapy for the treatment of people with locally advanced or metastatic urothelial carcinoma who have been previously treated with a platinum-containing chemotherapy or who are considered ineligible for cisplatin chemotherapy. The Phase III IMvigor211 study did not meet its primary endpoint of OS, compared with chemotherapy. However, the phase III study showed that the duration of response was faster for those receiving chemotherapy.
Source: Roche Media Release, Sept 22, 2017.

US FDA slams 13 firms for selling unapproved drugs online

Thirteen companies have received US FDA warning letters citing the unlawful sale of unapproved and misbranded drug products over the Internet. The web-based companies included 247Med, PharmCash, GlavMed, Worldwide Drug Store, Medicina Mexico, Rx-partners, Bulk2USA, CanAmerica Global, American Pharmacy Group, MediPK, Pharmempire, H Stores Ltd, and MyRXCash.
Source: http://www.in-pharmatechnologist.com, Sept 21, 2017.

Roche receives European approval for Actemra/RoActemra in giant cell arteritis

Roche announced that the EC has approved Actemra®/RoActemra® (tocilizumab) for the treatment of giant cell arteritis (GCA), a chronic and potentially life-threatening autoimmune condition. Actemra/RoActemra is the first therapy approved for the treatment of GCA in Europe.
Source: Roche Media Release, Sept 22, 2017.

Roche receives EU approval of Gazyvaro for people with previously untreated advanced follicular lymphoma

Roche announced that the EC has approved Gazyvaro® (obinutuzumab) in combination with chemotherapy, followed by Gazyvaro maintenance in people achieving a response, as a new treatment for previously untreated advanced follicular lymphoma. The approval is based on results from a phase III study showing superior progression-free survival over the current standard of care, tituximab-based treatment.
Source: Roche Media Release, Sept 22, 2017.

US FDA stem cell enforcement challenged by state legislation

State legislation allowing unapproved stem cell treatments could undermine efforts by the US FDA to clampdown on unregistered clinics. In response to increased industry activity in the field of personalized medicines, the US FDA has produced a series of guidance documents (https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/default.htm), a dedicated expedited Regenerative Medicine Advanced Therapy (RMAT) pathways, and recently began clamping down on unapproved stem cell treatments at unregistered clinics. In August the FDA sent a warning to a Sunrise Florida-base clinic for marketing autologous stem cells products without FDA approval and seized material for an un-approved stem cell product intended to be directly injected into patients in two clinics in California. However local state legislation may be holding back these efforts and undermining the FDA’s attempts at regulating the industry.
Source: http://www.biopharma-reporter.com, Sept 20, 2017.

Launch of Amgen–Allergan cancer biosimilar Mvasi after FDA approval

Amgen and Allergan have won the first U.S. approval for a biosimilar cancer treatment following FDA authorization of their Mvasi™ (bevacizumab-awwb), a near-copy of Roche subsidiary Genentech’s Avastin® (bevacisumab). Mvasi is the seventh biosimilar to be approved by the FDA, which expressed the hope that its action would lower the sky-high prices of new cancer treatments.
Mvasi has been approved for adults with five types of cancer, including in combination with chemotherapy for non-squamous non-small-cell lung cancer, in combination with chemotherapy for metastatic colorectal cancer, glioblastoma, metastatic renal cell carcinoma in combination with interferon Alfa, and in combination with chemotherapy for persistent, recurrent, or metastatic carcinoma of the cervix. When Mvasi will reach the market and how much it will cost patients remains unknown.
Source: www.genengnews.com/gen-news-highlights, Sept 15, 2017.

New dosing regimen brings Mylotarg re-approval for Pfizer

The US FDA has approved Mylotarg seven years after Pfizer withdrew the antibody-drug conjugate due to safety concerns and questions surrounding its clinical benefit. Pfizer re-submitted the product to the US FDA earlier this year and it was approved for the same indication acute myeloid leukaemia (AML), as well as for patients aged two years and older with CD33-positive AML under a new dosing regimen with a different schedule in combination with chemotherapy, and for new patient population.
Source: http://www.biopharma-reporter.com, Sept 5, 2017.

US FDA tells Cellectis to halt cell therapy trials after patient death

The US FDA has ordered Cellectis SA to halt studies of its cell therapy UCART123 after the death of a patient. The deceased man a 78 year old who was suffering with relapse blastic plasmacytoid dendritic cell neoplasm, died nine days after receiving the first dose of UCART123. According to Cellectis, after a preconditioning regimen involving fludarabinen and cyclophosphamide, the patient was treated with UCART123 on August 16. Five days later he experienced a grade 2 cytokine release syndrome (CRS) and a grade 3 lung infection which improved after treatment with tocilizumab and antibiotics. However at day eight the patient experienced a grade 5 CRS event and grade 4 capillary leak syndrome that did not respond to corticosteroids and tociluzmab. He died the following day. Cellectis also revealed that a 68 years old woman suffering acute myeloid leukaemia, who received the same preconditioning regimen and the same dose of UCART123, had recovered after experiencing similar complications.
Source: http://www.in-pharmatechnologist.com, Sept 5, 2017.

Novartis’ Kymriah wins FDA approval as first CAR-T cancer therapy

The FDA approved Novartis’ Kymriah (tisagenlecleucel), with the agency hailing the chimeric antigen receptor T-cell (CAR-T) treatment as the first gene therapy to be available in the U.S. Kymriah, previously known as CTL019, is indicated for the second-line (or later) treatment of relapsed or refractory (r/r) patients up to age 25 with B-cell acute lymphoblastic leukaemia.
Novartis is one of two leading developers of CAR-T therapies. The other is Kite Pharma, which is awaiting an FDA decision on its CAR-T treatment axicabtagene ciloleucel (formerly KTE-C19) for treating relapsed or refractory aggressive non-Hodgkin lymphoma in patients who are ineligible for autologous stem cell transplant.
Source: www.genengnews.com/gen-news-highlights, Aug 30, 2017.

Samsung Bioepis ups EU presence with Humira biosimilar approval

Imraldi is the second version of AbbVie’s best-selling biologic Humira (adalimumab) to be approved and the fourth biosimilar success for Samsung Bioepis in Europe. The EC announced its approval of the anti-TNF biosimilar for all indications of Humira, AbbVie’s lead monoclonal antibody which last year pulled in sales of over $16 B for the firm. The first version of Humira to be approved in Europe this year was the one from Amgen.
Source: http://www.biopharma-reporter.com, Aug 25, 2017.

Pfizer’s ADC ambition bolstered by US Besponsa approval

Pfizer has been granted US approval for its antibody-drug conjugate Besponsa, to be manufactured at the firm’s Pearl River, New York facility. Besponsa (inotuzumab ozogamicin), indicated for the treatment of adults relapsed or refractory B-cell precursor acute lymphoblastic leukaemia, was granted approval from the US FDA under its breakthrough therapy designation and priority review program.
Source: http://www.biopharma-reporter.com, Aug 23, 2017.

US FDA plans facility inspection efficiency drive

The US FDA has released a document to address the integration of pharmaceutical facility evaluations and inspections. The agreement on “Integration of FDA Facility and Inspection Program for Human Drugs: A Concept of Operations” was coordinated by the Center for Drug Evaluation and Research (CDER) and the Office of Regulatory Affairs (ORA). It details the responsibilities for pre-approval, post-approval, surveillance and cause for inspections in the US and abroad.
Source: http://www.in-pharmatechnologist.com, Aug 23, 2017.

EMA plans biomarker and drug-matched guidelines

The European Medicines Agency (EMA) is working on guidelines to help drug firms to develop companion diagnostics in parallel with medicines. The concept paper can be found here:
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/07/WC500232420.pdf
Source: http://www.in-pharmatechnologist.com, Aug 17, 2017.

EMA reflection paper on API starting materials

The EMA has revised its reflection paper on API starting materials to clarify what information drug firms should provide about their starting materials under ICH Q11. The paper can be found here: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500175228.pdf
Source: http://www.in-pharmatechnologist.com, Aug 16, 2017.

Teva and Amgen latest to submit trastuzumab biosimilars to US FDA for review

The US FDA has accepted submission of two further Herceptin (trastuzumab) biosimilars: ABP 980 developed by Amgen and Allergan, and CT-P6 developed by Teva and Celltrion. In January 2017 a tratsuzumab molecule developed by Indian drug firms Mylan and Biocon became the first biosimilar of Roche’s blockbuster anti-HER2 monoclonal antibody Herceptin to be accepted for review by the US FDA. In July an FDA committee voted unanimously in favour of its approval, paving the way for the first Herceptin biosimilar to arrive in the US. Two more Herceptin biosimilars have been successfully submitted to the FDA in August. ABP980 is one of four biosimilars co-developed between Amgen and Allergan whereas CT-P6 is the first biosimilar breakthrough in the US by Teva teaming up with Celltrion.
Source: http://www.biopharma-reporter.com, Aug 1, 2017.

Second US infliximab biosimilar to J&J’s Remicade launched at 35% discount

Merck & Co. will challenge both reference drug maker J&J and fellow biosimilar developer Pfizer through its version of Remicade, Renflexis. Pfizer’s Inflectra entered the market at a 15% discount to the wholesaler acquisition costs of the reference products, but Merck is looking to undercut this by introducing Renflexis with a discount of 35% of Remicade’s price.
Source: http://www.biopharma-reporter.com, July 25, 2017.

BrainStorm wins $15.9 M grant for Phase III trial of ALS cell therapy

BrainStorm Cell Therapeutics won a $15.9 M grant from California’s regenerative medicine agency toward a Phase III trial of its amyotrophic lateral sclerosis cell therapy candidate NurOwn®.
NurOwn uses mesenchymal stem cells that are converted using BrainStem’s proprietary technology into cells that secrete a variety of neurotrophic factors (NTFs) designed to treat neurodegenerative diseases by allowing for delivery of several NTFs at or close to the site of injury. The resulting neurotrophic factors-secreting mesenchymal stromal cells secrete a variety of NTFs, including glial cell-derived neurotrophic factor, brain-derived neurotrophic factor, vascular endothelial growth factor, and hepatocyte growth factor.
Source: www.genengnews.com/gen-news-highlights, July 21, 2017.

Janssen wins FDA approval for plaque psoriasis treatment Tremfya

J&J Janssen Biotech has won FDA approval for the plaque psoriasis candidate Tremfya™ (guselkumab), creating a potentially blockbuster-scale competitor for several recent arrivals to market in the indication. Tremfya™ is indicated for adults living with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. The treatment is the first and only approved biologic designed to work by selectively blocking only interleukin (IL)-23, a cytokine shown to play a key role in plaque psoriasis.
The FDA’s approval was based on data Janssen submitted from three Phase III trials assessing Tremfya in more than 2000 patients.
Source: www.genengnews.com/gen-news-highlights, July 14, 2017.

‘Unrealistic’ serialization deadline? FDA offers one year grace period

The US FDA has released draft guidelines offering a reprieve for manufacturers which have not integrated product identifier requirements by the November 26 serialisation deadline. The draft policy asserts actions will not be taken against manufacturers who do not affix or imprint a product identifier to each package of prescription drugs before November 26, 2018. For the draft policy see: https://www.federalregister.gov/documents/2017/07/03/2017-13979/product-identifier-requirements-under-the-drug-supply-chain-security-act-compliance-policy-draft
Source: http://www.in-pharmatechnologist.com, July 4 23, 2017.

Supreme court’s Sandoz–Amgen decision boosts biosimilars

A unanimous U.S. Supreme Court has handed biosimilar developers a key victory that could generate millions in future sales by ruling that they can bring their treatments to market upon FDA approval without waiting an additional six months. The High Court ruled in favour of Novartis’ Sandoz unit by reversing a decision by the U.S. Court of Appeals for the Federal Circuit (CAFC). The CAFC decision forced Sandoz to wait 180 days before it could launch Zarxio® (filgrastim-sndz), its biosimilar version of Amgen’s leukocyte growth factor Neupogen® (filgrastim).
Source: www.genengnews.com/gen-news-highlights, June 13, 2017.

Clinical Trial News

Phase III data shows Venclexta® /Venclyxto® plus MabThera®/ Rituxan® to help people with previously treated chronic lymphocytic leukaemia to live longer without their disease worsening compared to bendamustine plus MabThera®/Rituxan®

Roche announced that the phase III MURANO study, which evaluated Venclexta®/Venclyxto® (venetoclax) in combination with MabThera®/Rituxan® (rituximab) in people with relapsed or refractory chronic lymphocytic leukaemia (CLL), met its primary endpoint and showed a statistically significant improvement in the time people lived without their disease progressing (progression-free survival [PFS] as assessed by investigator) when treated with Venclexta®/Venclyxto® plus MabThera®/Rituxan® compared to bendamustine plus MabThera®/Rituxan®. No new safety signals or increase in known toxicities of Venclexta/Venclyxto were observed with the treatment combination of Venclexta®/Venclyxto® plus MabThera®/Rituxan®. Venclexta®/Venclyxto® (venetoclax) is being developed by AbbVie and Roche. It is jointly commercialised by AbbVie and Genentech, a member of the Roche Group, in the US and commercialised by AbbVie outside of the US.
Source: Roche Media Release, Sept 18, 2017.

Roche announces phase III study results of Zelboraf for adjuvant treatment of BRAF V600 mutation-positive melanoma

Roche announced data for the phase III study designed to investigate the efficacy and safety of Zelboraf® (vemurafenib) in the adjuvant (after surgery) treatment of people with completely resected, BRAF V600 mutation-positive melanoma. The study did not meet its primary endpoint of significantly reducing the risk of recurrence (disease-free survival; DFS) in patients with stage IIIC melanoma (cohort 2); however, a 46% reduction in recurrence risk was observed in stage IIC-IIIB patients (cohort 1). The safety profile was consistent with that seen in previous studies of Zelboraf in advanced melanoma.
Source: Roche Media Release, Sept 14, 2017.

Bayer submits BLA for long-acting factor VIII for Hemophilia A

Bayer has submitted to the FDA a Biologics License Application (BLA) for BAY94-9027 (damoctacog alfa pegol), a long-acting site-specifically PEGylated recombinant human Factor VIII designed to treat hemophilia A up to once every seven days.
The BLA is supported by positive data from the Phase III PROTECT VIII (PROphylaxis in hemophilia A patienTs via directly pEgylated long-aCTing rFVIII) trial. Bayer trumpeted positive results from PROTECT VIII in 2014, saying the study showed BAY94-9027 met its primary endpoint of protection from bleeding with fewer infusions.
According to Bayer, BAY94-9027 protected patients from bleeds when used prophylactically once every seven days, once every five days, and twice per week. The company added that the treatment was also effective for treatment of acute and breakthrough bleeds, with nearly all (91%) of events being resolved with one or two infusions.
BAY94-9027 is engineered to prolong activity in the body while preserving full coagulation activity through PEGylation. A polyethylenglycol (PEG) molecule is consistently attached to the Factor VIII protein at a specific site, with the aim of prolonging the time of drug circulation in the blood.
Source: www.genengnews.com/gen-news-highlights, Aug 31, 2017.

Cellectis starts BPDCN phase I trial with gene-edited CAR-T therapy

Cellectis reported that the first patient has been dosed in a Phase I clinical trial evaluating its TALEN® gene-edited chimeric antigen receptor (CAR) T-cell product UCART123 in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). The BPDCN study follows on from the start in June of a Phase I study to evaluate the safety and efficacy of UCART123 in patients with acute myeloid leukaemia (AML). Cellectis says UCART123 is the first allogeneic, off-the-shelf, gene-edited CAR T-cell program targeting CD123 to enter clinical trials in the U.S.
BPDCN is a rare, aggressive hematological cancer classified as an acute leukaemia, for which there is no standardized therapeutic approach. Most BPDCN patients may achieve transient responses when treated using combination chemotherapy regimens for acute leukaemia or lymphoma, but then they relapse. The new Phase I UCART123 study, carried out at the MD Anderson Cancer Center, will evaluate the cell therapy in BPDCN patients in the relapsed, refractory, and front-line settings.
Source: www.genengnews.com/gen-news-highlights, Aug 18, 2017.

EMA shares updated guidance for first-in-human clinical trials

The European Medicines Agency improved its guidelines for first-in-human trials to lower the potential risk participants’ face during preclinical studies. Building on a previous public consultation and a follow-up workshop from March 2017, the revised strategies will help stakeholders establish, among others, a starting and maximum dose to be administered. See: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2017/07/news_detail_002783.jsp&mid=WC0b01ac058004d5c1
Source: EuropaBio newsletter 22-28 July, 2017.

Human CAR-T cell glioblastoma trial generates clues for improving treatment

A chimeric antigen receptor T-cell (CAR-T) therapy for glioblastoma (GBM) successfully crossed the blood–brain barrier to reach tumours in the brain, appeared safe, and reduced levels of its epidermal growth factor variant III (EGFRvIII) tumour target in GBM cells, in a first-in-man trial carried out by researchers at the University of Pennsylvania. The study also found that wide variation in EGFRvIII expression among patients, coupled with active immunosuppressive changes in the tumour in response to CAR T-cell infusion, may represent barriers to the clinical utility of the CAR-T therapy on its own.
EGFRvIII is expressed in about 30% of newly diagnosed GBM cases; however, in patients who survive for a year or longer, EGFRvIII expression is thought to be associated with poorer prognosis. The reported pilot study with the CART-EGFRvIII candidate involved 10 heavily treated patients with refractory, recurrent GBM, who received a single infusion of the CAR T cells. Three of the patients did not undergo surgery following CAR-T therapy infusion, three patients, respectively, underwent late surgery at 34, 55, or 104 days after infusion, and four early surgery patients had clear symptomatic progression and underwent a combined regimen of CAR T-cell infusion followed by clinically indicated surgery.
Tests on tumours from patients who underwent surgery soon after therapy found CART-EGFRvIII cells and signs of activation within the first two weeks after CAR T-cell infusion. Circulating CAR T cells were also found in the blood of all patients receiving the infusion. Blood levels of the CART-EGFRvIII cells started to decline after two weeks and were undetectable after a month. Tumours from five patients who underwent surgery following therapy also exhibited lower levels of the target antigen EGFRvIII.
The primary endpoint of the Phase I study was safety, rather than efficacy, and it wasn’t possible to identify definitive clinical benefit of CART-EGFRvIII therapy. However, one patient achieved stable disease at 18 month follow-up and was still alive when the study data was published. Another two patients also survived, but demonstrated disease progression. The remaining seven patients lived incrementally longer than would be predicted based on their treatment history and multifocal tumour recurrence.
While the trial demonstrated that treatment was associated with on-target activity in the brain, it also found that there was a wide variation in EGFRvIII expression among patients over time and in different areas of their tumours. CAR-T therapy also triggered the production of immunosuppressive regulatory T cells that migrated into the tumour, and led to upregulation of additional immunosuppressive pathways. Both EGFRvIII variability and inhibitory responses in the tumour microenvironment will represent potential barriers to therapy.
Source: www.genengnews.com/gen-news-highlights, July 19, 2017.

Research News

Novel technique designs mini-proteins that may lead to new types of therapeutics

Researchers say they have developed a technique to generate many small, different proteins that can be designed to bind to therapeutic targets. They add that their methodology, which reportedly produces thousands of new drug candidates, may lead to protection against infectious diseases, such as influenza, and antidotes to nerve toxins.
The computer-designed proteins, which did not previously exist in nature, combine the stability and bioavailability of small-molecule drugs with the specificity and potency of larger biologics, according to D. Baker, Ph.D., who led the multi-institutional research project and is professor of biochemistry at the University of Washington School of Medicine and director of the UW Institute for Protein Design.
“These mini-protein binders have the potential of becoming a new class of drugs that bridge the gap between small-molecule drugs and biologics. Like monoclonal antibodies, they can be designed to bind to targets with high selectivity, but they are more stable and easier to produce and to administer” according to Dr. Baker. The study was published in Nature.
Source: www.genengnews.com/gen-news-highlights, Sept 28, 2017.

Cellular messaging finding opens door to new drug-delivery methods

Harvard scientists have recently discovered a cellular messaging mechanism might lead to a new approach for delivering therapeutics to diseased tissues. The team, from the Harvard T.H. Chan School of Public Health, found that a type of extracellular vesicle (EV) known as ARMMs, or arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicles, also carries receptors that allow signalling without direct contact between cells. This capability may make ARMMs uniquely suited to be engineered to send therapeutics directly to affected areas of the body, according to Q. Lu, Ph.D., associate professor of environmental genetics and pathophysiology.
“ARMMs…are extracellular vesicles that bud directly at the plasma membrane; however, little is known about the molecular composition and physiological function of these vesicles. Here we report that ARMMs contain active NOTCH receptors and mediate a non-canonical intercellular NOTCH signalling,” write the investigators.
The team found that ARMMs contain molecules used for NOTCH signalling, a type of intercellular communication that normally requires cell-to-cell contact. NOTCH receptors are plasma membrane proteins involved in critical physiological roles, such as embryonic development, tissue homeostasis, and stem cell function. According to the new findings, ARMMs are able to facilitate NOTCH receptor signalling at a distance. The study has been published in Nature Communications.
Source: www.genengnews.com/gen-news-highlights, Sept 27, 2017.

Gene immunotherapy reverses paralysis in mouse model of multiple sclerosis

Scientists at the University of Florida in Gainesville have developed a gene immunotherapy method that can stop the development of multiple sclerosis (MS) in a mouse model of the autoimmune disorder, and even reverse paralysis in animals with pre-existing disease. Rather than use gene therapy to deliver a therapeutic or curative protein for MS, Dr. Hoffman’s team is using gene therapy to exploit the liver’s ability to induce immune tolerance. The approach uses an adeno-associated viral (AAV) vector to deliver the gene for the myelin sheath protein, myelin oligodendrocyte glycoprotein (MOG), to the liver. Expression of MOG by liver cells triggers the immune system to produce highly specific Tregs that prevent the rogue auto-reactive effector T cells from attacking the protein in the myelin sheath.
Previous research has shown that administering Tregs to a murine model of MS, known as experimental autoimmune encephalomyelitis (EAE), can halt or reduce neurological symptoms, but the effects are temporary. Treg cell injections have also been shown to be a safe treatment approach for patients with other autoimmune disorders, such as type 1 diabetes and graft-versus host disease. The problem with this method, however, is generating enough of the cells. The team has instead developed a liver-targeting AAV vector encoding the full coding sequence for MOG, which they delivered to the mouse EAE model.
When the researchers administered the gene therapy prophylactically to the mouse EAE model, they found that treatment had an immunosuppressive effect, which prevented mice from developing the disease. Whereas control mice started to develop neurological deficits within 10 days of EAE induction, mice receiving the AAV vector developed no clinical signs of EAE.
Importantly, liver cells in the prophylactically treated mice continued to express Treg-stimulating MOG over the whole 200-day experimental timeline, without any discernible adverse immune effects. Moreover, the gene therapy completely reversed clinical symptoms, including paralysis, in animals that were treated for the first time after they had already developed moderate disease. Mice with hind leg paralysis gradually began to regain the use of their legs following treatment and were eventually able to move around freely again.
Animals with much more severe, late-, or end-stage disease also derived some clinically relevant, but less dramatic, benefits following the MOG vector therapy. The disease had progressed too far for gene therapy alone to completely reverse the symptoms. However, even in these animals, combining the MOG-encoding AAV vector therapy with a course of treatment using the immunosuppressive drug rapamycin led “remarkably” the authors admit to near-complete remission. Among the two groups of end-stage disease animals with either complete tail and hind-limb paralysis or near quadriplegia, 71%, and 80% of treated animals demonstrated near-complete remission. The research was published in Molecular Therapy.
Source: www.genengnews.com/gen-news-highlights, Sept 22, 2017.

Microtissue magic: 3D-printed tech for cell culture production ‘degrades on demand’

Researchers at Brown University have developed a 3D printing technique, which they say could be used to make cell cultures for biopharmaceutical production. The structures are made using 3D printing technique called stereolithography, which links photoactive polymers together to create reversible bonds. A computer-aided design system, in conjunction with an ultraviolet laser, traces patterns across the surface of a sodium alginate polymer solution, which causes the polymers to link together and form solid 3D structures. The technology could be used to print biomaterials with well-controlled shapes and tunable degradation kinetics, which could be used for bio-fabrication of micro-tissues and with perfusion and vascular-like channels. The work has been published in the journal Lab on a Chip.
Source: http://www.in-pharmatechnologist.com, Sept 14, 2017.

Scientists identify new immunotherapy target for paediatric cancers

Scientists in the US and Canada have identified a key immunotherapy target for high-risk neuroblastoma and other childhood cancers, and developed an antibody-drug conjugate (ADC) targeting the cell surface co-receptor, glypican 2 (GLP2), which regressed tumours and prolonged life in a mouse model of neuroblastoma.
Neuroblastoma is a cancer of the developing peripheral nervous system, and the most common infant cancer. Long-term survival is less than 50%, even following aggressive cytotoxic therapy. Although a monoclonal antibody targeting the cell surface disialoganglioside GD2 has been approved for treating neuroblastoma, other types of immunotherapy, including ADCs, haven’t been studied against this cancer, primarily because there is a lack of known differentially expressed cell-surface molecules coupled with targeted therapeutics.
To identify proteins that might be suitable targets for neuroblastoma immunotherapy, the team compared RNA sequencing data from 126 high-risk primary neuroblastomas, with RNA sequences from samples across 31 normal tissue types. They filtered an initial list of 296 differentially expressed genes to identify those that had the qualities of an optimal candidate immunotherapeutic target. Through this process the team narrowed down their search to the extracellular glycosylphosphatidylinositol (GPI)-anchored signalling co-receptor glypican 2 gene. GPC2 is one of a family of six (GPC1-6) GPI-anchored, extracellular proteoglycan signalling co-receptors that play diverse roles in growth factor signalling and cancer cell growth. Interestingly, the glypican family member glypican 3 (GPC3) has recently been validated as a bona fide immunotherapeutic target in hepatocellular carcinoma, they point out.
When the researchers looked for GPC2 expression in a number of different neuroblastoma tumour datasets they confirmed that high levels of cell surface GPC2 were associated with worse overall survival, and were also evident in the tumours of patients with high-risk neuroblastoma. Direct analysis of tissue samples and cultured cells identified elevated GPC2 in high- and intermediate-risk neuroblastoma primary tumours, patient-derived xenografts (PDXs) derived from high-risk human primary tumours, and the majority of neuroblastoma cell lines evaluated. The researchers then confirmed that GPC2 protein was only present at very low levels, if at all, in the cell surface membranes of a wide range of normal paediatric tissues, and neural- and neural-crest-derived tissues.
To find out whether GPC2 was required for neuroblastoma cell proliferation the team next depleted the protein in neuroblastoma cell lines that normally expressed GPC2 at high levels. This resulted in reduced cell growth and increased apoptosis. In contrast, stably overexpressing GPC2 in otherwise low GPC2-expression neuroblastoma cell lines resulted in increased cell proliferation.
They next analyzed RNA sequencing and gene expression profiling datasets spanning a number of paediatric malignancies, and identified similarly high GPC2 expression in paediatric medulloblastoma and retinoblastoma, as well as in subsets of other childhood cancers. High-level cell-surface GPC2 expression was also confirmed directly in the majority of diagnostic medulloblastoma and retinoblastoma tissues tested.
The team worked with colleagues at the National Cancer Institute to develop an ADC candidate, D3-GPC2-PBD, which targeted the cytotoxic drug pyrrolobenzodiazepine directly to cell surface GPC2. In vitro and in vivo tests showed that the ADC effectively killed GPC2-expressing cell lines, without damaging normal cells, but also led to tumour regression and increased the lifespan of a PDX neuroblastoma mouse model, without causing any discernible toxicity. The study was published in Cancer Cell.
Source: www.genengnews.com/gen-news-highlights, Sept 12, 2017.

Could Zika virus be developed to treat glioblastoma?

Scientists in the U.S. have demonstrated how modified strains of Zika virus can prolong the lifespan of mice with glioma by specifically targeting and killing cancer stem cells that drive tumour progression. Studies by researchers at Washington University School of Medicine in St. Louis, the University of California, San Diego, and the Cleveland Clinic Lerner Research Institute, showed that Zika virus preferentially targets and kills proliferating glioblastoma stem cells (GSCs) in human glioblastoma cell lines, in human brain tumour tissue, and in tumour-bearing mice without affecting healthy neural cells or differentiated glioblastoma cells (DGCs). “Zika very specifically killed brain tumour stem cells with little effect on differentiated tumour cells and adult neural cells”.
The researchers suggest that their studies represent a starting point for the development of safe oncolytic Zika virus strains that could be exploited as part of a two-pronged anticancer treatment approach that combines cytotoxic drugs to kill differentiated tumour cells, with Zika virus therapy to target and destroy the proliferating, treatment-resistant GSCs. The research was published in the Journal of Experimental Medicine.
Source: www.genengnews.com/gen-news-highlights, Sept 5, 2017.

Researchers say bioavailability ‘shortcut’ could become industry standard

Researchers developing a method to determine drug bioavailability say the approach could become a ‘shortcut’ for scientists in drug discovery and development. The method, which can be adopted to any cell type of interest, measures the unbound quantity of the drugs in the cells, taking into account how the drugs partly disappear when it binds to various cell components where it cannot exert its intended effect. This disappearing proportion of the drug varies from one molecule to another and has been hard to predict, but can now be easily determined with the researchers small-scale method. The research was published in Proceedings of the National Academy of Sciences.
Source: www.genengnews.com/gen-news-highlights, Sept 5, 2016.

Cell therapy can be fast and easy: just add mRNA nanocarriers

According to scientists at the Fred Hutchinson Cancer Research Center, nanoparticles can be used to deliver transient gene changes to targeted cells, making therapies for a variety of diseases including cancer, diabetes, and HIV/AIDS faster and cheaper to develop, and more customizable.
First it was demonstrated that nanocarriers delivering mRNA encoding a genome-editing agent can efficiently knock-out selected genes in anti-cancer. Second a long-lived phenotype, exhibiting improved antitumor activities into T-cells, was imprinted by transfecting them with mRNAs that encode a key transcription factor of memory formation. Third, it was shown how mRNA nanocarriers can program hematopoietic stem cells with improved self-renewal properties.
Essentially, nanoparticles carried a gene-editing tool to T cells of the immune system that snipped out their natural T-cell receptors, and then was paired with genes encoding a chimeric antigen receptor, or CAR, a synthetic molecule designed to attack cancer. Next, nanoparticles were targeted to blood stem cells and equipped with mRNA that enabled the stem cells to multiply and replace blood cancer cells with healthy cells when used in bone marrow transplants.
Finally, nanoparticles were targeted to CAR T cells and equipped with Foxo1 mRNA, which signals the anticancer T cells to develop into a type of “memory” cell that is more aggressive and destroys tumour cells more effectively and maintains antitumor activity longer. The work has been published in Nature Communications.
Source: www.genengnews.com/gen-news-highlights, Aug 30, 2017.

Cells held three times as long in ‘delayed crosslinking’ microgel tech

Dutch scientists have developed a microgel chip that is capable of holding single cells for analysis and research for far longer than currently available 3D culturing technologies. Current microgel chips can only hold cells for a few days and the cells can escape from commercially available microgels if they are not in the correct position at the centre of the gel. To address these shortcomings researchers modified the composition of the hydrogels used to make the microgel and the process by which it is formed. The researchers discovered that rather than crosslinking the individual polymers while the droplet is still forming, the trick is to trigger this process just afterwards, a technique referred to as “delayed gelation”. This allows the cell to reposition to the centre of the hydrogel precursor droplet, before the droplets are transformed into stable microgels. According to the publication the technology enables scientists to culture and retain individual cells under controlled conditions for at least 28 days, with a 90% survival rate. The work was published in the nanotech-focused journal Small.
Source: http://www.outsourcing-pharma.com, June 22, 2017.

Stem Cell News

Manipulating water content in stem cells influences differentiation fate

Scientists in the U.S. have shown that intentionally altering the amount of water in cells to change their volume impacts directly on cell stiffness, which can influence the direction of stem cell differentiation, a finding that could have implications for the future use of stem cells in a therapeutic context. The studies, led by Ming Guo, Ph.D., at the Massachusetts Institute of Technology (MIT), and David Weitz, Ph.D., at Harvard University, demonstrated that removing water from mouse mesenchymal stem cells (MSCs) caused the cells to condense, which changed cell stiffness and prompted the cells to differentiate into one cell type, while adding water to the cells caused them to swell and differentiate into an alternate cell type, irrespective of microenvironmental cues.
The findings could help scientists better understand cellular function, potentially in relation to disease, by providing “an entry point to think about the impact of physical properties and water content in cells,” The research has been published in the Proceedings of the National Academy of Sciences (PNAS).
Source: www.genengnews.com/gen-news-highlights, Sept 27, 2017.

CDI to market iPSC-derived tissue with Nanion instruments

Cellular Dynamics International (CDI), a Fujifilm company, said it will co-market its suite of induced pluripotent stem cell (iPSC)-derived human tissue with Nanion Technologies’ instrument platforms for ion channel drug discovery and screening, through an agreement whose value was not disclosed. Under the agreement participating research customers will receive Nanion’s CardioExcyte® 96 instrument in conjunction with a supply and participation agreement with CDI for a one-year period.
Source: http://www.outsourcing-pharma.com, Sept 21, 2017.

Stem cell injections rejuvenate aging rat hearts

Researchers at the Cedars-Sinai Heart Institute have shown that injecting cardiac stem cells from young rats into the hearts of old rats can help to reverse the natural cardiac aging process.
Dr. Marbán’s team completed the world’s first human cardiac stem cell infusion back in 2009 as part of a Phase I trial in heart attack patients. In the latest animal studies, the researchers tested whether cardiosphere-derived cells (CDCs) from newborn rats could reverse or hold back aging in the hearts of old animals. CDCs are cardiac progenitor cells that can differentiate into the three primary cardiac cell types cardiomyocytes, endothelial cells and smooth muscle cells.
The researchers injected CDCs directly into the hearts of aged rats that had undergone echocardiogram testing, treadmill stress tests, and blood analyses at baseline. Equivalent tests were then carried out a month after the stem cell injections. The results of these and other analyses showed that the CDC treatment led to improved heart function and structure and boosted exercise capacity by about 20%.
CDC injections also led to a range of non-cardiac-specific effects, such as speeding hair growth, reducing systemic levels of inflammatory biomarkers, improving renal function, and helping to prevent weight loss secondary to cachexia or sarcopenia. Notably, stem cell therapy was associated with lengthening in heart cell telomeres, resulting from activation of the enzyme telomerase. Promisingly, rejuvenating effects were also seen when human heart cells from older donors were co-cultured with young CDCs.
Genetic analysis identified treatment-related changes in the expression of 37% of the 168 genes implicated in tissue aging and cellular senescence pathways, primarily those involved in cell cycle control and immune response. “Most of the CDC-related changes (85.5%) directionally recapitulated the gene expression patterns of young animals. The study was published in the European Heart Journal.
Source: www.genengnews.com/gen-news-highlights, Aug 14, 2017.

CRISPR corrects disease mutation in human embryos

A landmark study, published in Nature described that CRISPR was used to repair a germline mutation in human embryos created through in vitro fertilization. The study was a collaboration between the Salk Institute, Oregon Health and Science University (OHSU), and Korea’s Institute for Basic Science. The scientists behind the work concluded that the technique to replace a mutation in the gene MYBP3C could help prevent hypertrophic myocardiopathy (HCM), a disease that eventually leads to heart failure. This study is the first in the US to demonstrate that modifying single-gene defects using the gene-editing technology CRISPR has the potential to be safe and accurate enough to use in human embryos.
The researchers set out to determine if they could prevent the germline transmission of a genetic mutation causing HCM. In samples with afflicted sperm, which were confirmed via pre-implantation genetic diagnosis (PGD) to carry the mutation that causes HCM scientists used CRISPR to cleave out damaged sections of DNA. Then, they replaced the mutation with new genetic information, trying a few different methods to incorporate the corrected gene. Once edited, 42 out of 58 embryos lacked the HCM mutation. In an unexpected twist, the investigators discovered that once the paternal gene was excised, the genetic material originating from the mother (i.e., the homologous wild-type maternal gene) was more easily substituted than the synthetic DNA the scientists attempted to introduce.
To reduce mosaicism, which is characterized by a population of cells that originate from one egg but are genetically distinct, researchers injected sperm cells and CRISPR components directly into oocytes early in their cell-cycle phase, only 18 hours post-fertilization. The authors assumed this would be the best time for genome editing to occur, as the sperm at that time only has a single mutant copy. In addition, injecting genetic material early, before DNA replication occurred, meant that the CRISPR components stayed in the cytoplasm longer. As a result of prolonged cytoplasm residency, the CRISPR components degraded quickly, before further replication of mutant alleles could occur.
Employing CRISPR in embryos, rather than in stem cells, yielded better results. The overall targeting efficiency in human embryos was found to be 72.2% (13/18), which was higher than the rate in induced pluripotent stem cells exposed to the same construct (27.9%, or 17/61). The higher targeting efficiency “suggests that human embryos employ different DNA repair mechanisms than do somatic or pluripotent cells, probably reflecting evolutionary requirements for stringent control over genome fidelity in the germline.
Because off-target cutting is also a concern with CRISPR/Cas9, researchers evaluated all of the potential off-target sites via a whole-genome sequencing analysis. They determined that their technique did not produce “any detectable” off-target mutations in the blastomeres. Because Cas9 was used in purified protein form, and was not contained in a plasmid, off-site targeting was further reduced.
Source: www.genengnews.com/gen-news-highlights, Aug 3, 2017.

Stem cells guided by electric fields may offer new therapies for brain diseases

Scientists at the University of California, Davis School of Medicine’s Institute for Regenerative Cures report that electric fields can be used to guide neural stem cells transplanted into the brain toward a specific location. Their study published in Stem Cell Reports, opens the door for potentially guiding stem cells to repair brain damage.
Dr. Zhao, and his colleague, Junfeng Feng, M.D., a neurosurgeon at Ren Ji Hospital, Shanghai Jiao Tong University, and Shanghai Institute of Head Trauma, developed a model of stem cell transplants in rats. They placed human neural stem cells in the rostral migration stream, which is a pathway in the rat brain that carries cells toward the olfactory bulb. Cells move along this pathway, partly carried by the flow of cerebrospinal fluid and partly guided by chemical signals.
By applying an electric field within the rat’s brain, the scientists found that they could get the transplanted stem cells to swim upstream against the fluid flow and natural cues and head for other locations within the brain. The transplanted stem cells were still in their new locations weeks or months after treatment.
Source: http://www.outsourcing-pharma.com, July 12, 2017.

Truly functional arterial cells reportedly created for the first time

Scientists at the Morgridge Institute for Research and the University of Wisconsin-Madison say they have produced, for the first time, functional arterial cells at both the quality and scale to be relevant for disease modelling and clinical application.
The researchers working in the lab of James Thomson, VMD, Ph.D., reported their study in Proceedings of the National Academy of Sciences and describe methods for generating and characterizing arterial endothelial cells that exhibit many of the specific functions required by the body. Furthermore, these cells contributed both to new artery formation and improved survival rate in mice used as a model for myocardial infarction, according to the research team. Mice treated with this cell line had an 83% survival rate, compared to 33% for controls.
The team applied two pioneering technologies to the project. First, they used single-cell RNA sequencing to identify the signalling pathways critical for arterial endothelial cell differentiation. They found about 40 genes of optimal relevance. Second, they used CRISPR/Cas9 gene-editing technology that allowed them to create reporter cell lines to monitor arterial differentiation in real time.
The research group developed a protocol around five key growth factors that make the strongest contributions to arterial cell development. They also identified some very common growth factors used in stem cell science, such as insulin, that surprisingly inhibit arterial endothelial cell differentiation.
In many cases with vascular disease, patients lack suitable tissue from their own bodies for use in bypass surgeries. And growing arteries from an individual patient’s stem cells would be cost prohibitive and take too long to be clinically useful. The challenge will be not only to produce the arteries, but find ways to insure they are compatible and not rejected by patients.
Source: http://www.outsourcing-pharma.com, July 11, 2017.

Agenda

1st European Alliance for Personalised Medicine Congress
27-30 Nov 2017, Belfast, Northern Ireland
More info: http://eapmbelfast2017.com

18th European Congress On Biotechnology
1 – 4 July 2018, Geneva, Switzerland
More info: http://www.ecb2018.com

©2017 ACTIP

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