volume 34 issue 12 july 2017 - marketing …july 2017 page 169 * including recombinant factor...

Notice: International Blood/Plasma News© is Protected by Copyright Law. Reproduction or Photocopy of Any Part Without The Publisher‘s Permission is Prohibited by Law.

ISSN 0742-7719

EDITOR: KEITH BERMAN PUBLISHER: PATRICK ROBERT

Published by: The Marketing Research Bureau, Inc. 284 Racebrook Rd. Orange, CT 06477

VOLUME 34 ISSUE 12 JULY 2017

BUSINESS BRIEFS 166

BLOOD & BIOTECHNOLOGY 170

RESEARCH & DEVELOPMENT 174

PLASMA FRACTIONATION NOTES 175 PRODUCT SAFETY UPDATE 175

PEOPLE 176

RECENT U.S. PATENTS 177 MEETINGS / SUBSCRIPTION FORM 180

____________________COMPANIES IN THIS ISSUE__________________

ADMA BIOLOGICSALNYLAM PHARMACEUTICALSAPTEVO BIOTHERAPEUTICSBAXALTA GmbHBAYER HEALTHCAREBioMérieuxBIOTESTCANTOR FITZGERALD CANADACATALYST BIOSCIENCESCELLULAR DYNAMICS CHUGAI PHARMACEUTICALCSL BEHRINGCSL BEHRING GmbHGENENTECHGigaGenGRIFOLSGRIFOLS INNOVATION (GIANT)IDFJANSSEN PHARMACEUTICALSJEFFREY MODELL FOUNDATION

KEDRION S.p.ALFBMedImmuneNEW YORK BLOOD CENTEROCATA THERAPEUTICSPFIZERPlatelet BioGenesisPOMONA RICERCA S.r.L.QIMING U.S. HEALTHCARE FUNDROCHESALPSANGAMO THERAPEUTICSSANOFI GENZYMESHIRESHIRE INTERNATIONAL GmbHSPARK THERAPEUTICSTALECRIS BIOTHERAPEUTICSTHERAPURE BIOPHARMAuniQure

international blood/plasma news

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BUSINESS BRIEFS

* Platelet BioGenesis, a Boston-based spinout from Harvard University laboratories, announced that it has raised $10 million in Series A fi nancing to advance development of a proprietary process to produce human platelets from human induced pluripotent stem cells (hiPSCs). This fi nancing round was led by QIMING U.S. HEALTHCARE FUND, a U.S. venture capital fund headquartered in Seattle. This investment will enable the fl edgling company to “repeat investiga-tion new drug-enabling studies and establish a scalable industrial process to manufacture clinical grade platelets,” said co-founder and CEO Jonathan Thon, PhD. “This technology truly has the potential to reshape the blood industry and positively impact millions of patients,” added Qiming managing partner Mark McDade.

In collaboration with OCATA THERAPEUTICS, Platelet BioGenesis demonstrated in 2014 the feasibility of creating and growing megakaryocytes from hiPSCs using scalable serum- and feeder-free cell culture protocols, and triggering platelet production by these megakaryocytes by creating an “integrated microfl uidic platform” designed to model bone marrow architecture ex vivo. The company says it can now “reproduce physiological platelet production and increase the overall rate and extent of platelet release.”

Platelet BioGenesis believes human platelets manufactured directly from stem cells can address a number of problems it sees with sourcing platelets from human donors, including high cost, re-sidual risk of bacterial and viral contamination, and platelet shortages due to dependence on human volunteer donors. These mass-produced HLA-matched platelets additionally offer the potential for longer shelf life and improved in vivo survival and reduced allosensitization risk, according to the company.

* SHIRE has issued a letter alerting German prescribers of Cinryze, its human plasma-derived C1 esterase inhibitor, about a potential near-term shortage of the product, and asking physi-cians to institute certain prescribing changes to try to avert or minimize a shortage. “In view of the growing prescription of Cinryze, the requirements for this product may soon exceed the current production capacity. In order to meet the needs for Cinryze in the coming months, Shire requests the following:

• For the treatment of acute angioedema attacks and for pre-operative surgery, look for alter-native therapies.

• For routine prophylaxis of acute angioedema attacks, (a) patients who are cur-rently treated with Cinryze (i.e. patients who cannot tolerate oral prophylaxis, or for whom it does not bring suffi cient protection, or patients for whom an appropriate oral acute treatment does not bring adequate relief) can continue to obtain Cinryze since no other approved long-term prophylaxis therapy is available [in Germany]; (b) no new patients should be prescribed routine prophylaxis.

If Cinryze becomes temporarily unavailable, Shire will provide separate information.” This letter was written in consultation with European Medicines Agency (EMA) and the Paul Ehrlich Institute (PEI), where it has been published. Further details can be found on the PEI website: www.pei.de.


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* The U.S. Federal Trade Commission (FTC) announced that it is currently accepting public comments relating to an application by GRIFOLS to amend the terms of a divestiture ordered by the agency in 2011 to settle allegations that Grifols’ $3.4 billion acquisition of TALECRIS BIOTHERAPEUTICS was anti-competitive. Grifols is proposing to extend the duration of an FTC-ordered contract manufacturing agreement with Kedrion that will enable Kedrion to continue to compete in the U.S. plasma products market with its Kedrion-branded products.

As a condition for Grifols to complete its acquisition of Talecris, the FTC ordered the companies to divest a Talecris plasma fractionation facility in Melville, New York, as well as plasma collec-tion centers owned by Grifols in Alabama and North Carolina, to KEDRION S.p.A.

As Kedrion is still working to secure U.S. FDA approval for its own fractionation and therapeutic plasma protein purifi cation capabilities, the company needs to continue to send plasma to Grifols for fractionation and purifi cation into fi nished products.

* Continuing a trend identifi ed in earlier reports released in 2011 and 2013, newly published fi ndings from the 2015 National Blood Collection and Utilization Survey reveals continued decline in blood collections and transfusions in the U.S. between 2013 and 2015. This survey conducted by the U.S. Centers for Disease Control and Prevention (CDC) collected responses from 72 non-hospital-based community blood centers, 102 hospital-based blood centers and 2,138 hospital facilities.

Distribution and transfusion of red blood cells (RBCs) declined by 11.6% and 13.9%, respectively between 2013 and 2015. Transfused units of RBCs in surgery (including transplant sur-gery) fell by 41.5% over this two-year period, according to survey fi ndings, while RBC usage in inpatient medicine (including hematology-oncology) declined by 5.0% and usage in critical care increased by 10.9%. Platelet distributions (combined apheresis and whole blood-derived) declined by 0.5% over this period. Apheresis platelet distribution declined 3.6%, while whole blood-derived platelet distribution, while a small proportion of the total, appeared to increase signifi cantly (+55.0%).

Platelet transfusions dropped 13.1%, with a 15.4% drop in apheresis platelet transfusions partly counterbalanced by increased whole blood-derived platelet transfusions (+33.7%). Distribution of fresh frozen plasma (FFP) fell by 14.4% between 2013 and 2015, accompanied by a precipitous 24.8% drop in plasma transfusions over that two-year period.

Prices paid by hospitals for blood components decreased signifi cantly: median price for leukore-duced RBC units declined by $10 from $221 to $211, while the median price for apheresis plate-lets fell by an average of $16 per unit, from $540 to $524. The median price of FFP was $54 in 2015, down from $59 in 2013. Median prices paid by hospitals performing the fewest (100-999) inpatient surgeries were consistently higher than prices paid by hospitals performing the largest number (>8000) inpatient surgeries.

While donor deferrals were down slightly from 15.5% to 14.3%, an estimated two million fewer people presented to donate blood in 2015 than 2013. Complete fi ndings are published in the June 2017 Supplement of the journal Transfusion.


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* Below are selected highlights from BIOTEST’S 2016 annual report:

• Earnings before interest and taxes (EBIT) in 2016 rose to €64 million ($73 million) from €37 million in 2015. Year over year research and development expenditures were reduced by 38% to €48.7 million and marketing and distribution costs were reduced by 11% to €52.7 million.

• Biotest’s 2016 global sales amounted to €553 million ($630 million), a 3.5% increase over the previous year. This included €346.8 million of “Therapies” sales and €199.3 million of “Plasma Services” revenues. Eighty percent of sales (€444.8 million) were generated in more than 80 countries outside of Germany: 28.5% in the rest of Europe, 21.0% in the U.S., 24.0% in Central and South America, 21.8% in the Middle East and Africa, and 8.9% in Asia and Pacifi c Rim countries. Biotest currently has 2,527 employees.

• To reduce risks and costs of future product development, Biotest plans to pursue further R&D activities with a partner once current studies in the area of monoclonal antibodies are completed.

• The sale of Biotest U.S. therapy and toll manufacturing businesses to ADMA BIOLOG-ICS in late 2016 (see the January 2017 issue of International Blood/Plasma News) was part of a strategy to limit the group’s risks, more widely utilize expertise through partner-ships, and create additional options for further strategic development.

• As part of its initiative to expand plasma collections, Biotest opened two new centers in Hungary, and four new centers in the U.S., bringing the total to 35 plasma collection centers. Biotest operates 13 centers in Europe and 22 centers in the U.S. By the start of 2019, the company is scheduled to acquire two additional U.S. centers from ADMA.

• A “typical” Biotest plasma center has 25 to 40 employees, collects 20,000 to 30,000 liters of plasma per year, has about 30 donation chairs, is open about 70 hours per week, and processes 700 to 800 donors per week, and have certifi cations from the International Qual-ity Plasma Program (IQPP) of the Plasma Proteins Therapeutics Association (PPTA).

• Biotest’s “IgG Next Generation” product is planned to be the successor of its Intratect intravenous immunoglobulin (IVIG) product. Phase III studies have been initiated to evaluate this new IVIG in patients with primary immunodefi ciency disorders (PI) and with immune thrombocytopenia purpura (ITP); an additional Phase III study in patients with chronic infl ammatory demyelinating polyneuropathy (CIDP) is planned to start this year. “IgG Next Generation,” which the company says has much higher yields from plasma than its Intratect 5% and 10% IVIG products, will be commercialized in Europe, the U.S. and other countries.

• A new polyclonal antibody product IgM concentrate, intended primarily for intensive care patients with severe community-acquired pneumonia (SCAP), is an important component of Biotest’s product portfolio expansion. A phase III clinical study is expected to begin in Europe and the U.S. in late 2017.


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* Including recombinant factor analogs of therapeutic plasma proteins, the 2016 U.S. plasma proteins market totaled just over $13.8 billion, up 11.9% from 2015, according to The Market-ing Research Bureau’s newly released report titled The Plasma Proteins Market in the U.S. - 2016. Excluding recombinant products, the 2016 U.S. plasma proteins market reached $9.5 billion, an 11.1% increase over 2015. Sales of recombinant products accounted for 31.3% of the combined plasma-derived and recombinant market, marginally ahead of its share in 2015 and indicative of increasing penetration of newer recombinant therapies.

Sales of polyvalent immunoglobulin products grew by 10.5% between 2015 and 2016, and accounted for nearly 57% of all revenues generated by therapeutic plasma proteins in the U.S. last year. In addi-tion there was double-digit year-over-year growth in sales of C-1 esterase inhibitor products, alpha-1 proteinase inhibitor products and multiple product categories intended for the treatment of hemophilia A and B. Below are 2016 U.S. sales of the fi ve highest-revenue plasma-based products:

Product $ Million

Polyvalent and subcutaneous IgG 5,419.8

C-1 esterase inhibitor 906.0

Alpha-1 antitrypsin 773.0

Albumin 632.8

Plasma-derived factor VIII 266.3

All other products 1,513.3

Total 9,511.2

SHIRE was the market leader in 2016 with more than 31% of the U.S. plasma proteins market, closely followed by CSL BEHRING and GRIFOLS. Including recombinant products, Shire again led all competitors with a 35% market share, driven by about $1.6 billion in sales of its three recombinant factor VIII products.

Just over 73 metric tons of polyvalent intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin (SCIG) were distributed in 2016, equating with 226 kilograms per million in-habitants. More than 178 metric tons of albumin were distributed, equating with more than 550 kilograms per million inhabitants. Approximately 3.1 billon factor plasma-based, recombinant and extended half-life recombinant VIII units were sold for treatment of hemophilia A, representing about 9.1 units per capita.

Several new standard and extended half-life recombinant coagulation factors were launched in 2016, fueling the rapid ongoing evolution of the hemophilia A, hemophilia B and von Willebrand therapeutics markets. At the same time, positive results reported for novel non-factor therapies such as emicizumab (ROCHE) and several gene therapy trials sponsored by SPARK THERA-PEUTICS, SANGAMO THERAPEUTICS, uniQure and others point to the possibility of profound change in the future management of hemophilia A and B.

In 2015, approximately 33 million liters of plasma (including both source and recovered plasma) were collected for fractionation in the U.S., representing 6.4% increase in collections from 2015.


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* The JEFFREY MODELL FOUNDATION (JMF) announced that, in partnership with CSL BEHRING, it will open the North African Network for Primary Immunodefi ciencies. As the fi rst enterprise dedicated to helping persons with primary immunodefi ciency (PI) in Africa, this new network will offer advanced diagnostic evaluation to patients with a suspected PI. “In Africa, it is estimated that the diagnosis rate of PI…is only about 0.3%. This is why we remain committed to our promise of improving patient care…and to partnering with JMF and ASID to increase the awareness, diagnosis and treatment of PI in countries throughout the world,” said Markus Staempfl i, CSL Behring’s vice president & general manager, Intercontinental Commercial Operations.

* GRIFOLS announced that it has reached an agreement to acquire a 43.96% stake in GigaGen, a development-stage biopharmaceutical whose technological platform enables identifi cation and analysis of the genetic diversity of B cells to produce prospective polyclonal recombinant antibody therapeutics. In addition to new therapeutics development projects underway with several pharmaceutical companies, GigaGen’s in-house research projects include what would be the world’s fi rst recombinant intravenous immunoglobulin (IVIG), as well as a diverse portfolio of immune-oncology therapies. Grifols acquired its stake in GigaGen for $35 million (€29.7 million) in a cash transaction carried out by GRIFOLS INNOVATION AND NEW TECHNOLOGIES LIMITED (GIANT), which oversees all of the company’s external R & D investments.

In addition, Grifols and GigaGen have entered into a research and collaboration agreement whereby, in exchange of a collaboration fee of $15 million in the aggregate, GigaGen will commit to carry out research activities to develop recombinant polyclonal immunoglobulin therapies derived from human B cells.

BLOOD & BIOTECHNOLOGY

* SHIRE announced the submission of an Investigational New Drug (IND) application to the U.S. FDA for SHP654, also designated as BAX 888, an investigational factor VIII gene therapy for the treatment of hemophilia A. SHP654 is intended to protect hemophilia A patients against bleeds through the delivery of a long-term, constant level of factor expression.

Shire’s gene therapy program for hemophilia A uses a recombinant adeno-associated virus serotype 8 (rAAV8) vector to deliver a codon-optimized, B-domain deleted factor VIII gene (BDD-FVIII) specifi cally to the patient’s liver, where it can be expressed as functional factor VIII. This factor VIII expression is further controlled by incorporating a liver-specifi c transthyretin (TTR) promoter/enhancer.

The IND fi ling for SHP654 was based on results of pre-clinical studies documenting its potential utility. A total of four oral and poster presentations at the 26th Biennial Congress of the Interna-tional Society on Thrombosis and Haemostasis (ISTH) held this month in Berlin characterized the development, safety profi le, dose response and long-term expression of SHP654 gene therapy in a mouse model.


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* Research and development partners ALNYLAM PHARMACEUTICALS and SANOFI GENZYME announced the initiation of three separate Phase 3 clinical studies to evaluate fi tusiran, an investigational RNA interference (RNAi) drug designed to lower antithrombin levels as a means to boost thrombin levels, restore hemostasis and prevent bleeding in per-sons with hemophilia A or B. Fitusiran utilizes Alnylam’s ESC-GalNAc conjugate technology to boost the drug’s potency and durability, enabling once-monthly subcutaneous administration.

The three “ATLAS” trials include the following:

• ATLAS-INH: A nine-month, open-label, randomized, active-controlled trial that will enroll approximately 50 patients with hemophilia A or B with inhibitors receiving prior on-demand factor or bypassing agent therapy; the primary endpoint is the annualized bleeding rate (ABR). Among key secondary endpoints are the annualized spontaneous bleeding rate (AsBR) and annualized joint bleeding rate.

• ATLAS-A/B: A nine-month, open-label, randomized, active-controlled trial that will enroll 50 patients with hemophilia A or B without inhibitors receiving prior on-demand therapy. Primary and key secondary endpoints are the same as for the ATLAS-INH study.

• ATLAS-PPX: An open-label, one-way crossover study designed to enroll approximately 100 patients with hemophilia A or B with or without inhibitors, who are receiving factor or bypassing agent prophylaxis as the prior standard of care. Patients will receive standard of care prophylaxis for six months, then transition to fi tusiran treatment for seven months. The study’s primary endpoint is the ABR in the fi tusiran period and in the factor/bypassing agent prophylaxis period. Key secondary endpoints are similar to those for ATLAS-INH and ATLAS-A/B trials.

Alnylam and Sanofi Genzyme expect top-line data from the “ATLAS” trials in mid-to-late 2019. In late 2016, Sanofi Genzyme elected to expand its partnership with Alnylam to co-develop and co-commercialize fi tusiran.

* South San Francisco-based CATALYST BIOSCIENCES announced that it has initiated a Phase 1/2 open-label, proof-of-concept study to evaluate CB 2679d/ISU304, an investigational subcutaneous factor IX variant in development for the prophylactic treatment of hemophilia B. The trial, being conducted by its development collaborator ISU Abxis at three centers in South Korea, is expected to enroll up to 17 individuals with severe hemophilia B and to have top-line data available by year-end 2017.

Study objectives include studying the pharmacokinetics, subcutaneous bioavailability and steady-state factor IX levels that result from daily dosing with BC2679d/ISU304. The clinical trial will include single intravenous and subcutaneous dosing cohorts, followed by daily subcutaneous injections of CB 2679d/ISU304 for six days. To date ISU Abxis has completed dosing of the fi rst of up to fi ve patient cohorts.

(continued on page 172)


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“We believe that individuals with hemophilia B would welcome a subcutaneous prophylaxis therapy that eliminates intravenous infusions required to manage or control spontaneous bleed-ing,” said Catalyst president and CEO Massim Usman, PhD. The clinical-stage biopharmaceutical company also announced that CB 2679d/ISU304 has been granted orphan medicinal product designation by the European Commission.

* Once-weekly subcutaneous prophylactic administration of an investigational bispecifi c hu-manized monoclonal antibody, emicizumab (ACE910), was associated with a signifi cantly lower rate of bleeding events than no prophylaxis in a Phase 3 study (HAVEN 1) involving 109 male participants with hemophilia A and inhibitors, according to a report in the July 10 online issue of the New England Journal of Medicine. Emicizumab bridges activated factor IX and factor X to restore the function of activated factor VIII, which is defi cient in persons in he-mophilia A.

The annualized bleeding rate (ABR) was 2.9 events (95% confi dence interval [CI], 1.7 to 5.0) among 35 participants randomly assigned to emicizumab prophylaxis (group A) versus 23.3 events (95% CI, 12.3 to 43.9) among 18 group B participants assigned to no prophylaxis. This represented a signifi cant difference of 87% favoring emicizumab prophylaxis (P < 0.001). A to-tal of 22 participants in group A (63%) experienced zero bleeding events, as compared with one participant (6%) in group B.

Among 24 participants in group C who had participated in a non-interventional study, emicizumab prophylaxis resulted in a bleeding rate 79% lower than the rate with previous prophylaxis with a bypassing agent, primarily recombinant factor VIIa (NovoSeven, NOVO NORDISK) (P < 0.001). No antibodies against emicizumab were detected in any study participant. Co-developers ROCHE, GENENTECH and CHUGAI PHARMACEUTICAL are conducting additional studies to evaluate the pharmacokinetics, safety and effi cacy of emicizumab in children with hemophilia A and inhibitors, and the feasibility of reduced frequency of prophylactic injections.

Roche reports that results from the HAVEN 1 and pediatric HAVEN 2 studies have been submitted to the U.S. FDA and the European Medicines Agency (EMA) for approval con-sideration.

* Days after the July 10 publication of its HAVEN 1 study fi ndings, CHUGAI PHARMACEUTI-CAL announced that it has fi led for approval of a new drug application for its factor IXa/X humanized bispecifi c monoclonal antibody emicizumab (ACE910) with the Japanese Ministry of Health, Labour and Welfare (MHLW) for the planned indication of routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with congenital factor VIII defi ciency (hemophilia A) with factor VIII inhibitors.

This fi ling is based on results of the HAVEN 1 study in adults and adolescents aged 12 years and older, and an interim analysis of the HAVEN 2 pediatric study in children under age 12 years. Emicizumab obtained an Orphan Drug Designation from the MHLW for the prevention and re-duction of bleeding episodes in patients with congenital factor VIII defi ciency with inhibitors in August 2016.


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* Separately, SHIRE’S Germany subsidiary, SHIRE INTERNATIONAL GmbH, announced that it has obtained a preliminary injunction from a court in Hamburg, Germany against ROCHE, to address what Shire claims are “incomplete and misleading statements that may impact important issues of patient safety regarding the investigational treatment emici-zumab.”

Under the injunction, Shire seeks to prevent further dissemination of “the inaccurate and mislead-ing characterization of the serious adverse events that occurred in the HAVEN 1 Phase 3 trial of emicizumab, specifi cally the assertion that ‘all events occurred when repeated high aPCC (acti-vated Prothrombin Complex Concentrate) doses were used concurrently with emicizumab.” The injunction also seeks to correct promotion of the primary data results relative to “treated bleeds” (a secondary endpoint) as compared to the primary endpoint of “number of bleeds over time” established at the outset of the trial.

“Based on Roche’s [publicly] available information to date (as of 7 July 2017), physicians, patients and caregivers may be misinformed about the appropriate management of breakthrough bleeds uncontrolled by emicizumab. In addition, through these actions, Shire believes Roche has unlaw-fully disparaged Shire’s proven bypassing agent, FEIBA (Anti-Inhibitor Coagulant Complex). Shire has issued multiple unheeded requests to Roche in an effort to resolve these concerns in an appropriate manner. As a result, Sire made the decision to seek court intervention,” the company said in a public statement.

* The European Medicines Agency (EMA) has granted orphan medicinal product designation (OMPD) to SB-525, a clinical-stage hemophilia A gene therapy platform in development by SANGAMO THERAPEUTICS and PFIZER. The EMA’s OMPD is granted to medicines intended for the treatment, prevention or diagnosis of life-threatening or chronically debilitating conditions that are rare and affect fewer than fi ve in 10,000 persons in the European Union (EU). The OMPD provides incentives to advance the development and commercialization of orphan medicines, including access to the EU centralized authorization procedure and potential for market exclusivity for a period of up to 10 years.

In May the two companies announced an exclusive global collaboration and license agreement for the development and commercialization of gene therapy programs for hemophilia A, includ-ing SB-525 (see the May 2017 issue of International Blood/Plasma News). A Phase 1/2 clinical trial is currently evaluating SB-525 in adults with hemophilia A. Initial fi ndings from this study are expected in late 2017 or early 2018.

SB-525 uses a recombinant adeno-associated virus (rAAV) to deliver a human factor VIII cDNA construct and proprietary, synthetic liver-specifi c promoter to the nucleus of liver cells with a single infusion. Clinical testing is evaluating a single-treatment strategy intended to provide continuous, therapeutic expression of factor VIII protein.

Last month the U.S. FDA granted SB-525 a Fast Track designation, which is designed to facilitate the development and expedite the review of drugs and biologics that treat serious conditions and fi ll unmet needs. SB-525 has also received both a U.S. FDA Orphan Drug designation and FDA clearance to be evaluated in clinical trials.


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RESEARCH AND DEVELOPMENT

* The U.S. FDA has accepted for review CSL BEHRING’S supplemental Biologics License Application (BLA) for Hizentra (Immune globulin subcutaneous [Human] 20% liquid) for the treatment of chronic infl ammatory demyelinating polyneuropathy (CID)) as maintenance therapy to prevent relapse of neuromuscular disability and impairment. The application was based on data from the PATH (Polyneuropathy And Treatment with Hizentra) trial, described by CSL Behring as the largest-ever randomized clinical trial assessing an investigational treatment for CIDP.

Completed in March, the PATH trial was designed to demonstrate the effi cacy, safety and toler-ability of two different subcutaneous doses of Hizentra, compared to placebo, in the maintenance treatment of CIDP patients previously treated with intravenous immunoglobulin (IVIG). Hizentra was self-administered by patients and care givers throughout the study. Subjects were allowed to dose volumes up to 50 mL per infusion site, and infusion rates of up to 35 mL per hour, to facilitate “greater fl exibility and autonomy to infuse when and where they choose.” A long-term open-label extension study is ongoing and expected to be completed later this year.

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PLASMA FRACTIONATION NOTES

* In its 2016 annual report, BIOTEST reports that its Biotest Next Level (BNL) project aims to (1) double its fractionation capacity from 1.3 million liters to 2.7 million liters by 2020 with a €250 million ($285 million) investment at its Dreieich fractionation facility, creating 300 new positions, (2) expand its product portfolio from three to fi ve product lines, and (3) increase the production yields. This project includes the development of an “IgG Next Generation,” an IgM concentrate and fi brinogen.

Interior construction of the BNL production building is currently progressing, and most equip-ment has been installed. Ahead is implementation of production and validation to prepare for manufacturing and sale of new plasma products beginning in 2019/2020.

* In response to a request by plasma fractionators for permission to use plasmapheresis to generate source plasma to fulfi ll the domestic need for therapeutic plasma derivatives, the Governing Body of India’s National Blood Transfusion Council (NBTC) issued the following stance in a memorandum released last month:

“Recovered plasma would continue to remain the main source of raw material for plasma 1. fractionation.”

While plasmapheresis is required in 2. India, “it should not be encouraged as ‘Standalone plasma collection centers’ but ‘in collaboration with blood banks with blood component separation units or apheresis.’ Piloting could be done with Govt or Pvt Sectors in this regard.”

“Blood donation is a voluntary activity. Plasma donation shall be promoted only through 3. non-remunerated voluntary blood donors. No modality for fi nancial compensation/rec-ognition beyond what is acceptable by the NBTC in the form of badges/tokens etc. shall be admissible.”

This request on the part of industry had been previously deliberated in a multi-stakeholder National Consultation Meeting held under chairpersonship of the Directorate General of Health Services (DGHS).

PRODUCT SAFETY UPDATE

* In conjunction with leukoreduction by fi ltration, ribofl avin and UV light treatment resulted in complete reduction (100%) of Trypanosoma cruzi, the protozoan responsible for Chagas disease, in artifi cially contaminated whole blood units, according to Spanish researchers report-ing in the June 2017 issue of Transfusion. The level of pathogen reduction was quantifi ed by both a real-time polymerase chain reaction (qPCR) and a real-time reverse transcription–polymerase chain reaction (RT-qPCR). “Both strategies could complement other blood bank measures already implemented to prevent the transmission of T. cruzi via blood transfusion,” the study authors concluded.


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* Implementation of a bacterial screening protocol for all platelet components by the UK’s Na-tional Health Service Blood and Transplant (NHSBT) sharply reduced the rate of transfusion-related bacterial transmissions over a reporting period from February 2011 to September 2015, compared to a similar time period before implementation. A total of 1,239,029 platelet components – roughly 78% of which were apheresis units and 22% were pooled buffy coat units – were screened using the bioMérieux BacT//ALERT 3D Automated Microbiology Detection System, which involved sampling and inoculation of 8 mL into each of aerobic and anaerobic culture bottles, with incubation until the end of the seven-day shelf life.

Initial-reactive, confi rmed-positive and false-positive rates of bacterial contamination were 0.37%, 0.03% and 0.19%, respectively. False-negative cultures, all with Staphylococcus aureus, occurred on four occasions; three were visually detected prior to transfusion and one confi rmed transmission resulted in patient morbidity. The NHSBT screening protocol reduced the rate of clinically adverse transfusion transmissions by 90%, compared to the preceding fi ve-year period (2006 to 2010). The investigators concluded that implementation of bacterial screening with the BacT/ALERT protocol was an effective risk reduction measure and increased the safety of the blood supply. Complete fi ndings appear in the May 2017 issue of the journal Transfusion.

PEOPLE

* The IMMUNE DEFICIENCY FOUNDATION (IDF) announced that John G. Boyle will serve as the organization’s next president and CEO, succeeding IDF president and founder Marcia Boyle, who will end her 37 years of leadership in mid-August. Mr. Boyle has held a number of executive positions with leading national non-profi t organizations and currently serves as vice president of external relations at IDF. His childhood diagnosis with primary immunodefi ciency (PI) also served as the impetus for the founding of IDF by Ms. Boyle and his father in 1980, to address the absence of educational materials and advocacy groups for people with PI.

Mr. Boyle earned a Master’s Degree in Nonprofi t Management from Notre Dame of Maryland University and a Bachelor’s Degree in Communications from Boston University.

* David Holliday has joined THERAPURE BIOPHARMA as its chief commercial offi cer, and will be responsible for all marketing, sales and commercial activities for the company’s Plasma Products Division. Mr. Holliday has over 30 years of experience in progressively senior roles in the pharmaceutical and biologics industry, most recently as vice president of commercial opera-tions for Octapharma USA.

Previously he managed UK business unit and served as global vice president of hemophilia marketing operations for Baxter BioScience (now Shire), which followed a 17-year career with Novartis, also based in the UK.


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RECENT U. S. PATENTS

* Megakaryocyte and Platelet Production from Stem Cells. #9,574,178. Assigned to New York Blood Center, Inc. (New York, NY). A method for producing platelets for clinical transfusion in vitro comprising:

(1) culturing stem cells in a fi rst growth medium to produce a megakaryocyte (MK) progenitor cell population, wherein the fi rst growth medium comprises aryl-hydrocarbon inhibitor/stem regenin-1 and notch-ligand delta-1;

(2) maturing the expanded MK progenitor cells in an artifi cial bone marrow niche environ-ment comprising a second growth medium in the presence of an oxygen concentration between about 10% and 30% PO2 to differentiate the MK progenitor cells into MKs, wherein the second growth medium comprises thrombopoietin (TPO), stem cell factor (SCF), nicotinamide, and a Rho/Rock inhibitor;

(3) isolating the mature megakaryocytes;(4) culturing the mature megakaryocytes in a three-dimensional matrix and a third growth

medium and in the presence of an oxygen concentration between about 10% and about 30% PO2 and a shear stress between about 100 and 400 μl/min to produce platelets, wherein the third growth medium comprises fi brinogen, fi bronectin, von Willebrand factor (vWF), an MLCK inhibitor, a Rho/Rock inhibitor, and nicotinamide; and

(5) collecting the platelets in a number suitable for transfusion.

* Hematopoietic Precursor Cell Production by Programming. #9,574,179. Assigned to Cel-lular Dynamics International, Inc. (Madison, WI). An in vitro method of providing human he-matopoietic precursor cells by forward programming of human induced pluripotent stem cells.

* Method of Producing Recombinant Vitamin K Dependent Proteins. #9,587,008. Assigned to Aptevo Biotherapeutics LLC (Seattle, WA). A method of producing a vitamin K dependent protein, comprising the steps of (a) transfecting a population of mammalian cells with a gene encod-ing the vitamin K dependent protein operably linked to a promoter, wherein the mammalian cells do not contain heterologous genetic material encoding proteins involved in the post-translation modifi cation of the vitamin K dependent protein; (b) performing at least one round of cloning and screening to identify cells which produce at least 30 mg/L of the vitamin K dependent protein, wherein at least 10% of the vitamin K dependent protein is biologically active; (c) optionally, repeating step (b) one or more times; and (d) harvesting the vitamin K dependent protein.

* Models of Thrombotic Thrombocytopenic Purpura (TTP) and Methods of Use Thereof. #9,587,249. Assigned to Baxalta GmbH (Opfi kon, Switzerland) and Baxalta Inc. (IL). A mouse model for testing the effi cacy of a therapeutic agent in the treatment of a blood clotting disorder characterized by histopathological changes indicative of disseminated intravascular coagulopathy (DIC) or TTP, said mouse comprising a circulating level of recombinant human von Willebrand factor (VWF) polypeptide comprising ultra-large VWF multimers in an amount suffi cient to induce DIC or microthrombosis.


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* Monoclonal Antibodies Against Antithrombin B. #9,593,166. Assigned to Bayer Healthcare LLC (Whippany, NJ). A monoclonal antibody capable of binding AtβH, wherein the heavy chain of said antibody comprises a HCDR1 comprising SEQ ID NO: 40, a HCDR2 comprising SEQ ID NO: 45, and a HCDR3 comprising SEQ ID NO: 50; and wherein the light chain comprises a LCDR1 comprising SEQ ID NO: 21, a LCDR2 comprising SEQ ID NO: 26, and a LCDR3 com-prising SEQ ID NO: 31.

* Antibody Purifi cation Via Affi nity Chromatography. #9,598,460. Assigned to University of Notre Dame du Lac (Notre Dame, IN). A method of binding an immunoglobulin, comprising:

providing a small molecule that specifi cally binds a nucleotide binding site on an immuno-globulin;

contacting a composition containing an immunoglobulin with the small molecule under condi-tions suitable for binding of the immunoglobulin to the small molecule; and

separating the small molecule from the composition, wherein the immunoglobulin remains bound to the small molecule:

wherein the small molecule is indole 3-butyric acid and has a monovalent Kd of about 150 μM or less for a nucleotide binding site defi ned in the patent.

* Method of Purifying Therapeutic Proteins. #9,598,461. Assigned to CSL Behring GmbH (Marburg, Germany). A method of reducing the level of protease in a solution comprising fi brino-gen, the method comprising:

(i) applying a feedstock comprising fi brinogen to a hydrophobic charge-induction chromato-graphic resin equilibrated at a pH from 6.5 to 8.5, wherein upon application to the resin, the proteases bind to the resin while the fi brinogen passes through the resin in the unbound fl ow-through fraction; and

(ii) recovering a solution comprising the fi brinogen which passes through the resin;wherein the concentration of proteases in the recovered solution is reduced by at least 50% com-pared to the feedstock.

* Anti-Hemagglutinin Antibodies and Methods of Use. #9,598,481. Assigned to Genentech, Inc. (South San Francisco, CA). A method for treating, inhibiting or preventing infl uenza A virus infection in an individual in need thereof, the method comprising administering an effective amount of a composition comprising an anti-hemagglutinin monoclonal antibody that specifi cally binds infl uenza A virus hemagglutinin, wherein the antibody comprises three heavy chain hypervariable regions (HVR-H1, HVR-H2, and HVR-H3) and three light chain hypervariable regions (HVR-L1, HVR-L2, and HVR-L3), wherein the amino acid sequence of each heavy and light chain hyper-variable region is specifi ed in the patent.

* Monoclonal Antibodies Capable of Reacting With a Plurality of Infl uenza Virus A Subtypes. #9,598,482. Assigned to Pomona Ricerca S.r.l. (Turin, Italy). A method of inhibiting infl uenza A virus infection in an individual, comprising administering an effective amount of a monoclonal antibody directed again hemagglutinin antigen.


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* Methods for Processing Coagulation Factors. #9,598,687. Assigned to MedImmune LLC (Gaithersburg, MD). A method for purifying a recombinant coagulation factor protein, the method comprising:

(a) providing a mixture comprising the recombinant coagulation factor protein;(b) fi ltering the mixture through at least a fi rst anion exchange column to produce a fi rst anion

exchange column product;(c) loading the fi rst anion exchange column product onto a poly(ethyleneimine) (PEI) column

and eluting with a linear sodium chloride gradient to produce one or more fractions of a PEI column product; and

(d) recovering one or more fractions of PEI column product with a combined pre-peak of <30% to obtain the purifi ed recombinant coagulation factor protein,

Wherein the purifi ed recombinant coagulation factor protein comprises less than about 0.8/10, 0.7/10, 0.6/10, 0.5/10 or 0.4/10 missing D-carboxylated glutamic acid sites and wherein the pre-peak of one or more PEI column product is determined by high performance liquid chroma-tography (HPLC).

* Infl uenza Virus-Neutralizing Antibody and Screening Method Therefor. #9,605,053. Assigned to Fujita Health University (Aichi, Japan). A method of passive immunotherapy for infl uenza comprising administering an effective amount of an antibody to a mammalian or avian subject that has been infected, or can get infected, with infl uenza virus, wherein the antibody is an isolated antibody comprising a heavy chain variable region comprising SEQ ID NO:15 and a light chain variable region comprising SEQ ID NO:26, wherein the antibody binds with virus HA.

* Thrombin-Binding Antibody Molecules and Uses Thereof. #9,605,082. Assigned to Janssen Pharmaceuticals, Inc. (Titusville, NJ). A method for treating or inhibiting a thrombin-mediated thrombosis or embolism, comprising administering an antibody molecule that specifi cally binds to the exosite 1 region of thrombin and comprises LCDRs and HCDRs having amino acid sequences specifi ed in the patent.

* Removal of Tumor Cells from Intraoperative Autologous Blood Salvage. #9,605,242. As-signed to Horst Lindhofer (Munich, Germany). An ex vivo method for removal of tumor cells from blood of a tumor patient.

* Albumin-Purifi cation Method Comprising a Nanofi ltration Step, Solution, and Composition for Therapeutic Use Containing the Same. #9,611,311. Assigned to LFB (Les Ulis, France). A method for purifying a virus particle-containing albumin solution to produce a virally safe product, comprising a step of submitting an aqueous albumin solution, with specifi ed concentration, ionic strength, pH and temperature, to nanofi ltration carried out on qualifi ed fi lters with porosities of 15±2 nm to 20±2 nm.

____________________________________________________________________________

Publishers of International Blood/Plasma News© are careful to report accurately from sources believed reliable, but cannot assume liability for any information published. Errors will be promptly corrected when discovered.


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September 11-14, 2017ESID 2017 European Society for Immunodefi cienciesEdinburgh, UKEdinburgh International Conference Centre - EICC Phone: +41 22 906 9149Email: [email protected]: www.esid.org

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Products and services for hemostasis research • Purified blood coagulation factors • Antibodies• Factor deficient plasmas• Customized blood collection tubes• R&D assay services

HTI is a manufacturer of highly-purified, native plasma proteins and associated products involved in the hemostatic system. Development of assays for research or destined for cGMP testing is also offered.

Testing and services for protein biotherapeutics• Thrombin generation assays• Analytical testing for IVIG products• Immunogenicity testing• Stability & release testing• Host cell protein mitigation

HBS is a cGMP-certified, QC testing laboratory that specializes in providing services for protein biotherapeutics manufacturers from drug inception through market release.

haemtech.com haemtechbiopharma.com

One Company

Two Solutions

150+

Facilitating the Growth & Innovation of Quality Plasma Products in Asia

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Hours of Networking

W: www.imapac.com/business_conference/bioplasma-world-asia-2017/home/ E: [email protected] C: +65 3109 0131

8 Focused Roundtable Sessions

3 Case Studies

Attendees of international and regional plasma fractionators, blood establishments, national health & regulatory organizations and cold chain and technology providers

Speakers from China, Israel, Iran, India, Singapore, USA, Europe andmore!

Distinguished Panel of Speakers

Dr. Hamid R. Beheshti, President/Chairman of the Board, IBRF,Iran

Mr. John E.McCullough, Manager ofInternationalOperations,GenBio SA de CV,Mexico

Dr. Ubonwon Charoonruangrit, Director National Blood Centre Director, The Thai Red Cross,Thailand

Dr. Hari Nair, Managing Director, BST Biologics Pte Ltd, Singapore

Organized and Produced By

Mr. Guan Tao,President, Beijing Haemophilia Home, China

Dr. Ranjeet S. Ajmani, CEO, PlasmaGen BioScience Pvt. Ltd, India

Mr. Zhou Daoping,General Manager, Plasma Department,Shanghai RAAS, China

Dr. Scott Liu CEO, Henlius Biopharmaceuticals,China

Dr. Guangquan Wang, Head of Technical Services Lab & Pilot Plant, Shire,USA

Prof Yu Liu, Director of Transfusion Research Centre,The Institute of Blood Transfusion, China

Prof. Moon Jung Kim, Professor,Seonam University Collegeof Medicine,South Korea

Dr. Sami Chtourou, Executive VP Innovation & Scientific Affairs, LFB Biotechnologies, France

Dr. Murali Tummuru, Founder and ExecutiveDi rector, Virchow Biotech Pvt. Ltd., India

Silver Sponsor Exhibitors

Dr. Pierre-Francois Falcou, Consultant, PFF Consulting,France

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Quality and Regulatory Framework for Plasma Products in AsiaProgress of Developing Plasma Products in Emerging Economies: New Plants and Case StudiesPlasma Industry in 2020Focused sessions on:Pathogen Safety Best PracticesInnovations in Plasma Collection & Processing Clinical Development & New Plasma ProductsPlasma Products Supply Chain, Optimization Strategies and Distribution

Advisory Board MembersDr. Shigeaki Nonoyama, Professor and ChairmanDepartment of Pediatrics, National Defense Medical College, Japan

Dr. Namjil Erdenebayar,General Director, National Center for Transfusion Medicine,Ministry of Health, Mongolia

Dr. Ivan Hung, Clinical Associate Professor& Honorary Consultant,Queen Mary Hospital/University ofHong Kong, Hong Kong

Ms. Zhang Hua, Deputy Director, Shanghai Center for Drug Evaluation and Inspection, ShanghaiFDA, China

Ms. He Shuqin,Quality Director,Jiangxi Boya Bio-Pharmaceutical,China

Dr. Nguyen Chi Tuyen,Head of R&D, Vicohn Biopharmaceutical (An Phat Group), Vietnam

Dr. Alan Liss, GXP Pharma, (Former FDA Regulator), USA

Dr. Ananda Gunasekera, Immediate Past President, Asian Association of Transfusion Medicine,Sri Lanka

Dr. Albrecht Gröner, Consultant, PathoGuard(Former Head Pathogen Safety CSL Behring)Germany

Dr. David Tsur, Founder and Deputy Chairman, Active Board Member, Kamada Ltd, Israel

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