June 28, 2017

From Darwin to Recombinant Fc Multimers

Topics from a Darwinistic viewpoint on how business models are evolving in the Life Science industry to breakthrough research data from Momenta Pharmaceuticals on a recombinant trivalent Fc protein targeting improved therapies in autoimmune diseases. The conference attendees of the 10th Plasma Product Biotechnology meeting on Malta provided a wide spectrum of topics from May 15-18.

The Plasma Product Biotechnology (PPB) meeting series is a joint organization by CSL Behring and GE Healthcare Life Sciences and has been going on since 1999. Always organized on an island, this year’s event was returned to Malta, which previously hosted the meeting in 2001. Appropriately, in his opening statement, conference chairperson Joe Bertolini, R&D director from CSL Behring Australia, reflected on what has happened in the plasma fractionation industry during these 16 years.

Conference Chairperson Joe Bertolini, R&D director from CSL Behring Australia

PPB 2017 had a full program with six scientific sessions focusing on issues and possibilities around manufacturing, development, and clinical use of plasma products in general. In addition, a poster session allowed for an open discussion around some of the latest trends and innovations within the industry in combination with excellent networking opportunities. This year, PPB had 131 participants from 26 different, comprising representatives from all the major plasma fractionators, as well as both smaller and larger biotech companies. 

The meeting opened Monday night with a presentation by John Perkins, CEO at Bio Products Laboratory Ltd., UK. BPL manufactures a range of products from blood plasma and has been a regular attendee at PPB. Perkins emphasized the importance of having a healthy plasma fractionation industry not just for the patients, but also for the donors and the people within the industry. He presented data showing how the plasma industry is growing, and how the share prices have increased more than share prices for big pharma and medical device companies.

The expected growth from 2017-2020 is expected to be 6-8%, reaching a business size of $20 billion. IgG market will continue to dominate with 46% of market, followed by albumin, 18%, John Perkins stressed the importance of other plasma proteins to have a good process economy. 

Some of the reasons the industry is performing well are, according to Perkins:

• Serving more patients, thanks to
      Increased diagnosis
      New indications
      New products
      Geographic expansion
      Aging populations
• Competitive players
• Uniqueness of products, i.e. no biosimilars
• Continued innovation, investment and progress

To ensure future vitality of the industry, Perkins talked about the importance of securing plasma supply, donor and patient safety vigilance, clarity on reimbursement and other policies, and continued innovation and investments.
Of special interest to the audience was how the acquisition of BPL last year by the Chinese investment group Creat will affect the business. While not all questions could not be answered in this public forum, press releases already revealed that Creat will invest £100 million in BPL to expand production capacity. Perkins expected more mergers and acquisitions to be happening in the future, with China involved when “East meets West.” 

The first session of the conference was Manufacturing Perspectives, chaired by Geoffrey Pot from Shire, Belgium. This session has always scored the highest in feedback surveys. This year was no exception and the topics covered different aspects of manufacturing. One case study presented by Gert Verheyden at Shire showed that the orientation of depth filter membrane during assembly can have significant impact in achieving a robust filtration step. Joakim Lundkvist from GE Healthcare presented data from a real-life case study with a plasma fractionator on buffer management, which show significant savings in CAPEX, tank space, floor space, and number of buffers when using in-line conditioning to achieve optimized automated approaches. Damien Bataille from LFB presented how affinity chromatography with a novel chromatography resin, VIISelect, together with a QbD approach, delivered a robust process control strategy to deliver a high-level purity and quality recombinant VIIa (rhFVIIa) from a somewhat unusual expression system: milk of transgenic rabbits. LFB’s objective is to develop an rhFVIIa treatment especially for hemophilia A and B patients with inhibitors to Factor VIII or IX. 

Albert Farrugia from Kedrion Biopharma chaired the Quality and Regulatory Trends session. The first presentation in this session covered the policy evolution for hemophilia therapies in Germany. Uwe Schlenkrich, publisher of Hemophilia News, presented the patient perspectives on the industry and the regulations, especially how the German healthcare system affects patients’ lives. Another presentation that scored high in the survey was given by Lars Sejergaard from Novo Nordisk Denmark. In the era of QbD, there has been a lot of focus on Design of Experiment (DoE) approaches. Though considered as a good and established approach, Sejergarrd pointed out several of the inherent drawback of the DoE approach and Latin Hypercube Sampling (LHS) was introduced as a possible alternative.   

The two final talks in the Quality session had the commonality of tech transfer and were presented by Estelle Darnon from LFB France and Robert Forrest from CSL Behring Australia. LFB has made a big commitment to expand its manufacturing capacity with an investment of €300M, and initiated a new facility project in Arras, north of France in 2016, with an objective to fractionate 3 million liters of plasma per year. Darnon presented the challenges of the tech transfer of manufacturing processes from two current manufacturing French sites to the new facility, and how the project included both an increase in scale and some process improvements. Forrest covered the R&D contribution to a tech transfer for the IVIg Privigen® process from Switzerland to Australia. This included a secondment of an R&D employee to Switzerland, to be actively involved in process development and commissioning activities, and who upon returning to Australia, would provide local expertise and facilitate cross-site communication. R&D staff were then providing scientific support during equipment and process qualification, were involved in engineering batches to monitor manufacturing performance, and also contributed to the process control, validation, and regulatory activities. 

The third day of the conference opened with the Pathogen Safety session, chaired by Albrecht Gröner, Pathoguard, Germany. In the session, Nathan Roth from CSL Behring Australia presented approaches towards Hepatitis E virus and Zika virus, two recent emerging pathogens, and studies confirming the effectiveness of existing virus clearance steps against these pathogens. Dr. Roth stressed how important it is to maintain the trust of the public opinion and take emerging risks and pathogens very serious. As an example, he mentioned all the press alerts around Zika virus and the “high CNN factor,” but stated that this flavivirus was relatively easily removed by existing virus reduction steps.  

The poster session has always been a key element of the PPB meeting series. This year, more than 20 posters were presented. Networking is important and has been one of the primary objectives of the PPB meeting series. Posters topics covered: Continuous chromatography in plasma applications, Viral clearance study optimization for virus filters, Buffer management via in-line conditioning systems, Radial flow chromatography, Novel chromatography resins, Ukraine plasma market, and Novel analytical assays based on Surface Plasmon Resonance.

More than 20 posters were presented at PPB this year.

The Applications of Plasma Products and Clinical Developments session, chaired by Merche Faro from Grifols, Spain, contained presentations on novel approaches to improve existing treatments as well as clinical applications of novel plasma derived proteins. Cedric Vonarburg from CSL Behring Switzerland talked about the issue of subclinical infections in the upper part of the lungs of IVIg treated primary immunodeficient (PID) patients. CSL was interested to test the approach of topical application of immunoglobulins into the lungs and performed initial feasibility assessment studies of nebulization of IgG. The conclusion was that nebulization as well as topical application of immunoglobulins into the lungs seems feasible, and this approach might prevent these types of infections in PID patients. Harald Butterweck from Shire Austria presented data on CUVITRU™, a launched subcutaneous immunoglobulin (SCIg) preparation, and said that this subcutaneous product was fully comparable to an intravenous immunoglobulin preparation. One of the strongest benefits with SCIg preparations is the possibility of self-administration by the patients. Matthias Germer from Biotest Germany presented a novel polyclonal antibody preparation containing IgM (23%), IgA (21%), and IgG (56%) for the treatment of severe community-acquired pneumonia (sCAP), which is a leading cause of death worldwide. Positive data from the clinical Phase II study was presented and the project will now progress into Phase III.   

Carlos Bosques from Momenta Pharmaceuticals had a presentation titled IVIg-Inspired Drugs for Improved Therapy in Autoimmune Diseases in the Application session. IVIg has been a treatment option for several autoimmune and inflammatory diseases for more than 30 years. However, the mechanism of action of IVIg remains to be a topic of significant debate and has also been a topic of discussion on several PPB meetings. Carlos Bosques said that since IVIg was not intentionally designed to target a specific anti-inflammatory mechanism, it is likely that multiple mechanisms are involved. He also stated that the IVIg preparation, in this case, is not a very potent drug, meaning that high doses must be administered.   

Probably showing the complexity of the interactions, the progress towards the development of therapeutics targeting the Fc-R family for autoimmune and inflammatory diseases has been slow despite ongoing research. At PPB 2017, Bosques presented data from preclinical studies and how the drug candidate M230 has demonstrated greater efficacy and 10–40 times greater potency than IVIg in three different animal models of autoimmune diseases.   

The final presentation of the third day also generated significant interest. Karl McCann, from CSL Behring Australia highlighted the use of SOMAscan as an analytical tool in the plasma fractionation industry. Working with complex biomolecule systems, it is not guaranteed that all possible modifications from a process change are detected in routine release testing. Therefore, additional residual protein testing is required during process validation to fully establish comparability. McCann talked about the potential of a DNA-based multiplex method that allowed analysis of up to 1,300 plasma proteins in a single sample. 

The Markets, Policies and Strategies session, chaired by John Curling, Sweden, gave the opportunity to get an overview of the global plasma fractionation market and is definitively recommended to anyone who wants to learn more about the plasma market. Jan Bult from PPTA (Plasma Protein Therapeutics Association) in the US, focused on the situation regarding plasma supply and plasma fractionation in the world. There is currently a strong dependence on US plasma and Bult said that it would be healthier for the industry and the market to reduce this dependency. However, it is problematic with the various policies in place in the world. There are two different starting materials for plasma fractionation: source plasma (collected through plasmapheresis) and recovered plasma (collected through whole blood donation). Both sources are needed and Bult stressed that efforts are urgently needed to remove the political barriers limiting the availability of plasma for manufacturing.   

Leni von Bonsdorff from Sanquin Oy in Finland and David Stubbings from National Bioproducts Institute (NBI) in South Africa presented individual insights in the current situation from two very different regions, the Nordic countries and South Africa. Interestingly, the Nordic countries have so many similarities and have many close collaborations, but have major differences in the welfare system and supply of critical plasma products. von Bonsdorff presented that the Nordic countries were among the first in the world to produce plasma products to secure national needs, but today all countries depend on global suppliers for plasma products. NBI is currently processing approximately 200,000L of plasma annually, which meets the needs of South Africa. However, Stubbings said that many other challenges still need to be addressed. NBI is primarily focusing on technology transfers and acclimatizes products to local conditions. Storage and shipping temperature were mentioned as examplse, as many hospitals do not have cold room storage.   

Before the final session, Professor Brian Smith, from Pragmedic, UK, presented the focus lecture titled "Darwin’s Medicine: How Business Models are Evolving in the Life Sciences Industry." In his talk, Professor Smith said that ”..what is happening in our industry is not like evolution, it is evolution..” Drivers of industry change, according to Professor Smith, and he showed examples of how large pharmaceutical technology companies are adapting their strategies and capabilities. He also introduced the term “capabileome” following the genome and the proteome projects.

The closing session at PPB 17 was New Products & Innovations in Plasma Processing, chaired by Sami Chtourou at LFB Biotechnologies France. The session covered both new plasma products as well as products and technologies for plasma processing or characterization. Fabian Käsermann from CSL Behring Switzerland talked further about the Fc multimers, and the biochemical and biological properties of these recombinant Fc hexamers. As discussed during the presentation, there are several similar projects ongoing. Some examples mentioned were GL-2045 from Gliknik/Pfizer, Hexagard™ from Liverpool School of Tropical Medicine (LSTM) and ARGX-113 from Argonex. In two talks from LFB France (from Jean-Luc Plantier and Philippe Mondon), data on both a modified factor X and Fibrin Glue containing fibrinogen and activated Factor VII were presented. As an example of improved plasma characterization tools, Fredrik Sundberg from GE Healthcare presented how an established analytical technology such as Surface Plasmon Resonance also could be beneficial in plasma analytics, with improved reliability and with a high degree of simplification. Data for all subclasses of IgG, albumin, Ig A, and transferrin were presented as examples.   

In his concluding remarks, Joe Bertolini emphasized the high quality of the presentations, covering a diverse range of subjects during PPB 2017. Many subjects had changed compared to 16 years ago when PPB also was organized on Malta. This reflects the change of the industry. On the other hand, several topics remain interesting and show that you should know your history. In summary, the 2017 PPB meeting series was considered to be another successful event to learn about and discuss topics related to plasma fractionation. Judging from the feedback from several returning conference visitors. 55% scored the conference “Excellent” and 41% scored it “Good. Whether a new conference should be held in 2019, 99% responded, “Yes.” The conference organizers have already started the search for a new island that could host the next meeting. Stay tuned.

Tags: IVIG, PPB, conference, fractionation, plasma