ACROSS CANADA

HiGHliGHTs

FROM THE BUSINESS OF REGENERATIVE MEDICINE COURSE

By Mark Curtis, Business Development Analyst

Centre for Commercialization of Regenerative Medicine (CCRM)

Ask a student of any age what makes a course great and it always comes down to the teacher. Interesting subject matter helps, but a great teacher can make any subject worth staying awake for.

The “students” who attended The Business of Regenerative Medicine course, in Toronto, in July 2014, were treated to more than 40 great “teachers” all sharing their vast knowledge of critical issues relevant to commercialization in the world of regenerative medicine and cell therapy (RM). As experts in their fi elds – whether they were discussing investing, drug screening, reagents/tools/manufacturing, tissue engineering/regenerative molecules or cell therapy – they all brought frankness, enthusiasm and insight to their talks.

Here are some highlights from the 2.5 day course.

Reimbursement and accelerated approval were popular themes. It is clear that demonstrating value to payers will be absolutely essential for the successful uptake of RM technologies.

Activity in the RM space is picking up as clinical data continues to substantiate the use of live cells for myriad different disease areas and indications. Importantly, the global clinical pipeline shows a greater percentage of ongoing mid-stage RM studies versus early-stage, suggesting a bolus of commercial outputs could be on its way.

Pharma is becoming more comfortable working in the RM space, having identifi ed the major bottlenecks and gaps in the industry, which is refl ected by increased partnering activity. Accelerated approval regulatory pathways are also contributing to Pharma involvement, as clearer and shorter paths to market are forged.

Early-stage biotechnology companies will have to be creative, at least in the short-term, and take advantage of Pharma’s willingness to partner to secure funds for development. Last quarter saw an alltime historical low for fi rst-time venture capital (VC) fi nancings in the biotech space.

The fi nancing outlook for mid-to-late-stage companies is more promising, as these companies can still take advantage of the IPO (initial public offering) window that burst open in 2013, but this window is beginning to constrict.

Reimbursement and Accelerated Approval

There was particular excitement around accelerated approval regulatory pathways that are being developed to facilitate the commercialization of live cell technologies. As Gil Van Bokkelen, chairman and CEO of Ohio-based Athersys put it, we’re experiencing a “magical era of accelerated approval.” But he also wonders about the fate of cell therapy technologies upon approval, and what is being done to link accelerated approval with reimbursement.

This sentiment was echoed by cell therapy consultant Lee Buckler, who pointed to Korea as an example of a country that has been progressive with RM approval, having approved 16 therapies to date – the most of any country in the world – but has failed to support technologies through reimbursement. So far, none are paid for or exported out of the country.

Lee stressed the need to show effectiveness in the clinic, worried that if the necessary precautions are not taken we could wake up and fi nd ourselves working in a “withering industry with a plethora of approvals.” It is evident that if these therapies are to gain market access, a dialogue between regulators and payers must be opened imminently. On the topic of reimbursement, we heard from Chris McCabe, a leading health economist based out of the University of Alberta. He laid out the path to de-risking reimbursement through valueengineered translation: completing therapeutic headroom analysis, value-based market access risk assessment, and effi cient research and development design.

The impact of reimbursement on RM companies could not be illustrated more clearly than in the case of U.S. company Organogenesis, which currently manufactures and markets the two dominant skinsubstitute products for chronic wounds – Apligraf and Dermagraft. Geoff MacKay, CEO, gave a heroic account of corporate survival following a decision by the Centers for Medicare and Medicaid Services (CMS), late in 2013, to bundle payment of cellular products for wound healing with acellular products.

To get by, the company slashed $200 million from its cost-structure, cut competition by purchasing the primary competing product Dermagraft from Shire, and put an end to its R&D program across multiple indications to shift its focus to being a manufacturer of products solely for wound healing.

Attendees also discussed the notion of conditional approval of cell therapies – essentially leap-frogging Phase 3 studies and launching a Phase 4 study post-marketing. Arnold Caplan, professor at Case Western Reserve University and founder of the course seven years

ago, argues this might be an effective means of getting cell therapies to the bedside more rapidly by approving them with only preliminary safety and efficacy data.

A precedent can be found with Japan, where the government has recently implemented a conditional approval system. Cell therapy developers are only required to have a single, albeit larger, Phase 1 study to get marketing approval. Remarkably, all cell therapies currently approved in Japan are entitled to reimbursement.

Manufacturing, Tools, and Logistics

Cost of goods in manufacturing cell therapies is typically high, primarily due to expensive growth factors required to drive differentiation of stem cells to specific cell types. Nick Timmins, director of Product and Process Development at CCRM, gave an overview of some of the cost reduction efforts being pursued at the Centre, using natural killer (NK) cells as an example.

NK therapies for cancer are expected to have an all-in cost per patient of $100,000 to $150,000. Through bioprocess optimization, he and his team were able to reduce the cost of consumables from $20,000 to ~$8,000, by minimizing media, serum replacement, and growth factor requirements.

Bioprocess optimization must occur early in cell therapy development. Once a therapy’s protocol is locked in from a regulatory perspective, it is very difficult to go back and carry out this type of cost of goods reduction.

Dr. Timmins explained some of the tools that will facilitate the efficient production of cell therapies, including analytical devices for timely measurements of process quality. He urged us to think beyond scale-up and scale-out, and focus on yield.

Jessica Carmen, Business Development manager at Lonza, provided some keen insight into issues around the logistics of moving live cells. She believes that the clear-cut distinction in a RM business model should be dictated by patient-specific versus bulk cell therapies rather than by specific cell types.

Different therapies will have different requirements in terms of intake and shipping. Dr. Carmen says frozen-in and frozen-out is generally easy to manage; however, receiving cells fresh, and particularly having to ship cells fresh, comes with significant logistical challenges.

Patient-specific therapies have the greatest logistical and regulatory burden, and hence cost, as they must be tracked within a chain of custody. They are shipped fresh, which means they have a short shelf life. Advances in logistics and the supply chain will be critical in driving down costs of patient-specific therapies.

Tissue Engineering and Drug Screening

A company to watch in the 3D printing space is Aspect Biosystems, which is out to create disruptive tissue engineering technologies, “on demand.” Sam Wadsworth, co-founder and director of Biology for this Vancouver-based start-up, explained that whole organ replacement is their goal, but we must first focus on understanding the individual building blocks of the organ before we can pursue synthesizing whole organs. The company’s first product focus will be airway tissue followed by liver.

A more immediate use of these tissue constructs is in drug screening, which is evolving to use multicellular, 3D constructs as a more predictive means to screen for toxicity during preclinical development. Between 1990 and 2010, there were 160 Phase 3 or postmarket withdrawals due to toxicity issues.

Estimates for the all-in cost of developing a drug have ballooned to $4 billion (when accounting for development costs of alternate leads that didn’t make it into the clinic). Increasing the current success rate from 10-20 per cent would save a pharmaceutical company ~$1.5 billion in development costs. So, this is big business.

While screening for cardiac drugs presents a large market opportunity, targeting disease areas where animal models have failed to translate to humans is a smart business model. Dr. Wadsworth pointed out that airway fibrosis is a great example of this, with 100+ treatments that have proven successful in mice, but zero that have gone on to succeed in the clinic.

Bottom-Line

Reimbursement is everything. While accelerated approval will get RM developers to approval, ultimately they will need to demonstrate value to the patient and cost-effectiveness to payers. Without this, easing of regulatory burdens will do little to facilitate the adoption of RM technologies and unlock their health benefits. Product and process development, and scale-up, will be essential for the industrialization of the cell therapy industry and cost of goods reduction, which will give a boost to cost-effectiveness. Logistics and a consistent, reliable, global supply chain for cellular products will help cement cell therapies as the next pillar in health care.

The Business of Regenerative Medicine course was hosted in Canada, for the first time, by the Centre for Commercialization of Regenerative Medicine. To see a copy of the program, please visit http://events.ccrm. ca/program/preliminary-schedule/

To see this story online visit www.biotechnologyfocus.ca/highlights-from-thebusiness-of-regenerative-medicine-course

Microplates BrandTech Scientific, Inc. announces the availability of inertGrade™ microplates for the cultivation of non-adherent cell lines, spheroids, and stem cells in a 96-well plate format. These polystyrene plates are manufactured in one of the largest, most modern cleanroom facilities for laboratory disposable items in the world. Rather than the more common treatments to enhance the natural hydrophobic characteristics of polystyrene, these new microplates are treated with a proprietary

hydrogel. This creates a hydrophobic interface between the surface of the plastic and cellular material to inhibit cell and protein attachment. This unique low-binding microplate surface successfully suppresses the adhesion of a wide variety of adherent cell lines, can enhance the formation and maintenance of uniform spheroid cultures, and can inhibit early differentiation of stem cells or neurospheres. The microplates are available with round, flat, or curved bottoms in clear, white, black, and colored with transparent bottoms. Web: www.BrandTech.com

Columns Designed for separation of monoclonal antibodies (MAbs) and related biologics by hydrophobic interaction, the Thermo Scientific™ MAbPac™ HIC-10 LC column is a high resolution silica column. The MabPac HIC-10 column’s unique chemistry provides high resolution, excellent biocompatibility, and selectivity that is different from other HIC columns on the market and is able to separate many native mAbs, fragments, aggregates, oxidation variants, PEGylated mAbs and ADC. The column’s proprietary chemistry is designed to provide the new selectivity in a high-resolution column with excellent biocompatibility and high recovery. The column is compatible with organic solvent and aqueous mobile phase. It is designed for rugged stability and very low carry-over. Web: www.thermoscientific.com/ mabpacHIC

Liquid Chromatography Shimadzu

Scientific Instruments has introduced two new integrated liquid chromatography systems, Prominence-i and Nexera-i.The iSeries systems feature innovative, intuitive and intelligent design so users can begin building the lab of the future. Through the integration of these systems with LabSolutions software, Shimadzu fosters a new relationship between users and instrumentation. The data acquired by the Prominence-i and Nexera-i via interactive communication mode (ICM) is sent to a lab’s data center by the LabSolutions network and managed uniformly by a server. ICM allows users to perform operations such as purging mobile phases and con-

firming analytical results from anywhere in the facility with a smart device. It also permits easy access to a system installed in a closely supervised area such as under a hood where highly active ingredients are being analyzed.In addition to the temperature control function in flow cells, the systems harness new technology for detector optical systems called TC-Optics, which provides excellent baseline stability. This ensures high precision of validation and quantitation of trace components. The i-Series also allows the direct injection of highly concentrated samples without dilution. Even when injecting ultra-low sample volumes, the systems provide repeatability of one percent or less. The i-Series can be used for a wide range of industries such as pharmaceutical, biopharmaceutical, chemical, environmental, food, and academic teaching. Web: www.ssi.shimadzu.com/products/product.cfm?product=i-Series_1. Western Blotting System The Trans-

Blot® Turbo™ Transfer System from Bio Rad Laboratories is a high-performance western blotting system designed to provide rapid transfers with high efficiency. It combines traditional blotting techniques with modern filter paper and buffers, allowing rapid transfer of proteins from gels to membranes with minimal preparation time. The system integrates a high amperage power supply that directs current between a built-in platinized titanium anode and a stainless steel cathode. This enables blot transfer of protein in as little as three minutes without sacrificing performance. The entire system is in a readyto-use format that allows researchers to obtain their results faster and easier, with reproducibility that is difficult to achieve using traditional blotting methods. Paired with Trans-Blot Turbo Transfer Packs or Trans-Blot RTA Kits, it provides a complete solution for incredibly fast, high efficiency transfers-including high molecular weight proteins. Web: www.bio-rad.com

Fluid extraction The Supercriti-

cal Fluid Technologies (SFT) bench top supercritical fluid extractor (SFE) model SFT-110XW is the latest addition to the SFE product line. The completely redesigned restrictor valve with integrated micrometer allows for very precise flow control, which is essential for demanding applications. A completely removable oven lid and large side panel allow the user easy access to the high pressure vessel(s). An indicator light on the SFT-10 pump module alerts the user to proper operation of the Peltier pre-cooler, ensuring CO2 is maintained in the liquid state. A robust outlet from the restrictor ensures that users will not accidently damage the outlet tube when inserting it into the collection container. Extraction vessels up to 500 ml, single or dual configurations, afford maximum versatility.The SFT-110XW SFE is well suited for both research and process development applications. Web: www.supercriticalfluids.com.

Liquid Handling Pumps VICI Valco’s

Cheminert Model M6 and M50 liquid handling pumps are a new generation of pumps for precision handling of liquids and/or gases. Producing a bidirectional pulseless flow with a range of over six orders of magnitude (5 nL/min to 5 mL/

min for the M6 Pump; 1 µL/min to 25 mL/ min for the M50 Pump), they represent an option to syringe pumps by eliminating the need for refill cycles and syringe changes. The M6 and M50 are positive displacement pumps, which means they are self-priming and tolerant of any gas which may find its way into the fluid lines. There is no separate fill cycle, and the capacity is unlimited. RS-232 and RS-485 communication protocols are incorporated into the microprocessor-driven controller. (USB interface requires an adapter.) The included software package controls flow rates, flow direction and metered volumes. While the standard package includes software and instructions to run the M6 as a stand-alone unit, the software can also integrate a multi-position stream selection valve.

weighing cell, which measures the weight of each individual fill with an accuracy rate of +/-0.002g. Additionally, it handles filling requirements for clinical trials and medium batch production with peristaltic aseptic filling technology from 0.1 to 100ml fill sizes. For operator convenience, the FPC50W new card:Layout 1 1/31/2013 9:09 AM Page 1system can also accommodate a wide range of vial sizes and neck finishes without the need of extra format parts. The weighing cell is connected to the filling system, allowing for fully automatic recalibration of the pump throughout the batch. Additionally, the unit can employ a changeover of the single-use fluid path, which includes pharmaceutical grade silicone tubing and plastic filling needles, to adapt to multiple batch processes or different product fill volumes. The system is equipped with an automated precision turntable infeed, an in-line filling station, and a rubber plug closure applicator that is capable of filling and capping vials at rates up to 20 vpm. The FPC50W comes standard with a onetouch 12 inch screen/HMI for easy setting of all process parameters. If desired, the machine can be configured for password protection in three levels ensuring batch security ease of validation. Web: www.watson-marlow.com

Web: www.vici.com

Automated Filling System Watson-

Marlow offers its Flexicon FPC50W, an operator-friendly, fully-automated filling,

plugging and capping system that offers accuracy, flexibility for aseptic filling in clinical trials and scale-up applications. The FPC50W is equipped with a Wipotec

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octoBEr 2014

October 5-8

ABIC 2014 Venue: Saskatoon, SK Tel: 306-668-2650 Email: abic2014@agwest.sk.ca Web: www.abic.ca/abic2014/

October 7-8

Bio Investor Forum Venue: San Francisco, CA Email: bd_registration@bio.org Web: www.bio.org/events/conferences/ 13th-annual-bio-investor-forum

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Canadian Science Policy Conference Venue: Halifax, NS Web: http://cspc2014.ca/

October 20-21

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October 20-23

30th Annual International Conference on Soils, Sediments, Water and Energy Venue: Amherst, MA Tel: 413.549.5170 Email: brenna@aehsfoundation.org Web: http://www.aehsfoundation.org/ Events.aspx

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AusBiotech 2014 National Conference Venue: South Yarra, Australia Tel: (03) 9828 1400 Email: admin@ausbiotech.org Web: https://www.ausbiotech.org/

novEMBEr 2014

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MEDICA 2014 Venue: Dusseldorf, Germany Tel: 416-598-1524 Email: messeduesseldorf@germanchamber.ca Web: www.medica-tradefair.com

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Company & advertiser index

coMPanY PagE WEBsitE

Ag-West Bio .........................................................................................................2 ............................................................................................www.agwest.sk.ca AlbertatBay ........................................................................................................23 .................................................................................... www.albertatbay.com Bereskin & Parr .................................................................................................17 ..................................................................................www.bereskinparr.com Best Western Victoria Park Suites ..................................................................23 ...................................................................................www.victoriapark.com Bio Rad Laboratories ................................................................................... 26....................................................................................... www.bio-rad.com BrandTech Scientific Inc. ............................................................................. 26..................................................................................www.BrandTech.com Canadian Government Executive ..................................................................21 ....................................................www.canadiangovernmentexecutive.ca Centre for Commercialization of Regenerative Medicine ........................... 10.............................................................................................. www.ccrm.ca Children’s Miracle Network..............................................................................7 ................................................................www.childrensmiraclenetwork.ca Concordia Healthcare Corp......................................................................... 10................................................................................www.concordiarx.com Eppendorf ..........................................................................................................32 ......................................................................................... www.eppendorf.ca Knight Therapeutics .................................................................................. 9,10 ...............................................................................www.gud-knight.com OncoGenex Pharmaceuticals Inc.................................................................. 6..................................................................................www.oncogenex.com Oncolytics Biotech Inc. ................................................................................ 6....................................................................... www.oncolyticsbiotech.com Nuvo Research Inc. ...................................................................................... 6..............................................................................www.nuvoresearch.com Ontario Bioscience Innovation Organization ..............................................13 .....................................................................................................www.obio.ca POI Business Interiors ......................................................................................31 ....................................................................................................... www.poi.ca Qu Biologics ................................................................................................. 9................................................................................. www.qubiologics.com Thermo Scienitific....................................................................................... 26.........................................................................www.thermoscientific.com VICI Vlaco.................................................................................................... 27............................................................................................. www.vici.com VWR ......................................................................................................................5 ........................................................................................................ ca.vwr.com Zymeworks Inc. .......................................................................................... 10................................................................................ www.zymeworks.com