East Hills, NY (January 26, 2005) - - Pall Corporation (NYSE:PLL) was invited by the Advisory Committee for Blood Safety and Availability of the Department of Health and Human Services to present the latest data on its innovative prion reduction technology in Bethesda, Maryland, today. The Company has been developing the Leukotrap® Affinity Prion Reduction Filter to remove infectious prions, associated with several fatal neurodegenerative diseases including variant Creuztfeldt-Jakob Disease (vCJD) and leukocytes (white blood cells) from blood prior to transfusion in a single step. Variant CJD is the human form of "mad cow disease." The Company expects to launch the product commercially in Europe in a few months.
Hal Baker, Senior Vice President of Pall Medical, reviewed the latest study results that validate the filter's removal of infectious prions from red cell concentrates, the most widely transfused blood component. He reported that the filter's innovative surface modification technology provides the dual benefit of concurrently reducing leukocytes (log 5) and infectious prions (below the limit of detection of the Western blot assay). Roughly 40 percent of prion infectivity in blood resides in leukocytes (cell-associated) and 60 percent in plasma (non-cell associated). The new filter removes 99 percent of vCJD infectious agent, both cell- and non-cell associated, and also removes all types of prions including aggregated, denatured and normal.
He also presented results from a battery of in vitro and in vivo studies demonstrating the safety and efficacy of the filter for use with red blood cells. The filter does not damage red cells and does not impact their therapeutic value based on parameters of purity, efficacy and 42 days stability.
Transfusion medicine professionals and the public perceive the risk of developing vCJD from a blood transfusion as a growing, not a declining, threat to public safety. Public health officials believe that the problem is not limited to the UK, where a majority of the early cases of vCJD have been identified, or to Europe, but is a potential global threat that includes the U.S. and Canada.
"Due to worldwide public health concern about whether outbreaks of mad cow disease (Bovine Spongiform Encephalopathy or BSE) will result in the large-scale spread of the infection to humans, there is a need to consider new methods to safeguard the blood supply from the risk of transmission of infectious prions," Mr. Baker said. Animal studies demonstrate that the agent that causes vCJD can be transmitted through blood transfusion. The United Kingdom confirmed that a patient who received donor blood during an operation in 1997 developed vCJD and died six years later. The latest scientific findings show that vCJD is not confined to a single genotype, thereby placing a majority, not a minority, of the population at risk. The existence of asymptomatic prion carriers means that there may be many more cases of undetected prion infections lying dormant. Combined with the unknown time interval between exposure and onset of symptoms, estimating the true size of a second wave of transmission or a vCJD epidemic is increasingly complex.
"Equally important, there is a serious need to determine whether the current measures to prevent the disease are sufficient," added Mr. Baker. "We need to balance the efficacy of these measures against the safety and availability of life-saving blood components." Mr. Baker explained how donor deferral policies have a reverberating impact on blood availability. A loss of one percent of donors involves approximately 75,000 to 85,000 individuals in the first year, not to mention their future potential donations. There is currently a ban on blood donations from people who lived in countries with BSE infected cattle.
In addition to deferral policies, Mr. Baker addressed the myriad difficulties associated with testing human blood for prions, specifically the potential impact on donors who are subjected to it. Although no human blood test is available, he explained that any new prion test, regardless of its makeup, raises ethical concerns. These tests must have the absolute highest sensitivity and specificity performance to minimize false positive results when applied to an always-fatal neurodegenerative disease. He also noted that since prions lack nucleic acid, they can not be inactivated by pathogen inactivation procedures that exist today or in development.
"The Leukotrap Affinity Prion Reduction Filter represents the first of a new generation of proprietary "Smart" filters that will concurrently reduce leukocytes and infectious prions to minimize the risk of transmission of variant CJD through blood transfusion," said Mr. Baker. "Smart" filters can selectively capture and remove target contaminants or components while allowing the desired components to pass through even those of equal size.
He explained the advantages of targeted removal of prions through affinity filtration. Filtration is more cost effective than molecular biology testing, more efficacious than inactivation technology and is a widely applicable process that can be easily scaleable and efficiently integrated with current blood handling logistics and good manufacturing practices.
"Pall's approach to improving the safety of the global blood supply grows out of our core competency in material science engineering and proprietary surface modification technology combined with our legacy of leadership in blood filtrations technology," Mr. Baker added. "We are uniquely positioned to introduce novel "Smart" filter technology as a key element in a new blood safety paradigm."
Pall Corporation expects to introduce the Leukotrap Affinity Prion Reduction Filter commercially in Europe this spring followed by submission to regulatory agencies in both Canada and the U.S. The Company is also studying the filter as a device to aid in the detection of BSE in cattle before entering the food supply.
About Pall Corporation Pall Corporation is the global leader in the rapidly growing field of filtration, separations and purification. Pall's business is organized around two broad markets: Life Sciences and Industrial. The Company provides leading-edge products to meet the demanding needs of customers in biotechnology, pharmaceutical, transfusion medicine, semiconductors, water purification, aerospace and broad industrial markets. Total revenues are $1.8 billion. The Company headquarters are in East Hills, New York with extensive operations throughout the world. Visit Pall at http://www.pall.com/.
Forward-Looking Statement This release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995. These statements are based on current Company expectations and are subject to risks and uncertainties which could cause actual results to differ materially. Such risks and uncertainties include, but are not limited to: fluctuations in foreign currency exchange rates; regulatory approval and market acceptance of new technologies; changes in product mix and product pricing and in interest rates and cost of raw materials; the Company's success in enforcing its patents and protecting its proprietary products and manufacturing techniques and its ability to achieve the savings anticipated from its cost reduction initiatives; global and regional economic conditions and legislative, regulatory and political developments; and domestic and international competition in the Company's global markets. Additional information regarding these and other factors is available on the Web at www.pall.com and is included in the Company's reports filed with the U.S. Securities and Exchange Commission. Copies of such reports can be obtained, without charge, at www.sec.gov.
Management uses certain non-GAAP measurements to assess Pall's current and future financial performance. The non-GAAP measurements do not replace the presentation of Pall's GAAP financial results. These measurements provide supplemental information to assist management in analyzing Pall's financial position and results of operations. Pall has chosen to provide this information to facilitate meaningful comparisons of past, present and future operating results and as a means to emphasize the results of ongoing operations.
Hal Baker, Senior Vice President, Pall Medical Advisory Committee On Blood Safety and Availability (BSAC) Meeting January 26, 2005
Although neither the appearance of Bovine Spongiform Encephalopathy (BSE) in North America or the apparent transfusion transmission of variant Creutzfeldt-Jakob disease (vCJD) are entirely unexpected, these events provide impetus for further consideration of new methods to safeguard the blood supply from the risk of transmission of infectious prions. While many feel that existing measures to deal with this risk are sufficient, there is still a serious need to balance their potential efficacy against the safety and availability of life saving blood components.
Over the past few years, public health officials around the world have been concerned about whether the outbreak of Mad Cow disease or BSE would result in the large-scale spread of the infection to humans.
Since the first case of vCJD reported in 1995, one hundred and fifty-three (153) people worldwide have contracted the disease. As a result, in North America and Europe, several measures are now currently used to reduce the risk of transmission of variant CJD. These include geographic residency restrictions (travel deferral) and bans on importation of beef from BSE counties. In addition to these preemptive measures, many countries have implemented universal leukocyte reduction as a precautionary principle because up to 40% of pathogenic prions are found in donor leukocytes.
Animal studies have demonstrated that the agent that causes the human form of Mad Cow disease can be transmitted through blood transfusion. With the recent news from the United Kingdom confirming that a patient who received donor blood during an operation in 1997 developed variant CJD and died six years later, transfusion medicine professionals and the general public now perceive the risk of developing vCJD from a blood transfusion may be a growing, NOT a declining, threat to patient safety. The existence of asymptomatic prion carriers raises real concerns of a second-wave of transmission. Because Mad Cow disease has spread to other countries?and given the unknown time interval between exposure and symptoms?public health officials are faced with the complexity of estimating the true size of the vCJD epidemic. Are there thousands of dormant carriers of vCJD at risk of developing clinical disease? This question needs to be addressed with priority and urgency because it raises deep concerns that many more cases of undetected prion protein infection may underlie the overt epidemic--with major implications for future estimates and the surveillance of vCJD.
The UK vCJD epidemic has two striking features. All of the affected individuals are 129MM homozygotes (carry one genotype), which is present in 37% of the UK population, and are mostly less than 30 years old. The tailing off of this epidemic has been assumed to be the end of the vCJD threat. But it seems unlikely that infection would be confined to just one age group or to a single genotype.
These fears are supported by recent scientific findings. One of the two recent cases involving preclinical vCJD was detected in a patient heterozygous (methionine/valine or MV) at codon 129 of the prion gene. This finding suggests that susceptibility to vCJD infection is not limited to the homozygous (methionine/methionine or MM) genotype. Their are two levels of infection: one that results in overt vCJD, as in the 129MM genotype transfusion recipient, and another that results in a sub-clinical or dormant carrier, as in the 129 MV recipient. The combination of the MM and MV genotypes comprise approximately 90% of the UK population.
These events have spurred increasing concern about the possibility of a second and bigger wave of mad cow disease in humans. Public health officials and risk assessment experts believe that the problem is not limited to the UK, where a majority of the early cases of vCJD have been identified, or to Europe, but is a potential global threat that includes the U.S. and Canada.
Donor deferral policies have a reverberating impact on blood availability as each future generation is lost. The accessible donor population is limited and even small slices cut from the pie add up. A loss of 1% of donors involves approximately 75-80,000 individuals in the first year--not to mention their future potential donations.
Those who are concerned about blood safety would like to improve the sensitivity of current methods designed to protect against transfusion-transmitted infections. Those who are concerned about blood availability would welcome standard methodologies to detect infectious prions in blood. Such a solution is easy to think about, but hard to achieve.
The causative agent for BSE and vCJD is believed to be an infectious protein, which lacks nucleic acid and therefore can not be detected, or inactivated, by existing procedures targeting nucleic acid components of the pathogen. Any new prion test, regardless of its make-up, comes with a significant price of its own--the potential impact on donors who are subjected to it. Most important are the ethical concerns associated with the use of a test with unknown sensitivity and specificity performance characteristics (will require detection at the centigram level to minimize false positive test results) when applied to an always-fatal neurodegenerative disease.
Pall?s approach to improving the safety of the global blood supply grows out of our core competency in material science engineering and a legacy of leadership in blood filtration technology. It is only natural that our solution involves a novel, proprietary surface modification technology that removes all types of prions including: aggregated, denatured and normal. We know that blood collectors are constantly balancing the need for greater blood availability with the reduction in eligible donations resulting from ever more stringent donor selection criteria. When you include the added expense of viral nucleic acid testing at a cost of $1 million per infection prevented, it is easy to understand why Pall is uniquely positioned to introduce novel "Smart" Filter technology as the third element in today's Blood Safety paradigm.
Because only a low titer of prion infectivity is believed to exist in a unit of blood--the use of affinity filtration would be an efficient and effective method of reduction while eliminating the higher costs and additional steps associated with an antemortem detection assay or pathogen inactivation process.
Pall will address the potential for transmission of infectious prions through blood transfusions with the European market introduction (CE Mark) of the Leukotrap® Affinity Prion Reduction in the Spring 2005. The filter?s innovative technology is designed to provide the dual benefit of reducing leukocytes (1x10e5) and infectious prions (2 to 4 log reduction based on Western Blot assay) in a single step. Roughly 40 percent of prion infectivity in blood resides in leukocytes (cell-associated) and about 60 percent in plasma (non-cell associated). Our proprietary surface modification technology does not damage cells, impact red cell parameters, purity, or 42 day stability.
The advantages of targeted removal through filtration as a safety process are compelling.
Filtration is more cost-effective than escalating molecular biology testing.
Filtration is more efficacious than pathogen inactivation technologies, which can damage cells, thereby reducing the therapeutic value of blood components.
Filtration is a widely applicable process, easily scalable and efficiently integrated with current blood handling logistics and good manufacturing practices.
Over the past twelve (12) months we have been conducting tests to validate the removal of infectious prions from red cell concentrates using our new prion removal filter. In these validation studies, which I will discuss in a moment, we used all of the methods that are currently available for validating the removal of prions. At the same time, we have completed an extensive battery of in vitro and in vivo studies demonstrating the safety and efficacy of the filter for use with packed red blood cells for transfusion.
Exogenous infectivity study: Infectious prions were obtained from the brains of infected hamsters. Typically, the brains of scrapie infected hamsters are homogenized in saline to obtain about 10% brain homogenate containing infectious prions. These prions (about 30mL) are then added to a unit of red cell concentrate. The red cell concentrate was filtered with either our standard Leukocyte reduction filter or our new prion and leukocyte reduction filter.
We measured the level of infectious prions in the red cell concentrate before and after filtration using the Western blot assay.
The results from the Western blot assay show that all the infectious prions were removed well below the limit of detection of the assay. In contrast, our standard leukocyte reduction filter (BPF4) failed to remove a significant amount of infectious prions. Note that the results (above) were obtained using brain materials that were spiked or added into red cell concentrate.
Endogenously Infected Red Cell Concentrate: In this study, we initially injected hamsters with an agent that induces scrapie in hamsters. This particular strain is called the 263K. About 150-200 hamsters were injected intracerebrally with the scrapie agent. After 70 days the animals developed scrapie and blood samples were collected into CPD anticoagulant.
About 500mL of blood were collected and then processed into red cell concentrate using standard blood bank procedure. The red cell concentrate was then filtered with the new prion reduction filter in a manner that was similar to what I showed you earlier.
Note that the level of infectious prion in the red cell concentrate before filtration is very low and the sample had to be concentrated in order for us to detect it on the Western blot assay. After filtration with our new prion and leukocyte reduction filter, all the infectious prions were removed well below the limit of detection of the assay.
In order to determine whether we had completely removed the infectious prions from the red cell concentrate, we injected intracerebrally (directly into the brains) samples of the unfiltered and filtered red cell concentrates into 20 normal hamsters. We then monitored the hamsters every week over a period of 300 days for clinical symptoms of the prion disease such as wobbling gait, irritability, and head bobbing.
The hamsters that received the filtered red cell concentrate DID NOT develop clinical signs of prion disease during the 300 day test period. In order to be certain that none of the animals had any infectious prions in their brains, we examined the brains of the animals for the presence of infectious prions. Just as we were unable to observe any outward signs or clinical symptoms of disease, we did not find any infectious prions in the brains of the hamsters that received the filtered red cell concentrates. In contrast, three (3) of the 18 control hamsters that received the unfiltered red cell concentrate--not only displayed clinical symptoms of disease--they developed prion disease as determined by using the Western blot assay of their brain materials.
Initial bio-assay (prototype filters) in hamsters confirmed removal of about 4 logs of infectious prion. Additional bioassays using CE Mark filters are planned to confirm log removal. After 300 days, 0/20 hamsters injected with filtered red cell concentrate developed scrapie. In contrast, 3/18 control hamsters that received unfiltered red cells developed scrapie.
Summary: Our preliminary results using scrapie animal models show that prototypes (non CE Marked versions) of the Pall prion removal filter are effective in removing infectious prions from blood and plasma.
Market Introduction: Pall Medical is completing the safety and efficacy testing required to declare CE Mark compliance on the Leukotrap® Affinity Prion Reduction Filter (for sale in Europe in the Spring 2005). The new filter is also expected to enter the regulatory process in the US and Canada later in the calendar year. This product represents the first of a new generation of proprietary "Smart" filters that will concurrently reduce leukocytes and infectious prions to minimize the risk of transmission of variant CJD through blood transfusion.