GDVMARCH NOTES ON/ABOUT ENZO’S 1/14/04 ASM, ETC.

DISCLAIMER:   NOTE:  I am not a spokesperson for Enzo nor a medico-related techie, lab researcher, scientist or physician.  Therefore, these limitations in relevant expertise makes likely the possibility I will have to post future clarification and correction with respect to my comprehension and/or interpretation of Management’s ASM reports on, e.g., the newer science and tech areas discussed at the ASM.  For these same and other reasons, readers MAY NOT ACT in reliance on my ASM notes in making investment or other decisions. My RECOLLECTIONS below, offered solely as a courtesy and FWIW, are neither (a) a verbatim transcript of Enzo’s 1/14/04 ASM, nor (b) binding on Enzo, its Management, any ASM speaker or me.   References herein to literature and/or links are SOLELY the gratuitous contributions of this writer.

I.  ASM MEETING OPENED at 9A.M. by Enzo President/CFO & Director-Barry Weiner.  He introduced from dais and audience:  VP (Business Development)-David C. Goldberg, CEO/Chairman-Elazar Rabbani, Ph.D, Executive VP-Dean Engelhardt, Ph.D,  COO/Secy/Treas./Director-Shahram K. Rabbani, VP (Corporate Development)-Barbara  E.Thalenfeld, Ph.D, Senior VP-Norman E. Kelker, Ph.D, VP (Finance)-Herbert B. Bass, and Director-Melvin F. Lazar.

II.  PRELIMINARIES: Spread on record:  First:  l1/26/03 sworn Affidavit of Service re: Notice of Annual Meeting and related Proxy materiel by American Stock Transfer Company employee-agent; Second:  List of shares and shareholders entitled to vote at meeting; and Third:  Inspector of Elections report that valid Quorum then existed of shares and shareholders present in person or by proxy.

III.  FIRST ITEM OF BUSINESS:  (1) Nomination and election of two directors to Enzo’s Board of Directors for a 3-year term through July 31, 2007 and/or until such time as successors are elected and qualified; and (2) Approval of Independent Auditors for Enzo’s during its FY-2004.

(1) MOTION made and duly seconded nominating existing DIRECTORS, Shahram K. Rabbani and Irwin C. Gerson, for re-election.  No further nominations being made; they were closed.  Report of Inspector of Elections read into the record disclosed motion carried by majority (i.e., 98+%) vote of issued and outstanding shares present and entitled to vote.  Ballots cast declared open to shareholder inspection during meeting.

(2) MOTION made and duly seconded to approve selection of accounting firm, Ernst & Young, as Enzo’s INDEPENDENT AUDITORS through FY-2004. Report of Inspector of Elections read into record disclosed motion carried by majority affirmative (i.e., 99%) vote of issued and outstanding shares present and entitled to vote. Ballots cast declared open to shareholder inspection during meeting.

IV. SAFE HARBOR NOTIFICATION screened in full and read aloud by Barry Weiner (“BWW”).  Shareholders advised Safe Harbor Statement also contained in Enzo’s Annual SEC FORM-10-K filed October 2003 (see Enzo website). [Also written in Enzo’s 1/14/04 Press Release published at ASM and distributed on same day to all Enzo shareholders. The “Safe Harbor Statement” acts to notify if and/or when liability may or may not attach as a result of shareholder reliance on Managements statements about historical events versus forward looking future events.

V.  PRESENTATIONS: -- Given in order by BARRY W. WEINER (“BWW”), DEAN  ENGELHARDT, Ph.D (“DE”) and ELAZAR RABBANI, Ph.D (“ER”).  Limited space and time results in the integration of their comments herein.  Perhaps because of poor acoustics in the Yale Club’s very large and high ballroom, this writer and many other attendees had difficulty hearing most of ER’s comments; hence, there’s a scarcity of reports thereon herein, but efforts may be made to relate more if ascertainable from others at some future date.

BWW commented his report would focus on what Enzo has done in the past in many business-related areas and what it plans to do in the future.   He did, but the material delivered at great speed proved too voluminous for total inclusion in this message board report.  BWW supplemented his oral report by screening a well-organized and informative series of visual graphs, charts and photographs.  He reported that Enzo Biochem, Inc., via its clinical labs, life science diagnostics and therapeutics companies discussed below, is (a) a leading biotechnology company specializing in gene identification and genetic and immune regulation technologies for diagnostic and therapeutic applications; and (b) engaged in the research, development and manufacture of innovative health care products based on molecular biology and genetic engineering techniques, and in providing diagnostic services to the medical community.

A.MY OVERALL IMPRESSION was that Management is very confident about Enzo’s outlook and proud of its achievements to date.  Collectively, Management’s message was (a) Enzo Biochem has and continues to make significant progress; (b) its strategies and actions in expanding Enzo Life Sciences’ direct sales efforts were very positive steps and moved Enzo towards a more-centralized (rather than supply-distributorship) marketing of its proprietary products; (c) Enzo Clinical Labs is seen as strongly positioned to continue both its financial growth and its expansion of lab-service sites; (d) development of the EnzoTherapeutics pipeline is growing rapidly and now offers important new potential treatments for a variety of medical conditions; and (e) new and existing research studies and trials are moving forward.  In addition, Management believes Enzo Biochem still enjoys a strong financial position, continues to be cash positive, and is dominant in areas such as, e.g.,(a)  gene visualization, labeling, detection, amplification and other diagnostic technologies; (b) state-of-the-art and other esoteric testing, and (c) in developing unique potential genetic and immune regulation and therapies.

B.  GENERAL COMMENTS RECOLLECTED include BWW’s observations: (1) that: Enzo’s last and current fiscal year gradually became very challenging and would likely continue that way; (2) in both its FY-2003 and its future outlook, Enzo’s progress was and continues to be extremely good;  (3) the state of Enzo’s operations is in excellent condition; and (4) in addition to its well-formulated strategies (see, pp.4-5 , Enzo 2003 SEC Form 10-K),, Enzo’s core strengths are its Financials, Product Development, Diversification and Discipline.

(i) As to FINANCIALS:  Some figures were reported at the ASM, but are NOT dealt with herein because they are more than adequately dealt with and available on Enzo’s website, www.enzo.com, accessible by clicking on “Corporate”>>”SEC Filings”>> Annual FORM 10-K filed October 2003, and subsequently dated and filed Enzo Press Releases and SEC Forms 10-Q.

 BWW emphasized: (1) the importance of Enzo remaining liquid, observing this was one of its strengths in an industry where capital is a constant concern for many; (2) advised that despite the FY-2003 reductions in Enzo per share earnings (allegedly occasioned by the Affymetrix actions and/or omissions that led Enzo to sue and terminate the S/D contract with Affx.), Enzo continued to generate increased cash from operations; (3) that out of the top 400-ranked publicly traded biotechnology companies, Enzo placed around 30th in revenue and 13th in profitability; and (4) (a) Enzo’s revenues from Clinical Labs and Life Sciences financed all of Enzo’s therapeutic R&D and other corporate  operations and administrative expenses; (b) Enzo had not returned to the public market for money since it’s 1980 IPO raised ~$4-million, and (c) Enzo did not have any long-term debt.

(ii) As to PRODUCT-DEVELOPMENT:  BWW discussed (1) the growing market in genomics is expected to expand past $1-billion this year; (2) Enzo has a predominant proprietary position in this product market due to the superiority of its extensive line of nonradioactive labeling, detection, amplification, reagent and other gene-related products, including those that enable highly improved and expanded visualization of genes in diagnostic and therapeutic areas over products produced by competitors.

(iii) As to DIVERSIFICATION: BWW addressed Enzo’s business mix and in Q&A responded that Enzo Clinical Labs, Enzo Life Sciences and EnzoTherapeutics were structured to facilitate their individual spin-off should an appropriate time present..  He noted that, at this time, diversification of Enzo’s businesses enabled each of those companies to support and greatly assist each company.  In turn, that enabled Enzo to keep a lid on related R&D development, testing and other costs.

(iv) As to DISCIPLINE – one of Enzo’s reported core strengths, BWW noted Enzo was highly focused and took a clearly defined, conservative and deliberate approach to identifying, researching and, if warranted, developing its therapies, technologies and other products and services. He felt StarTrek’s claim that its Enterprise crew “only goes where none have gone before,” accurately portrayed Enzo’s unique approach to R&D and development of clinical lab testing and development of proprietary life science products and therapeutics.  He observed  (as did ER later) Enzo’s pipelines of life science products and therapeutics were being developed at internally-generated costs others believed not possible – ER noting the per product $800-million R&D costs that other pharmaceutical and biotechnology companies claim is the norm.  BWW and ER again noted that Enzo moves or marches to a different drummer. 

BWW discussed briefly some of Enzo’s strategies and informed their focus was to:  (1) (1) Apply Enzo innovative technology to the infectious disease market; (2) Maximize Enzo’s resources by collaborating with others in research and commercialization activities; (3) Apply our biomedical research products to the clinical diagnostics market; and (4) Further develop and maximize Enzo’s new centralized direct sales and marketing  programs while still seeking to leverage marketing and distribution infrastructure of leading life science and other companies for Enzo’s existing life science/diagnostic products and those of its future therapeutics.  BWW also gave a detailed discussion of Enzo’s core technologies and products.  Some mention of them is made in my notes on Enzo’s Clinical Labs, Life Sciences and Therapeutics businesses.

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C.  REPORT ON ENZO CLINICAL LABS:  Much information and commentary provided – including:

(1) Enzo has increased its Clinical Labs sales force, marketing efforts and number of lab sites in the tri-state area (i.e., outside of metropolitan New York).  It has opened a new clinical lab in New Jersey and will be opening 3 more new lab centers in the next 6 months – extending its reach into Northern and Central New Jersey and Connecticut. 

(2) Enzo’s Clinical Labs are fully competitive with larger national clinical lab chain-type companies -- primarily on the basis of (a) quality and specialized nature of testing, (b) reporting and information services, (c) reputation in the medical community, (d) pricing of its services, (e) reliability and speed in performing diagnostic tests, and (f) ability to employ qualified laboratory personnel. 

(3) Enzo is currently providing many new tests – including, new types of flow cytometry, blood and metal tests, superior gene identification and typing, etc.

(4) Enzo also makes extensive use of its Clinical Labs to: (a) demonstrate the benefits of gene-based products developed at Enzo Life Sciences, (b ) develop and perform tests needed to support Enzo Therapeutics’ ongoing clinical trials, and (c) meet testing requirement pre-FDA commercial marketing approval/licensing of Enzo Life Science diagnostic platforms and medical devices, including Enzo’s multi-tiered ISOthermal amplification and diagnostic INCHWORM platform currently in beta testing at Enzo’s Clinical Lab.

Other matters of interest included that: (1) the long-recognized expertise of Enzo Clinical Labs in microbiological agent identification and testing has resulted in it being appointed part of New York State’s RAPID RESPONSE TEAM should accident, catastrophe or terrorism trigger a future “Biological Event”; and (2) Enzo Clinical Labs’ state-of-the-art online computer and communication system, “ENZO DIRECT” is operating well and has proven extremely beneficial to Enzo and its physician-clients.

ENZO DIRECT allows physicians (a) to go online with Enzo, (b) access a physicians’ reference library, (c) order tests rapidly, and (d) have test results speedily transmitted to them worldwide at their offices or the point of patient service. Among its other important uses, ENZO DIRECT also allows Enzo and its physician-clients speedy and ongoing online interaction to monitor more effectively and on a worldwide and individualized needs basis patients and participants at medico-related facilities and/or clinical trial sites.  Management noted the ENZO DIRECT data is securely transmitted to physician-clients and trial sites in compliance with Federal physician-patient confidentiality requirements under the US Health Insurance Portability Accountability Act of 1996 (“HIPAA”) and its final regulations that were adopted in February 2003, to provide and govern electronic transaction privacy and security standards.  

D.  REPORT ON ENZO LIFE SCIENCES, INC. – BWW first reiterated Enzo’s proprietary labeling and detection products for gene sequencing and genetic analysis, with approximately 200 patents worldwide, are sold to the life sciences market throughout the world.  Then, referring to its prior reports regarding Enzo Life Sciences’ plans for increasing product sales, etc., Management advised Life Sciences had moved forward with an aggressive marketing program designed to service its end users more directly, while simultaneously positioning the Company for its  unprecedented upcoming new products expansion of its current 300-plus line of products.  BWW indicates this had been accomplished by: (1) hiring a new Vice President, Jim Chenitz, to manage its now expanded Enzo Life Sciences’ Centralized Direct Marketing program; (2) increasing the number of the LFS Centralized Direct Marketing Field Sales Force to cover the majority of the US by the end of Enzo’s FY-Q3; (3) adding more personnel to this Sales Force as new life science products come on line; and (4) initiating a comprehensive advertising campaign that includes (a) placing more articles and advertising in industry trade magazines, (b) increasing attendance and participation by Enzo Life Sciences at top industry trade meetings, life science product exhibitions, and at professional presentations.  Management noted all of its increased sales and marketing activity is directed toward accelerating revenue growth in subsequent quarters and to bringing the Company into more direct contact with its customer base.

Among other strategic decision-making, Management noted its Life Sciences’ Centralized Direct Selling and Marketing Program would focus on increasing the sales of Enzo’s BioArray line of products to the ever-quickly expanding genomics market.  It commented that Enzo’s BioArray (Linear RNA and other type) Amplification System is superior to other systems and allows for multiple amplification, etc.  Enzo added its amplification and diagnostic products have applications in the growing clinical, genomics and life science markets, and that patents covering these products constitute an important contribution to Enzo’s portfolio of intellectual property.

Management briefly mentioned other of Enzo’s products, paying more attention to some over others, but included commentary on its (a) gold standard non-radioactive labeling and detection reagents – which it said were a leading worldwide enabler of microarray technologies used in gene expression and genomic analysis applications; (b) its BioProbe products used for labeling random primed DNA, Nick Translation DNA, Oligonucleotides, RNA Transcript, etc.; (c) products for diagnosing human papilloma virus and various other bacterial, viral and ST diseases, (d) modified nucleotides, and (e) innovative patented property in the fields of  molecular biology and monoclonal antibodies.   While talking about Enzo’s signaling and die-labeling-detection products, Management noted it produced both high and low density product – mentioning, in particular, Enzo’s BioArray GeneBeam First Strand cDNA labeling systems for microarray applications, including hybridization.  Enzo informed its GeneBeam system was developed to meet stringent requirements of nucleic acid array analyses.  It has the advantages of  (a) Strong, clear signals (i.e., for highly efficient labeling results in robust signals and extremely low backgrounds), (b) Convenience (i.e., the system supplies all reagents, including cyanine dyes, in a convenient, straightforward, ready-to-use format), and (c) Versatility (i.e., the GeneBeam™ is formatted for a wide variety of research applications).

 Management then described Enzo’s GeneBeam system as a superior product for the purpose of gene visualization.  To this end, it screened slides of separate squares -- one using Enzo’s products and the other square depicting results from competitor products. The purpose of the screen was to illustrate Enzo’s product superiority in the areas of quantity of genes able to be visualized, plus the fact that the Enzo product had the added benefit of also being able to identify in each sequence the types of genes present.  [NOTE:  All looked terrific through the squinting eyes of this non-techie, non-scientist, layperson.  To me, Enzo’s square produced a much brighter and fuller example of identifiable genes than did the competitor’s square.  In addition, because Enzo’s method includes die labeling-detection that marks different types of genes with different colors, typing individual genes (such as, e.g., messenger, etc.) was purportedly possible.  This latter product is perhaps a $40-million dollar market and the way it works purportedly adds superiority and value to Enzo’s product.  DE later confirmed this statement in noting it is essential for a researcher to be able to distinguish (a) not only the presence and number of genes in a certain square, but also what types of genes are presented in any particular gene sequence, and (b) what gene(s) are working or not working.  Then the scientist can determine what genes to turn on or off or to otherwise regulate up or down. According to DE, to be able to do the foregoing has million-fold implications and adds considerable value to Enzo’s BioArray product market.  To this end, it screened slides of separate squares -- one using Enzo’s products and the other square depicting results from competitor products. The purpose of the screen was to illustrate Enzo’s product superiority in the areas of quantity of genes able to be visualized, plus the fact that the Enzo product had the added benefit of also being able to identify in each sequence the types of genes present.  [NOTE:  All looked terrific through the squinting eyes of this non-techie, non-scientist, layperson.  To me, Enzo’s square produced a much brighter and fuller example of identifiable genes than did the competitor’s square.  In addition, because Enzo’s method includes die labeling-detection that marks different types of genes with different colors, typing individual genes (such as, e.g., messenger, etc.) was purportedly possible.  This latter product is perhaps a $40-million dollar market and the way it works purportedly adds superiority and value to Enzo’s product [*CAUTION*: Knowledge in this area is way over this writer’s non-technie, non-scientists head, as well as above her non-pay grade.  Hence, nobody should act in reliance or belief that this portion of Management’s presentation is accurately reported.]

INCHWORM – i.e., Enzo’s patented ISOTHERMAL MULTI-TIERED DIAGNOSTIC PLATFORM – was addressed at the ASM.  Attendees learned its various tiers could be used as separate diagnostic devices as Inchworm tiers include (a) a hand-held Pathologist’s unit; (b) a portable unit for Stat Labs and other walk-in patient service centers -- such as, e.g., hospital emergency rooms, doctors’ office labs, etc., and (c) a bigger tier for diagnostic and testing uses in large clinical laboratories

INCHWORM’s isothermal technology apparently keeps the same temperature throughout its processing, and produces cleaner/clearer (?) diagnostic results in less than an hour – i.e., around 40-minutes.  BWW said he hoped in good time Enzo’s Inchworm-type diagnostic technology will replace the concept of culture-based diagnostics because use of the former, he felt, would provide more accurate results more effectively and swiftly and, therefore, provide better service, especially for patients in need of prompt diagnosis prior to the initiation of inappropriate and sometimes costly and toxic treatments.

Management conveyed its conviction that Enzo’s multi-tiered INCHWORM was much faster, more accurate, cleaner, less expensive, and a more user- friendly, (a/k/a idiot proof) diagnostic platform than the similar sounding products offered by competitors.  DE later described INCHWORM as a “cheaper, better, faster, easier, more accurate, diagnostic platform, adding that it also only requires use of a single enzyme, while other products offered for similar purposes require more that add to costs, etc.  DE’s contribution followed a Q&A inquiry as to the implications or effect on Enzo’s Inchworm if Gen-Probe, plus another competitor, gets the TIGRIS (Sp.?) or other isothermal products to market next summer.  The prospect of the coming events did not seem to perturb management.  Instead, it screened a slide which depicted part of the Inchworm prototype, with a lab researcher reading output on a smallish and allegedly simple to use Inchworm reader that had been manufactured to have applicable use with multiple units.

When obliquely queried as to if and when the FDA will license commercial marketing of the multi-tiered INCHWORM, Management did not suggest a timeline.  Instead, and keeping in mind INCHWORM is at least three tiers, each capable of being used as separate units, Management explained that the FDA has a number of procedural testing and commercial marketing licensing routes for various kinds of medical devices – depending on (i) the state-of-art of the product, and/or (ii) its intended type of use.  Depending on which of this varied criteria is applicable to the product(s) FDA required testing and licensing may take from months to years.  Management identified a couple of application routes and exemptions.

[NOTE:  For those interested, limited information about types of medical devices subject to testing and FDA commercial marketing licensing via 510-K clearances. PMA approvals, etc., and/or those otherwise exempt or deemed to be in the RUO (research use only) categories, is available on pp. 13-14 of Enzo’s 2003 SEC filed Form-10K.  See heading, “Regulation of Diagnostics”.] 

Re: Enzo LIFE SCIENCE REVENUES after Affymetrix:  Management responded to an inquiry about whether life science revenues had recovered from the slump in then that followed the Affymetrix fall-out. In effect, Management said its Life Science Direct Sales and Marketing programs had achieved some improvement in this area of revenue.  It added shareholders should be able to get some idea of future life science revenues by a look at the financials for the end of the next fiscal quarter (1/31/04) and then project out from there.

E. REPORT on ENZO THERAPEUTICS, INC.  – BWW noted Enzo Therapeutics is in various stages of clinical evaluation of its proprietary gene medicine.  Management then took the opportunity to comment extensively about various aspects of Enzo’s research using, what is referred to as, Enzo’s FIVE (5) therapeutic platforms,  They currently are its:  (1) GENE REGULATION PLATFORM, (2) IMMUNE REGULATION PLATFORM, (3) IMMUNE POTENTIATION PLATFORM;  (4) EX VIVO CELL TRAINING AND TRANSFER PLATFORM; and (5) GENE EDIT, REPAIR AND DELIVERY PLATFORM.   [Below, appearing in like-numbered order, are comments on these platforms selected from a voluminous amount presented at the ASM.]

ITEM (1) -- GENE REGULATION PLATFORM (“GRP”) – Management informed this GRP involves the introduction into cellular DNA of a gene that codes for a complementary RNA molecule that leads to inactivation of a specific gene product.  To deliver the gene to the appropriate target cell, Enzo developed a proprietary vector technology (“Bio-stealth Vector”) that: (a) produces Efficient Transduction; (b) is Immunologically Quiet – i.e., does not express extraneous proteins; (c) is Smart – i.e., it preferentially transduces the intended cell type; and (d) has Broad Applicability in and to the field of gene medicine.

Management also advised that in addition to HIV-infection, its Gene Regulation Platform has important implications for the treatment of a broad spectrum of other non-HIV infectious diseases and/or genetic conditions.  In Q&A, Management gave a guestimate that the HIV patient market in the U.S. for this GRP may reach ~15-million.  Neither requested nor given was a guestimate of the market that could use this GRP to treat non-HIV infectious and/or other genetic conditions, such as liver cancer, etc.

(a) HGTV-43 HIV/AIDS GRP CLINICAL STUDIES: -- They include the: (i) in vitro (in glass) lab pre-clinical at Cornell Hospital in the mid-1990’s, and (ii) the first

arm of Enzo’s FDA 1998 approved Phase I clinical trial at UCSF -- where gene expression of Enzo treated progeny was detected by monitoring the circulation, etc., of UCSF trial participants for more than 4-years.  Management also announced that, a few

days prior to this ASM,  Enzo’s HGTV-43 Phase I/II (i.e., patient entry) had started at the  New York Presbyterian Hospital-Weill-Medical College of Cornell University in New York City. [NOTE:  Enzo’s new cell therapy – to wit, its HIV Complementary Treatment is discussed below in ITEM (2) IMMUNE REGULATION PLATFORM.]

STATUS OF HGTV-43 PHASE I/II:  --  In June 2003, the US-FDA lifted its regulatory “hold” on Enzo’s next 3 HGTV-43 HIV/AIDS Phase I/II clinical trials. Then in November 2003, Enzo released the news the Cornell local IRB and IBC had also cleared its Phase I/II HGTV-43 HIV trial to proceed at Cornell and trial personnel would now be trained and trial site leukopheresis labs, etc., equipped.  As previously reported, at this ASM Management announced it had initiated (i.e., patient entry/treatment) the study  Cornell a few days earlier.

HGTV-43 TRIAL HISTORY: -- Management noted that this particular gene regulation therapy had been a long time in gestation.  A causal reason offered among others was the recent 1+-year delay that ensued due to imposition of a regulatory “hold/halt” placed by the FDA on Enzo’s 3 HIV/AIDS multi-site Phase I/II human trials and 27 other U.S. based gene therapy trials following 2 reports from a gene therapy trial in France that 2 of 10 X-SCID babies in whom immune systems had been created via gene therapy had thereafter developed a leukemia-like onco condition – possibly caused by the design of that trial’s retroviral vector, that either caused splicing or mis-sequencing of inserted genes and turn-on of onco-like gene replication.  DE explained briefly that Enzo’s HGTV-43 retroviral vector has been designed so as not to trigger either of the theorized problematic events.  He added Enzo was able to persuade the FDA to its position during its Phase I/II HGTV-43 re-clearance process mentioned below.

BWW described the lengthy period of paralysis that befell the industry following the aforesaid FDA “hold/halt” directive.  [Note: A similar type of paralysis settled on much of the gene therapy industry following the imposition of a “hold/halt” on trials using similar vectors to the one used in a gene therapy trial in Pennsylvania during September 1999, when a 19-year old died as a result of procedures implemented in that trial.]  In the period of the Enzo-related FDA “hold/halt”, in consultation with its Advisory Boards and various other entities, including NIH-RAC, the FDA came up with a program under which the “hold/halt” US gene therapy trials might be re-cleared to proceed by doing further tasks and presenting the results thereof for FDA review.  Among other things, the new FDA program required Enzo to (1) re-examine the USCF trial participants it re-infused with its HGTV-43 more than 4 years ago, test them for leukemia, etc., and submit their results to the FDA;  (2) prepare and submit a new very long-term post-trial participant monitoring plan; and (3) revise and submit the Informed Consent acknowledgements containing FDA draft language that recruitees will need to sign prior to becoming an HGTV-43 trial participant.

STATUS OF HGTV-43 PHASE I/II:  -- In June 2003, the US-FDA lifted its regulatory

“hold” on Enzo’s next 3 HGTV-43 HIV/AIDS Phase I/II clinical trials. Then in

November 2003, Enzo released the news the Cornell local IRB and IBC had also cleared its Phase I/II HGTV-43 HIV trial to proceed at Cornell and trial personnel would now be trained and trial site leukopheresis labs, etc., equipped.  As previously reported, at this ASM Management announced it had initiated (i.e., patient entry/treatment) the study at Cornell a few days earlier.

PURPOSE & GOAL OF CURRENT CORNELL TRIAL:-- BWW observed that what had NOT happened after the participants received Enzo’s HGTV-43 at UCSF was major increases in the numbers of bone marrow-engrafted genetic antisense treated stem cell constructs and new progeny therefrom that carried the anti-HIV treatment through the thymus and into the participant’s circulation and places serving as HIV replication reservoirs and compartments.  He also reminded attendees that UCSF participants had not been partially or fully ablated prior to HGTV-43 re-infusion, noting that ablation at various levels facilitates the making of more space for engraftment of stem cells into the participants respective bone marrow receptacles because it destroys some or all of the bone marrow then occupying the receptacles.  As a result, few of the re-infused genetic antisense treated stem cell constructs were able to squeeze in to engraft, etc., in bone marrow.  Hence, the treated progeny produced were also low in number.  Both BWW and DE advised that “the objective of the current Phase I/II HGTV-43 trial started at Cornell is to increase engraftmentin bone marrow of the number of engineered cells that contain the anti-HIV-1 antisense RNA genes so as to eventually produce a sufficiently increased number of anti-HIV treatment containing progeny in each participant’s circulation [GDV adds: “and his/her other HIV reservoirs (e.g., latent memory and other cells lymph nodes, spleen, macrophages and other tissues) and anatomical sanctuaries (e.g., thymus, kidneys, brain, sperm and anal compartments, genitalia, etc.).].

DLE believes there needs to be at least 10% more treated stem cell constructs entering and engrafting into the participant’s respective bone marrow receptacles, there to differentiate, mature and produce the progeny that continues to carry the anti-HIV medicine in to the above-described areas of the participant’s body.  To create this extra engraftment space, DE advised attendees the Cornell clinical trial staff will first partially ablate a trial participant using a low-level of radiation, coupled with an immune conditioner and MMF.  To ablate means to destroy part or all of the existing bone marrow containing the participant’s existing (and sometimes already HIV-infected) stem cells in the bone marrow receptacles.  Partial ablation with MMF at Cornell may create, and eventually reveal, sufficient increased engraftment space for Enzo treated stem cell constructs in the receptacles. After destruction of some of the participant’s existing bone marrow, the MMF will also help prevent rejection, as foreign matter, of the newly infused constructs should the ablation cause participant’s immune system to temporarily not recognize the re-infused autologous matter as that of the participant.  The immune conditioner will help to enhance the engraftment and to increase production of sufficient numbers of new treated progeny containing the anti-HIV medicine. [GDV NOTE: As neither partial nor full ablation of former UCSF participants took place, temporary loss of recognition and/or rejection was not then an issue.]  Management believes if the number of engrafted stem cells and treated progeny is sufficiently increased, Enzo’s HGTV-43 approach will be a once a lifetime treatment for those infected with HIV. 

 [GDV NOTE: As neither partial nor full ablation of former UCSF participants took place, temporary loss of recognition and/or rejection was not then an issue.]

PRELIMINARY PHASE I/II RESULTS –When?: -- Background:  Six (6) trial participants are proposed under Enzo’s Cornell Phase I/II protocol.  Pursuant to a mutual arrangement reached during the Cornell protocol hearing before NIH-RAC, it was agreed that certain concerns expressed by 1 of the 13 RAC panel would be dealt with by starting this trial with 2 of the 6 participants.  After these 2 participants are partially ablated and

re-infused via HGTV-43 a team of physician-immunologists are to examine and test the 2 participants to learn whether his/her respective thymus has been adversely affected by partial ablation using low-level radiation.  The decision to proceed, modify protocol or stop this study will be made when these results are evaluated.  [NOTE: FWIW, the planned low-level partial ablation is not expected to trigger thymus problems.  Dr. Jeffrey Laurence, Principal Investigator for Enzo’s HGTV-43 trial at Cornell, is a board certified immunologist with years of experience in research and treatment of HIV/AIDS patients. At the 2001 NIH-RAC protocol hearing, Dr. Laurence noted that many HIV/AIDS patients received similar radiation treatment at Cornell without adverse consequences.]

This background, coupled with the time nature takes to have the treated stem cells engraft, differentiate, mature and produce new progeny containing the anti-HIV treatment, led BWW to estimate it will likely take around (a) 6 months after treatment of first 2 participants, and (b) 12 months if all participants are treated, to be able to arrive at a reasonable preliminary determination on (i) whether ablation at the planned level was safe; (ii) if the ablation procedure created sufficient space in the bone marrow receptacles for engraftment of increased numbers of genetic antisense treated stem cells; (iii) what the percentage of increased engraftment, if any, of stem cells measured; (iv) did those treated stem cells survive and produce increased numbers of progeny; and (v) was the increased number of surviving progeny produced, if any, at a level sufficiently high to EVENTUALLY be effective against HIV after they have traversed through the thymus, the other HIV reservoirs and sanctuaries, and expressed in circulation.

[GDV CAUTION:  This Cornell trial is testing “SAFETY” (i.e., of HGTV-43 when used with partial ablation via low-level radiation and MMF) and “EFFECTIVENESS” (i.e., of HGTV-43 with partial ablation to enhance both the engraftment numbers of treated constructs and treated progeny survival numbers expressing in circulation.  The question to be answered IS:  Has the combined HGTV-43 plus ablation per protocol actually and safely produced the enhancement in engraftment space, enhancement in numbers engrafted and enhancement in progeny produced from treated stem cell constructs?  At this stage, the question is NOT:  Have the participants been cured of HIV at this time?]  If enhanced levels of space, engraftment and progeny numbers actually result, but further increase is required, the protocol can likely be further modified to meet the need.]

According to Management, it believes Enzo’s future achievement at Cornell lies in increasing the engraftment space in the participants’ bone marrow receptacles so as to sufficiently enhance both the numbers of engrafted treated stem cell constructs in bone marrow and the production of subsequent progeny to continue in circulation, etc., the anti-HIV treatment.  Such success will enable Enzo to attain its ultimate goal:  It is to use its HGTV-43 approach as a once in a lifetime treatment that will reconstitute a healthy immune system in treated individuals that will (a) initially manage and control HIV-infection throughout the body so as to delay and prevent AIDS, and (b) then eradicate HIV from all cells and places in the treated individual’s body.

[GDV NOTE:  FWIW, my personal feeling is that before start-up of the other 2 regulatory cleared Phase I/II HGTV-43 HIV/AIDS studies, Management will first await results from this partial ablation approach at Cornell..]

Finally, Management informed Enzo’s StealthVector® HGTV43™ gene constructs also represents a novel strategy for managing patients likely to have on-set of AIDS because their resistance to current therapies does not delay that event.  [See, also, comments regarding Enzo’s new HIV Complementary Therapy Treatment discussed below in ITEM (2) IMMUNE REGULATION PLATFORM.]

****NEXT TOPIC:  IMMUNE-MEDIATED DISEASE THERAPIES (3 PLATFORMS):

Management reported Enzo now has THREE platforms that utilize different approaches to treating immune-mediated disease.  Enzo believes its ongoing exploitation of these significant and powerful platforms may well enable it to develop and launch even more products for treating a broad range of immune-mediated diseases. 

Among its current preclinical and clinical projects are:  Crohn’s Disease (and other forms of Inflammatory Bowel Diseases “IBD”); Hepatitis B virus (“HBV”) and Hepatitis C virus (“HCV”) associated liver disease; various Hepatocellular Carcinoma and other Cancers and Antiviral Diseases; Non-Alcoholic SteatoHepatitis Disease (“NASH”) and Obesity; Non-Alcoholic Fatty Liver Disease (“NAFLD”) and Diabetas; HIV Complementary Therapy(ies); and Graft versus Host Disease (“GvHD”).   (See below, Immune-Mediated Disease Platforms ITEMIZED as:  (2) “IMMUNE REGULATION PLATFORM”; (3) “IMMUNE POTENTIATION PLATFORM”; and (4) “ EX VIVO CELL TRAINING AND TRANSFER PLATFORM”.)

[GDV NOTE:  Some of  Enzo’s approaches to treatments for particular illnesses seem to fall under more than one of its above-named Platforms.  A subsequent posted correction will be made should a treatment be listed under an incorrect platform.]

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ITEM (2) -- IMMUNE REGULATION PLATFORM (.“IRP”) REPORT: -- Enzo explained “its proprietary Immune Regulation technology seeks to control an individual 's immune response to a specific antigen, a substance that the body perceives as foreign and

to which it typically mounts an immune response.”  Enzo achieves regulation via “ORAL administration of a specific formulation of a known protein that adjusts (up or down) the particular immune response against the specific antigen.  Noting Enzo’s “strategy is based on the recent finding that immune responses can be regulated by the ORAL presentation of antigens,” Management related “the oral presentation of specific antigens in certain ways has both the effect of (a) suppressing the immune response toward those particular antigens, and (b) initiating other complementary immune responses” – adding that: (i) the desired effect can be achieved when the oral presentation occurs either before or after the body has mounted a specific immune response to the antigen”; and (ii) it has been shown in certain animal model systems this effect can be transferred through the transfer of the immune cells.” 

Management spoke of Enzo’s prior IRP animal pre-clinicals that (i) suppressed hepatocellular carcinoma; and (ii) showed immune regulation alleviated the symptoms of experimental ulcerative colitis in animals.  Also mentioned was Enzo’s ongoing IRP pre-clinical work in developing an orally administered HIV Complementary therapeutic treatment (see notes below). 

Both BWW and DE spoke about Enzo’s use of its #(2) IRP in past, existing and upcoming trials to treat the following diseases:  (a) Crohn’s Disease (i.e., a form of  “IBD”); (b) Hepatitis-B (Chronic) Disease, a/k/a “HBV”, and (c) Hepatitis-C (Chronic) Disease, a/k/a “HCV”; (d) current and potential next level of HIV Complementary Therapy; and (e) Non-Alcoholic Steato-Hepatitis (“NASH” – and sometimes called fatty liver) and Obesity.  Each is commented on in the foregoing order below:

(a) Re:  CROHN’S DISEASE: -- Facts:  Management reminded that Enzo’s pre-clinical studies for both Crohn’s Disease and Ulcerative Colitis were done at the Hebrew University-Hadassah Medical Center in Jerusalem, Israel (“Hadassah”). It has also completed an open labeled Phase I at Hadassah and is in process of completion of a randomized double-blinded controlled Phase II clinical trial at Hadassah.

Crohn’s Disease was described “as a highly debilitating intestinal illness” that has a growing MARKET.  Not including other forms of IBD, the Crohn’s market is currently estimated at ~1-million people -- of which, 500,000 are in the U.S.

Management explained Enzo’s treatment for Crohn’s Disease is a form of very “personalized” oral medicine; adding that Enzo formulates a protein from a specific antigen that is extracted from the relevant participant’s own intestinal biopsy.  As happened in Enzo’s aforementioned Phase I Crohn’s clinical at Hadassah, the newly formulated protein is administered orally to the participant from whom the antigen was extracted.  The oral regimen is administered over a 15 week period, but in Phase I that period lasted 16-weeks.  Each participant is thereafter monitored for an additional 12 weeks.

Reprising past reports, Management informed the results of its prior open-labeled Crohn’s Phase I showed Enzo’s achieved a high-degree of success in meeting its protocol “safety” and “efficacy” end points. . DE detailed that: (i) all 10 participants in this Phase I responded well to the experimental treatment, (ii) none of the participants suffered trial related adverse effects, (iii) 7 participants met the gold standard used in Crohn’s Disease to denote achievement of complete clinical remission, (iv) 2 of the 10 participants scored very close to the clinical remission criteria, and (v) 1 participant responded well but relapsed before the Phase I trial ended. 

A reference made reminded this Phase I Crohn’s clinical was one of several Enzo-Hadassah studies presented for peer-review one Sunday in October 2003, at both the AASLD’s Annual Conference in Boston, and in Dr. Yaron Ilan’s lecture on “Oral Tolerance: Mechanisms and Applications” at the New York Academy of Science medical conference in New York City.

DE’s made a few brief and humorous comments about a recent magazine article.  First noting Enzo wasn’t consulted or involved in its publication, he told of reported comments of prior participant(s) in Enzo’s Phase I Crohn’s trial at Hadassah.  One participant observed (a) he’d been so sick and discommoded by debilitating Crohn’s Disease, he’d been unable to work for many years; and (b) post treatment with Enzo’s “personalized” Crohn’s treatment in Phase I felt so well he’s since been engaged in fulltime employment. DE added that article had also reported commentary from an RN allegedly assigned to Enzo’s current double-blinded Phase II Crohn’s clinical.  Her clinical work was to record daily self-reports by participants about their manifestations, if any, of Crohn’s -related symptoms and general well-being or the lack thereof.  The article showed that named R.N. had, in effect, said she believed those Phase II participants currently reporting reduced or lack of Crohn’s symptoms were likely receiving Enzo’s “personalized” treatment, while those reporting Crohn’s degenerative symptoms and discomforts were likely taking the inactive placebo.

Referring to the fact Enzo’s Crohn’s Phase II was a randomized double-blinded controlled clinical study in which participants, trial staff, physicians, and trial sponsors are precluded from knowledge about which participants are administered an inactive placebo and which receive the experimental trial medicine, DE made plain why the RN’s conclusions were not acceptable “as a matter of science”.  Then, to laughter, DE said “his hunch was the nurse was correct.”

Re: PRELIMINARY PHASE II RESULTS & NEXT TRIALS --WHEN?: --  BWW reported:  (1) all 30 participants in Enzo’s Crohn’s Phase II had enrolled on a staggered basis and entered treatment (i.e., was administered either an inactive placebo or Enzo’s “personalized” experimental oral medicine);  (2) participant monitoring continues; (3)

 The current belief is that results from Enzo’s randomized double-blind Phase II Crohn’s study seem likely to be available in Spring 2004; and (4) if Crohn’s Phase II results proved as successful as those of Phase I,  Enzo plans are to submit them to the US-FDA as support of its current application to start a multi-center Phase III Crohn’s Disease clinical in the U.S., Europe and Israel during 2004.

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(b) IRP for HEPATITIS B VIRUS – Facts:  HBV affects more than 2-billion people worldwide.  It is deemed “chronic” if the HBV infection continues for more than 6 months. HBV-associated chronic active hepatitis affects more than 350-million

people worldwide. [GDV NOTE: Enzo can tackle stages of HBV under its:  #(1) Gene Regulation Platform, #(2) Immune Regulation Platform, and #(3) Immune Potentiation Platform.]

Management talked briefly about its pre-clinical studies.  Demonstrated therein was that Enzo’s experimental EHT899 for chronic Hep-B (a) achieved complete suppression of HBV-associated human liver cancer; and (b) significantly reduced mortality in laboratory mice.  Remarking Enzo’s completed open labeled Phase I and Phase II clinical studies for chronic HBV at Hadassah, BWW reiterated prior reports that both phases met their respective protocol’s endpoints by successfully achieving a high level of “safety” and the “efficacy” indicated by the respective results.

Re: STATUS of Chronic HBV CLINICAL TRIAL(S):  -- Management noted preparations are proceeding to start a double-blinded controlled Phase II clinical trial of

Enzo’s chronic HBV experimental EHT899 in the U.S. in/or about 2005.  Enzo currently has a pilot manufacturing program in the process of complying with US-FDA’s revised current Good Manufacturing Practices (“cGMPs”) for Enzo’s in-house manufacture of its HBV experimental EHT 899.  When FDA-OBA clears under cGMP compliance requirements, Enzo will seek other regulatory clearances to commence its proposed double-blinded HBV Phase II clinical at an academic institution in the U.S.  [GDV NOTE:  Need to clarify if this double-blind will also be multi-centered in, e.g., Europe and or Israel; will re-post results of inquiry.]

Re:  IMPROVED TECHNIQUES REDUCE MEDICINE COST: -- Both BWW and ER noted Enzo’s achievement and use of specifically improved techniques in it in=house manufacture of EHT899 will enable it to reduce its cost per dose from US$100.00 to $5.00. Ergo, this HBV treatment is affordable in Africa and other lesser- developed and poorer countries where most of the chronic HBV 350+million sufferers reside.  BWW noted these demographics necessitate the manufacturing, marketing and distribution of EHT899 abroad and reiterated Management’s intention to partner on HBV to get these post-regulatory approval services.

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(c)IRP for HEPATITIS C VIRUS (“HCV”):-- Queried as to the potential MARKET for HCV, Management advised HCV affects ~170-million people worldwide, including 3.9 million in the U.S. of which, ~2.7 million are chronically infected.  There are ~30,000+ new HCV infections recorded each year in the U.S. Approximately 85% of HCV-infected people go on to develop chronic hepatitis; ~20% develop liver cirrhosis, an incurable disease; and ~50% of these cases progress to end-stage liver disease, including liver cancer.  HCV-related deaths in the U.S. may soon exceed those caused by AIDS-related disease.

EHC18, Enzo’s experimental biologic for chronic Hep-C, was developed in earlier pre-clinical studies and then tested for “safety” in the first prong of Enzo’s Hep-C Phase I clinical at Hadassah. The second approved prong of that Phase I related to research on ii) Hepatocellular Carcinoma (“HCC”). 

[GDV NOTE:  I don’t know if that second prong was started or completed.  Perhaps Enzo prefers to develop a different treatment approach for HCV HCC.]

Management did advise it was: (a) awaiting regulatory approval of its submitted protocol and application to start another Hep-C Phase I clinical trial under its #(2) IRP; and (b) its small molecule therapy in its new #(3) Immune Potentiation Platform shows in pre-clinicals it can provide anti-viral, anti-cancer therapy and treatment of HCV when it is involved with Gaucher’s Disease.   [GDV NOTE:  I do not recall an advisement of forthcoming clinical trials involving Hep-C in Enzo’s #(3) IPP.]

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(d) IRP for HIV COMPLEMENTARY THERAPY:  Management advised of ongoing

preclinical research and development of an HIV Complementary therapy under its #(2) IRP.  [GDV NOTE:  I do not recall with certainty whether Enzo is preparing to pursue this research in a Phase I.  I think so, but will seek clarification and re-post to confirm one way or t’other.]..

Both BWW and DE spoke about this new HIV Complementary Therapy.  BWW mentioned Enzo had a proprietary oral presentation method of regulation involving

Utilization of Interleukin-6 (“IL-6”).

[GDV NOTE:  IL-6 has been described as “having an important role in immunity and as both a pro-inflammatory and anti-inflammatory molecule, a modulator of bone resorption, a promoter of hematopoiesis, and an inducer of plasma cell development.  The gene for IL-6 is located on chromosome 7p21 (2).  Many types of cells, including macrophages, T cells, fibroblasts, and endothelial cells, produce IL-6 in response to stimuli such as bacteria, viruses, and other cytokines.  Cells known to express IL-6 R include CD4+ and CD8+ T cells,82 hepatocytes,83 CD34+ stem cells84 neurons,85 neutrophils,86 monocytes74,  and osteoblasts.”]

DE briefly explained the treatment approach involves the growing/cloning of certain Natural Killer T-Cells (“NKT”) and inserting into them Enzo’s anti-HIV treatment.  As a result of this therapy these new replacement cells remain resistant to HIV and replace old immune cells and others unable to replace themselves because of repeated turnover of the new (and immature) cells called for when HIV attacks the immune systems cells.  DE noted that (a) onset of AIDS in an HIV-infected person is an indication the body cannot meet its need to turn out a new healthy supply of immune cells to assist and/or replace those attacked by HIV; and (b) in the course of progressing into AIDS, individuals stop making the white T-cells. [e.g., CD8, etc.]  My take from the foregoing was that Enzo’s orally presented HIV complementary therapeutic may serve an important role in either stopping degeneration into AIDS and/or helping to restore an AIDS-infected person’s immune system to a level at which it can retain management and/or control over HIV so as to not to again slide into AIDS and its opportunistic diseased states.

Management noted several times how essential it was to develop a pipeline of oral treatments for managing and/or defeating HIV/AIDS, especially where millions of such infected people exist—such as in Africa, Asia, Eastern Europe, the Caribbean, etc.  It

seems hopeful it will be able to fully develop this orally presented HIV Complementary therapy for these tens of millions of HIV/AIDS-infected individuals.

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(e) NON-ALCOHOLIC STEATOHEAPTITIS (“NASH”) and OBESITY:  -- NASH is also sometimes called Fatty Liver Disease (see GDV NOTES below).

[GDV NOTES: (i) There are at least TWO (2) types of fatty liver disease..  Treatment for another type also being researched by Enzo is discussed below at #(4) EX VIVO CELL TRAINING AND TRANSFER PLATFORM..  This second form of fatty liver disease is herein and elsewhere referred to as NON-ALCOHOLIC FATTY LIVER DISEASE (“NAFLD”).  The use herein of NAFLD as an acronym for the second type of fatty liver disease should help readers distinguish commentary directed at NAFLD from that intended for NASH.

 (ii) That said, my cursory reading leaves me with the perhaps incorrect surmise that the distinction between NASH and NAFLD exists mainly in a measurement of the degree of severity and progression of each fatty liver condition, though some molecular distinctions may play a role in classifying type.  It appears to me that many similar signs and symptoms exist in both NASH and NAFLD, but onset of these diseases may derive from different genes, enzymes, environment and other factors.  In any event, it seems all these considerations and other factors must be part of developing the patient’s baseline so that a correct differential diagnosis can be made.

(iii) Reading that may help those interested in distinguishing NASH from NAFLD may be found at:  (1) HEP-Net:--: http://www.hepnet.com/hepc/uldh98/marleau.html ; (2) GOOGLE Search: http://www.att.net/cgi-bin/websearch?cmd=qry&qry=non-alcoholic+steatohepatitis&image.x=12&image.y=5; (3) Abstract Definition of NASH in Am J Gastroenterol. 2002 Nov; 97(11): 2714-24, Harrison SA, Kadakia S, Lang KA, Schenker S., “Nonalcoholic Steatohepatitis: What We Know in the New Millennium”  (4) NASH with HCV:  http://www.hivandhepatitis.com/2003icr/DDW2003/docs/hcv_052103f.html ;  (5) http://www.jhucct.com/nash/open/NASHpapers/449315_print.pdf re: RE;  TWO TYPES OF FATTY LIVER DISEASE; and  (6) Gastroenterology Expert Column, , Pouneh S. Mofrad, MD, Arun J. Sanyal, MD, “Nonalcoholic Fatty Liver Disease,” at: http://www.medscape.com/viewarticle/449315_print?WebLogicSession=QBm8nV4sSzxhlaJulv4QpF86lAN1e8ZNVajZSIznl91ITlAIB
WFQ|1981213934248902309/184161394/6/7001/7001/7002/7002/7001/-1.]

(iv) DEFINITION OF NASH by NIH:  It simply describes it as follows: >>“NASH is a common but poorly understood liver disease that is characterized by accumulation of fat in the liver (steatosis), accompanied by inflammation, cell injury and fibrosis (hepatitis) that closely resembles alcoholic liver disease but occurs in patients who drink little or no alcohol.  NASH is most common in adults above the age of 40 who are overweight or have diabetes, insulin resistance or hyperlipidemia.  However, the disease also occurs in children and in persons who are not obese or diabetic. Currently, there are

no effective therapies for NASH and its natural history and prognosis are not well understood.”<<  NOTE, however, a “strict definition for the histologic diagnosis of NASH includes in addition to steatosis and inflammation, either hepatocyte ballooning or degeneration or hepatic fibrosis.”]

MANAGEMENT’S ASM COMMENTS ON NASH and OBESITY: -- Management reported animal preclinicals being done at Hadassah under its IRP still is/are in process.  It was not clear to me if NASH and OBESITY were combined in one pre-clinical study or being approached separately in different preclinicals.

[GDV NOTES:  In some instances, but not all, NASH and OBESITY seem intertwined or derived from the same root.  In addition, I sense this type of similarity or pronounced overlap in and between the medico-science of NASH and OBESITY and that of NAFLD and DIABETAS discussed below.  The only clear mental distinction I can make at this point is based on Enzo’s decision to pursue different treatment approaches to similar ends under Platform #(2) for NASH/OBESITY, and Platform #(4) for NAFLD/DIABETAS.  Both NASH and NAFLD can and do in many instances involve both OBESITY and DIABETAS.]

NEXT LEVEL -- During the ASM information to the effect that Management intended to proceed to a Phase I clinical trial when animal preclinicals were completed under Platform #(4) for NAFLD and DIABEETAS.  However, it is not clear to me that the same information applied to completion of preclinicals under Platform #(4) for NASH and OBESITY.

***

OBESITY (and Leptin): .On this subject --as it pertains to and/or predominates in both NASH and NAFLD – Management estimated a potential MARKET that exceeds 300+-million people and is growing daily.  BWW spoke briefly about the role of LEPTIN in obesity and the consequences visited upon the individual who is resistant and/or insensitive to Leptin:  That is, s/he is unable to use the Leptin for the purposes required (e.g., to convert calories into energy, etc.), though his or her system may be producing adequate quantities of it.  He also noted the likelihood individuals who are resistant and/or insensitive to Leptin are also generally resistant and/or insensitive to Insulin and likely become diabetic with Diabetes Mellitus II (a/k/a Diabetes 2).

(5)  http://mentalhealth.about.com/library/sci/0402/blobese402.htm?terms=research+info+obesity

(6) Diabetes. 1998 Feb; 47(2): 230-8; Erratum in:Diabetes 1998 May;47(5):855.,

Mantzoros CS, Frederich RC, Qu D, Lowell BB, Maratos-Flier E, Flier JS.,

” Severe Leptin Resistance in Brown Fat-Deficient Uncoupling Protein Promoter-Driven Diphtheria Toxin A Mice Despite Suppression of Hypothalamic Neuropeptide Y and Circulating Corticosterone Concentrations.”]      See, more info on NAFLD/DIABETAS in discussion on Enzo’s Platform ITEM #(4) below.

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ITEM (3) IMMUNE POTENTIATION PLATFORM (“IPP”) (Small Molecule): -- Management described this platform as “an additional platform for immune-mediated diseases.  Its preclinical studies have to date focused on use of a small molecule pill to treat diseases in which an intermediate metabolite called “glucosylceramide (“GC”) plays a role.    Research involved identifying GC as a molecule that acts on immune regulatory Natural Killer T-Cells (“NKT”).  It therefore can impact the immune response in the body by modulating its function and adjusting it to a normal state.

Enzo pre-clinicals at Hadassah currently focus on developing GC small molecule pills for use in  (a)(i) HCV as a co-infection in GAUCHER (pronounced ”goSHAY’”) disease, and (a)(ii) Liver Failure Disease; (b) ANTI-VIRALS treatments; and (c) ANTI-CANCER treatments (see below).   Some of the information from these IPP and other Enzo preclinicals done at Hadassah was peer-reviewed at the AASLD’s annual conference  last October 2003. 

(a)(i) GC for HCV-Co-INFECTION IN GAUCHER’S DISEASES: -- Enzo’s research not only identified that: (1) glucosylceramide (GC) administered in small molecule pill form can impact the immune response and modulate its function back to a normal state by regulating the subject’s NKT-cells; but (2)  in subjects cross-infected with Gaucher’s Disease and Hepatitis-C Viru (“HCV”) it showed a significant protection of their livers to HCV-associated liver damage when compared to other HCV-infected people.

[GDV NOTES:  (i) SIMPLIFIED DEFINITION OF GAUCHER DISEASE.  Gaucher Disease is categorized into 3 types.  It is apparently “an inherited illness caused by a gene mutation. Normally, this gene is responsible for an enzyme called glucocerebrosidase that the body needs to break down a particular kind of fat called glucocerebroside. In people with Gaucher disease, the body is not able to properly produce this enzyme and the fat cannot be broken down. It then accumulates, mostly in the liver, spleen and bone marrow.” (If interested, click on Diseases and Conditions and search for Gaucher Disease at http://www.1uphealth.com/; and http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=150961]

Since Gaucher Disease is one in which GC accumulates in the liver, Enzo scientists concluded that GC accumulation protects the patient against immune mediated attack on the liver.

NEXT LEVEL-PHASE I CLINICAL:  Management noted an application has been filed to initiate a new clinical trial for the treatment of hepatitis C virus infection utilizing the Company’s IMMUNE POTENTIATION PLATFORM using novel small molecule immune modulation.  This will be a Complementary form of treatment done in accordance with the Helsinki Declaration and will be a different approach than Enzo took in its prior Hep-C Phase I at Hadassah. 

[GDV NOTE:  To me, Management’s mention of the Helsinki Declaration as controlling this HCV-GC trial, would seem to indicate that trials for this Phase I will be done abroad, though the Helsinki provisions are internationally applicable.]

(a)(ii)  GC and LIVER FAILURE: --  Management talked briefly regarding a second GC-related pre-Clinical completed at Hadassah.  This second study is described as a study with laboratory animals that were induced to undergo acute liver failure mediated by an immune attack. When these animals were treated with GC, the liver failure was reversed.

NOTE:  Management had previously advised that, taken together, these (a)(i) and (a)(ii) animal pre-clinicals identify GC as an important candidate drug in the treatment of certain immune mediated disorders of the liver.

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(b) ANTI VIRAL SMALL MOLECULE TREATMENTS:  -- Other than HCV in Gaucher’s Disease, I don’t remember Management supplying either a: (1) listing of viruses that may be able to benefit from its IPP small molecule treatment; or (2) information indicating the sole use of GC versus other small molecules in different viruses. 

[GDV NOTES:  Those interested in distinguishing Viruses versus Bacterial infections and categorizing or learning of the source and types of the former can click on the following links:  (1)  GOOGLE search VIROLOGY at : http://www.att.net/cgi-bin/websearch?cmd=qry&qry=List+of+Viruses+in+Humans&image.x=18&image.y=7; (2) “All the Virology on the www,” at: http://www.virology.net/garryfavwebindex.html;  (3) Interesting viral web pages and other resources; and (4) The Big Picture Book ofViruses at: http://www.virology.net/Big_Virology/BVHomePage.html.

Click in Left Column to find VIRUSES by:  (1) Names (i.e., Lists of Virus Families, Individual Viruses);  (2) Structure Genome;  (3)  Hosts;  (4) Disease, etc.]

****

© ANTI-CANCER SMALL MOLECULE TREATMENT:-- Other than remarking on the existence of this IPP for -Cancer Treatment, I don’t recall Management mentioning either (1) specific cancers of the type this approach might treat; or (2) if anti-cancer treatment under Enzo’s IPP is to use the GC molecule or employ other types of small molecules.

[GDV NOTES:  Those interested in more information about the cancers that are currently known can research at:  (1) GOOGLE:  “Cancers and Oncology,” @http://www.att.net/cgi-bin/

websearch?cmd=qry&qry=CANCERS+and+ONCOLOGY&image.x=11&image.y=5; (2) Cancer Center…Mass. Gen. Hosp.-- http://www.cancer.mgh.harvard.edu/cancer_ptcare_clinicalprog.htmhttp://www.cancer.mgh.harvard.edu/cancer_ptcare_clinicalprog.htm; (3) About Cancer -- http://www.cancerindex.org/clinks14.htm; and(4)  Adult Cancer –

http://www.cancerindex.org/clinks14.htm#adult…Also.lists Global Cancer and Child Cancer deaths, etc. ] 

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ITEM (4) EX VIVO CELL TRAINING AND TRANSFER PLATFORM (“ECT/TP”): -- Management explained that Enzo’s new ECT/T platform involves the transfer of immune regulatory (NKT) cells.  These NKT cells are either just transferred or are first trained outside the body (i.e., “ex vivo”) before transfer.  BWW commented on 3 groups of pre-clinicals done under this new ECT/T platform at Hadassah, noting their results were peer-reviewed October 2003, in Boston, at the AASLD’s Annual Conference and/or in New York City at the New York Academy of Science’ Medical Conference.

Attendees learned that Enzo’s ex vivo cell training and/or transfer approach was studied in various pre-clinical models for:  (a) Graft versus Host Disease (“GvHD);  (b)(i) Non-Alcoholic Fatty Liver Disease (“NAFLD) and Diabetes; and (b)(ii) Obesity (non-hepatic) and Diabetes; and (c) Hepatocellular Carcinoma (“HCC”) Complementary treatment.  ASM-derived information on each category

(a)GRAFT VERSUS HOST DISEASE (“GvHD”):  -- Background:  Management has described GvHD as a major complication of human bone marrow and stem cell transplantation accounting for many of the failures of these transplant procedures.  GvHD is characterized by an immune response mounted by the immune cells within the engrafted tissue against the

recipient that leads to a wasting syndrome and occasionally death.  It

is estimated that there are only 15,000 bone marrow transplants performed annually worldwide due, in part, to GvHD.  It is assumed that the elimination of GvHD would lead to a dramatic rise in the number of these procedures.  GvHD is currently treated by immuno-suppressant drugs, which are toxic and only reduce the extent of the wasting reaction.  During Q&A BWW responded that GvHD had a potential market of 0.2-million people.

PRE-CLINICAL RESULTS:  Management reiterated the overall GvHD pre-clinical result reported in peer-review last October:  I.e., infusion of large numbers of the treated immune regulatory NKT cells led to an elimination of the symptoms of GvHD. 

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(b)(i) NON-ALCOHOLIC FATTY LIVER DISEASE (“NAFLD) and DIABETAS:

E (“NAFLD”) and DIABETES

[GDV CAUTION:  In reading, it may be difficult for non-medico-scientific professionals to always differentiate between NASH, NAFLD and other conditions giving rise to OBESITY that may not also then or thereafter show fatty liver disease. 

References enabling differentiation of the more severe NASH (i.e., non-alcoholic steato-hepatitis) from NAFLD and other types of OBESITY are hereinabove supplied.  See,

 e.g., relevant trial subsection for NASH in discussion of Enzo’s IMMUNE REGULATION PLATFORM ITEM #(2).  Also included thereat are Reference to literature on Obesity and Leptin. These latter topics are also relevant to (b)(i) NAFLD and DIABETES and (b)(ii) OBESITY and DIABETES discussed below.

[References applicable to differentiation of NAFLD and some types of DIABETES are included in (b)(i) and (b)(ii) below.]

NAFLD DIFFERENCES:  These were not detailed at the ASM, though Management made clear that though NASH (i.e., non-alcoholic steatohepatitis) was sometimes also referred to as “fatty liver disease” the NASH-type should not be confused with the fatty liver found in NAFLD (i.e., non-alcoholic fatty liver disease a/k/a “non-alcoholic steatosis”).

[GDV NOTES:  IM [uneducated] O, the language set in parenthesis above seems to indicate to this layperson that fatty liver in NASH involves one or more forms of hepatitis, while fatty liver in the NAFLD condition does not. 

This EXCERPT from an online [PDF] article is helpful in distinguishing NAFLD.  See, http://www.medscape.com/viewarticle/449315_print?WebLogicSession=QBm8nV4sSzxhlaJulv4QpF86lAN1e8ZNVajZSIznl91ITlAIBWFQ|19812139342
48902309/184161394/6/7001/7001/7002/7002/7001/-1         >>”There are 2 principal lesions of fatty liver disease: a pure fatty liver alone and steatohepatitis (Table 1). When fatty liver occurs in an individual who does not consume alcohol in quantities considered to be harmful to the liver, it is referred to as nonalcoholic fatty liver disease (NAFLD). [1]

This condition was originally identified in morbidly obese individuals, especially after weight loss surgery, and in women who were diabetic. [2,3] It is now known that NAFLD occurs in men as well as in individuals who are not diabetic, and it is increasingly being recognized as a major cause of liver disease.

 Epidemiology: The prevalence of NAFLD in the general population ranges from 13% to 15%. These data have been obtained from a number of studies that have used varying criteria for the diagnosis of NAFLD. Studies that have used histologic characterization of the condition have all focused on specific patient populations within a hospital environment and are therefore potentially subject to selection and ascertainment bias. [4-6] However, population-based studies have used sonographic methods to make a presumptive diagnosis of NAFLD. [7-11] The latter studies are unable to distinguish between a fatty liver and steatohepatitis. Even more important, sonography cannot effectively distinguish between a fatty liver and other medical disorders of the liver. Perhaps the studies least subject to selection bias are those of air crash victims who have undergone autopsies. Despite the heterogeneity of study methodologies, the overall prevalence of NAFLD in all investigations is similar, and ranges between 13% and 18%. Studies of liver biopsies of unselected autopsies or living donors for liver transplant indicate that the prevalence of steatohepatitis ranges from 2% to 4%. [12,13]   This  condition can affect any age group, including about 2.6% of children and up to 52.8% of obese children. NAFLD was originally believed to occur primarily in middle -aged obese women; however, more recent studies have shown that it occurs with equal frequency in men. [14]

Risk Factors Associated With NAFLD:  The most common risk factor associated with NAFLD is the presence of the metabolic syndrome. The metabolic syndrome is defined by the presence of 3 or more of the following criteria (Table 2) [15] : (1) increased waist circumference, (2) hypertriglyceridemia, (3) hypertension, (4) high fasting glucose, and (5) a low high-density lipoprotein (HDL) level. NAFLD is now recognized to be the hepatic manifestation of the metabolic syndrome. Given the fact that approximately 47 million individuals in the United States have the metabolic syndrome, [16] NAFLD represents a major health concern. Insulin resistance is the common pathophysiologic denominator that links all of the various components of the metabolic syndrome.

Of all of the individual clinical components of the metabolic syndrome, obesity has the strongest association with NAFLD. Obesity is defined as a body mass index (BMI) > 30 kg/m 2 . [17] The more obese the patient, the higher the risk of having a fatty liver. Thirty percent of patients who are obese have fatty liver, and up to 80% of morbidly obese patients (BMI > 35) have NAFLD. [18,19]  Regardless of BMI, patients with truncal obesity are at greater risk of fatty liver disease.

Other risk factors associated with NAFLD include type 2 diabetes, total parenteral nutrition, jejunal-ileal bypass operations for weight loss, and use of certain medications, including calcium-channel blockers and amiodarone (Table 3).”<< 

At the ASM, Management reminded about the pre-clinical studies done at Hadassah that were peer-reviewed last October.  In this NAFLD with DIABETES mouse model study --  in which transfer of immune regulatory (NKT) cells significantly altered this particular immune-mediated disorder -- Enzo has reported the infusion of large numbers of the NKT cells, led to an elimination of the symptoms of these conditions. It was observed that in this and other cell-based procedures the primary cell target was the immune NKT cell and that this cell type has a significant role in regulating the functioning of the immune system.

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(b)(ii) OBESITY and DIABETES: -- [GDV NOTE:  I am unable to determine if all of Enzo’s preclinicals only studied OBESITY as part of one or more fatty liver diseases (e.g., NASH and NAFLD).  Many people can be obese and not have NASH or NAFLD.  Hence, my insertion of this (b)(ii) sub-categorization under and into which some of Management’s comments about the role of Leptin (See references above in ITEM #(2) IMMUNE REGULATION PLATFORM) and that of various types of Diabetes are relevant.  Also reported in (b)(ii) is Management’s advisement on another AASLD peer-reviewed mouse model pre-clinical for OBESITY [fatty liver type] and DIABETAS.] 

After noting that many persons resistant/insensitive to Leptin are also resistant/insensitive to insulin, Management expressed enthusiasm about the results in the aforementioned and peer-reviewed separate Enzo-Hadassah OBESITY and DIABETES pre-clinical mouse model study.  It re-iterated its prio report to the effect that in this study the induction of immune regulation via administration of specific antigens manufactured from liver tissue significantly reduced the hepatic [i.e., liver] fat content of treated mice compared with the mice in the control group.  The results also showed that glucose intolerance (a characteristic of diabetes) improved significantly in these treated mice when compared with untreated controls.  Management noted the science folks believe these results suggest that immune modulation may serve as a therapeutic tool in patients with fatty liver disease or certain types of diabetes.

[GDV NOTE:  I’ll leave it to another time to define what, if any, are the distinctions in using the words (a) resistant/resistence, (b) insensitive/insensitivity; and/or (c) intolerant/intolerance, as used in comments concerning Leptin, Insulin, Glucose, etc.  The use of “insensitive/insensitivity” to either or both Leptin and/or Insulin does not suggest there is either an insufficiency or over-abundance thereof. Rather, it connotes an affected individual’s inability to utilize his/her produced Leptin and/or Insulin to adequately or otherwise fully perform its assigned regulatory, signaling, conversion, and other chores within the person’s body.]

FUTURE STATUS:  Management observed that there is more work being done in other animal preclinicals on insensitivity to Leptin and/or Insulin.

It added that when the preclinicals on the animal models are finished, Enzo will likely move into human trials. 

MARKET:  Management had already noted in Q&A that the obesity market exceeded 300+ million people.  The market in the U.S. for Diabetas 2 is close to 20-million. [GDV NOTE:  Though not always the case, Diabetes 2 is closely associated with obesity, and I think Enzo’s pre-clinicals may have just focused on this type.  Other types of diabetes are not associated with weight gain.  Markets for other types of diabetes were not discussed.]

[GDV NOTES: (1)  A GOOGLE search “DIABETES-MELLITUS” at:  http://www.att.net/cgi-bin/websearch?cmd=qry&qry=diabetes+mellitus&image.x=8&image.y=5

provides (a) Diabetes Tutorial at:  http://medlib.med.utah.edu/WebPath/TUTORIAL/DIABETES/DIABETES.html; and (b) Diagnosis and

 Classification of Diabetes Mellitus: New Criteria at:  http://www.aafp.org/afp/981015ap/mayfield.html.

(2) A GOOGLE search under LEPTIN-DIABETES shows, among other items, Leptin-Diabetes info at:  (a) Diabetes: The concept of selective leptin resistance: evidence. (Articles > Diabetes > Feb, 2002.) at: http://www.findarticles.com/cf_dls/m0922/2_51; 

(b) Diabetes: Leptin resistance during aging is independent of fat. Articles > Diabetes > April, 2002, at: 

http://www.findarticles.com/cf_dls/m0922/4_51/... ; and (c) Obesity Researchers Identify Protein That Overcomes Leptin ... obesity. (Developmental Cell, 16-Apr-2002)  at: http://mentalhealth.about.com/library/sci/0402/blobese402.htm?terms=research+info+obesity.]

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(c) HEPATOCELLULAR CARCINOMA (“HCC”) COMPLEMENTARY: --Management indicated HCC described Liver Cancer/Disease.

[GDV NOTES:  DEFINITION (General) of Liver Cancer can be found at the AASLD website.  In essence, the AASLD definition instructs:  “Cancer of the liver is uncontrolled growth of malignant cells in the liver. It may be a primary cancer, resulting from abnormal cells in the liver or bile duct, or it may result from the spread of cancer from another site.  Liver cancer can affect people of all ages but is most common in men over 60 years old.  The cause of liver cancer is unknown, but there is a strong association between chronic hepatitis B and C and liver cancer. People with cirrhosis of any form also have an increased risk.  Signs of liver cancer include loss of weight, weakness, pain or mass in abdomen, accumulation of fluid in the abdomen with swelling (ascites), and fever.  Surgery, chemotherapy, and forms of local ablation such as alcohol injection, and transplantation are treatment options, depending on the type and spread of the disease.  About 23,000 new cases of primary liver cancer are diagnosed each year. Thousands of others result when other forms of cancer metastasize to the liver.”]

I did not pick-up any info on whether or not the studied HCC was a viral or another type of liver cancer.

Management commented briefly on this HCC pre-clinical model at Hadassah.  It had previously been reported that in this model, the Enzo study used a procedure to*treat* these NKT cells outside of the body [so as] to enhance their capacity to manage human cell-mediated hepatocellular carcinoma. Added was that when the NKT cells were exposed ex vivo to certain specific cancer-cell antigens, and were administered to mice with a fatal type of human liver cancer, the cancers were largely eliminated

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ITEM (5) GENE EDITING/REPAIR PLATFORM: - Management spoke briefly about Enzo’s proprietary Gene Edit/Repair/Insertion Platform (“GERP”).  It supplies, among others, a procedure for correcting inborn errors of metabolism and point mutations.  Sickle cell disease is one of the areas for which this platform can be used.  Enzo has started some preclinical collaborative work under this platform with an (or more)

academic research institution.  BWW did not dwell on this gene edit/repair plantform; however, he referred to this platform as Enzo’s “Buck Rogers’ Platform”.

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F.  Re:  INTELLECTUAL PROPERTY AND LAW SUITS: -- Enzo considered its intellectual property program to be a key asset and a major strategic component to the execution of Enzo’s business strategy. “A broad portfolio of issued patents and pending patent applications both here and abroad supports Enzo’s core technology platforms,” he said, adding that Enzo’s policy is to seek patent protection for its core technology platforms, as well as for ancillary technologies that support these platforms and provide Enzo with a competitive advantage.  Management advised that as of the end of FY-2003, Enzo owned or licensed 42 U.S. patents and over 190 foreign patents.  These patents relate to Enzo’s products, methods and procedures that result both from Enzo’s internal or sponsored research projects.  He also advised patents relating to Enzo’s BioProbe nucleic acid probe have issued in both the U.S. and Europe.

In Q&A and in response to one or more questions from attendee(s) as to the number of lawsuits Enzo has been/is involved in with respect to claims of patent infringements, Management again emphasized the importance of fighting to protect Enzo’s patents, indicating a failure to do so would mean Enzo’s patent portfolio and, consequently, its businesses would be taken away.  BWW pointed out the lawsuit Enzo initiated against Affymetrix in October 2003 was a breach of contract action and not one for patent infringement.

Responding to another inquiry as to progress in some of these litigations, BWW advised that:  (1) In the Digene lawsuit, where it is claimed that Digene utilized an Enzo patented process in one or more of its products, BWW thought that the trial would get underway in/or about March 2004;  (2) Enzo’s suits against former supply/distributors, including Amersham, PerkinElmer, et al., are still at/or in discovery, though start-up of trials is expected in 2004; and (3) its action against Affymetrix has been scheduled for court conferencing in March 2004 at the Federal District Court for the Eastern District of New York.  The action involving GenProbe, Becton Dickenson, et al., was returned to the Federal District Court for the Southern District of New York for further findings after the Circuit Federal Appeals Court. sua sponte, reversed its prior decision in the Appellee’s favor.

G. FURTHER Q&A ISSUES:  (1) t1wirth asked BWW what he thought might be considered weaknesses and/or threats in or to Enzo’s businesses.  BWW

gave a long response.  I’ll leave it to the questioner to relate the “he said/he said” report.  BWW touched upon the importance of Enzo maintaining its cash independence for R&D via Clinical Labs and Life Science revenue, noting that the therapeutics Enzo has are more potentially valuable candidates than many small pharmaceuticals have; the need not to rely in great part on outside distributors, but to gain

greater control over the sale and distribution of Enzo’s own products; the need for Enzo to keep focusing on the development of products outside of the box, etc.

A question about joint ventures and funding sources to move products through the pipeless earned a response from BWW to the effect that Enzo doesn’t have to mortgage the future to its products at this point in time – adding the further along Enzo can sustain the development of its pipeline, the higher return there will be to shareholders.  He added Enzo will partner on Hep-B further along the lines, and since Enzo is not a traditional giant pharmaceutical it may likely seek to leverage the worldwide marketing and distribution to such larger companies after the products are developed.  BWW thought Enzo would require those services as Enzo cannot building up the worldwide sales those companies can.

A question on IB coverage brought the response Enzo does not seek to do offerings or arrange major loans with IBs at this time, and therefore that sort of coverage is unlikely at this time.  He also noted that events involving IBs and related IB analysts had almost paralyzed that sector and the drafting of new rules under which IB’s cannot in the future influence (by pay or duress) the type and tenor of an analyst’s opinion means the IB’s lending and related business may be impacted.  He further noted that action by the NYSAG, et al., seeking all in-house opinions by major brokerage houses and IB’s be sent to the client accompanied by same security reports written by independent non-brokerage/IB house analysts.

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NOTE:  The DISCLAIMER appearing at the head of this 27-part post is applicable to each and every of its parts,