Another Perspective: Failure or Success?
By: gdvmarch
NOTICE: By reference thereto I include as a part hereof the first FOUR paragraphs of my post #60196 - in particular, its DISCLAIMER advising I am not a scientist and do not write in any professional capacity. Unless expressly stated to the contrary, I post only my own personal views and opinions.
(1) This post continues my post #60196. It focuses on the second example in Post #60032, wherein it is asserted: (a) the Enzo-RAC 3/8/01 video [Anthony's Unofficial Enzo Page at: http://www.grq.net/enzo/ proves Enzo's Phase 1 HIV-HGTV-43 trial at UCSF failed; and (b) Dr. Conant unambiguously admitted the Phase 1 trial failed. I disagree with the KIS' conclusions and the manner used to persuade others to adopt them. Below are some reasons and support for my disagreement.
(2) Cut and pasted in this paragraph is the second example on which KIS based his conclusions that Enzo's USCF Phase I was a "failure". Specific analysis and discussion of this second example is in paragraph (5) below. Here is its language:
>>>"More meaningful for purposes of evaluating previous company comments (and the ongoing workings of the rumor mill):
"...[A] very good question, why didn't the original protocol work? You know, you transduce CD34 cells, you show you're making CD34 cells that are protected, in the peripheral circulation, why didn't HIV just kill off the other cells and leave those behind? And the answer is, the number of transduced CD34 cells in that appropriate ratio, that we're not seeing the numbers go up. We estimate that we need to get up to ten percent tranfected CD34 cells in the marrow, making a significant number of CD34 cells in the peripheral circulation."
"Note well: in answer to the question of why the protocol failed, Dr. Conant did not respond that it had not failed, but rather commented on the manner in which it had failed. Unambiguously, Dr. Conant admits that the phase 1 at UCSF failed. ..."<<<
[NB: Paragraph (5)(a)(i) below also quotes continuing language in Post #60032 used to intimate that perhaps Enzo mislead shareholders, et al. Post #60032 fails to supply sources against which readers can check accuracy of alleged word content and the context in which the words, if any, were set and could be interpreted.]
(3) Before dissecting the paragraph (2) quoted language, I'll address here the intimation underlying Post #60032 that Enzo mislead and/or failed to inform its shareholders accurately of the purpose, end-points and real outcome of its initial portion of the Phase 1 HIV-HGTV-43 trial at UCSF. To accomplish this I'll review below what information was available publicly before the RAC 3/8/01 meeting and publication of Post #60032. The RAC 3/8/01 video and all documents referred to are available for independent review by readers either on Anthony's and/or Enzo's websites (i.e., RAC video and Press Releases) and on the NIH-RAC website (i.e., Protocol Abstracts by numbers herein provided and RAC video).
The identified subparagraphs of this paragraph (3) discuss the following: (a) Abstracts filed by Enzo with the FDA setting forth the purpose and end-points of Enzo's 1998 UCSF Phase 1 clinical trial under NIH Protocol Number Report 230-(1998-01); (b) Enzo's HIV-related Press Releases prior to 3/8/01, plus one thereafter; and (c) Abstracts submitted in January 2001 for the Enzo-Cornell NIH Protocol Number Report 443-(2001) that (i) re-iterate the UCSF Phase 1 purposes, endpoints and results; and (ii) state the purpose and end-points of the proposed Cornell expansion of the UCSF Phase 1 clinical.
(a)(i) Enzo's Non-Technical Protocol 230 (1998-1) Abstract says: "In the proposed studies blood-cell producing stem cells will be collected from the circulating blood of HIV-1 infected individuals. The genetic antisense genes will be introduced into each patient's stem cells in the laboratory, and the treated cells will then be introduced back into these patients. We will study the patients to determine that this procedure is safe. We will also monitor the cells in each patient's blood for the presence of functioning antisense genes for a period of several months. In this way we can determine the stability of the functioning antisense genes within the body. We will also compare two separate dosing protocols to see if one is better."
(a)(ii) Enzo's Scientific Protocol Abstract says: "In this protocol we propose to isolate from circulation a population of cells enriched for the CD34+ antigen (peripheral blood stem cells or PBSC). These cells will be isolated from HIV-1 infected subjects previously treated with granulocyte colony stimulating factor (GSCF). They will be transduced with Enzo's triple U1/HIV-1 antisense MMLV vector. The transduced cells containing the anti-HIV-1 antisense genes will then be infused into the HIV-1 subject from which [sic.] they were originally derived. The end points of this study are: the safety of the procedure; the extent of engraftment and proliferation of THIS engineered cell population; and the relative efficacy of two separate dosing protocols."
(b)(i) Enzo's Press Release of July 13, 1998, announced Enzo "had initiated Phase 1 human clinical trials [note plural] of HGTV-43, a genetic antisense-based therapeutic product designed to treat HIV-1 infected individuals." In relevant part it said: "[T]he Phase I trials [again note plural] are designed to evaluate the safety of Enzo's novel therapeutic product. In addition, certain aspects of the trial will provide insight on how to formulate and deliver this medicine in the most effective manner."
The Release further advised that "in LABORATORY [i.e., in vitro] studies, the active genes cloned into HGTV-43 had achieved between 92% and greater than 99% protection for human immune cells against HIV-1 infection." [BACKGROUND NOTE: New posters and lurkers may review the successful results of Enzo's HIV-HGTV-43 pre-clinical laboratory trial at Cornell that preceded USCF Phase 1. The paper written by Liu, et al., and published at J Virology 71: 4079-4085 (1997), is still available on both Enzo's official and Anthony's unofficial websites.]
Continuing, Enzo said: "We have succeeded in developing a transducing vector that we believe is immunologically silent -- that does not produce any product that can be recognized as foreign to the body." [I.e., something then never before accomplished -- HECK, IT WORKS!] "Furthermore, we have successfully demonstrated that we can create in the LABORATORY setting human immune cells that are resistant to HIV-1 and maintain that resistance to the virus over a prolonged period." [I.e., something else never before accomplished -- HECK, IT WORKS TOO - "THEY BOTH WORK."]
(b)(ii) Enzo's June 2, 2000 Press Release advises: "Enzo's HGTV-43 medicine incorporates TWO proprietary technologies. One involves the insertion of a new type of genetic material into blood cells in order to inhibit the growth of HIV-1. This technology, known as genetic antisense, utilizes a mirror image of a gene, called an antisense molecule, to block the virus. [HECK IT ALSO WORKS IN HUMANS]. The second technology is based on a novel vector designed to DELIVER the antisense molecule ... into target cells with the objective of integrating the gene into the chromosome of the cells."[HECK, IT ALSO WORKS IN HUMANS!]
(b)(iii) Enzo's January 11, 2001, Press Release told us the first Phase 1 trial had attained its purpose and end-points, noting: "[E]ach of the five HIV-1 infected patients currently enrolled in the study tolerated the procedure well, and that in each case the transduced cells engrafted, propogated and were producing new differentiated CD4+ cells to fight the [HIV] virus." The Release continues: "In the study, three antisense genes designed to interfere with the growth of HIV-1 were put into blood stem cells, the cells that are present in blood, spleen and bone marrow, where they serve as a reservoir of progenitor cells that divide and develop into CD4+ immune cells, the cells predominantly infected by HIV-1."
In other words, Enzo's Release said the study was SUCCESSFUL in that it demonstrated HGTV-43 was SAFE. Using that stealth vector, Enzo said: "the anti-HIV-1 genes could be successfully put into stem cells and that these engineered stem cells survived, grew, and developed into CD4+ cells." [NB: THE PRE-STATED PURPOSE AND END-POINTS OF THE FIRST PORTION OF ENZO'S PHASE 1 AT USCF WAS ACHIEVED.]
SAY IT AGAIN, ENZO: "All five patients MET the TRIAL END POINT of six months after infusion of the engineered stem cells. During that time antisense RNA was shown to be present in the circulating immune cells, indicating that the gene therapy HAD WORKED and that the anti-HIV-1 GENES WERE PRESENT and FUNCTIONING in the cells."
AND ONCE MORE: "[S]ix months after infusion, antisense RNA was present in CD4+ cells, a subset of the immune cells and the target cells that are infected with the HIV-1. CD4+ cells are the cells that are depleted with time and that are associated with the progressive loss of immune functioning with time that defines the MAJOR pathogenesis of AIDS. Finally, the presence of the anti-HIV-1 antisense RNA was found in the bone marrow of 4 of the 5 patients. While the fifth patient had antisense RNA in both his circulating immune cells and CD4+ cells, his bone marrow produced an insufficient number of stem cells for a valid assay."
[BACKGROUND NOTE-- FYI: On publication of the above information I sought clarification as to why the fifth patient had "an insufficient number of stem cells for a valid assay." To the best of my recollection and understanding Enzo said, in effect, (i) it felt an insufficient number of the requisite cells were able to be retrieved from the material initially taken from the patient; and (ii) a second attempt to extract more was not pursued because the protocol did not provide for same and it was not done on other trial participants.]
In Enzo's 1/11/01 Press Release, Dr. Conant refers to FUTURE GOALS, saying: "We are anxious to begin the next phase of the trial in which we will try to give these protected CD4+ cells a survival advantage over HIV infected CD4+ cells that are not protected..." Enzo continues, "that the study had met the goals established at its initiation [and] that the Company is in the process of expanding the trial [i.e., Phase 1] with the PURPOSE of INCREASING the DOSAGE of ENGINEERED CELLS within the body." Dr. Engelhardt also advises: "The new, expanded studies are designed to [1] confirm our preliminary findings and [2] to enhance the capacity of the anti-HIV-1 antisense RNA to block the growth of the virus."
[BACKGROUND COMMENTARY: The "survival advantage" is both (i) a desired numbers goal for infusion of treated cells, and (ii) a hoped for numbers-related resulting EFFICACY endpoint. This goal and efficacy end-point is forward-looking and is sought to be accomplished in the FUTURE in the next step of Enzo's expanded Phase I's at both UCSF and Cornell and at the planned Phase 2 at the unnamed third trial site. All of the past and current documents evidence this is so.
Hence, a legitimate QUESTION still remains: "Why were some members of RAC on 3/8/01 calling a failure the lack of an achievement not undertaken or even scheduled as a goal or efficacy end-point of that portion of the Phase 1 initially carried out at USCF? A strongly suggested ANSWER is: "Could it be possible some RAC members were either jumping the gun or hadn't read adequately, if at all, the Enzo materiel made available to them?"
The documentation clearly shows UCSF Phase 1 wasn't meant to accomplish an unstated efficacy end-point -- which, if done, would have required extraction from and then re-infusion into patients of an as yet unknown but sufficient number of treated gene constructs to produce both enough differentiation and treated surviving progeny to adequately treat or cure the HIV. Phase 1 merely tested whether the product used was (i) immunologically safe; (ii) could get genetic antisense lab-treated constructs into targeted, but shut-down, infected cells; and (iii) could get the re-infused treated cells to take a particular pathway and perform a certain formulae of functions -- such as, engraftment, propogation, differentiation and continued expression - necessary to get to Enzo's next task of determining and facilitating a level of re-infusion and efficacy sufficient to reconstitute an immune system able to control and defeat HIV infection. That's why Dr. Engelhardt told a reporter seeking confirmation that Enzo's early results had produced a successful anti-HIV treatment, "it would have been a miracle if it had." I.e., he meant the early study's use of low-level extractions and re-infusions was to prove the methodology worked and safely. The Enzo procedure had merely confirmed the path chosen to get there was correct; however, absent force majeure and without more it could not timely eradicate HIV and more work was necessary.]
(b)(iv) Enzo's February 6, 2001 Press Release reports on its presentation at the Chicago Retrovirus Conference. It said: "Enzo has achieved the first successful autologous stem cell gene therapy conducted in HIV-infected adults." It also notes: "Dr. Engelhardt reported successful engraftment of autologous transduced CD34+ cells and CONTINUED EXPRESSION of the anti-HIV-1 antisense gene in HIV-1 infected individuals." It continues: "The Phase 1 trial was designed to TEST the SAFETY of the procedure and to TEST for ENGRAFTMENT and DIFFERENTIATION of the transduced cells, as well as to DETERMINE whether MULTIPLE INFUSIONS of transduced cells led to a higher extent of engraftment when compared to a single infusion."
[BACKGROUND NOTE: In an earlier post I reported the result of my inquiry to the company seeking clarification as to the dosage levels given in each of the so-called "multiple infusions". I posted Enzo's answer. It was to the effect that the two patients involved in the test of "multiple infusions" had received the same total dose re-infusion that the other patients received in a single infusion - the only change being the total dose was "stretched-out" by being given in two parts.]
[ANOTHER OBSERVATION: Obvious from an intensive review of the 3/8/01 RAC video is that, in addition to their unfamiliarity with the purpose and endpoints of the UCSF Protocol 230, the RAC members were unacquainted with the UCSF Report of its Phase I study results. That report showed the actual level of dosing the patients received in both the single and the multiple infusions. From it RAC should have known the two multiple infusions merely stretched out into two parts delivery of the same dosage level as given by single infusion. Nevertheless, some RAC members publicly categorized a non-purpose, non-endpoint of the UCSF trial as a "failure to achieve" because they negligently and incorrectly assumed that (i) "multiple infusions" meant two of the patients received "more" rather than the "same" total dosage given "single infusion" patients, and (ii) ipso facto, the "multiple infusion" patients should have, but didn't, show a higher level of treatment efficacy. DUH!
In promoting the erroneous "Phase I failure" conclusion, Post #60032 also neglects to advise readers the RAC video reveals the reported failure sentiment was not unanimous among RAC members. It clearly shows Dr. Fung was smart enough to declare he could not determine whether a failure occurred because, in effect, the RAC had a "relative lack of information regarding the [alleged] failure of multiple infusions." He then proceeded with a list of information RAC needed to examine before it could arrive at a "failure" determination. Included therein was: (i) whether the multiple infusions gave more treated cells to patients than did the single infusions; (ii) a need to verify and examine the amounts given so as to learn whether it was more or the same, or just a "stretched out" amount given in more than one infusion; (iii) whether the reason more engraftment and additional measured expression had apparently not occurred was a result of an immune response in the individual recipients; and (iv) other technical issues, etc. Dr. Fung's comments start at ~ 1 hr. 8 mins into the video tape.]
Returning to information in the 2/6/01 Press Release: "While much remains to be done," said Dr. Engelhardt, he also noted: "Until now no one has been able to achieve successful autologous gene therapy in an un-ablated individual ... The fact that the number of transduced PBMC REMAINED APPROXIMATELY CONSTANT over a number of months supports the conclusion that STABLE ENGRAFTMENT of the antisense RNA-producing blood cells has OCCURRED."
[BACKGROUND COMMENT: Based on the foregoing documents, I can only ask: "Where's the misleading or exaggerated information or lack of accurate information to shareholders that Post #60032 seems to insinuate has occurred?]
(b)(v) After the RAC 3/8/01 meeting and before message #60032 was posted, Enzo's June 4, 2001 Press Release notes that participants at the annual conference of the American Society of Gene Therapy (ASGT) in Seattle were told by Dr. Engelhardt that Enzo had followed-up the initial portion of the Phase I trial at UCSF and had found "the continued expression of anti-HIV antisense RNA in T4 cells ... for as long as 21 months." The Release added, " The results demonstrated long-term survival and functioning of antisense RNA in white blood cells and CD4+ [T4 cells]."
The 6/4/01 Release also indicates Dr. Engelhardt advised ASGT conferees Enzo had solved a major HIV-induced problem. It discovered how to enter "switched-off" HIV-infected cells via an always "turned on and functioning house-keeper" gene. "With the use of this "housekeeping" gene," said Dr. Engelhardt, " long-term functioning of the anti-HIV antisense genes in the clinical trial subjects was achieved." .
[COMMENT: This illustrates another successful Enzo FIRST in Phase I. The problem was noted in a University of California at San Diego (UCSD) study published in the July 2001 issue of Genome Research. The problem, in essence, is that within 30 minutes of a victim's HIV exposure, HIV shuts down (a/k/a "switches or turns off") more than 500 genes in the infected cell that normally defend against its invasion, while at the same time it activates (a/k/a "switches or turns on") some 200 other genes in the infected cell that help the HIV survive and replicate. At the time UCSD's study viewed this event as a major problem in fighting HIV, Enzo had already solved it by entering its genetic antisense medicine into the shutdown HIV-infected cells via a "housekeeper" gene.]
(c) (1) The Enzo-Cornell Protocol (i.e., NIH Number 443-(2001) Phase I) was submitted to NIH-RAC in January 2001 - i.e., two months before the 3/8/01 Enzo-RAC meeting, and made publicly accessible at http://www4.od.nih.gov/oba/rac/Protocolquery.asp
Again, both the Scientific and Non-Technical Abstracts to Protocol 443 clearly spell out: (i) the previously recited goals and end-points of the Phase I trial at UCSF; (2) the results of the UCSF Phase 1 trial; and (3) the purpose and desired end-points of the proposed Enzo-Cornell expanded UCSF Phase I trial. The expanded purpose and end-points were identified in the Cornell Non-Technical Abstract as the following:
>>>"In this present study, Dr. Jeffrey Laurence working with Dr. Michael Schuster of New York Presbyterian Hospital-Cornell...and Dr. Marcus Conant, of the Medical School of the University of California at San Francisco plan to build upon these [UCSF initial Phase 1] results by TESTING A PROCEDURE DESIGNED TO INCREASE THE NUMBER OF CELLS CONTAINING THE ANTI-HIV-1 RNA gene . . . The procedure they plan on testing involves outpatient radiation of the patient subjects coupled with treatment with a course of a medicine that has been shown to block the growth of HIV-1. The goal of this study is to produce a continuous and renewable supply of CD4+ cells in large enough numbers to provide a stable immune diversity from only the cohort of cells containing the anti HIV-1 RNA genes ... We will study the subjects to determine that this procedure is safe. We will also monitor the cells in each subject's blood for the presence of functioning anti HIV-1 RNA genes for a period of several months. In this way we can determine the stability of the functioning anti-HIV-1 genes within the body and the effect of the presence of these genes on the viral load and CD4+ cell count."<<<
(4) CORRECT CONCLUSIONS: Reading the documents discussed in (3) above and listening carefully to the Enzo-RAC portion of the 3/8/01 video leads me to the following conclusions: (a) Enzo neither withheld nor falsely reported the goals, end-points or results of its' UCSF study; (b) the ENZO Phase I UCSF was NOT A FAILURE as claimed in Post #60032. It was a SUCCESS as it (i) accomplished the goals and end-points set forth in the 1998 NIH Protocol # 230, and (ii) produced new diagnostic tech and procedures; and (c) Protocol 230 neither required Enzo derive nor produce sufficient levels of treated gene replication to efficaciously eradicate the HIV. It required Enzo to test whether the design specifications of a system and procedure delivering genetic antisense treated gene constructs to targeted cells did so in an immunologically silent and safe manner which then permitted engraftment of the treated cells into the bone marrows of 5 patients (as well as into their spleens and peripheral blood plasma), there to mature, differentiate, and produce treated progeny which survived and continued to express in the patients for some 21+ months.
An objective review and balanced report of the printed information available on the Internet produces the unavoidable conclusion that, while there is still a lot of work to be done (as is the case with all multi-phased trials), Enzo's UCSF Phase I trial was CLEARLY SUCCESSFUL in that IT DID WHAT IT WAS DESIGNED and INTENDED TO DO IN UNABLATED INDIVIDUALS; AND IT DID IT SAFELY.
In addition, it (i) enabled improved and new procedures to be created and successfully tested (e.g., 18-hour instead of 3-month re-infusion), (ii) solved major HIV access and treatment problems (e.g., accessing shut-down protected HIV-infected cells via "turned-on housekeeper" gene), and (iii) facilitated innovation of superb diagnostic technology for use both in HIV/AIDS and in connection with many other diseases and conditions (e.g., improved immunologically silent stealth-vectors and high-tech assay measuring devices).
(5) EVALUATING: (a) THE KIS' LANGUAGE IN (2) ABOVE, and (b) OTHER RAC VIDEO EXTRACTS and CONSIDERATIONS:
(a)(i) Review of the Post #60032 language cut and pasted in paragraph (2) sandwiches the reader between the sotto voce insinuations of "don't/can't trust Enzo" hinted at in the first sentence starting: >>>"More meaningful for purposes of evaluating previous company comments...", followed by the paragraph muddling attributions, and the subsequent KIS' paragraph's question which asks readers: >>>"How does one square that with company comments to the effect that the trial had exceeded expectations? ("Better than expected ... better than better than expected," I believe were phases [sic.] attributed to Dr. Engelhardt at some point, although I cannot right now cite the time and place.)"<<<
(a)(ii) The 7-line paragraph in (2) that starts with: "...[A] very good question, ..." fails to tell us what the question was and/or who asked it. It clearly misleads the skimmer and leaves the astute reader wondering who really is the originator of the thoughts expressed therein. The confusion, if spotted, is confounded by use of only one opening and one closing quotation mark. It leaves the impression the entire paragraph expresses the original thoughts of Dr. Conant and, thereby, gives credibility to the erroneous sentiment of the sentence stating, "Unambiguously, Dr. Conant admits Phase 1 failed". It did not.
What actually happened? Beginning ~ 1hr. 20 mins into the RAC video the careful listener will note Dr. Marcus Conant's modus operandi. First he summarizes prior questions and comments of RAC members; and, second, he generally attributes the particular comment or question to one or more named RAC member(s) before responding. In this instance, he named RAC Chairperson, Dr. Michelson as the proponent of the questions and accompanying statement. Post #60032 does not so attribute.
Yet, fairness and accuracy dictate the poster report the 7-line quoted paragraph in a manner that guarantees others' questions and sentiments are not attributable as the original thoughts of the responder. Here, inclusion of a clarifying introduction was appropriate and could, for example, have been: "Dr. Conant first summarized previous comments and questions of Doctors Michelson, Markert and Aguilar-Cordova to the effect: "Why didn't the original protocol work?" and "You know, you transduce[d] CD34 cells, you show[ed] you're making CD34 cells that are protected in the peripheral circulation, why didn't HIV just kill off the other cells and leave those behind?"
In other words, omitting Dr. Conant's prior proper attribution of those inquiring statements to Dr. Michelson produced deception in that the reader was left to believe the words between the quotation marks constituted Dr. Conant's original thoughts admitting his UCSF Protocol failed instead of it being a regurgitation of another's comments. The reader was entitled to know Dr. Conant neither said nor agreed on his own account that the protocol failed. Time being of the essence, Dr. Conant simply summarized the thoughts conveyed by Dr. Michelson and other RAC members so he could get and respond to the kernal of the collective RAC question and commentary. In essence, taken in context, the video shows the RAC members querying: Why, having successfully transduced and re-infused targeted cells, didn't multiple infusions in some patients provide GREATER ENGRAFTMENT and sufficient numbers of treated progeny to kill off more or all of the remaining cells?
(a)(iii) From this poorly attributed, out-of-context 7-line paragraph and an omission to refer readers to either other RAC video extracts, official Abstracts and/or other Internet Press Release statements Poster #60032 proceeds to advise readers: >>"Note well: in answer to the question of why the protocol failed, Dr. Conant did not respond that it had not failed, but rather commented on the manner in which it failed. UNAMBIGUOUSLY, DR. CONANT ADMITS THAT THE PHASE I AT UCSF FAILED ..."<<<
The above conclusion, although stated in pretty strong and deliberate language, is a false one. There are extremely few instances in life and/or law where an individual who is not under oath and who fails to comment one way or the other to another's statement is presumptively deemed to have actually or irrefutably engaged in an ADMISSION BY OMISSION. Sometimes silence is golden, or wise, and/or at least an exercise in diplomacy. The reasoning employed by Poster #60032 could clearly be used to render actionable some of the RAC members' obvious and, perhaps, negligent failure to adequately read and understand the trial purposes, end-points and results to date of Phase I before some cavalierly announced publicly their under-informed "failure" allegations.
At least the admissions -- first, by Doctor Michelson, that the RAC did not "really understand engraftment" and, second, by Dr. Fung, that RAC had a "relative lack of information" on which to conclude "multiple infusion" and its sequelae was a failure -- redeemed the poor RAC performance. The watered down RAC recommendations evidenced that their respective comments had a salutary, if not a totally awakening, effect upon their colleagues.
(b) Other RAC Extracts and Evaluative Considerations:
(b)(i) Dr. Conant could have ripped RAC's inaccurately premised questions apart and denied directly that the UCSF protocol was a failure. He might also have challenged RAC's obvious failure to review the Phase 1 study results that reported on the nature and dosage of single and multiple infusions and made clear "multiple infusions in two patients" did not mean two patients received higher levels of re-infusion than did single infusion patients. Much time might have been saved and misunderstanding avoided had they done so. Dr. Conant might also have corrected the RAC error: "why didn't HIV just kill off the other cells" and leave the treated cells behind. It was a non-sequitor, flawed by ambiguity, and based on erroneous assumptions. HIV replicates by infusing into healthy cells more HIV-infection, shutting down the genes within that fight it. It does not, as the RAC position implies, kill off other HIV-infected cells. Indeed, perhaps Dr. Conant should have re-iterated RAC Chairperson, Dr. Mickelson's prior ADMISSION: "I AM NOT SURE WE [RAC] REALLY UNDERSTAND ENGRAFTMENT AT ALL." [see RAC video @ ~ 1 hr. 4 mins.]. He could have simply pointed out the RAC members' failures to read the Phase 1 results report and the respective Protocols' abstracts resulted in their erroneously categorizing a "failure" something neither fixed nor intended as a purpose or efficacy end-point in the preliminary "safety" Phase I USCF trial.
He didn't take any of those approaches. Why? Common Sense: Enzo's team was the involuntary applicant called to appear before competitors swathed in the hallowed mantle of a government "public protection" approval advisory board that had authority to give or withhold a recommendation affecting or delaying the future course of Enzo's HIV/AIDS work. Dr. Conant correctly judged it more judicious to resist patronizing the RAC board at a public meeting. Instead, he remained restrained and diplomatic while moving Enzo's work forward to the next level of needed study.
As Dr. Conant did not have unlimited time to respond [see, RAC schedule for 3/8/01], he sensibly chose not to alienate the RAC members, and simply and hurriedly addressed their summarized question about failure as follows: >> "And the answer is: The number of transduced cells [were] in that appropriate ratio. That's [why] we're not seeing the numbers go up. We estimate that we need to get up to ten percent transfected CD34 cells in the marrow - making a significant number of CD34 cells in the peripheral circulation."
[NB: That is the goal of the future expanded Cornell Phase I trial where, it is hoped, low level irradiation will produce the extra space needed in the bone marrow receptacle necessary to receive the substantially increased numbers of re-infused treated cells for bone marrow engraftment, etc.]
(b)(ii) Poster #60032's failure to include Dr. Michelson's and Dr. Fung's separate admissions of RAC's insufficient understanding and information regarding important portions of Enzos science and work was important. Admitted RAC deficiencies would have both negated the anti-Enzo opinions into which readers were being directed by the Poster, and enabled adoption of a proper perspective and some essential balance. Clearly, inclusion of such admissions would have undermined the Poster's anti-Enzo argument.
(b)(iii) Another important omission was Poster #60032's failure to include Dr. Conant's substantive response to Dr. Fung's inquiry into possible reasons why similar low efficacy levels resulted from both single and multiple infusions. Had it been included, readers would have realized that RAC unanimity of opinion did not exist with respect to the "efficacy failure" contention. Moreover, Dr. Conant's response made clear the non-goal, non-endpoint event was not then an issue and that RAC needed to move on.
RAC video listeners will recall Dr. Conant's first comments: In no uncertain terms he advised RAC members that HAART is not and will not be the solution for HIV/AIDS, and that a new approach desperately needs to be found. [COMMENTARY: Simply put, the emphasis by some RAC members on viral load issues as a measurement of efficacy was misplaced. A test result revealing viral load is not detectible does not indicate HIV/AIDS has been defeated. For patients not resistant to its medicine, HAART can reach and, for a time, reduce measurable HIV viral load in blood plasma. However, current HAART anti-retrovirals do not reach the actively replicating and/or the latent/dormant HIV-infected cells found in sperm compartments, kidneys, latent memory, macrophage and other HIV reservoirs. Indeed, HAART protease inhibitors cannot even enter HIV reservoirs. See, e.g., "HIV Persists and Actively Replicates in Patients on HAART," dated 2/23/01. See, also, "Depletion of HIV Reservoirs With Bi-Specific Antibodies and Chemokine Toxins," dated 2/6/01. These two summary reports are written by Brian Boyle, M.D. at: http://www.HIVandHepatitis.com/ The hope is that Enzo's treated gene constructs will engraft into bone marrow in sufficient quantities to eventually get taken up by the thymus and these other tissues and places that act as reservoirs for HIV. That would include treated cells becoming latent memory cells --whose life expectancy is 60 to 70 years and not 90-days -- so as to enable them to reactivate when HIV latent memory cells do and defeat them.]
Dr. Conant did finally persuade RAC to move on. He responded to Dr. Fung's inquiry by telling RAC "ongoing work" was needed even to clarify what the causative factor might be. He also said, "The reason we have not pursued finding the number of transfected cells that are there is because they are so close to background we cannot tell whether there is a difference between the single infusion and the multiple infusion. We think what we need to do is to increase the number of cells that are engrafted or implanted into the patients." He is, in essence, saying to a colleague: the "stretched-out" time to administer the full dose did not do any harm, but neither did it have more of a beneficial effect than did treating with a full dose single infusion. In other words, though sotto voce, he is clearly saying, "we're on the right track, but further study and modification is needed." Dr. Fung does transplants and is familiar with the role of radiation on patients' bone marrows.
(b)(iv) Dr. Conant subtly continues his let's go forward "more study is needed" theme by raising another possibility: "Could it be when we take out a CD34 cell to treat it, it immediately starts to differentiate?" This latter comment also enabled Dr. Conant to re-direct RAC's attention to WHY there's a need to pursue the Cornell studies: He is clearly re-emphasizing the absolute need to do "safely" whatever is necessary to: (i) create more bone marrow space by low-level irradiation so that greatly increased levels of treated constructs can be re-infused to engraft therein; and (ii) pursue ways to delay immediate differentiation of re-infused cells. [Differentiation involves new treated cells selecting their future function and direction --e.g., whether to become bone, muscle, brain, bone marrow, spleen, peripheral blood cells, etc.] Both the 443 Protocol Abstracts and Enzo's Primary Investigators explained on the RAC video the purpose of Enzo's decision to use mycophenotic acid on the transduced CD34 cells following re-infusion of the treated constructs into the patients was to stop premature differentiation.
[FWIW, my personal interpretation is Enzo will seek to encourage more of the increased number of re-infused treated cells to migrate and engraft into space the partial ablation creates in the bone marrow receptacle - its purpose being to assure eventual processing of increased numbers of needed treated progeny into circulating peripheral blood plasma, thymus, latent memory cell, macrophage and other HIV-type reservoirs.]
(b)(v) Other video statements not used in Post #60032 show Dr. Conant did NOT ADMIT his UCSF protocol failed. First, his pointed response to attorney-King clearly illustrates he did not agree with her incorrect assumption that low-level engraftment and replication of treated cells in early Phase I constituted a Protocol "failure". Though admitting lack of a scientific background, attorney King eventually got wind that her assumptions and conclusions were erroneous. Nevertheless, she foolishly attempted to chastise the Enzo applicants for allegedly failing to show in current Protocol 443 what the end result of the proposed Cornell Phase 1 would be in terms of achieving anti-HIV efficacy from low-level irradiation and HIV-HGTV-43 infusions. Said Dr. Conant, "You are saying 'tell us what you are going to find before you do it.' The purpose of science is to ask reasonable questions and then do a trial to find out?" Dr. Conant was telling them all Enzo hasn't thus far attempted to prove what they wish to hear and there is a need to continue exploring for the most efficacious way to control and, hopefully, eventually eradicate HIV.
Hence, again it is clear from the video and the Protocols that what attorney-King rubber-stamped as "failure" was an end-point to be met in the future and not one that should have been attained in the past. A logical conclusion is: If the goal RAC thought should have been found was not a purpose or end-point of the first portion of Phase I at UCSF and Enzo successfully achieved the pre-set purposes and end-points of Protocol 230, then Phase I at UCSF did NOT FAIL and was a SUCCESS. Ergo, why would Dr. Conant "unambiguously admit Protocol 230 failed" when it did not? He did not!
(6) SUMMARY CONCLUSIONS: I submit: (i) The conclusions in Post #60032 that Enzo's UCSF Phase I failed and Dr. Conant admitted it failed were UNFOUNDED and CLEARLY ERRONEOUS. (ii) RAC members failed to acquaint themselves with the purposes, end-points and results of Enzo's prior UCSF Phase I clinical and lacked sufficient information and comprehension to determine the efficacy of its' science. (iii) As a consequence, some RAC members went off on a tangent and insinuated the initial UCSF portion of Phase 1 trial failed; but common sense admissions -- first, by Doctor Michelson, that the RAC did not "really understand engraftment" and, second, by Dr. Fung, that RAC had a "relative lack of information" on which to conclude "multiple infusion" and its sequelae was a failure -- had a salutary effect upon their ill-prepared colleagues. (iv) The final "13 to 0" RAC vote to recommend a diluted form of recommendations of additional procedures to which Enzo had agreed enabled Enzo to go forward and prepare for its expanded Phase I at Cornell without further recourse to FDA-CBER. (v) In short, Enzo's UCSF Phase 1 was a success, as was the outcome of its meeting with RAC on 3/8/01.