CIRCARE InfoMail 2002-08-13

Subject: Johns Hopkins University Determination Letter
Date: 2002-08-13

CIRCARE wishes to alert friends and media regarding the determination letter from the Office for Human Research Protections, issued June 18, 2002 (and responded to by Johns Hopkins University on July 26, 2002.) According to the letter, serious problems existed in a study on oral cancer treatment conducted in India by Dr. Huang. Basic human subject protection was absent, including 1) Prior testing for safety and efficacy 2) Informed consent of any specific risks involved in the study and 3) an absence of review by the JHU Institutional Review Board. We are concerned that as protections are increasingly insured for U.S. citizens that citizens from other countries may be put at risk by experimental medicine.

The determination letter revealed that Hopkins own internal study admitted:

That experimental compounds drugs were used on humans without prior systematic investigation or any pharmacological study. For example, drugs normally are tested on animals prior to human study.
The consent form failed to warn patients of any risk at all of the two specific compounds used, and instead mentioned generic risks like soreness at infection site.
When higher officials found that clinical trials were carried out without prior Hopkins IRB approval, they advised delaying any action even though they knew an inquiry was warranted.

The Office For Human Research Protections determination letter found that:

Research was carried out without review and approval of the JHU IRB. As the trial did not satisfy the criteria for exemption from oversight by an Institutional Review Board, it represented a serious noncompliance with regulations.
Senior officials of JHU did not ensure that there was prompt reporting of this noncompliance.
JHU does not have certain written IRB policies for procedures that the review board must follow, including those guiding the conducting of its initial and continuing review of research, or procedures for ensuring prompt reporting of any unanticipated problems involving risks to subjects.
Minutes giving sufficient detail of the IRB meeting were lacking and did not, for example, show how IRB members voted for or against a particular study.

Since the shut-down of research at Hopkins and this determination letter, Johns Hopkins has taken serious steps to remedy some of these problems. However, it remains to be seen if these measures will be effective.

McNeilly PJ. OHRP Determination Letter to Johns Hopkins University. 2002-06-18: http://www.hhs.gov/ohrp/detrm_letrs/YR02/jun02c.pdf

Michael A. Susko MS, CIRCARE President
(410) 499-4895

Adil Shamoo Ph.D., CIRCARE Co-Founder
(410) 706-3327

Update: 2006-04-25.

Background: Between 1999 and 2001, Johns Hopkins University biology professor Ru Chih Huang, Ph.D. conducted clinical research on subjects diagnosed with cancer in Kerala, India at the Regional Cancer Centre (RCC). Research testing a compound named tetramethyl NDGA was undertaken without requisite FDA investigational drug export approval, without requisite IRB approvals, without preliminary toxicity testing or adequate pre-clinical studies, and without disclosure of the latter to subjects injected with the unapproved test drug. A patent for the investigational drug had previously been filed with the US Patent and Trademark Office to secure ownership for Dr. Huang and Johns Hopkins University, a standard practice in academic research. A significant interval of time elapsed between the point at which JSU research administrators became aware of Dr. Huang's non-compliance and the institution's report of this to OHRP. According to JSU information provided to OHRP (determination letter, above), Dr. Huang was firmly convinced she was on the verge of a breakthrough in cancer treatment. The local population was less enthusiastic and in fact, the conduct of the study caused great consternation in India, where the affair was rapidly dubbed a scandal.

The RCC in Kerala was apparently under the assumption that not only was the research approved by JSU, but that they were engaged in a valuable collaborative project with a prestigious American academic research institution. As it became increasingly apparent that the research had no approval from JSU, and lacked preliminary safety data to support the trials already underway, the RCC made a surprising announcement: the Indian institution claimed to have documents attesting to the fact that JSU funds were paid to them to conduct the non-compliant unapproved research. Following their investigation, JSU prohibited Dr. Huang, a biologist by training, from acting as a principal investigator in human studies conducted at the institution. Abroad, the RCC in Kerala was accused of foot-dragging whilst conducting a half-hearted investigation, after which it failed to discipline physicians involved or disclose details of its findings despite repeated requests to do so from local activists and members of the media.

The research in Kerala was the subject of a 2003 post-mortem by de Castro et al.:

A recent Johns Hopkins University research on a cancer drug in India is illustrative of the complexity of this issue. A study of two experimental cancer drugs was conducted and led by Hopkins biologist Ru Chih Huang, in collaboration with Indian Regional Cancer Centre (RCC) director M. Krishnan Nair. The trials at the RCC in the southern India state of Kerala, involving 26 oral cancer patients, ran from November 1999 to April 2000. Initial reports of patients responding within days to the injections led Huang to conclude that this is a wonderful drug, and it's not toxic in humans (Science, 2001:1024).

In July 2001, reports appeared in the Indian news media of complaints by RCC radiobiologist V. Narayaman Bhattathiri that the trial had been improperly conducted. Bhattathiri said that he had alleged that the patients did not give proper informed consent, did not receive timely standard therapy, and were exposed to a potentially toxic substance. He also challenged the trial after seeing some of the patients. I asked for details of the study, and they were not given to me, he says. Then I complained to the ethical committee: No action. Two months passed, and then I complained to the Human Rights Commission (Science, 2001:1024). The charges by Bhattathiri that patients in India were being used as guinea pigs had prompted the Indian health ministry and Johns Hopkins to launch independent investigations of the trials.

Hopkins appointed a three-member panel of experts to develop the facts. The Johns Hopkins faculty committee found that:

The scientist was negligent for failing to submit a proposal for the clinical trial to a Johns Hopkins University Institutional Review Board (IRB). Under university policy and federally mandated procedures, faculty experiments involving human subjects must have prior IRB approval, whether conducted in the United States or abroad.

The trial did not meet Johns Hopkins standards for research with human subjects. For example, the committee found there was inadequate safety testing of the drugs in animals before they were injected into human patients. The committee also said that consent forms used to recruit patients for the study were inadequate.

The scientist carried drugs used in the study to India without either an investigative new drug approval from the Food and Drug Administration or explicit FDA export permission.

The scientist, without authority, signed several versions of a document committing the university to collaboration with the RCC.

The committee also found no evidence that any patient had been harmed or that any patient's conventional treatment was delayed by the clinical trial. However, the report criticized the university's initial handling of the case. It said that an inquiry should have begun in March 2001, when the university, which had earlier been aware of the 1999-2000 trial, first learned that the scientist had run it without university IRB approval. Assured by the scientist that ethics committee approval had been received in India, the university did not begin an inquiry then, but instead counseled the scientist that all future human studies had to be submitted to a Hopkins IRB (John Hopkins News Releases, 2001).

Charges of making guinea pigs out of the Indian participants, inadequate safety measures, and dubious ethics review of the research figured in the context of evolving exploitation in research. Even in the context of international research that appears legitimate, new forms of such exploitation could arise.

There are many ways by which researchers can take advantage of people who participate in their investigations. The most obvious ones are those that fail to secure the informed consent of the people who have to undertake the risks involved. However, the single-minded focus on informed consent tends to take attention away from equally atrocious forms of exploitation. For example, people belonging to a community where biomedical research is being conducted can be taken advantage of when the aims of the study are not relevant to their own needs and interests; when the research does not take into account the self-determined priorities (whether medical or otherwise) of the participating community; when the community's own researchers are not given the chance to participate; or when their participation is limited to non-essential roles that open no opportunity for the transfer of technology.

Source: de Castro LC, Sy PA, Alvarez AAA, Mendez RV, Rasco JK. Bioethics in the Asia-Pacific Region: Issues and Concerns: Proceedings of Regional Meeting on Ethics of Science and Technology. 2003-11-07. pp. 28-30. Accessed on 2006-04-25 at: http://web.archive.org/web/20050228001323/http://www.unescobkk.org/ips/ebooks/documents/ethic_in_asia_pacific/1_109BIOTHICS.PDF

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Articles and Press Releases

It seems this matter was relatively under-appreciated in the US. The media articles below give some idea of the international response to Dr. Huang's misconduct. The articles are followed by (limited) information about Dr. Huang's current business associations, with the company founded to develop the drug at issue in the violative research conducted in Kerala, as well as several other corporations.

Trial and Errors. R. Krishnakumar. Frontline. 22(25):2005-11-08. Available from http://www.flonnet.com/fl2225/stories/20051216005102200.htm

An award and some claims. R. Krishnakumar. Frontline. 22(25):2005-11-08. Available from http://www.flonnet.com/fl2225/stories/20051216006402800.htm

'Johns Hopkins is committed to acting ethically, morally and legally.' R. Krishnakumar. Frontline. 22(25):2005-11-08. Available from http://www.flonnet.com/fl2225/stories/20051216005403000.htm

'Erimos has broadened the research.' R. Krishnakumar. Frontline. 22(25):2005-11-08. Available from http://www.flonnet.com/fl2225/stories/20051216004602400.htm

Drug Trials and Ethics. R. Krishnakumar. Frontline. 2001-12-18 — 31.
URL: http://www.frontlineonnet.com/fl1817/18170040.htm (Contains an excellent summary of financial issues.)

Claims and contradictions. R. Ramachandan. Frontline. 2001-12-18 — 31.
URL: http://www.frontlineonnet.com/fl1817/18170110.htm

Srinivasan S, Pai SA. Research: history repeats itself. Indian Journal of Medical Ethics. 2001;9:4. Available from http://www.issuesinmedicalethics.org/094ed108.html

The truth of the 'drug' trials. R. Krishnakumar. Frontline. 2001-12-07.
URL: http://www.flonnet.com/fl1824/18241140.htm

Complying with established policy. R. Krishnakumar. Frontline. 2001-12-07.
URL: http://www.flonnet.com/fl1824/18241150.htm

India Acts on Flawed Cancer Drug Trials. Pallava Bagla. Science. 2001;293(5539):2371-2373. (Abstract) available from http://www.sciencemag.org/cgi/content/full/293/5539/2371

Johns Hopkins Faults Researcher in Human Drug Trial. Shankar Vedantam. The Washington Post. 2001-11-12.
URL: http://www.washingtonpost.com/ac2/wp-dyn/A18596-2001Nov12?language=printer (Requires free registration.)

Hopkins Scientist Sanctioned over Drug Trial in India. Johns Hopkins University News Releases. 2001-11-12.
URL: http://www.jhu.edu/news_info/news/home01/nov01/india.html

Hopkins Reviews Investment in Indian Cancer Drug Trial. Pallava Bagla and Eliot Marshall. Science. 2001;293(5532):1024. (Abstract) available from http://www.sciencemag.org/cgi/content/full/293/5532/1024

Kerala govt orders probe into cancer drug scandal. George Iype. Rediff.com. 2001-08-01.
URL: http://www.rediff.com/news/2001/aug/01drug.htm

Statement on Investigation Regarding Drug Trial in India. Johns Hopkins University News Releases. 2001-07-01.
URL: http://www.jhu.edu/news_info/news/home01/jul01/india.html

Concern over irregular drug trials on patients. M. Dinesh Varma. The Hindu. 2001-07-16.
URL: http://www.hindu.com/thehindu/2001/07/16/stories/0416404o.htm

Hopkins Professor's Work is Focus of Unique Start-Up. Johns Hopkins University News Releases. 2000-06-26.
URL: http://www.jhu.edu/news_info/news/home00/jun00/huang.html

A Chinese 'Notable' Of The Century. Michael Purdy Homewood. The Gazette Online. 2000-01-31. Available from http://www.jhu.edu/~gazette/2000/jan3100/31chih.html

Laboratory of Professor Ru Chi Huang Ph.D. 2000-06-06. Available from http://web.archive.org/web/20000606222646/http://www.bio.jhu.edu/faculty/huang/huang.html

Laboratory of Professor Ru Chi Huang Ph.D. 2006. Available from http://www.bio.jhu.edu/Faculty/Huang/Default.html

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Something is wrong with Dr. Huang's statements as reported in the Frontline article of 2001-12-18. The article reports that:

O'Shea told the journal Science: I am not saying we know where these funds came from. Just because Johns Hopkins cuts a cheque it does not necessarily mean that it approved the project being funded. Making sense of the financial transactions is a task for the new investigative panel.

O'Shea's remark that the study was not directly funded by the JHU assumes significance in the light of Huang's comments to Science. She told Science that the funding for the project came entirely from private sources, including the JHU and a Minnesota-based company, Biocure Medical LLC. The company was set up with the objective of designing and conducting clinical trials of compounds derived from nor-dihydro-guaiaretic acid (NDGA).

According to Huang, the supporters of the project have committed about $2.5 million to conduct pilot trials in four places in Asia. Dr. Krishnan Nair had stated that Phase II trials were also to be carried out at, besides RCC, the K.J. Hospital, Kanpur, and the Banaras Hindu University, Varanasi, under the RCC's supervision.

Source: Claims and contradictions. R. Ramachandan. Frontline. 2001-12-18 — 31. Available from http://www.frontlineonnet.com/fl1817/18170110.htm

The reported information is extremely peculiar for a number of reasons.

According to the Minnesota corporate database, Biocure Medical LLC first filed to do business in the state on 2000-09-11.

Biocure Medical LLC is a Delaware corporation with a registered address at 1209 Orange Str Corporation Trust Co Wilmington, DE, 19801 – this is the address of an incorporation business, rather than where Biocure does business.

According to the Minnesota corporate database, Biocure Technologies LLC also first filed to do business in the state on 2000-09-11.

Like Biocure Medical LLC, Biocure Technologies LLC is also a Delaware corporation with a registered address at 1209 Orange Str Corporation Trust Co Wilmington, DE, 19801.

The problem is obvious: the clinical trial began in India in 1999 on the basis of an application in 1998 (Frontline, above) — one year or more before BioCure first filed to do business in Minnesota. Since non-existent corporations cannot make payments, what then was the source of the funds paid to Johns Hopkins and subsequently disbursed to investigators at the RCC in Kerala to conduct the research? In what state was the corporation doing business? How can anyone run a business if they don't know their own address? And why on earth did Johns Hopkins admit they couldn't discover the source of these funds? The institution receives thousands of research grants each year and grants, especially federal ones, require annual reports describing what was spent and how. Surely they don't return these forms without filling them out. It's also safe to say that if you pay state and federal taxes in the United States, you know the source of your money – unless you'd care to have all your wages assessed at the highest tax rate. The claim is mind-boggling.

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A recent news article (Deep pockets Singapore billionaire funding Centennial Campus biotech. Leo John. Triangle Business Journal. 2004-01-02. Available from http://triangle.bizjournals.com/triangle/stories/2004/01/05/story2.html?page=2) describes how Biocure was preparing to submit phase I clinical data to FDA in January 2004. In addition to providing some detail about the company's financial sponsorship by Singapore real estate baron Ang Tiong, the article contains blaffling information:

Singapore real estate baron Ang Tiong – while on a visit to Johns Hopkins in June 2000 – offered to fund the company. BioCure initially set up shop in Minnesota but moved to Raleigh in June 2003 because the company's chief medical officer, Dr. Neil M. Frazier, was based here.

Since Biocure first registered to do business in Minnesota on 2000-09-11, how was it possible for Mr. Ang Tiong to fund the company in June 2000, before it existed ?

Don't get excited by the implication of the question because it would be too simple. BioCure Technologies owns two Drug Master Files (DMFs) filed with FDA, both of which suggest the company has been producing tetramethyl NDGA, or related extracted compounds, for many years. Below, from left to right, are the DMF number assigned by FDA, date of assignment, name of DMF owner, and drug process/product described in the DMF at the specified processing facility:

7916 27-Jan-89 BIOCURE TECHNOLOGIES LLC EXTRACTION OF M-NDGA BULK FORM IN EL PASO, TEXAS

4656 15-Sep-82 BIOCURE TECHNOLOGIES LLC NORDIHYDROGUAIARECTIC ACID (NDGA), BULK FORM AS MANUF IN CHIHUAHUA, MX.

Source: U.S. Drug Master Files / DMF Database. Betterchem Inc. Available from http://www.betterchem.com/plus/dmf/type2holderb-c.htm. Accessed 2005-01-10.

Hmm … one thing is certain in this confusing picture: Minnesota isn't in Texas, or Mexico.

The article goes on to describe the corporate history of Biocure:

As it has taken its baby steps, BioCure has endured some spills. A clinical study in 2001 among patients at a hospital in India led to an investigation by that country's government. Some doctors complained the study was conducted without the approval of patients.

Frazier describes those complaints as mudslinging. He says they were driven by internal strife among the hospital's doctors and that a later investigation proved the allegations to be false.

The reporter appears to lack experience in the pharmaceutical industry: not only does the clinical trial date not match other sources, the statement that the study was conducted without the approval of patients is devoid of meaning. Patients do not approve clinical trials, rather research subjects must give consent to be enrolled in them.

Biocure Chief Medical Officer Dr. Neil Frazier is entitled to his opinion just like everyone else. The fact that Johns Hopkins and the U.S. Office for Human Research Protection upheld the substance of the Indian physicians' complaints argues against his opinion that such complaints were mudslingling. Moreover, under the U.S. federal system, human subject protection obligations are based upon the investigator's affiliation with a covered research institution. Compliance means compliance with policies of the institution with which the investigator is affiliated, as Dr. Frazier surely knows. I am aware of no later investigation which disproved charges that Dr. Huang failed to comply with Johns Hopkins' faculty rules and U.S. federal regulations. On the contrary, the OHRP determination letter of 2002-08-13 issued to Johs Hopkins in this matter confirmed the university's findings that:

Dr. Huang was obliged to obtain JHU IRB approval before starting her research, and failed to do so
Dr. Huang was obliged to obtain FDA approval to export her investigational drug, and failed to do so
The informed consent given to subjects in India failed to disclose material risks and the lack of sufficient pre-clinical safety data, and accordingly was judged inadequate.

It's disturbing to read statements like this, especially when attributed to a licensed physician who is ostensibly responsible for the well-being of research subjects on whom Biocure proposes to test its investigational drug products. If Dr. Frazier genuinely believes Johns Hopkins and OHRP made inaccurate judgments about the trial in India, he has an obligation to take the matter up with OHRP directly rather than attempting to re-try the issues in the court of public opinion.

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What does the U.S. Food and Drug Administration think about Chapparal? Not much:

Illnesses and Injuries Associated with the Use of Selected Dietary Supplements. U.S. Food and Drug Administration Center for Food Safety and Applied Nutrition. 1993. Available from http://www.cfsan.fda.gov/~dms/ds-ill.html. Accessed on 2006-04-25.

Clinical Trials

In the October 24, 2004 issue of the newsletter CancerDecisions, classical philologist turned alternative medicine proponent Ralph Moss, Ph.D described his excitement over preliminary data from a US clinical trial testing tetramethyl NDGA, now called EM-1412, on patients with treatment-refractory cancers of the head and neck, and directs readers to an abstract presented at the 2004 Annual Meeting of the American Society of Clinical Oncology, which is reproduced below:

Phase I clinical results of intralesional injection of tetra-o-methy nordihydroguaiaretic acid (M4N) in refractory head and neck cancer.

Abstract No: 5614

Citation: Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004:5614

Author(s): F. R. Dunphy, K. K. Dukelow, J. Provenzal, J. Crawford; Duke Comprehensive Cancer Center, Durham, NC

Abstract:

Background: Patients with relapsed-refractory Head and Neck cancer have a poor prognosis with a 10% 2- year survival. Novel treatments are being explored in this poor prognostic group. M4N, a derivative from the plant, Larrea tridentata, has shown activity in murine models after intratumornal injection. Methods: Intratumor injections were administered at the same dose each week x 3 weeks with a target dose of 20mg/cm3 tumor volume. Three patients (1 female and 2 males) were treated, median age 65 (54-82). The first received 10mg/cm3 x 3 weeks, the second received 15mg/cm3 x 3 weeks, the third received 15mg/cm3 x 1 week. Using fanning intratumoral injection technique a total of 7 intratumoral injections were performed. Pharmocokinetics were obtained preinjection and 1, 2, 4, 8, 24 hours post-injection on the first and last week of intratumoral injection. Results: Major toxicity was brief heart-block requiring two hospitalizations in one patient observed after day 8 and day 15 injection. One patient developed a tracheal-cutaneous fistula one week after day 1 injection which necessitated removal from study. All patients experienced pain at the intratumoral injection site requiring intravenous morphine, median 25mg (range 10-40mg). In all three patients, injected tumor volumes were observed to respond by crusting within one week of the first injection, followed within two weeks by necrosis and ulceration. Two patients that completed 3 weeks of intratumoral injection were observed to have total necrosis of the injected tumor site, followed by disease progression outside the boundaries of the injected tumor volume. Conclusions: M4N intratumor injection was feasible and showed promising antitumor activity in relapsed-refractory squamous cell cancer. Pain was the major complication, but was less intense as injection technique experience was acquired. This approch is worthy of futher investigation.

Accessed 2005-01-09 from http://asco.org/ac/1,1003,_12-002627-00_18-0026-00_19-003310,00.asp

The results described by Dr. Dunphy directly contradict the earlier assessment of Dr. Huang, to whom the statement that this is a wonderful drug, and it's not toxic in humans was attributed in Science, 2001:1024. Far from being not toxic in humans, of a total of three subjects enrolled in Dunphy's trial, one subject was removed from the study after developing a tracheal-cutaneous fistula (essentially a hole extending from the windpipe out through the skin of the neck), a second patient (presumably) required hospitalization twice upon developing heart-block – both of which were presumptively adverse drug reactions – and all patients experienced pain severe enough to require intravenous morphine for relief. According to public statements given out by the RCC in Kerala, India however, none of the research subjects contacted suffered any adverse events, complications, or harm upon receiving intratumoral injection of the same investigational drug.

Such statements strain credulity in light of Dunphy's recent data.

Dr. Moss also reminds us of the reason for his, and others', interest in tetramethyl NDGA: the compound is an active ingredient in Chapparal, an alleged dietary supplement more properly described as an unregulated botanical drug implicated in acute liver failure and subsequent deaths of more than 20 persons. Chapparal has a rich regulatory history in the hands of unscrupulous promoters touting this hepato-toxic botanical drug as a cure for numerous disorders, including a clinical trial on subjects with cancer conducted decades ago — in which chapparal did not cause tumor reduction — but rather appeared to cause noticable tumor growth.

To his credit, Dr. Moss urges readers not to use tetramethyl NDGA (M4N) for self-treatment. Source: Moss R. Herb-derived drug fights head-and-neck cancer, part 2. Cancer Decisions Newsletter. 2004-10-24. Available from http://www.cancerdecisions.com/102404_page.html. Accessed 2005-01-09.

The clinical trial registration for the study titled Open-Label Phase 1 Dose Escalation Study of Intralesional Injection of M4N in Patients with Refractory Malignant Tumors of the Head and Neck was first received in April, 2003 and listed the sponsor as BioCure Medical: http://web.archive.org/web/20040108090926/http://www.clinicaltrials.gov/ct/show/NCT00057512?order=1.

The trial registration was updated on 2006-01-31 and the updated entry indicates the sponsor is Erimos Pharmaceuticals: http://www.clinicaltrials.gov/ct/show/NCT00057512?order=1.

Details in this trial registration indicate the study began in January, 2003 and planned to recruit 28 subjects prior to the projected closing of enrollment in October, 2003. Yet the registration indicated study completion on 2006-01-31, more than two years after the projected study closure date. This may indicate serious difficulty in subject recruitment.

In addition to the completed study (above), as of 2005-04-25, Erimos Pharmaceuticals is conducting two clinical trials registered with Clinicaltrials.gov:

A Pilot Study of EM-1421 for the Treatment of Cervical Intraepithelial Neoplasia. Official title: Official Title: A Pilot Translational Study of Tetra-O-Methyl Nordihydroguaiaretic Acid (EM-1421) for the Treatment of Cervical Intraepithelial Neoplasia Induced by Human Papilloma Virus. Sponsor: Erimos Pharmaceuticals. Expected enrollment: 8. Study start date: September, 2004. Available from http://www.clinicaltrials.gov/ct/show/NCT00154089?order=2. Accessed on 2006-04-25.

A Phase I Dose Escalation Study of EM-1421 for the Treatment of Recurrent or Refractory Solid Tumors. Official title: An Open-Label Phase I Dose Escalation Study of Intravenous Infusion of Tetra-O-Methyl Nordihydroguaiaretic Acid (EM-1421) in Subjects With Refractory Malignant Tumors. Sponsor: Erimos Pharmaceuticals. Expected enrollment: 30. Study start date: December, 2005. Available from http://www.clinicaltrials.gov/ct/show/NCT00259818?order=3. Accessed on 2006-04-25.

This information is substantially reiterated in the Clinical Trials section on the Erimos Pharmaceutical, LLC web site at http://www.erimos.com/clinical_trials.html.

In August, 2004 Erimos published a press release describing the presentation of data on six subjects enrolled in a study titled Open-label, Phase I, Dose Escalation Study of Intralesional Injection of EM-1421 in Head and Neck Cancer by Dr. Terry Day at the VIth International Conference on Head and Neck Cancer. Source: Erimos Pharmaceuticals presents positive safety and preliminary efficacy results from a phase I clinical trial of EM-1421 in refractory cancer patients at the VIth International Conference on Head and Neck Cancer. Erimos Pharmaceutical, LLC Press Release. 2004-08-09. Available from http://www.erimos.com/news/08-09-2004.html. Accessed on 2006-04-25.

To date, Erimos has presented data on a total of nine subjects dosed with EM-1412: six at the VIth International Conference on Head and Neck Cancer, and three at the 2004 ASCO Annual Meeting. We await publication of the results from the 28 subjects projected to be enrolled in the phase I trial of EM-1412.

Several weeks ago Erimos announced they filed a patent application in collaboration with North Carolina State University for the use of EM-1412 in the treatment of influenza, and possibly avian flu. Source: Triangle science collaboration could impact influenza, avian flu treatment; NC State, Erimos Pharmaceuticals file patent for joint efforts. Erimos Pharmaceutical, LLC Press Release. 2006-04-04. Available from http://www.erimos.com/news/04-04-2006.html. Accessed on 2006-04-25.

The Erimos web site offers this description of Erimos drug products in development:

Erimos has exclusively licensed a portfolio of proprietary small molecules. From this portfolio, Erimos is developing new therapeutics to treat cancer, HIV and autoimmune diseases. The products in development are drawn from a novel class of drugs preventing tumor cell replication and promoting selective tumor cell death, or apoptosis. The drugs are designed specifically to target abnormal tumor cells while causing little or no toxicity to healthy cells.

Erimos has exclusive license for nordihydroguaiaretic acid (NDGA) derivatives from The Johns Hopkins University. We have developed a novel process to extract NDGA from the resin of the leaves of Larrea tridentata, a desert plant indigenous to the southwestern US and Mexico. EM-1421, our lead candidate, is a semi-synthetic derivative of NDGA. It is designed to target specific differences between normal human cells and those cells that are abnormally aggressively dividing.

The cells in our bodies are continuously involved in a carefully orchestrated system of programmed growth, division, rest, and death. The regulation of these cellular pathways is essential in order to maintain tissue viability and bodily health. The transition of a healthy cell to a precancerous or cancerous cell is initiated by the disruption of these regulatory pathways. Cancer cells then redirect the cellular systems to allow for uncontrolled cell growth, replication, and resistance to programmed cell death (apoptosis).

Our lead drug candidate, EM-1421, prevents tumor cell replication and selectively induces tumor cell death (apoptosis). EM-1421 achieves this by preventing Sp1-regulated production of cdc2 (p34) and survivin. Survivin is an inhibitor of apoptosis protein (IAP) over-expressed in pre-cancerous and cancerous cells, and rarely found in healthy adult cells.

EM-1421 also prevents proliferation of human immunodeficiency virus (HIV), herpes simplex virus (HSV), and human papilloma virus (HPV). This is achieved through the deactivation of viral Sp1-dependent promoters that are essential for viral propagation. This suggests that EM-1421 may also be an important therapy for HIV, herpes and HPV infection.

Source: Technology Focus. Erimos Pharmaceutical, LLC web site. 2006. Available from http://www.erimos.com/technology.html. Accessed on 2006-04-25.

Corporate Organization

Delaware: there appear to be three (possibily) related entities incorporated in Delaware.

1. Erimos Pharmaceuticals LLC (file no. 3285406), a domestic limited liability company incorporated on 2000-09-28.

2. Erimos Technologies, LLC (file no. 3285407), a domestic limited liability company incorporated on 2000-09-28.

3. Erimos Executive, LP (file no. 4068916), a domestic limited partnership incorporated on 2005-11-30.

Source: Delaware Department of State, Division of Corporations. General Information Name Search. Available from https://sos-res.state.de.us/tin/GINameSearch.jsp. Accessed on 2006-04-25.

There do not appear to be any records for either BioCure Technologies or BioCure Medical in the Delaware Division of Corporations database. There is, however, a record for Biocure, Inc. (file no. 2900935), a domestic company incorporated on 1998-06-04. It's unclear whether or not Biocure, Inc. is affiliated with one or more of the Erimos corporations.

North Carolina: According to the State of North Carolina, Department of the Secretary of State, Erimos Pharmaceutical, LLC was initially incorporated in Delaware on 2000-06-29. On 2004-07-06, Erimos filed an Application for Certificate of Authority for Limited Liability Company: http://www.secretary.state.nc.us/imaging/Dime/IVTIFF_11511459.pdf.

According to the Erimos Pharmaceutical, LLC North Carolina Limited Liability Company (LLC) Annual Report for the fiscal year ending on 2003-12-31, BioCure Technologies, LLC of Edina, MN was the single corporate member of Erimos Pharmaceutical, LLC: http://www.secretary.state.nc.us/imaging/Dime/IVTIFF_11711138.pdf.

The Erimos Pharmaceutical, LLC North Carolina Limited Liability Company Annual Report, filed on 2005-03-09, indicates that Erimos Pharmaceutical, LLC was formerly known as BioCure Medical, LLC: http://www.secretary.state.nc.us/imaging/Dime/IVTIFF_13333616.pdf. This same annual report identifies Erimos Pharmaceutical, LLC as the single corporate member.

The History section of the Erimos Pharmaceutical web site provides this information:

Erimos was originally founded as Biocure Technologies, LLC in 2000, in collaboration with researchers at The Johns Hopkins University. Dr. Ru Chih Huang, Chief Scientific Advisor to Erimos, is a biology professor at JHU and is the lead inventor of Erimos' technology. Erimos has exclusive worldwide license for technologies developed in her laboratories.

In 2004 the company was renamed Erimos Technologies, LLC, and today is headquartered in Houston, Texas. Research and development offices (Erimos Pharmaceuticals) and laboratory facilities are located in Raleigh, North Carolina, on the Centennial Campus at NC State University. Erimos also has a processing plant in Juarez, Mexico.

Source: History, About Erimos. Erimos Pharmaceutical LLC web site. Available from http://www.erimos.com/history.html. Accessed on 2006-04-25.

It appears that Erimos consists of more than one company — this isn't illegal but it's certainly confusing. Erimos Technologies, LLC seems to have been formerly known as Biocure Technologies, LLC. It's unclear how Erimos Pharmaceutical, LLC could have been formerly known as BioCure Medical, LLC. It's also unclear when and where Biocure Technologies and BioCure Medical were incorporated.

Texas: the Texas Comptroller of Public Accounts database, Erimos Technologies, LLC (taxpayer no. 14119826866) was chartered in Texas on 2004-07-09. Source: Texas Comptroller of Public Accounts search. Available from http://ecpa.cpa.state.tx.us/coa/Index.html. Accessed on 2006-04-25.

As of April, 2006 Dr. Huang appears to be involved with the following businesses:

Member, Board of Advisors, 3V SourceOne Capital LLC. Source: Our Team, 3V SourceOne Capital LLC web site. Available from http://3vs1.com/team.html. Accessed on 2006-04-25.

Chief Scientific Advisor, Erimos Pharmaceutical, LLC. Source: Advisors, Erimos Pharmaceutical, LLC web site. 2006-03-01. Available from http://tinyurl.com/nozgy. Accessed on 2006-04-25.

Patents

Title: Nordihydroguaiartic derivatives for use in treatment of tumors. U.S. patent application no: 20050267208. Inventors: Huang, Ru Chih C.; (Baltimore, MD); Heller, Jonathan D.; (Dundalk, MD); Hwu, Jih Ru; (Hsinchu, TW); King, Ko Yung; (Hsinchu, TW). Assignee: Johns Hopkins University. Date filed: 2005-05-04. Available from http://tinyurl.com/ok8cz. Accessed on 2006-04-25.

Title: Method for treatment of tumors using nordihydroguaiaretic acid derivatives. U.S. patent application no. 20040127562. Inventors: Huang, Ru Chih C.; (Baltimore, MD) ; Heller, Jonathan D.; (Dundalk, MD) ; Chang, Chih-Chuan; (Baltimore, MD). Assignee: Johns Hopkins University. Date filed: 2003-12-16. Available from http://tinyurl.com/ngppp. Accessed on 2006-04-25.

Title: Method for treatment of tumors using nordihydroguaiaretic acid derivatives. U.S. patent application no. 20030171416. Inventors: Huang, Ru Chih C.; (Baltimore, MD); Heller, Jonathan D.; (Dundalk, MD); Chang, Chih-Chuan; (Baltimore, MD). Assignee: NA. Date filed: 2002-10-15. Available from http://tinyurl.com/n4uk5. Accessed on 2006-04-25.

Title: Nordihydroguaiartic derivatives for use in treatment of tumors. U.S. patent application no. 20030065016. Inventors: Huang, Ru Chih C.; (Baltimore, MD); Heller, Jonathan D.; (Dundalk, MD); Hwu, Jih Ru; (Hsinchu, TW); King, Ko Yung; (Hsinchu, TW). Assignee: NA. Date filed: 2002-04-11. Available from http://tinyurl.com/odsop. Accessed on 2006-04-25.

Title: Antiviral compositions and methods of use. U.S. patent application no. 20020151584. Inventors: Huang, Ru Chih C.; (Baltimore, MD); Elazem, Ibrahim Shawky Abd; (Baltimore, MD); Chen, Hong Shan; (Beijing, CN). Assignee: Johns Hopkins University. Date filed: 2001-09-25. Available from http://tinyurl.com/qa752. Accessed on 2006-04-25.

Title: Method for treatment of tumors using nordihydroguaiaretic acid derivatives. U.S. patent application no. 20020065310. Inventors: Huang, Ru Chih C.; (Baltimore, MD); Heller, Jonathan D.; (Dundalk, MD); Chang, Chih-Chuan; (Baltimore, MD). Assignee: NA. Date filed: 2001-05-09. Available from http://tinyurl.com/jd8ll. Accessed on 2006-04-25.

Because the inventions were developed in part with funding from the National Institutes of Health, the U.S. government claims an interest in patent application nos. 20050267208, 20030171416, 20030065016, 20020151584, and 20020065310.

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Link: To create an HTML link to this InfoMail cut and paste the following:

<a href="http://www.circare.org/im/im13Aug2002.htm">Johns Hopkins University Determination Letter</a>. CIRCARE InfoMail (2002-08-13)

Last Updated: 2007-10-10

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