HE2000: a new HIV treatment in early research

Following is information I've pieced together on a newtreatment for HIV in early human studies. The company developing this newdrug is called Hollis-Eden. I have not researched this information yet butthink its of interest. The information comes from the company so it maybe worded in such a manner to reflect that.

Hollis-Eden's three technology platforms are:

Cellular Energy Regulators


Cellular energy regulators focus on ways to interrupt theuse of energy supplies and factors within human cells that are needed byviruses and other microorganisms to replicate in their host cells. The companyintends is beginning testing its leading drug candidate, HE2000, for safetyand efficacy in HIV/AIDS patients. A Phase I/II study is beginning in SouthAfrica looking at safety, pharmacokinetics and preliminary antiviral activityand dosing. This study is described below. HE2000 will be administered byinjection in this study. HE2000 is a new more bioavailable formulationrecently developed from analog PPB2.

Mechanism of Action
Traditional Approach: Targeting Viral Proteins...and "Blocking"the Virus

Currently approved antiretroviral therapies are designedto block the action of specific HIV viral proteins that have critical functionsat particular stages of the replication process. Though temporarily effective,this protein-specific therapeutic approach can be foiled by HIV mutationthat displaces the targeted protein structure, resulting in drug resistance.

Hollis-Eden Approach: Targeting Cellular Energy Proteins...and"Starving" the Virus

Instead of targeting specific HIV viral proteins, HE2000,in in vitro testing, appears to work by inhibiting cellular energy-producingenzymes and proteins, which are necessary for retroviral replication.

The company's researchers discovered that HIV deprivesthe host cell of a molecule that regulates cellular factors, thereby causingan increase in energy-producing enzymes and proteins that HIV uses to replicate.The company believes that HE2000 regulates the supply of these key cellularfactors, reducing HIV's source of energy enzymes and proteins, and thus"starving" the virus of the energy it needs to replicate.

Moreover, because HE2000 is not directed at specific viralproteins, it may not be subject to the same viral mutation problems seenwith traditional therapies.

Immune System Regulators

Immune system regulators focus on ways to "up regulate"or "down regulate" the body's immune system as a way of treatingvarious disorders. HE317-the company's drug candidate for up regulatingthe immune system-will be tested in immune-suppressed patients sufferingfrom HIV/AIDS. IDPS-the company's drug candidate for down regulating theimmune system-will be tested in accepted animal models to treat organ transplantrejection.

Mechanism of Action
"Up Regulating" and "Down Regulating"

The immune system regulator platform was developed fromresearch into alpha-fetoprotein (AFP). AFP is produced by women during pregnancyso that the fetus is not rejected by the mother's own immune system. Thecompany's observation that the body can naturally modulate its own immunesystem, increasing (up regulating) or decreasing (down regulating) its intensityaccording to various bodily conditions, ultimately led to the discoveryof HE317 and other immune system regulatory candidates.

The company believes that HE317 works in two ways. First,HE317 may enhance the body's depleted immune system and, second, it mayallow the patient's own immune system to recognize and remove HIV-infectedcells.

Synthesis Regulators

Synthesis regulators focus on ways to control cellularenzymes involved in RNA and DNA biochemical synthesis pathways that an infectiousorganism needs in order to replicate in its host human cells. The companyhas several drug candidates that are being tested to treat a variety ofinfectious diseases. In the near term, the main focus of the company's firstdrug developed from this platform is cytomegalovirus (CMV): a disease thataffects AIDS patients worldwide.

Mechanism of Action
"Stopping DNA/RNA Synthesis"

The company has discovered, developed, and patented a rangeof modified nucleosides, or cytokinins, that are used as antibacterial,antiparasitic, antifungal, and antiviral agents for the treatment of a varietyof infectious diseases. The company's drug candidates are directly involvedwith the control of protein RNA and DNA synthesis and have demonstratedthe ability to selectively inhibit RNA synthesis and protein synthesis ofa variety of intracellular infective organisms. The company's drug candidatesinteract with a very important high-energy signal molecule called cyclicnucleotide adenosine monophosphate (cAMP), and, because of its unique multi-targetedapproach, they may be universally effective at inhibiting a wide array ofinfectious organisms and viruses in very small concentrations. Furthermore,the company has demonstrated in vitro and in vivo that, with very low levelsof these drug candidates, it may be possible to inhibit both RNA and DNAviruses. This approach has been shown to be non-toxic to normal body cells.

The Need for HE2000

Today, the most commonly used therapies for treating HIVdisease are reverse transcriptase/protease inhibitor (RTI/PI) combinations,so-called drug "cocktails." Growing drug resistance, the seriousside effects of these agents, the escalating cost, complexities of treatmentand compliance represent serious problems for HIV/AIDS patients and physiciansalike. Other than prescribing a different therapeutic combination, the physiciancan do little else to treat HIV/AIDS.

One aspect of the emerging resistance to combination therapycenters on the clinical regimen itself. Currently, most HIV patients onRTI/PI therapy must take from 20 to 50 pills each day at the proper timeand in the appropriate sequence in order to stave off the disease. Compliancewith this regimen by patients outside of tightly controlled clinical settingsis estimated to be only 60%. As the concentration of the drug combinationdrops during periods of noncompliance, the virus recovers, mutates, anddevelops resistance to the drugs.

Another aspect of drug resistance focuses on drug therapiesthat directly interact with the HIV viral structure. Based on so-called"rational drug design" theory, current RTI/PI therapies are designedto block the action of specific HIV viral proteins. Because the affectedproteins have critical functions at particular stages of the HIV replicationprocess, the blockage of these proteins is hypothesized to interfere with- if not eliminate - the process of replication. However, HIV is a rapidlymutating virus, and often shifts blocked functions to other viral proteins,negating the effect of protein-specific therapies and thereby making thevirus resistant to the drug's operation.

Finally, current combination therapies are known to causenumerous side effects, including nausea, rashes, depression, headaches,diabetes, high levels of lipids, and possibly increased risk of heart disease.

HE2000 development path

The cellular energy regulator HE2000 is Hollis-Eden's patentedanalogue of a human molecule that has been shown to inhibit energy-producingenzymes and other cellular proteins that are necessary for retroviral replication.

The company recently completed pre-clinical testing forHE2000. When tested in vitro against strains of HIV that had developed resistanceto all current combination therapies, HE2000 showed significant inhibitionof viral replication and a ten-fold increase in potency over the company'snative drug candidate that was previously tested in human clinical trials.

This clinical plan is supported by both in vitro and invivo studies. In one clinical study conducted with the company's nativedrug candidate for cellular energy regulation, multiple HIV/AIDS patientswere treated at Twelve Oaks Hospital in Houston, Texas. Preliminary findingsrevealed no observable toxicity and no adverse side effects. In addition,the trial in Houston demonstrated that, when the company's native drug candidatewas used as a monotherapy, clinically and statistically significant reductionsin viral load were seen in HIV-infected patients with CD-4 counts between50 and 300 cells/mm3.

Trials outside the United States

Hollis-Eden Pharmaceutical's research affiliate, Edenland,Inc., has commenced two Phase I/II clinical trials with two different formulationsof the drug candidate for HE2000 in HIV infected treatment naïve patients(patients who have not received any anti-HIV drugs) in South Africa.

SAN DIEGO, CA. ­ March 11, 1999 ­ Hollis-Eden Pharmaceuticals,Inc. today announced that they have been approved by the South African MedicineControl Council (MCC) to initiate testing with their lead drug candidate,HE2000, in HIV/AIDS patients. This allows the Company to evaluate HE2000in patients who have not been treated with anti-HIV drugs.

Separately, the Company has been informed of reports ofpreliminary results from Phase I/II studies in HIV patients by its researchaffiliate, Colthurst Limited, of Ireland, using a research formulation basedon the Company's HE2000 drug candidate for the treatment of HIV. The SouthAfrican Press Association (SAPA) reported today on results following aninterview with a researcher in the trial. Hollis-Eden did not participatein the release of this data and does not have a report from the completedtrial and therefore cannot comment on its content.

"We are looking forward to initiating Phase I/II clinicaltrials in South Africa and the United States," commented Richard B.Hollis, Chairman and CEO of Hollis-Eden. The FDA recently cleared Hollis-Edento begin a Phase I/II clinical trial in the U.S.


The study protocol approved this week by the MCC usingHE2000 is designed to evaluate safety and the most efficacious dose of HE2000.The novel drug therapy will be used in a short 5-day regiment. The drugwill be administered by injection to 36 HIV positive patients that are naïveto treatment (never exposed to any anti-retroviral drugs). Hollis-Eden intendsto conduct the Phase I/II clinical trial with HE2000 in collaboration withthe National Institute of Virology in South Africa.

The trials in South Africa will evaluate HE2000 in 36 HIVpatients that have received no prior anti HIV therapy. Safety, tolerance,pharmacokinetics, and antiviral activity are the primary objectives of thisPhase I/II trial, however other important clinical and biochemical informationwill be obtained. The study will also evaluate whether or not resistantvirus emerges from the use of HE2000 without any other drugs onboard. "Thiswill be an important study to help determine the antiviral activity andthe potential duration of benefit from this novel approach in attemptingto stop HIV replication," said Richard Hollis, Hollis-Eden CEO. "Patientsviral load and CD4 counts in blood will be monitored for any change andmore extensive tests will be conducted, to explore what if any effect thedrug might have on latent virus hiding in cells." This study does notexclude patients that are co-infected with hepatitis, malaria and tuberculosisto determine if the drug has any potential activity in these diseases aswell as HIV.

SAN DIEGO, March 1 /PRNewswire/ -- Hollis-Eden Pharmaceuticals,Inc. (Nasdaq: HEPH - news) today announced that the U.S. Food and Drug Administration(FDA) has notified the company that they may initiate dosing in a U.S. PhaseI/II clinical trial for HE2000, an investigational new drug for the treatmentof HIV/AIDS.

The Phase I/II trial will evaluate HE2000 in treatment-experiencedHIV-infected patients to determine the safety, tolerance, pharmacokineticsand anti-HIV activity of the drug. Patients will be monitored during dosingand up to three months following the completion of the treatment regimen.The trial will be conducted at selected sites in the San Francisco Bay area,Chicago and Houston.