HE2000 Begins Clinical Trials: Interview with James Frincke, Ph.D.

HE2000 is a chemical relative of DHEA which was selected for development after it showed antiretroviral activity in laboratory tests. The immediate reason for interest in this compound today is that it apparently saved the lives of all three monkeys treated in a small animal study.1 A phase I/II human trials will be starting soon in Chicago, Houston, Palo Alto (California), and San Francisco in the U.S., and is ongoing in Cape Town, Johannesburg, and Pretoria in South Africa; for more information about the U.S. study, call Bob Marsella at Hollis Eden, 619-587-9333. HE2000 is currently given by injection for five successive days followed by a 30-day observation period, but oral and other formulations are being developed. The mechanism of action is largely unknown at this time.

Hollis Eden sees HE2000, if it works in people, as pioneering a new approach to treating the cells of the host, not the virus. It hopes to develop a treatment which could be affordable worldwide, avoid viral resistance, and be easier to administer, reducing adherence problems.

On May 24 we interviewed James M. Frincke, Ph.D., executive vice president for research and development at Hollis-Eden Pharmaceuticals (San Diego, California), the company which is developing HE2000.

ATN: What is HE2000, and what is its rationale or mechanism of action?

Frincke: HE2000 is an injectable formulation of a compound called alpha-epi-bromide. We are using an injectable form in this study to avoid clouding the results due to variable absorption with oral use. Eventually we hope to use the injectable form for a loading dose when a patient is first treated, but then switch to an oral drug for most other times. If the oral dose is insufficient for any reason, the patient could return to the clinic for injections to boost the effect again.

HE2000 has also shown activity in laboratory tests against malaria, CMV, polio, and influenza. It is possible that these infections and others use some similar mechanism to permit the infection to establish itself and persist in the human body. [On May 26 the company announced that it will work with the Navy on preclinical testing of the active ingredient in HE2000 for malaria.]

ATN: What is known about the toxicity of HE2000?

Frincke: We studied the drug both in rats and rabbits, and found minimal drug-induced toxicity up to a 160 mg/Kg dose; injection-site irritation may have been exacerbated by the drug, in a very sensitive rabbit species. The formulation used--a proprietary mixture of ingredients--at high volumes became toxic in rabbits before the drug itself did. So the drug toxicity appears to be low.

ATN: What dose will you be using in people?

Frincke: Our highest dose will be 3 mg/Kg--about 200 mg for a 70 Kg person. In pharmacology, one adjusts dose by using body surface area, so an equivalent dose for small animals is larger than if body weight only were used. Still, there is at least a 10-fold safety margin in the first and second human dose, and possibly in the third dose as well. Because in animals we found toxicity from the vehicle, not the drug (although the drug may have exacerbated the toxicity), we will be monitoring for all possible toxicities in the trial.


Mechanism of Action

Frincke: We also had to demonstrate that the drug has antiviral activity in animals. That was especially important for HE2000, since unlike the standard antiretrovirals, we could not do rational drug design on a computer screen against a viral target.

ATN: Because you don't know what the target is?

Frincke: Yes; the mechanism of action is still uncertain at this time. We know from the literature that the compound interacts with certain enzymes, including G6PDH (glucose 6 phosphate dehydrogenase); these enzymes could be involved in the mechanism. Also, the compound is in the steroid hormone series, and involved in control mechanisms in our cells that are much more complex, interacting with receptors and therefore changing the biochemistry of cells. This compound may have many modes of action; we are trying to understand what they may be.


The Primate Study

ATN: Describe the animal study that had the unexpected survival result.

Frincke: Retroviruses which infect mice would not have reflected the human situation. So to study antiretroviral activity in animals and make sure we had a sufficient therapeutic index (margin of safety between active and toxic doses), we used a virus called SHIV229--an artificially created virus which is a combination of HIV and SIV (simian immunodeficiency virus). This virus was created for vaccine studies, a virus which could infect monkeys and cause illness quickly. (HIV itself will not infect most primates; and when it does, it usually does not cause illness. SIV does cause illness in some monkeys, but that usually takes years--which would greatly slow the research.)

Eight animals were infected with SHIV229, and six were used for a small controlled study. In two to three weeks after infection, the animals' CD4 counts would drop to less than 100. And there was an increase in viral load to about 10 million, independent of the dose of virus which was given.

The six animals had been infected 24 weeks before we started treatment, so they were in end-stage disease. There had been no successful treatment of end-stage disease in any primates. But because we were looking for changes in viral load, we decided to go ahead and see if the drug had an effect.

Three of the six animals received an HE2000 injection daily for ten days, and then went without further treatment until eight weeks after the treatment began. We found only a modest effect on the virus, but the animals were doing quite well. So we decided to try another treatment regimen.

So we gave another 10 daily injections at a higher dose, and studied the animals for 11 weeks without further treatment; at that time the animals started to progress again. But what was important was that they were still alive.

So we went to a third dosing, giving it for ten consecutive days of a month, then repeated that treatment in the following month. At that point the primate center which was conducting the study told us that we had found something that might be very important--because the animals were still alive when they would not be expected to be. The three control animals which had not received HE2000 had a mean time from infection to death of 193 days; the three which had been treated had lived about 350 days at that time. So it appeared we had found a survival advantage, even though the viral load had not moved in ways seen with other antiretroviral drugs.

So we decided to continue this research as a survival study. We next administered the drug for five days and observed without treatment for 25 days. At that time we lost the most healthy of the three animals to an anesthesia death--the animals are anesthetized for blood draws, for the safety of the handlers working with them.

We treated the other two out to about 420 days; we had more than doubled their survival time, compared to the untreated controls. Then we stopped treatment to see how rapidly the animals declined. About five weeks later we lost the sickest monkey, who had a viral load of a billion and a CD4 count around 9. The final animal is still alive today, but is beginning to decline. So this experiment is about at an end.

The control animals had wasting syndrome, like that seen in AIDS. The animals which received the HE 2000, because they were in end-stage disease, had also begun to waste before their treatment started. After receiving HE2000, two of them went on to gain weight at a rate which would be expected of their age group. The wasting was halted and reversed in two of the three animals; in the third, the wasting stopped, but there was no increase in weight.

ATN: What is the next step?

Frincke: That study is now being repeated, with nine animals, four in the control arm. Five are receiving HE2000 for five days at a higher dose, about equivalent to the highest human dose planned, according to the surface-area dose calculations. After the five days, the animals are observed for the rest of the month, and then the monthly treatment is repeated. This study also includes extensive analytical work on the mechanisms of action of the drug.


Clinical Trials

Frincke: A phase I/II clinical trial is ongoing in South Africa, and a U.S. trial will begin enrolling patients in the first dose group.

In South Africa the protocol is five sequential days of injections, followed by observation for the remainder of a month. Testing includes viral load, proviral DNA, infectious virus in cells and serum, cytokine levels--TNF, gamma interferon, and a few others, standard chemistries, and markers for vehicle-related toxicity.

Three doses are being studied in South Africa: 50, 100, and 200 mg. There are 12 volunteers at each dose level. They are treatment naive; few individuals in that country can afford the treatments used in the U.S. to control the disease.

These patients are often co-infected with another illness, such as malaria, hepatitis B, hepatitis C, or tuberculosis; often they present with one of those at a clinic, and then when they are tested, they are found to also have HIV. Despite the co-infection, they may be able to enter the HE2000 trial.

These volunteers are eligible to receive a second and third monthly administration of HE 2000. At the end of that period, all patients who have received treatment are eligible to continue with the optimum dose, if the medicine is useful to them. So the protocol covers three administrations, but after the protocol closes, we will continue to observe the volunteers, and continue to provide drug.

ATN: Is there a placebo in this trial.

Frincke: No, everyone receives HE2000. There may be a placebo later in a phase II/III trial.

ATN: How is the U.S. trial different?

Frincke: In the U.S., the patient population that the FDA allowed is those who are failing their second HAART [highly active antiretroviral therapy] treatment, and have few viable treatment options. The FDA and the ethics committees felt that ethically these patients could be studied [while others who did have good options should use the approved treatments instead].

Because the U.S. volunteers will be further along in their disease and usually sicker than those in South Africa, we are starting with a lower 25 mg. dose; so there will be four doses, 25, 50, 100, and 200 mg, given for five sequential days, with an observation period for 30 days. In the U.S., the current protocol has only one treatment cycle. We will submit another protocol to the FDA to permit additional cycles if patients show a benefit with HE2000.

We are requiring a CD4 count greater than 100; this might be important as it is possible that there is an immune component in the action of the compound, and we want to make sure that the patients have enough immune potential so that we would not miss such an effect if it exists. Later, in a different study, we will test with volunteers who have a CD4 count less than 100.

We are also requiring a viral load between 5,000 and 250,000 copies, so that we can measure changes. And the patients' viral loads need to be stable, not moving drastically.

Exclusion criteria, both in the U.S. and South Africa, include G6PDH deficiency, any active serious infection, or current use of anabolic steroids, testosterone, DHEA, hydroxyurea or other metabolic inhibitors, or chemotherapy for malignant conditions. Volunteers must be at least 18 years of age, and have liver-function and certain other blood tests within normal range.


Comment

At this time the main evidence supporting HE2000 is from three monkeys. Why do we devote much space to a drug so early in development? There are three reasons:

(1) The monkey survival data is credible, and hard to explain away. And there is a good chance it will apply to people, although it might not.

(2) While HE2000 is not DHEA, and may have very different effects, the two are chemically related. We are glad to see more research attention in this area.

(3) When facing uncertainty, a useful way to judge a course of action is to compare the consequences of being right vs. the consequences of being wrong. If HE2000 does work as very early data suggests it might, it would be a fundamentally new drug suitable for use worldwide, with a survival benefit, little toxicity, little manufacturing difficulty, and no need for use every day. Also, it would establish a new mechanism of action, opening additional opportunities for medical research and drug development.

If HE2000 does not work, the down side would be the same as for the failure of any experimental medication--the inevitable risks of human research with a new drug.


References

(1) Frincke J, Ahlem C, Anderson D, Beck T, Agy M, Moton B, and Prendergast P. Treatment of SHIV229 in pigtailed macaques with HE2000. ICAR (12th International Conference on Antiviral Research), March 24, 1999, Jerusalem, Israel [late breaker abstract].