Treatment Conference Call May 2

Geneva Conference Communication Proposals for Minorities Due May 12

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T-20 and Trimeris

By John S. James

T-20 (also knows as pentafuside) a "fusion inhibitor," is an entirely new kind of HIV treatment being developed by Trimeris, Inc., a small biotechnology company in Durham, North Carolina. Because of its complex and unique mechanism of action, this drug and its development have not been widely understood; they have been "off the radar" of Wall Street and the media, even the AIDS press. We think this work is as important as anything now happening in AIDS research, for several reasons:

* T-20 has successfully shown "proof of principle" in patients, with a clear dose response and, at the highest dose, antiviral activity at least equivalent to a protease inhibitor in all four patients receiving that dose. No human toxicity has been seen. A larger trial is about to begin.

* T-20 works differently than any retroviral now in use (meaning that it targets a different step in the viral life cycle). Therefore, it is unlikely to have any cross resistance with existing treatments, and should work equally well no matter what treatment history a patient has.

* Both theory and laboratory tests suggest that resistance to T-20 will be slow to develop, although it can exist. None has been seen in people so far. In the laboratory, resistant virus has been produced--but then that virus was used to design a new drug like T-20 which was effective against it.

* T-20 is active only against HIV-1; however, the same mechanism may lead to the development of similar drugs active against other enveloped viruses--a group which includes influenza, hepatitis B, hepatitis C, and Ebola fever.

* T-20 is active against all strains of HIV-1 tested so far. Since the co-receptor used by the virus does not matter, the compound is equally active against both SI (syncytium inducing) and NSI (non syncytium inducing) viruses. (Incidentally there is a little activity against HIV-2, but not enough to be clinically useful. A different drug like T-20 has been developed against HIV-2.)

* Trimeris has two technologies for finding other drugs in the same class as T-20 (that is, which exploit the same viral target), either against HIV or other viruses. One analyzes viral sequences to find similar compounds which might work better than T-20 itself--for example, against resistant viruses. The other technology uses laboratory procedures to screen chemical libraries to look for small-molecule compounds which are chemically unrelated to T-20, but have equivalent antiviral action.

T-20 Disadvantages

The main disadvantage of this potential treatment is that it must be given by injection. It will probably be delivered subcutaneously by a portable infusion pump, which is worn like a pager--probably the pump made by MiniMed, Inc., which is currently used by tens of thousands of diabetics to inject insulin. Eventually, orally bioavailable compounds with the same mechanism of action may be developed.

Meanwhile, an injectable drug does have compensating advantages, especially for patients with advanced illness. Much greater control of blood levels is possible, because the pump can be programmed to deliver whatever amount is needed, continuously or on any schedule required. There are no daily peak and trough blood levels unless those are wanted, and no drug variation due to delay or forgetting to take pills.

Also, all problems of drug absorption go away, along with this source of unknown variation between patients. Diarrhea or other gastrointestinal problems will not affect blood levels. And there is never a need to have a full or empty stomach for this drug.

Instead, a needle is changed every three days. It is a small needle, since T-20 is given continuously, so a very low flow rate is required. The pump can be detached for activities like showers or swimming--and programmed to give a bolus dose first, which can maintain an effective blood level with the pump detached for up to several hours. The pump can be worn during sleep.

What Is T-20 and How Does It Work?

T-20 was discovered several years ago at Duke University by Thomas Matthews, Ph.D., in the Laboratory of Dani P. Bolognesi, Ph.D. Dr. Bolognesi's team, working to develop candidates for an HIV vaccine, compared viral sequences from different strains of HIV, looking for a part of the virus which changed very little from strain to strain. The idea was to use this piece of the virus for a vaccine which could provide immunity against many different variants of HIV from around the world. This search for a conserved sequence in the virus led to a part of gp41, the HIV protein which penetrates uninfected cells as the first step in viral entry. This 36- amino acid piece of gp41 was manufactured for further tests. It failed to work for a vaccine, however.

But before moving on, Dr. Matthews tested this piece of the virus against live HIV, and found that it was highly effective in stopping the virus from infecting new cells.(1) The potential drug which is code-named T-20 is therefore a piece of the HIV virus itself.

Exactly how T-20 works involves complex protein biochemistry.(2) But basically, at one step in the entry process, the T-20 portion of gp41 must bind with a complementary sequence which is also in gp41; this binding changes the shape of gp41 and exposes the portion which first penetrates the membrane of the cell. The binding is part of an elaborate process which recognizes the cell's receptors, a process HIV and other enveloped viruses have evolved in order to be selective. Otherwise these viruses would be likely to enter cells where they could not reproduce, or try to enter debris which was not a cell at all.

T-20 is believed to interfere with this cell entry process by binding to its target first, displacing the T-20 sequence within HIV. Therefore the gp41 cannot change its shape into that which is required to enter the cell.

Viral Resistance to T-20

HIV resistant to T-20 has been created in laboratory tests. This resistance may be slow to develop, however, because the sequence which T-20 binds to in gp41 is highly conserved among different strains of HIV. When part of a virus stays much the same from strain to strain, it usually means that the region is critical, and changes there could produce a defective virus which is not viable. The T-20 sequence can vary somewhat, but HIV seems to have less freedom here than it does elsewhere.

When HIV resistant to T-20 does occur, it appears straightforward to develop a new inhibitor like T-20 against it. Since there may be few options for resistance to this drug, due to the T-20 sequence being highly conserved, it might be possible to make T-20 drug variants to block any resistant virus which becomes a problem in practice. Much more research is needed, however, to find out to what extent T-20 resistance will occur in people, and to what extent this problem can be overcome.

Manufacturing and Supply

T-20 is a 36-mer peptide (a sequence of 36 amino acids). It is relatively easy to manufacture small amounts, enough for the initial clinical trials, by a technology called solid phase synthesis. Large quantities for major trials or for marketing will require a more difficult manufacturing process--either solution phase synthesis, or genetic engineering (creation of a genetically modified cell which produces the drug). Development is now proceeding on both of these approaches.

Use of an infusion pump to inject the drug continuously will that using the pump instead of twice-daily injections will allow the same amount of drug to treat up to 14 times as many patients, while maintaining the same minimum (trough) blood level. This is because T-20 has a relatively short half life in the blood, about 2.0 hours; if it is administered twice a day, a large excess must be given so that the required minimum blood level will still be present just before the next shot.

Toxicity

No toxicity of T-20 has been seen in human trials so far. In the laboratory, the drug inhibits HIV at concentrations 10,000 to 100,000 lower than those harmful to cells.

T-20 does not enter cells, which further reduces the likelihood of toxicity. This is because drugs which get into cells have many more opportunities to create mischief than those which do not.

Clinical Trial Results

The only human results so far are from a phase I trial reported at the IDSA (Infectious Diseases Society of America) meeting September 1997 in San Francisco.(3) In this study, T- 20 was injected intravenously twice a day, for 14 days. Four different doses were tested: 3 mg, 10 mg, 30 mg, and 100 mg every 12 hours--and four volunteers received each dose. There was a clear dose response, with little viral load change at the two lower levels, a half log drop at the 30 mg dose, and at 100 mg, all patients became undetectable (a mean change of 1.5 logs, but since the viral load became undetectable in every case, this number was the maximum possible in the design of this experiment; the drug clearly produced a larger change, but it could not be measured here). The average CD4 count increased by 52 cells at the high dose, increased by 21 cells at the 30 mg dose, and decreased at the two smaller doses.

In this trial the cutoff for undetectable viral load was 500 copies. Later analysis with a more sensitive test found that none of the volunteers went as low as 50 copies. But since they started with an average viral load over 10,000, they probably could not have reached 50 copies in 14 days even if new infection was completely shut off, because of the time required to clear the virus from the body.

According to Trimeris, outside experts looked at the data and agreed that the speed of viral decline may be greater than any published results with combinations of RT (reverse transcriptase) and protease inhibitors. Of course this conclusion is tentative, since only four patients have yet been treated with the most active dose.

One factor that may have contributed to these results is that T-20 gets into the lymphatic system very well. This is where most of the virus is and most of its replication occurs. A second factor could be that T-20 blocks both mechanisms by which HIV enters a cell--virus to cell infection, and fusion of an infected cell with uninfected cells.

Clinical Trial Plans

Trimeris is about to start a larger trial at several sites. Forty patients who have failed at least one protease inhibitor combination will receive different doses of T-20, all of which are calculated to be effective. For 10 days they will use T-20 alone, so that the effect on the virus can be seen; then they will combine it with a new protease-inhibitor combination. After the first 10 days, the combination phase of this trial will last for 24 weeks--and after that, no one will be denied the drug if they want to continue it.

The first goal of this trial--in the first 10 days--will be to confirm the dose of T-20 when given subcutaneously with an infusion pump (the previous trial gave it intravenously twice a day). While the drug is likely to get into the serum and lymphatic fluid regardless of how it is injected, the dose must be checked because the twice-daily injections had huge peak levels of the drug. The available information for this and other antiretrovirals suggests that it is the trough level--the minimum blood level--which is important for controlling HIV, and that the extra drug in the peaks is not required. But with some antibiotics, the peak level, or the total amount of drug, does matter; therefore it is important to confirm quickly that a proper T-20 dose has been selected for continuous use.

Later trials being planned include a large phase II with 360 patients, pediatric trials for children who have failed protease inhibitors, another large phase II trial in adults beginning HIV therapy, and a test of using T-20 for induction of combination treatment in patients with a very high viral load (to lower the viral load quickly in order to help avoid resistance to the protease inhibitors and other conventional treatments being started). There are also plans to test T-20 as a topical microbicide for prevention of HIV transmission in discordant couples.

A number of possible short-course uses of T-20 have been discussed; these would be most important in the hopefully unlikely case that long-term use is not feasible, either because of side effects, development of antibodies which could make the drug ineffective, or manufacturing difficulties which delay production of an adequate supply. Such short-course uses could be for patients who have to go off all oral medications, for example due to surgery, or when oral medications cannot be absorbed temporarily because of other gastrointestinal problems; when a drug holiday from conventional treatments is necessary due to their toxicity; when viral load increases greatly due to an opportunistic or other infection; for prevention of maternal transmission, possibly in the first trimester if the inability of T-20 to get into cells reduces its risk to the fetus; and for post-exposure prophylaxis (reducing the chance of HIV infection by short-term antiretroviral treatment shortly after accidental exposure).

Because the clinical research on T-20 is still in such an early stage, Trimeris does not expect to be able to file for marketing approval at least until the first quarter of 2000.

Technologies for Developing New Drugs Like T-20

Trimeris has two different technologies for creating or discovering new drugs with the same mechanism of action.

One uses a computer analysis of viral sequences to suggest new peptides which may be effective; these peptides can easily be manufactured in small quantities for initial tests. This methodology (called C.A.S.T.--Computerized Anti-Fusion Searching Technology(4)) has already been used to develop a drug which in the laboratory was 100 to 1000 times more powerful than T-20 against HIV. This particular compound, called T-1052, failed in animal studies, however, probably because it was inactivated by something in the blood. But even though this drug did not work, it illustrates the power of the methodology to design new sequences which are much better than the natural one found in the target virus--not surprising, since in the virus the binding must be weak enough to be reversible, while in a drug, the stronger it is, the better. T-20 may be the first example of a new area of drug development which is only now coming into view.

The other drug-development technology consists of laboratory tests to screen existing chemicals--usually small molecules, not peptides--to find any which happen to work like T-20. This screening procedure sets up a laboratory situation where T-20 binds to its target--a process which must happen naturally in HIV, aside from any treatment--and then determines if the chemical being tested can block this binding. Trimeris is beginning to screen chemical libraries, looking for potential drugs which could substitute for T-20, and might be orally available so that they would not need to be injected.

The Company

Trimeris currently employs about 45 people. It's scientific advisors include: Dani P. Bolognesi, Ph.D., whose laboratory at Duke University discovered T-20; Michael S. Saag, M.D., of the University of Alabama, who ran the phase I clinical trial; Joe Pagono, M.D., Chairman of the University of North Carolina Lineberger Comprehensive Cancer Center; Thomas Matthews, Ph.D., who discovered T-20; and Eric Hunter, Ph.D., chairman of the University of Alabama Center for AIDS Research. The president and CEO of Trimeris, M. Ross Johnson, has 25 years experience in major pharmaceutical companies.

Wall Street, however, has not been enthusiastic so far. Trimeris first issued stock last October, priced at 12.00. The price went up as high as 17, then down as low as 7, and at this writing is 8.

What seems to have happened is that the financial community has not understood what the company is doing. The only human data so far--the results of the phase I study--were presented at the IDSA conference last September; this happened during the SEC-mandated "quiet period," so the company was unable to explain these results or tell its story. Since then there has been no significant news about Trimeris or T-20, and no in- depth background article about the company or its technology. Publication of the phase I trial is expected in the next few weeks.

References

1. Wild CT, Shugars DC, Greenwell TK, McDanal, CB, and Matthews TJ. Peptides corresponding to a predictive alpha- helical domain of human immunodeficiency virus type 1 gp41 are potent inhibitors of virus infection. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, USA October 1994; volume 91, pages 9770-9774.

2. Lawless MK, Barney S, Guthrie KI, Bucy TB, Petteway SR, and Merutka G. HIV-1 membrane fusion mechanism: Structural studies of the interactions between biologically-active peptides from gp41. BIOCHEMISTRY. 1996; volume 35, number 42, pages 13697-13708.

3. Saag M, Alldredge L, Kilby M, Venetta T, DiMassimo B, Lambert D, Johnson MR, and Hopkins S. A short-term assessment of the safety, pharmacokinetics, and antiviral activity of T- 20, an inhibitor of gp41 mediated membrane fusion. Infectious Diseases Society of America 35th Annual Meeting, San Francisco, September 13-16, 1997 [abstract #771].

4. Lambert DM, Barney S, Lambert AL and others. Peptides from conserved regions of paramyxovirus fusion (F) proteins are potent inhibitors of viral fusion. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, USA March 1996; volume 93, pages 2186-2191.

Adefovir Dipivoxil (PREVEON) Improved Expanded-Access Program

Gilead Sciences has significantly broadened the entry criteria for access to PREVEON(TM) (adefovir dipivoxil), an experimental antiviral being tested for treatment of HIV. The new program will no longer require specific viral load or CD4 values, but is open to patients who have failed at least two nucleoside analogs and one protease inhibitor, who need new therapeutic options for treatment of HIV, and who are not excluded due to illnesses or laboratory values which raise safety concerns with the drug. This program resulted from discussions between Gilead and AIDS advocates, who wanted entry criteria based on the patient's overall medical condition, without automatic exclusions due to viral load or CD4 numbers (see AIDS TREATMENT NEWS #288, February 6, 1998).

The new program will also allow patients to either (a) be randomly assigned to the 60 mg or 120 mg dose, or (b) choose to be assigned to the higher dose. The drug is given as one tablet per day.

For more information about the expanded-access program for PREVEON, call 800-GILEAD-5 from 8:30 a.m. to 5:00 p.m. Pacific time.

Adefovir Dipivoxil (PREVEON) New Results with Hepatitis B, HIV

By John S. James

On April 6 Gilead Sciences released results of two clinical trials of adefovir dipivoxil (PREVEON(TM)) for the potential treatment of HIV, and another trial of adefovir dipivoxil at a lower dose (30 mg) for hepatitis B. The hepatitis trial (which used HIV-negative volunteers) was clearly a major success, with a reduction of hepatitis B viral load of 4 logs (99.99%) in the 12-week trial, with adefovir dipivoxil once daily as the only treatment.

The two trials of adefovir dipivoxil (PREVEON) for HIV both produced positive results; however, the sizes of the viral load and CD4 differences were small. It is possible that adefovir could be more important than the numbers indicate, since it is metabolized differently than nucleoside analogs, and may be effective in cells where those are not. However, the information released recently does not answer this question, which may be crucial for determining the role of the drug in HIV clinical practice.

One trial, called GS 411, assigned 85 treatment-naive patients to one of five regimens, all of which included indinavir (Crixivan(R)):

indinavir + adefovir + AZT, or

indinavir + adefovir + d4T, or

indinavir + adefovir + 3TC, or

indinavir + adefovir + AZT + 3TC, or

indinavir + AZT + 3TC. (The last one is a control regimen, including only standard treatments.) An interim analysis at 20 weeks found all of these groups were equivalent in viral load decline (2.1 to 2.5 logs viral load drops in the adefovir groups, vs. 2.15 logs in the control group), suggesting that adefovir may substitute for some approved nucleoside analogs, while providing an easier regimen (one pill a day), different side effects, and different drug resistance.

The other HIV trial, GS 408, randomly assigned 442 volunteers who were already receiving anti-HIV treatment to add either adefovir or a placebo to their existing regimen. At 24 weeks the average viral load drop was -0.39 logs in the adefovir group vs. -.01 logs in the placebo group, a statistically significant difference--about a 0.4 log benefit from adding adefovir in these pre-treated patients.

Comment

Adefovir dipivoxil has advantages of easy administration, and activity against other viruses besides HIV (including hepatitis B, CMV, HHV6, and Epstein-Barr virus). Also, it could provide a new treatment option, which is important because patients are different and many are not succeeding with the available regimens.

A central question is whether this drug can contribute to long-term control of HIV. Adefovir dipivoxil is active in many cell types, including lymphocytes, monocytes, and macrophages, and it works in both resting and activated T- cells. Even a small viral load drop compared to conventional treatment alone could be important, if this drop is accounted for by viral suppression in a small reservoir of cells not reached effectively by the other treatments, since otherwise these cells would allow HIV replication and therefore development of drug-resistant virus.

HIV drug development is moving too fast to wait several years to see which regimens give the best long-term suppression of HIV; a drug would already be obsolete by the time the answer is found. But a reasonable way to estimate long-term viral control, without waiting for a long time to see it, would be to look at how many patients reach a viral load below 20 copies (or even less, as even more sensitive tests become available). It is known that if viral replication is almost completely shut off, patients are less likely to have a rebound of resistant virus, compared to those who only get slightly below the 400-copy quantification limit of the currently approved viral load test.

Therefore--assuming a regimen can be tolerated indefinitely-- the proportion of patients undetectable on the best viral load tests, at perhaps three months to a year, may be the best indicator of long-term antiretroviral activity, and important for determining the place of new treatment regimens in HIV clinical practice.

HIV/AIDS Nutrition Book for Clinicians

A CLINICIAN'S GUIDE TO NUTRITION IN HIV AND AIDS, written by three registered dietitians and peer-reviewed and published by the American Dietetic Association, is an authoritative guide that any AIDS medical professional should be familiar with and have available for reference. About half of the 178- page book is easily readable narrative text, the other half is charts, tables, lists, patient worksheets, and references.

The major sections are: Overview and Nutritional Implications in HIV and AIDS; Nutrition Screening and Assessment; Oral Nutrition Interventions; Enteral and Parenteral Nutrition Strategies; Assessment and Intervention Issues in Various Health Care Settings; and the appendices: Glossary of HIV/AIDS Terminology; Nutrition Assessment; Selected In- service Outlines; and Resources.

A CLINICIAN'S GUIDE TO NUTRITION IN HIV AND AIDS, by Cade Fields-Gardner, M.S., R.D., Cynthia A. Thompson, M.S., R.D., and Sara S. Rhodes, R.D., can be purchased through online bookstores, or ordered for $26 plus $5 shipping and handling from: The American Dietetic Association, P.O. Box 97215, Chicago IL 60678-7215; or call the ADA Customer Service, phone 800-877-1600, ext. 5000.

Treatment Conference Call May 2

People with HIV/AIDS and health-care professionals are invited to participate in a May 2 conference call at which they can ask questions of leading HIV/AIDS treatment experts.

The call, sponsored by the San Francisco AIDS Foundation and supported by an educational grant from Roche Laboratories, Inc., will take place Saturday, May 2, at 2:30 p.m. Pacific time (4:30 Central,, 5:30 Eastern). You must pre-register and reserve your place by calling 800-707-BETA; if space is available, you can pre-register up until a few minutes before the call begins. A recording of the call will probably be available later at 800-550-9235, and a transcript at www.sfaf.org/betalive.html.

Guest experts on this call will include Drs. Joel Gallant, Johns Hopkins University School of Medicine, David Hardy, UCLA School of Medicine, Robert Murphy, Northwestern Memorial Hospital, and Steven Becker, a San Francisco physician in private practice.

Geneva Conference Communication Proposals for Minorities Due May 12

"Non-profit organizations that provide services to people with HIV and AIDS are eligible to apply for funding for communications initiatives that extend the distribution of information and simplify data presented at the 12th World AIDS Conference being held in Geneva, Switzerland, June 28- July 3. This nationwide request for proposals is a special funding opportunity issued by Glaxo Wellcome Inc." (Quoted from Glaxo Wellcome press release, April 9, 1998.)

"Through the Request for Proposals (RFP) process, Glaxo Wellcome will fund a variety of communication initiatives, including treatment newsletters, which extend the distribution of information and simplify data presented at the international conference in Geneva. These initiatives should target African-American and Hispanic audiences. The number of grants and the amount of each grant will be determined during the proposal review process. Grant sizes are expected to range from $10,000 to $50,000."

This program is open to non-profit organizations in the United States.

The RFP was sent to more than 160 organizations. You can obtain a copy from Glaxo Wellcome's Health Care Coalitions office, 919-483-8584.

New Priority Email Delivery from AIDS TREATMENT NEWS

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AIDS TREATMENT NEWS reports on experimental and standard treatments, especially those available now. We interview physicians, scientists, other health professionals, and persons with AIDS or HIV; we also collect information from meetings and conferences, medical journals, and computer databases. Long-term survivors have usually tried many different treatments, and found combinations which work for them. AIDS Treatment News does not recommend particular therapies, but seeks to increase the options available.

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