Fuzeon Brand Enfuvirtide (T-20): Breaking Barriers or Breaking the Bank?
March 7, 2003
Research and advocacy have brought forth 16 approved antiviral medications targeting two different stages in the HIV lifecycle. These drugs, when used in potent combinations, have significantly reduced morbidity and mortality in people living with HIV. However, for the large number of people who have been treated for years and have developed drug-resistant viral strains, the present drugs are often insufficient to achieve durable viral control. Because HIV rapidly evolves resistance and cross-resistance to available drugs, there is a clear need for therapies that target other points in the HIV lifecycle.
T-20 is the first drug of a new class of HIV inhibitors that perform entry inhibition. More specifically, T-20 is one of a subset of entry blockers called fusion inhibitors. It acts by preventing the envelope of HIV from fusing to its target's cellular membrane. For treatment-experienced individuals with multiple-drug resistant virus, adding a drug from a new inhibitor class in combination with drugs from previously used classes is thought to be the most effective strategy for achieving durable viral suppression. As with all other HIV therapies, T-20 must be used in a combination, preferably with other new agents, in order to have the biggest punch.
T-20 has been shown to be active in vitro against virus using either CXCR4 or CXCR5 co-receptors, or both. Its mechanism of action occurs outside of the cell wall, and the drug does not appear to penetrate cells to any significant extent. Therefore T-20 is not expected to disrupt intracellular metabolic pathways or stimulate intracellular destruction.
Initially developed by Trimeris, Inc., since 1999, F. Hoffmann-La Roche and Trimeris (Roche/Trimeris, the sponsor) have collaborated on the development and production of commercial quantities of T-20. Both companies will market the drug within the U.S. and Canada, and Roche will solely market the drug in the rest of the world. It is hoped T-20 will be licensed for commercial sale and will be in U.S. pharmacies by the second quarter of 2003.
It is high time that a new HIV drug class becomes available. Based on positive results from two large phase III pivotal studies, Roche/Trimeris have submitted an application to the Federal Food and Drug Administration (FDA) for final approval and the FDA has granted priority review status.
Based on data from ongoing and completed studies, TAG believes that the Roche/Trimeris application for accelerated approval of Fuzeon brand enfuvirtide to treat HIV infection in combination with other antiretroviral agents in adults and adolescents should be approved by the FDA.* FDA should ensure that Roche/Trimeris advertising materials specify that the drug has only been studied in heavily pretreated individuals with low CD4 counts (in the Phase III TORO 1 and TORO 2 studies).
* A large minority of the community present at an ATAC strategy session at the 10th CROI voiced opposition to T-20 accelerated approval, based on a number of key scientific points as well as overarching feelings of frustration. Never has one drug had such an ominous ripple effect.
Although therapeutically promising, unfortunately T-20 is not an easy drug to use and may be difficult for some to access.
Its drawbacks include:
Twice Daily Injection
Because it is a complex protein peptide, T-20 has to be administered by subcutaneous (subQ) injection twice daily, a substantial issue for most people. Adherence to life-long oral HIV therapies is already inherently difficult. The technical demands of self-administering a twice-daily injectable drug are even more so, and we find the Roche/Trimeris video of people effortlessly incorporating T-20 into their daily lives misleading. Interestingly, the T-20 educational plans do not take into account the difficulties outlined below and how people can deal with them. A specific program is needed to deal with the complexity of drug reconstitution and self-injection. Patient experience may be very helpful in elucidating some basic "dos and don'ts." Fuzeon has challenges in common with other injectable drugs, including the significant concerns many former injection drug users in recovery have regarding any use of needles as a potential trigger for relapse.
Problematic Injection Site Reactions (PISRs)
The Achilles heel of T-20 may be the ISR's. T-20 injections cause a local, painful skin reaction, somewhat like a wasp sting, in almost all (98%) people studied thus far. Many people, especially users of T-20, are frustrated with the lack of importance given to this issue by the sponsor. Because both the cause and the resolution of these may be key to success on this drug, we will be using the term PISR (problematic injection site reactions) in this paper, not the sponsor term ISR. Roche/Trimeris needs to learn more about why these PISRs occur and must look into other delivery mechanisms for the compound. Besides PISRs, T-20 has side effects (grade 3 and up, in less than 10% of people) of nausea and vomiting, neutropenia, anemia, and elevated SGPT and amylase.
The unreconstituted drug can be maintained out of the refrigerator. Reconstitution is the first drawback to ease of use. After mixing the sterile water with the powder, T-20 can take up thirty minutes or longer to dissolve completely. It is unclear whether total reconstitution is necessary for efficacy. Often the solution is drawn up in the needle before the drug is completely dissolved. What is "completely" dissolved? Is injection of unreconstituted substance contributing to PISRs? Although waiting for the drug to reconstitute is another barrier to efficient delivery, recently it has been shown that a reconstituted vial, if not used immediately, can be stored in the refrigerator for up to 24 hours. Consequently it is possible to reconstitute 2 vials simultaneously and place one in the refrigerator. In this way the stored vial, once brought back to room temperature, could be used without the need to wait for reconstitution. This practice allows people to reconstitute their second vial along with the first, cutting the daily waiting time for this step in half.
Fuzeon is reported to be the most difficult HIV drug heretofore manufactured. It is a complicated protein requiring at least 106 steps to produce and is dependent on large quantities of processed materials supplied by third parties. Trimeris, the originator and designer of T-20, entered into partnership with Roche in order to manufacture the complicated peptide. According to the sponsor, the commercial manufacture of T-20 is the first time that synthetic peptides have been produced at this scale. Once the companies believed they had a worthwhile product, they scaled up production by designing a new, specialized production plant in Colorado. However, difficulties in developing production capacity and acquiring raw materials have limited drug supply and have held back implementing the expanded access program. Until the new plant came on-line, small-scale production had only been able to meet the needs of clinical trials and a small expanded access program (1,200 slots world-wide that took an excessive six months to enroll). Full-scale production for marketing had been promised to be up and running without hitches by the beginning of 2003. But after reports that only half the amount hoped for would be available at time of launch, a limited initial distribution plan has been developed.
Producing enough T-20 for all the research, the expanded access program and expected market demand has been a major stumbling block in the development of this drug. Because of the production difficulties, and the fact that a drug of this complexity has never been produced before, there is no promise that enough drug can be produced in a timely manner to reliably supply all who need it. The sponsor is reserving a 5 month supply for every patient who begins therapy with T-20. This plan is heartening, although it may be contributing to the astronomical price.
A wholesale price of $20,440 has been announced for the European market. Although there had been rumors and pre-emptive justification of a high price, this drug is showing us that there need not be relationship between price and efficacy. Is this the drug that will break payers' backs? Will providers be unable to justify or afford the high cost and refuse to add T-20 to their formularies, despite patient need?
An aggressive commitment to patient and provider education will be required as the number of people using T-20 swells from 2,000 to perhaps 15,000 by year's end. Up to now, the sponsor has not shown itself ready, willing, or able to do this. Education, for both the user and provider, must be the top priority on the Roche/Trimeris agenda and the educational program must be set up and in place at the time of approval.
Minimize Barriers to Adherence
Toxicity management issues need to be better studied. Health care providers and patients need to understand the time commitment required to use T-20 correctly to be more comfortable prescribing it and obtaining the best advantage from its use. Treatment fatigue is common with oral HIV treatments. The desire to "skip" one dose per month (a fairly common occurrence even with oral meds) may be more risky in heavily pretreated people.
Quality of life issues resulting from the use of injectable drugs remain problematic. The trend in HIV treatment is towards drugs that are simpler to use. T-20 bucks this trend. Adherence issues and PISRs must be dealt with aggressively by the company, with more scientific research, studies into different ways to administer the drug, and careful clinical programs to counsel people on the best, safest methods of injection in order to make T-20 more user friendly. It is important that T-20 not join a person's list of quickly "used up" therapies. The FDA should recommend a patient/health care provider advisory board to work on these issues.
Get to the Bottom of PISRs
According to data from the sponsor, PISRs occur in nearly all who use T-20 and have been the major adverse event in all studies to date. Fifty percent are reported as mild, while the other 50% are between moderate and severe. Erythema (of more than 4") and pain have been reported in 80% of people and induration of 2" in 85% of people. Twenty percent of the PISR nodules do not go away even after 7 days. There does not seem to be improvement over time.
PISRs may be caused by injecting too close to the skin, which people may do to avoid the nodules. Others who inject "deeper" may be accumulating sub-derma scar tissue that also doesn't go away. Some insulin injectors have suggested to warm the syringe before injection. Also, the skin surface in general may harden as surface scar tissue.
In a poster at CROI 2003, in an analysis of the pathology of the (P)ISRs, one of the results was that the single patient (out of seven studied) who did not have (P)ISRs "had insulin-dependent diabetes and had self-injected insulin for many years using optimum injection techniques, according to various healthcare providers associated with the patient." Are PISRs nothing more than bad injections? If so, the sponsors' education plan has not worked. Easier modes of delivery need to be looked into. If it is something else (allergy, etc.), then that needs to be clarified. Does the incomplete dissolution of T-20 have anything to do with the PISRs? Is there a point when, although not completely dissolved, it is safe and efficacious to use?
Continue Dosing Research
Questions have been raised concerning the potency of the control regimen and the small sample size used in the Phase II study T20-206. Trimeris never ascertained the maximum tolerated dose for T-20 and based its dosing decision solely on the tolerability of the number of injections, as well as on the viability of maintaining adequate drug levels at that dosing schedule. While it was relatively easy for people on the approved sub-optimal dose of saquinavir to double the dose, that will not be possible with T-20. Roche/Trimeris should continue to look for the maximum tolerated dose, which will mean more investigation into delivery systems.
Help Identify Optimal Background Regimens
In multi-drug experienced people, therapy optimization should be ascertained via genotyping or, when appropriate, phenotyping. The recent news that only 25% of practicing clinicians know how to use the results of these resistance tests is very disconcerting. T-20's label needs to specifically mention continuing medical education (CME), etc. A clear understanding and reading of the resistance results would allow for an individualized optimization of the background therapy, and thus improved response.
Guarantee Access to Those Who Need It Most
With only a 16% success rate for binging viral load <50 copies/mL in the heavily pre-treated trial participants, and with drug supply limited, this drug may need to be rationed to those most in need -- those without other treatment options. Use in other populations has not been studied, and the risk-benefit ratio in a treatment-naive population has yet to be determined. Finally, it should be noted that there are no study results demonstrating the impact of T-20 on the clinical progression of HIV disease.
When the expanded access program was being planned, activists demanded that it enlist people equitably and from as many diverse populations as possible. The community was assured that new and different investigators would be chosen by the company to ensure that the drug was offered to people who typically were left out of such access programs, and to ensure that those needing a salvage therapy would receive T-20. Unfortunately, as with most expanded access programs to date, the sponsor delivered "too little, too late." The program has only recently begun providing significant amounts of drug even as final FDA approval is days away. This timing has allowed little access to the drug outside of clinical trials. T-20 has been studied primarily in a pre-treated population, in adults who are multi-therapy experienced, with multi-resistance and limited treatment options. This population; i.e., those most in need, must be guaranteed continued first access to this drug, regardless of the ultimate label indication approved by the FDA.
Assure Equitable Access
Roche/Trimeris must assure that scaled-up production will be able to meet demand with no further supply issues. Roche/Trimeris must ensure that there is an adequate supply of the drug for continued clinical trials, expanded access, and for sale throughout the world. They must show that it is possible within reason to meet patient demand, and work to avoid anticipated access problems that may arise. Because 25% of the Phase III trials took place in Brazil, it is fair that the sponsor guarantee a proportionate share of drug to Brazil, as soon as it is available. Sufficient drug to conduct Phase IV studies of treatment options and side effects should be assured.
There will be a maximum of 15,000 T-20 slots available in 2003. Roche/Trimeris need to come to reasonable terms over its price with all payers, whether they be insurance companies, Medicaid or ADAPs. Details of the sponsor's "Patient Assistance Plan" (PAP) need to be defined (Roche has verbally promised 1/3 of drug to those most medically needy). The entry criteria for the PAP may well be determined by those who are unable to enter state ADAP plans. Administration of PAP eligibility should be coordinated with the ADAPs.
Tell the Truth
The FDA needs to take its role as monitor of pharmaceutical advertising very seriously and remember that the wording in the label and advertising for the use of this drug should not be ambiguous or misleading regarding target populations. The FDA should insist that those people most likely to benefit from T-20 have first access.
Both TORO studies are to continue to 48 weeks for full approval of T-20. The HIV Community asks that TORO 1 and TORO 2 be amplified and include other experimental agents. Then, background treatments could be stratified and analyzed. Also, the mechanisms of toxicity issues like PISRs, the inflammatory response, the eosinophilia and the hypersensitivity reaction, and how to either avoid them or respond to them, could be amended into the TOROs.
We support the accelerated approval of Fuzeon (aka, T-20) and look forward to its equitable availability, but more research is needed to insure that those who need it most will receive the full benefit, with minimal impact on quality of life.
T-20 is a peptide (a 36 amino acid chain) with amino acid sequences that are identical to a segment of the heptad repeat (HR-1 and HR-2) regions of the gp41 molecule on the HIV envelope. The drug binds to the HR-1 region and disrupts interactions between HR-1 and HR-2 that normally draw HIV into contact with the target cell. By blocking this step, T-20 blocks cell fusion, and consequently, HIV's entry into the cell.
San Sebastian (Phase I)
In the initial phase I/II studies (TRI 001), T-20 monotherapy was administered intravenously (IV) for 14 days in 16 people. There were 4 dosing groups -- 3 mg, 10 mg, 30 mg, and 100 mg twice daily. Dose related declines in plasma viral load were seen in all groups. Those receiving the 100 mg dose saw median reductions of 1.96 log10 HIV RNA, to <500 copies/ml but not <50 copies/ml. This initial study showed that fusion inhibition could result in an antiviral effect without short-term toxicity.
Since intravenous therapy would be impractical long term, a different study was performed to assess the feasibility of subcutaneous injections (TRI 003). An insulin pump was compared to subcutaneous (sub-Q) injection in a randomized, dose comparison study in 78 treatment-experienced people for 28 days. The study included four dosing groups with the pump (12.5, 25, 50 and 100 mg/day) and two groups receiving the drug by sub-Q injection (50 and 100 mg twice daily). There were significant technical problems with the infusion pump that resulted in more favorable data with the sub-Q injections. Problematic injection site reactions (PISRs) were the major adverse experiences noted in this study. Virologic responses peaked at 7-14 days but diminished by the end of the study.
Running With the Bulls (Phase II)
Longer-term safety was established in the next study (T20-205). People in the short term trials were offered slots in a 48 week study which offered a chance to optimize their background therapy by adding T-20, starting at 45 mg sub-Q twice daily. This study was designed to determine safety and tolerability. It was an open label trial, and the conclusions are difficult to interpret. At baseline, laboratory values in this highly treatment experienced group were a median >100,000 copies viral RNA/mL and median CD4 cell count of 90/mm3. An intent to treat analysis showed not very favorable results, with only one third of participants having viral RNA >10 fold below baseline or <400 copies/mL. The most frequent cause of withdrawal from this study was virological failure, in 14 people; three withdrew because of an adverse event.
In the next Phase II study (T-20 206), 71 people who were PI experienced but NNRTI naive were switched to an NNRTI-based regimen with three different doses of T-20 or maintained on a new background regimen, which consisted of efavirenz + abacavir + amprenavir/r. In this study, the combined T-20 arms showed better results than the control arm in terms of viral control (48% vs. 37% <50 copies/mL). Although the sample size of 71 participants was very small, the viral load results were comparable to previous studies, being most favorable in those receiving the 90 mg twice-daily dose (although it was not powered to distinguish efficacy between arms). Other doses used were 45 and 67.5 mg twice daily. Two people withdrew because of adverse events related to T-20, PISRs. The PISRs were common and showed up more in the highest dose. Other laboratory adverse events were similar in the control vs. the T-20 arms, although there was more nausea, dizziness and headache seen with the T-20 especially in the highest dose vs. the control. CD4 cells increased in the groups receiving T-20 by approximately 50 vs. no change in the control.
In the TORO studies, there was also a higher number of people with bacterial pneumonias, bronquitis and cough in the T-20 arms than in the control arm.
Traje de Luce (Resistance)
Virus in peripheral blood cells was taken from participants in the Phase II studies to look for resistance to T-20. Several substitutions observed in the gp41 sequence conferred resistance to T-20 resulting in subsequent drug failure. A presentation at CROI confirmed the main codon sequence, 36-45.
Although confirmation is needed, it appears that the second generation Roche/Trimeris fusion inhibitor, T-1249, may not have the same resistance pattern. A second presentation at CROI 2003 supports this, although only 50% of the people whose T-20 had failed were analyzed, and only 53% of these achieved >1 log drop. This means that some people who fail T-20 may be able to opt for T-1249 (depending on how long the person is failing on T-20, as well as depending on genotype confirmation -- which will need to be followed closely), although broad availability of this new agent is at least three years away. A study looking at this population is planned and needs to begin enrolling soon. Future drugs in this class will have to deal not only with inherent efficacy issues, but also T-20 resistance.
TORO, TORO, TORO (Phase III)
Two large Phase 3 studies were performed. TORO 1 enrolled 491 treatment-experienced people in North America and Brazil with documented resistance to all three drug classes. Baseline viral load was >100,000 copies/mL. Up to two additional investigational or newly approved drugs (depending on pheno or geno and toxicity issues of drugs) were allowed for people to create an optimal background regimen, alone or with T-20. A dose of 90 mg twice daily was self-administered by sub-Q injection. At week 24, the median reduction of HIV RNA was 1.697 log copies/ml compared with 0.763 log copies/ml in the background regimen alone. Again, PISRs were common, and insomnia, headache, peripheral neuropathy and dizziness occurred more frequently in the T-20 arm. Approximately 10% of participants in both arms discontinued by week 24.
TORO 2 was a similar study but conducted in Europe and Australia among 504 people. Median reductions of HIV RNA in this study were 1.43 log copies/ml compared with 0.65 log copies/ml in the control arm. As in TORO 1, PISRs were common. Discontinuation at 24 weeks was 17% in the T-20 arm and 5% in the control arm.
In a pooled efficacy analysis presented at CROI (TORO 1 + TORO 2), 15.9% of patients achieved a viral load reduction to <50 copies/mL. Also, use with lopinavir, one of the most commonly used PIs, was associated with a lower virological response.
In a sub-analysis of the TORO studies, the level of viral suppression depended on the amount of drug resistance at baseline. People who were randomized to receive T-20 with no active drug in their background regimen reached a -0.92 log suppression of HIV RNA compared to a -0.12 log reduction in people receiving background regimen alone. Those people receiving T-20 with three to four agents in their background regimen saw a -2.3 log reduction compared to a -1.5 log drop with the background regimen alone. This analysis shows better viral control in those who added T-20 to active agents in their background regimen. Could this be the reason to do T-20 in a limited fashion, in order to get a punch once in a while, but not continuous. If a person can achieve a -1.5 log reduction without T-20, why torture themselves for more?
Cutting the Ear Off (Pooled Safety Data)
An analysis looking at pooled safety data from three Phase II studies showed incidence and patterns of adverse events were similar in the second year of treatment to those in the first. Combining all three studies, 69% of participants remained on drug at 48 weeks, and in the one study with 96-week data, 46% remained on drug. Two percent of participants dropped out of the study due to PISRs, the most frequent adverse event reported.
Eosinophilia is a blood disorder characterized by an abnormally high number of eosinophils in the blood. When a foreign substance is detected within the body, eosinophil production is increased. While eosinophilia is not a disease in and of itself, a high number of eosinophils indicates the presence of abnormal cells, parasites, or allergens. Using T-20, the number of eosinophils was greater than the upper limit of normal in 10% of people on T-20.
Tie Me Up, Tie Me Down (Pediatric)
The PK parameters were established with a dose ranging study of T-20 in 12 children. 14 children participated in a second study, receiving either 30 or 60 mg per m2 body surface area sub-Q twice daily plus a stable combination background therapy. Three of 4 participants in the 30 mg arm and 6 of 8 participants in the 60 mg arm reached a >0.7 log decline in HIV RNA from baseline after seven days. A mean decrease of >1.0 log HIV RNA was seen at the 60 mg dose. At 8 weeks, 9 of 12 children had a >1.0 log reduction in HIV RNA. The 60 mg per m2 dose was converted to a dose of 2 mg/kg twice daily for further studies that are ongoing.
There are 1,200 slots open worldwide in the EAP, with half designated for North America. At this date, all 150 sites have been selected, however many patients have yet to receive drug. Unfortunately, once again beaurocracy impeded enrollment into the program.
AIDS Action Baltimore
AIDS Action, Washington DC
AIDS Survival Project, Atlanta
AIDS Treatment Activists Coalition (ATAC), USA
AIDS Treatment Data Network, NY
Canadian Treatment Action Council (CTAC)
The Center for AIDS: Hope & Remembrance Project, Houston
CHAMP (Community HIV/AIDS Mobilization for Power), Philadelphia
Gay Men's Health Crisis, NY
National AIDS Treatment Advocacy Project (NATAP), New York
Save ADAP, USA
Search For A Cure, Boston
Tennessee AIDS Support Services, Inc (TASSI)
Test Positive Aware, Chicago
Eric S. Goldman, Esq., NY
For more information, please contact Rob Camp at Treatment Action Group at 22.214.171.12422.
The authors would like to thank the following people for their time and insightfulness in creating this paper: L. Dee, B. Huff, D. Raymond, T. Swan, B. Munk, F. Schaichs, E. Goldman, G. Schmelz, M. Harrington, D. Rose, C. Clifton, L. Chou, K. Fornataro, T. Gegeny.
This article was provided by Treatment Action Group. It is a part of the publication TAGline.