Having Sired Twin Failures Hivid and Invirase, Roche Tempts Fate With High Profile T-20 Launch
By Rob Camp and Matt Sharp
|“If 12,000 people were to take Fuzeon at $20,000, Roche would reap about $240M in revenues. By 2005 that would grow to about $480M. Analysts say that Roche could turn a profit in three years: the industry average for a new drug is 16.”
Source: The Wall Street Journal, 3/13/03
ADAP Body Blow
On Thursday March 13th the U.S. FDA granted approval to T-20 (Fuzeon), the first of a new class of antiretroviral drugs that block HIV from infecting cells. Immediately after the news of Fuzeon’s approval, Roche officials said they would not disclose Fuzeon’s U.S. price until closer to the drug’s launch date. Then the company announced on Thursday, March 20 that T-20 would be priced at just shy of $20,000 for a year’s supply. This is more than double the next most expensive AIDS drug. Excerpts from a March 7th joint statement by AIDS organizations and individuals, prepared by TAG’s Rob Camp and San Francisco’s Matt Sharp, appear below. Click here for the complete position paper.
Research and advocacy have brought forth 16 approved antiviral medications targeting two different stages in the HIV life cycle. 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 life cycle.
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 high time that a new HIV drug class becomes available. Based on positive results from two large phase III pivotal studies, Roche/Trimeris submitted an application to the Federal Food and Drug Administration (FDA) for final approval and the FDA granted priority review status.
Although therapeutically promising, T-20 is unfortunately not an easy drug to use and may be difficult for some to access. Its drawbacks include:
- the requirement that T-20 be injected twice daily,
- a high incidence of problematic (painful and persistent) injection site reactions (PISRs),
- complex and lengthy reconstitution of each dose,
- inadequate drug supply, and
- high price.
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 ISRs. 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 fewer 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 two 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).
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.
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 five-month supply for every patient who begins therapy with T-20. This plan is heartening, although it may be contributing to the astronomical price.
With only a 16% success rate for bringing 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.
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 any relationship between price and efficacy. Is this the drug that will break payers’ backs?
Read the entire position paper, “Fuzeon Brand Enfuvirtide (T-20): Breaking Barriers or Breaking the Bank?”