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Fuzeon Story: new 48 week study results;
24-week results hold up at week 48
Reported by Jules Levin
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PARIS. Before describing the 48-week Fuzeon data, let me bid farewell to my stay in Paris. Despite my grumblings about Paris, such as not having fat free milk & no hot mustrard in the chinese restaurant, I found myself feeling warm musings about Paris & Parisians in my taxi ride to the airport this morning on my way back to Newark Airport & NYC. I had never before been to Paris & found it to be a wonderful city. I've been here about a week as I attended two conferences, the Lipodystrophy Workshop and the Intl AIDS Conference.
By the way after last year's Lipodystrophy Workshop in San Diego I urged the scientific committee to initiate a new section for the workshop on hepatitis, so for the first time the Lipodystrophy Workshop did in deed have oral presentations and a panel on hepatitis, as hepatitis has very relevant commonality with HIV complications and metabolics. Rember everything passes through the liver.
Back to Paris. While here I went to 2 museums, the Museum D'Orsay which is dedicated to impressionist paintings, and the Picasso Musuem which I found particularly interesting. I managed to go to several restaurants and cafes here. In Paris cafes are all called Brasseries and every block has an open street cafe/Brasserie where you can sit and drink coffee or eat. I went shopping and managed to buy a nice French sweater. The coffee in France is very good, even if they laugh at you when you ask for fat free milk. I have found the food here to be enjoyable, as I ate fish and chicken mostly, as well as eating twice at a Chinese restaurant across from my hotel.
HISTORY OF T-20. David Cooper from Autsralia reported the latest update on T-20 (Fuzeon) , the first entry inhibitor to be FDA approved. Actually, Fuzeon is a fusion inhibitor; fusion is one of several steps leading to HIV entry into the CD4 cell. Cooper presented the data at week 48 for studies TORO I and II, the US and European Fuzeon studies. The development of Fuzeon is a milestone in HIV drug development. Besides being the first entry inhibitor to be successfully developed this is the first time a new type of drug like this has been successfully manufactured. As a result there have been manufacturing difficulties in providing drug supply for patients. As I reported in a prior email from Paris Roche announced that they are able to increase the amount of drug for 2003. Previously they announced they could support drug for 12,000 to 15,000 patients through December 2003. In Paris they announced that they can have drug for 18,000 through December 2004.
Roche and Trimeris have set up state-of-the-art manufacturing facilities and expect manufacturing and supply to improve in the near and longer term future. The makers also are exploring alternative delivery systems to improve the method of administration for the drug. The presentation of the 48-week data for Fuzeon is a reminder that the successful development of this drug has been a long passage. Myself and other community advocates starting meeting with Trimeris and the developers of Fuzeon several years ago when the drug was in its early development stages. Right from the very beginning community advocates and the drug resarchers and the pharmacuetical company officials were consulting on the drug's development including the design of clinical studies. This was during phase I clinical studies and before Roche was in the picture.
I recall Trimeris officials asking us who of the big Pharma companies we thought would be a good partner for them to develop Fuzeon. Roche and community advocates starting meeting regularly to discuss and negotiate clinical study design. Roche met with us to discuss their ideas and our suggestions for design of phase III studies. The phase III studies were a milestone because we had to design studies which optimized background therapy for patients with advanced HIV and limited treatment options. I think it was the first time or one of the very first times that genotypic and phenotypic testing was used to select optimized therapy in large phase III studies. In addition, we had to consider T-20 administration by subcutaneous injection.
After studies were underway the manufacturing and supply issues became real and of more immediate concern. But early on in T-20 development the Trimeris team made it clear to us that this drug will be hard to manufacture and supply issues may occur. They were right. Unfortunately, community advocates and Roche have had some difficult negotiations and discussions about supply and access. So far we have not heard of any patients who want T-20 being denied access. And supply and manufacture should continue to improve.
Hopefully, once weekly or perhaps even once monthly Fuzeon administration is possible in the future, as Roche and Trimeris are considering this possibility. T-1249 is the second generation fusion inhibitor currently in development. It is entering phase II study in patients and shows effectiveness against HIV with T-20 resistance. By the way at the oral presentation for the TORO I and II studies at IAS the presenter thanked Mickey Salgo. Dr Salgo is the clinical director at Roche in charge of the TORO I and II studies. He has guided the T-20 studies throughout development.
THE STUDY
The patients in the TORO I and II were highly treatment experienced with all 3 HIV drug classes and with a good deal of HIV drug resistance. The study was an open-label, randomized, multicenter, international trial where patients were randomized to Fuzeon and an optimized background regimen or just an optimized background regimen without Fuzeon. Fuzeon (enfuviride) is administered by subcutaneous injection of 90 mg twice daily. Patients were permitted to switch to Fuzeon at virologic failure or at week 48. Genotypic/phenotypic resistance testing was used to select the optimized background regimens. Criteria for viral failure was based on two consecutive values:
--<0.5 log decrease from baseline starting at week 6 and 8.
--<1.0 log decrease from baseline starting at week 14 and 16.
--2 log or greater response and >1 log rebound at any time.
PATIENT CHARCTERISTICS
Baseline viral load: 5.1 log, about 100,000 copies/ml
CD$ count: 90 cells
Number of prior ARVs: 12
Years since initiating ARVs: 7
Prior NRTI> 6.3 years
Prior NNRTIs: 1.4 years
Prior PI use: 3.9 years
As you can see the patients in this study had quite a bit of prior treatment for HIV and had low CD4 counts and high viral load.
RESULTS
HIV Viral Load Reductions
Viral load reductions at week 48 held up well and were comparable to reductions at week 24 as measured by percent <400 and <50 copies/ml.
There were 661 patients receiving Fuzeon plus optimized backgound (OB) and 335 patients receiving OB. The analysis is Intent-to-Treat, discontinuation+viral failure=failure.
--At 48, weeks 34% of patients receiving Fuzeon+OB had at least a 1 log reduction in viral load compared to 17% of patients receiving just optimized background regimen This compared to 24 week results where 47% of patients receiving T-20+OB had 1 log viral load reduction or greater and 25% of patients receiving just OB had 1 log or greater VL reduction
<400 copies/ml
--30% of patients receiving Fuzeon+OB had <400 copies/ml at week 48 compared to 12% of patients receiving OB. This compared to week 24 where 32% of patients receiving Fuzeon+OB had <400 copies/ml and 15% of patients receiving just OB
<50 copies/ml
--at week 48, 18% of patients receiving Fuzeon+OB had <50 copies/ml compared to 7.8% of patients receiving just OB. At week 24 16% of patients receiving Fuzeon+OB and 6.3% of patients receiving OB had <50 copies/ml
All comparisons of Fuzeon+OB to OB, p<0.0001
The increase in CD4 count from baseline was 71 cells at week 24 for patients receiving Fuzeon+OB compared to 35 cells for patients receiving OB. At week 48 the increase in Cd4 count was 91 from baseline for patients receiving Fuzeon.
Median time to virologic failure was 32 weeks for patients receiving Fuzeon+OB vs 11weeks for patients receiving OB (p<0.0001).
Genotypic Sensitivity Score
For patients who were sensitive to 2 or more drugs in the optimized background 37.8% had <400 copies in the Fuzeon+OB group vs 17.5% in the OB group. For patients who were only sensitive to 1 drug 29% had <400 copies/ml in the Fuzeon+OB group vs 7.4% in the OB group. And for patients sensitive to 0 drugs 8% in the Fuzeon+OB group had <400 copies/ml and 0% had <400 in the OB group. CD4 count increases were greater as well when patients used 2 or more drugs to which they were sensitive: 116 cell (2 drugs or more) vs 88 cell increases (1 drug).
Injection Site Reactions
About 50% of patients reported mild tenderness at the sites of injection for Fuzeon. About 20% reported moderate pain. And about 1-2% reported severe pain requiring analgesics or limiting usual activities. Roche has developed educational materials instructing how Fuzeon should be injected and both doctors and patients should use these educational materials. Proper drug administration technique is crucial for success with Fuzeon. Otherwise drug resistance can develop.
The adverse event profile reported is similar for both treatment groups in the study except for injection site reactions. There was more sinusitis, peripheral neuropathy, and weight decrease reported for the Fuzeon arm in the study. There also was a higher incidence of bacterial pneumonia for patients receiving Fuzeon+OB vs just OB (6.6% vs 0.6%. The incidence was 9-10% for patients with <200 CD4s.
The study authors added that Fuzeon "did not exacerbate most of the known toxicities associated with most ARVs". This is in part referring to metabolic abnormalities. An analysis is ongoing to examine body changes and metabolic abnormalities in this study. But the study authors suggest they don't see major exacerbation of metabolics associated with Fuzeon, this is preliminary and speculative until we see the data.
Hyper sensitivity reactions have been attributed to Fuzeon (1% or less) and in some cases have recurred upon re-challenge.
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