Status: approved; marketed

Organizations involved:

Hoffmann-La Roche Inc. – Manuf.; R&D; Tech.; World mark.

Trimeris Inc. – R&D; Tech.

Duke University – R&D; Tech.

Novartis AG – Patent dispute

Description: Enfuvirtide (T-20) or Fuzeon is a fully synthetic 36-amino acid peptide (not a biopharmaceutical) with an acetylated N-terminus and a carboxamide C-terminus. This peptide, fully composed of L-amino acids, is slightly larger than the shortest marketed recombinant peptide, teriparatide (the first 34 amino acids of parathyroid hormone). T-20’s sequence is derived from the HIV-1 transmembrane glycoprotein on the surface of the virus. T-20 is an inhibitor of HIV replication, acting as a “fusion inhibitor” binding to HIV outer membrane and preventing the virus from fusing with and infecting cells.

Enfuvirtide is a chiral molecule composed of natural L-amino acid residues. The peptide has a molecular weight or 4,492 Dalton (4.492 kDa); a molecular formula is C204H301-N51O64; and a primary sequence of CH3CO-Tyr-Thr-Ser-Leu-Ile-His-Ser-Leu-Ile-Glu-Glu-Ser=Gln-Asn-Gln-Gln-Glu-Lys-Asn-Glu-Gln-Glu-Leu-Leu-Glu-leu-Asp-Lys-Try-Ala-Ser-Leu-Trp-Asn-Trp-Phe-NH2. Diastereoisomers and epimers produced during synthesis are considered as impurities. Enantiomeric purity is part of acceptance criteria for the amino acid starting materials. Enfuvirtide can exist in four solid amorphous forms, but only two are produced by the commercial manufacturing process. Enfuvirtide has negligible solubility in pure water, but solubility increases in aqueous buffers (pH = 7.5) to 85-142 g/100 mL.

Each single-use vial contains 108 mg of enfuvirtide for delivery of 90 mg after reconstitution with 1.1 mL Sterile Water for Injection, providing a volume of 1.2 mL for injection of 1.0 mL. Each mL of reconstituted solution contains ~90 mL enfuvirtide at a pH of 9.0, plus ~22.55 mg mannitol, 2.39 mg sodium carbonate (anhydrous), and sodium hydroxide and/or hydrochloric acid for pH adjustment. Fuzeon contains no preservatives. Fuzeon in packaged in Convenience Kits containing 60 single-use vials of Fuzeon and 60 vials of Sterile Water for Injection. Fuzeon is stored at 25˚C (room temperature), with excursions allowed from 15˚C (59˚F) to 30˚C (86˚F) for up to 24 hours.

Nomenclature: enfuvirtide, synthetic [BIO]; enfuvirtide [FDA USAN]; Fuzeon [TR; assigned to Roche]; T-20 [SY]; L-phenylalanin-amide, N-acetyl-L-tyrosyl-L-threonyl-L-seryl-L-leucyl-L-isoleucyl-L-histidyl-L-seryl-L-leucyl-L-isoleucyl-L-alpha-glutamyl-L-alpha-glutamyl-L-seryl-L-glutaminyl-L-asparaginyl-L-gluta-minyl-L-glutaminyl-L-alpha-glutamyl-L-lysyl-L-asparaginyl-L-alpha-glutamyl--L-glutaminyl-L-alpha-glutamyl-L-leucyl-L-leucyl--L-alpha-glutamyl-L-leucyl-L-alpha-aspartyl-L-lysyl-L-tryptophyl-L-alanyl-L-seryl-L-leucyl-L-tryptophyl-L-asp-araginyl-L-tryptophyl- [CAS]; 159519-65-0 [CAS RN]; pentafuside [SY]; DP-178 [SY]; no NDC number reported on product insert

Biological.: T-20 interferes with the entry of HIV-l into cells by inhibiting fusion of viral and cellular membranes. T-20 specifically binds to the first heptad-repeat (HR1) in the gp41 subunit of the gp160 HIV envelope glycoprotein, preventing conformational changes required for the fusion of the HIV envelope with human cellular receptors, primarily CD4 in conjunction with chemokine HIV co-receptors. T-20 blocks HIV gp41-mediated outer membrane fusion, including fusion of HIV-1 virions to CD4-bearing cells and fusion of HIV-infected cells to other infected cells (syncytia formation).

The initial step of HIV-1 entry into (infection of) human host cells is the binding of virions with specific cellular receptors, CD4 and its chemokine coreceptor molecules (e.g., CXCR4, CCR5), on the surface of CD4+ T-lymphocytes or T-cells. Entry of HIV-1 into the target cell is mediated by two viral envelope glycoproteins, gp120 and gp41 (which together form gp160), which form complexes with CD4 that facilitate entry of the virion into the host cell. The HIV-1 surface glycoprotein gp120 mediates CD4 and coreceptor binding. The trans-membrane glycoprotein gp41 anchors the gp120-gp41 glycoprotein complex (gp160) within the viral envelope and mediates envelope-host cell membrane fusion. Enfuvirtide binds to one of the two peptide domains (the first heptad repeat) within the HIV gp41 membrane subunit, and prevents conformational changes required for the fusion of viral and cellular membranes by blocking the ability of gp41 to form a coiled-coil structure. This effectively prevents HIV fusion with cell membranes and entry of HIV RNA into cells; and fusion of HIV-infected T-cells, bearing HIV gp120/41 on their cell membranes, with other CD4+ T-cells, including uninfected cells (leading to further infection). Enfuvirtide has no effect on monocytes, macrophages and other cells that may be HIV-infected but lack CD4 receptors on their surface.

Enfuvirtide has an in vitro 50% inhibitory concentration (IC50) for both laboratory and clinical HIV-1 isolates representing clades (subspecies) A through G or 4-280 nM (or 80-1,260 ng/mL); an IC50 for baseline clinical isolates of 0.089-107 nM (0.4-480 ng/mL) by the cMAGI assay (n = 130); and an IC50 of 1.56-1,680 nM (7-7,530 ng/mL) by a recombinant phenotypic entry assay (n = 612). The wide variation in sensitivity of strains is due to the wide variations of gene sequences found in HIV-1, due to its very high mutation rates. This contributes to the development of HIV-1 resistance to this and other HIV therapeutics. In vitro-selected resistant HIV isolates have mutations (amino acid substitutions) at the HR domain positions 36-38 of the HIV-1 envelope glycoprotein gp41 (which, with gp120, forms the HIV gp160 envelope glycoprotein), with these resistant strains showing a 5- to 684-fold decrease in susceptibility to enfuvirtide.

Enfuvirtide has synergistic effects against HIV-1 in various cell culture assays when combined with other antiretroviral drugs, including AZT (Retrovir), lamivudine (Epivir-HIV; 3TC), nelfinavir (Viracept), indinavir (Crixivan) and efavirenz (Sustiva), with these drugs including nucleoside and non-nucle-oside HIV reverse transcriptase inhibitors and HIV aspartyl protease inhibitors. Resistant strains have been isolated from patients receiving Fuzeon in combination with other antiretroviral drugs, with posttreatment HIV-1 from 185 patients showing 4- to 422-fold decrease in susceptibility compared to baseline virus and mutations in gp41 amino acids 36-45. HIV-1 isolates resistant to other classes of HIV drugs (nucleoside and non-nucleoside reverse transcriptase inhibitors and protease inhibitors) remain sensitive to enfuvirtide in vitro, i.e., there is no cross resistance.

Companies.: Enfuvirtide was originally developed by researchers at Duke University and exclusively licensed to Trimeris, Inc. In 1999, Hoffmann-La Roche Inc. licensed worldwide marketing and manufacturing rights from Trimeris. Hoffmann-La Roche manufactures and markets enfuvirtide. In the U.S. and Canada, the two companies equally share development expenses and profits. In all other countries, Roche funds development costs and pays Trimeris undisclosed royalties on net sales. Trimeris is also eligible to receive up to $78 million in milestone payments.

Manufacture: The manufacture (chemical synthesis) of enfuvirtide is very complex and involves 106 steps. Nearly 100,000 pounds of specialized raw materials are required for manufacture of about 2,200 pounds (1 ton). This is the first time a peptide of this size has been manufactured on the tonnage scale. Enfuvirtide is synthesized using standard fluo-renyl-methoxycarbonyl (Fmoc) solid-phase synthesis of three main fragments, followed by solution-phase condensation of the fragments, and purification of deprotected crude enfuvirtide by chromatography and precipitation. During development, synthesis was changed from conventional linear (one amino acid added at a time) peptide synthesis to a process involving fragment condensation, with this material used for Phase II and III trials. The finishing process involves: preparation of the bulk solution; prefiltratation and first sterile filtration; sterilization of primary packaging materials; and final sterile filtration and filling into vials, lyophilization, and capping of vials. No animal components are used for manufacture.

FDA class: Drug NDA

Approvals: Date = 20030315; accelerated approval

Date = 20041015; full approval granted

Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling]:

Fuzeon in combination with other antiretroviral drugs is indicated for the treatment of HIV-1 infection in treatment-experienced patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy.

This indication is based on analysis of plasma HIV-1 RNA levels and CD4 cell counts in controlled studies of Fuzeon of 24 weeks duration. Subjects enrolled were treatment-experienced adults; many had advanced disease. There are no studies of Fuzeon in antiretroviral naive patients. There are no results from controlled trials evaluating the effect of Fuzeon on clinical progression of HIV-1.

Status: On Sept. 17, 2002, Roche and Trimeris submitted an NDA for use of enfuvirtide for treatment of HIV-infection. The filing was granted priority review and received accelerated approval on March 15, 2003 (approval time = 0.5 year). Approval was based on an analysis of six months of data from two ongoing clinical studies involving approximately 1,000 patients, with the addition of Fuzeon to a combination of other antiretroviral medications reducing plasma viral load (PCR measurement of HIV-1 in blood, a surrogate marker of efficacy) more than the use of the combination of medications alone. Fuzeon was launched in the U.S. on March 27, 2003.

In May 2003, Fuzeon received European Union approval for treatment of HIV-infection in combination with other antiretrovirals in treatment-experienced patients.

The Oct. 2004 granting by FDA of traditional, full approval of Fuzeon was based on results from Phase III trials over 48 weeks, which confirmed the durable efficacy and safety of Fuzeon-based regimens.

On Dec. 16, 2003, Roche and Trimeris completed submission to FDA of clinical trials’s data expected to support full approval (based on clinical efficacy and safety, not accelerated approval, with efficacy based on surrogate endpoints). This included 48-week data from two Phase III pivotal studies demonstrating the utility of Fuzeon in combination regimens for the treatment of HIV. The trials also showed treatment can be extended to at least 48 weeks. The best responses were seen in treatment-experienced patients with less advanced disease, but even patients with few or no other treatment options may derive some benefit from Fuzeon therapy over the longer term. These trials are expected to support full approval and changes in official guidelines for using Fuzeon for HIV treatment.

In May 2005, Roche and Trimeris filed an NDA supplement (sNDA) for inclusion of information about the Biojector 2000 (B2000) needle-free injection device in the Fuzeon labeling, i.e., for approval for administration using this device. Roche and Trimeris filed its sNDA in May 2005 based on data from the T20-405 study, a single-dose pharmacokinetic study of Fuzeon administered by a nurse via the B2000 needle-free device, compared to standard needle-syringe administration. On Nov. 23, 2005, Roche and Trimeris reported receiving an approvable letter requesting additional information from the ongoing ENF-404 or WAND (With A Needle-Free Device, or ENF-404) study, a randomized, open-label, two-way, cross-over study assessing the tolerability of the B2000 device for administration of Fuzeon. B2000, made by Bioject Medical Technologies Inc., is a needle-free, carbon dioxide-powered injector that disperses liquid medication beneath the skin.

In Oct. 2005, the Department of Health and Human Services (DHHS) issued new “Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents.” These supported the use of Fuzeon with an active boosted HIV protease inhibitor drug in patients with virologic failure, as this treatment approach results in better and more prolonged virologic suppression.

Tech. transfer: Patents covering T-20 (DP-178) include U.S. 6,133,418, assigned to Duke University, and licensed to Trimeris.

Novartis challenged Trimeris' U.S. patents is federal court citing is U.S. patent, 7,285,271, "Antigenic composition comprising an HIV gag or env polypeptide," as covering Fuzeon. A settlement was reached in Sept. 2010. Under the terms of the settlement agreement, Roche and Trimeris will continue to sell FUZEON under a license to Novartis’ US patent No. 7,285,271. In exchange, Roche and Trimeris agreed to pay royalties to Novartis on net sales of FUZEON of 1% and 1.5% on sales occurring in the US and Canada, respectively, in a calendar year, and 1% on sales outside of the US and Canada in a calendar year. The royalty rate increases to 3% in the US and Canada and 1.5% in the rest of the world on any portion of FUZEON sales in excess of $50 million in the relevant region in a calendar year. Roche and Trimeris share responsibility for payment of these royalties equally. Trimeris also made an immediate payment to Novartis in the amount of approximately $2.45 million representing Trimeris’ 50% share of back royalties on sales of FUZEON through March 31, 2010. Trimeris was to pay an additional $0.13 million to Novartis no later than October 31, 2010 representing Trimeris’ 50% share of royalties on the sale of FUZEON for the second quarter of 2010.

Trials: Approval was based on results from the TORO and RESIST-1 Phase III trials in treatment-experienced patients. Both studies demonstrated substantial virologic and immunologic responses from antiretroviral regimens containing Fuzeon plus an active boosted HIV protease inhibitor (PI) drug.

In late 2002, 24-week results from a Phase III trial (TORO 1) in treatment--expe-rienced patients showed that the drug, when added to an optimized drug regimen (based on HIV resistance testing), not only provided benefit to treatment-experienced patients regardless of treatment history, but provided the greatest relative benefit to those patients whose HIV is sensitive (not resistant) to multiple antiretroviral drugs and whose immune systems are less compromised. This further increased demand beyond those having developed HIV drug resistance and needing salvage therapy.

In Dec. 2004, A retrospective subset analysis of 48-week data from the pivotal TORO (TORO I and TORO II) Phase III studies in patients failing/failed on other HIV drug regimens showed that almost twice as many (52%) treatment-experienced patients who took FUZEON with an active boosted HIV protease inhibitor (PI) regimen achieved undetectable levels of HIV (<400 copies/mL) compared to those receiving an active boosted PI regimen without Fuzeon (27%). Patients taking the Fuzeon/PI regimen also experienced a significantly greater immunological response, with a median increase of 104 cells/mL vs. an increase of 57 cells/mL among patients receiving an active boosted PI regimen without Fuzeon. These results demonstrate that, in triple-class experienced patients, the use of a new class Fuzeon significantly enhances the antiviral activity of new active boosted PIs.

In the RESIST-1 trial in tipranavir (a protease inhibitor) treatment-experienced patients, the highest response rates seen were in patients receiving both Fuzeon and boosted tipranavir together in their treatment regimen. Almost half (47%) of patients who took Fuzeon with boosted tipranavir and other anti-HIV drugs achieved undetectable levels of HIV (<400 copies/mL). Participants in the study were very treatment-experienced, including prior experience with several protease inhibitor-containing regimens.

In Aug. 2005, Roche and Trimeris initiated the Fuzeon WAND (With A Needle-Free Device, or ENF-404) study, an eight-week trial designed to assess patient acceptance and experience of Fuzeon administration via the B2000 needle-free device compared to the standard needle and syringe. The primary endpoints of this study are tolerability and injection site reactions. Final data are expected in the second half of 2006. In July 2005, results from a trial (T20-405) in 32 HIV-positive patients showed that injection site reaction-related signs and symptoms were reduced by 50% when patients switched from administering Fuzeon with needle and syringe to the Biojector 2000 needle-free device (p=0.001). Ease of use also improved significantly (p=0.001).

Medical: Fuzeon is administered by subcutaneous injection of 90 mg (1 mL) twice daily into the upper arm, anterior thigh, or abdomen. Since reaction site reactions are common, each injection should be at a different site from the preceding injection site, and only where there is no current injection site reaction from a prior dose.

With its novel mechanism of action, patients lack pre-existing HIV-1 resistant to enfuvirtide. This is unlike current first-line HIV drugs (HIV reverse transcriptase and protease enzyme inhibitors) for which most patients have already developed or will eventually develop drug-resistant virus. T-20 has demonstrated safety and efficacy, reducing HIV plasma concentrations (viral load), below the limits of detection in combination with patients’ existing antiretroviral drug regimen, including advanced HIV patients with HIV resistant to multiple conventional drugs.

In Aug. 2006, the International AIDS Society-USA revised its HIV treatment guidelines and recommended for the first time that the goal of therapy in heavily treatment-experienced patients should be to achieve undetectable levels of HIV (less than 50 copies/mL). Fuzeon in combination with other new HIV protease inhibitors, e.g,. TMC114 (darunavir), was associated with a significantly greater likelihood of achieving these levels of HIV. The new guidelines recognize that patients need the full potency of at least two fully active drugs, e.g., Fuzeon, and a newer boosted protease inhibitor.

Market: Total sales were $249.0 million in 2006, $208.2 million in 2005; $135.2 million in 2004; $36.5 million in 2003. Net sales in the U.S./Canada were $134.2 million in 2006, $85.7 million in 2004, and $28.3 million in 2003. Commercial sales began in March 2003 in the U.S. and June 2003 in the EU. All sales are recorded by Roche. Roche had originally projected peak annual sales of $405 million.

For "2007, Trimeris anticipates that total worldwide net sales of Fuzeon will show modest top-line growth compared to 2006," indicating that sales are leveling off.

Although sales have steadily increased since launch, about 25% of patients having received at least one Kit do not remain on therapy, with most discontinuing therapy during their first three months, and most of these patients stopping treatment during the first month. Most discontinuations are due to injection site reactions, and/or other adverse effects that may not be associated with Fuzeon. Approval and adoption of the B2000 needle-free injector may resolve these problems.

The 2007 Average Wholesale Price (AWP) per kit (60 vials, 30 day supply) is $2,333.93 ($2116.93 in 2005, $1,999 in 2004) (Red Book, 2007).

Largely due to its high cost of manufacture, Fuzeon is relatively expensive, e.g., over $20,000/year. Most HIV patients currently treated in the U.S. use combination drug regimens, e.g., one or more HIV reverse transcriptase inhibitors with a protease inhibitor, typically costing between $10,000 and $16,000 annually. Thus, adding Fuzeon to their existing regimen can easily double the costs for HIV treatment. With the high cost of Fuzeon, many state-run Medicare/Medicaid and other health insurance programs have elected not to include the drug in their formulary (i.e., not cover its cost), are severely rationing its use, and/or are covering Fuzeon by cutting back access/reimbursement for other HIV drugs.

Demand has sometimes and may continue to exceed supply (despite its cost, need for twice daily injections, and adverse effects, e.g., injection site reactions). With its novel mechanism of action against HIV, the primary market (those most needing the drug) is expected to be the ~50,000 to 186,000 (out of about 1.5 HIV-infected patients) advanced HIV patients in the U.S. and Europe estimated to have developed serious resistance to one or more of their current HIV drugs, i.e., for salvage therapy. The incidence of drug resistance among HIV-infected patients is increasing as more patients continue to receive conventional drug treatment and survive for longer periods, further increasing demand for effective drugs for which they have not yet developed resistance, e.g., enfuvirtide.

In March 2003, Trimeris and Roche reported that the supply of Fuzeon was sufficient to treat 8,000-10,000 U.S. patients through the end of 2003 (consistent with projections of supplies for 12,000-15,000 worldwide at the end of 2003). However, since each patient was allotted a dedicated half-year supply, only about 12,000-15,000 actually received the drug by the end of 2003. Roche is increasing annual production to about 2 metric tons or enough for up to 20,000 patients/month. Capacity was expected to be increased to about 39,000 patients in 2005.

In Dec. 2004, Roche and Trimeris launched the Fuzeon Accelerated Simultaneous Access Program (ASAP) to immediate access to Fuzeon for patients starting treatment with Fuzeon in combination with an investigational anti-HIV drug obtained through an expanded access program (EAP). Fuzeon ASAP will help facilitate simultaneous initiation of Fuzeon with an active investigational agent in a regimen where deemed medically appropriate by a physician. For patients who are starting treatment with Fuzeon in combination with an investigational drug in expanded access, Fuzeon ASAP provides up to a 60-day supply of Fuzeon at no cost to the patient, which consists of an immediate shipment of a 30-day supply and an additional 30-day supply if reimbursement is still pending. Roche and Trimeris ensure access to Fuzeon for all patients beyond the initial 60 days, if reimbursement is not then established.

R&D: Trimeris and Roche had been developing T-1249, a second-generation, synthetic, 39-amino acid residue, HIV fusion inhibitor peptide, which showed safety and efficacy in clinical trials. T-1249 was more active than enfuvirtide, and had pharmacokinetic properties indicating it would be amenable to once daily dosing (e.g., allowing a single dose of 20 mg/day). However, the drug presented solubility problems that eliminated the possibility of once daily dosing, e.g., 192 mg/day was the dosage used in a Phase I/II trial. Like enfuvirtide, T-1249 is also difficult to synthesize. With T-1249 providing only marginal improvements relative to Fuzeon, in Jan. 2004, Roche and Trimeris discontinued trials with (abandoned development of) T-1249, citing problems in attaining the “desired technical profile” for the drug. The companies were then reported to be examining alternative technologies, e.g., sustained release, for delivery of T-1249.

In Jan 2006, Roche and Trimeris announced a collaboration for co-development of two new HIV fusion inhibitor peptides – TR-291144 and TR-290999. If successful, one of these will likely replace Fuzeon.

In March 2007, Roche and Trimeris renegotiated their collaboration, with Roche returning all intellectual property concerning next-generation product to Trimeris for which Trimeris will pay unspecified royalties upon commercialization. Roche retained its exclusive license to manufacture and sell Fuzeon worldwide. Roche also retains the right to conduct research on certain HIV gp41 fusion inhibitor peptides at Roche’s cost for a specified period of time, with Trimeris having the option to join in co-development.