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Biotech / Medical : Ligand (LGND) Breakout! -- Ignore unavailable to you. Want to Upgrade?

To: RXGOLF who wrote (27957)	2/7/1999 10:47:00 AM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Greg, I have known about the peer review requirement for off-label use and for some reason assumed that this was regarding peer-reviewed papers of clinical trials. However, I'm not that sure about the content of the reports. Can pre-clinical data also be distributed? Thus, when Targretin oral is approved for CTCL, can reps give out peer reviewed publications on prevention and treatment of type II diabetes and breast cancer in animal models?

To: RXGOLF who wrote (27957)	2/7/1999 12:47:00 PM
From: Henry Niman	Respond to of 32384

greg, Here is the abstract of a peer reviewed journal showing ONTAK effectiveness in treating a small number of non-Hodgkins lymphoma patients (out of 17 treated, who had failed prior therapies, one had a complete response and two had a partial response): Blood 1998 Jan 15;91(2):399-405 Phase I trial of a ligand fusion-protein (DAB389IL-2) in lymphomas expressing the receptor for interleukin-2. LeMaistre CF, Saleh MN, Kuzel TM, Foss F, Platanias LC, Schwartz G, Ratain M, Rook A, Freytes CO, Craig F, Reuben J, Nichols JC South Texas Cancer Institute, San Antonio 78229, USA. The purpose of this study was to evaluate the safety, tolerability, pharmacokinetics, and possible antitumor activity of a ligand fusion-protein, DAB389IL-2, in a phase I trial. This was a multicenter, open-label, dose-escalation trial. Patients with preserved organ function and histologically confirmed relapsed cutaneous T-cell lymphoma (CTCL), other non-Hodgkin's lymphomas (NHL), or Hodgkin's disease (HD) were eligible if their cancer was shown to express the interleukin (IL)-2 receptor by an immunohistochemical assay for the p55 or the p75 subunit. Patients received up to eight courses of DAB389IL-2 given as a short intravenous infusion daily for 5 days with subsequent courses every 21 days. The maximum tolerated dose (MTD) and tumor response was determined according to standard criteria. Seventy-three patients (44 men/29 women), aged 16 to 81 years (mean, 50.7) with CTCL (n = 35), NHL (n = 17), and HD (n = 21) were enrolled. The patients were extensively treated, failing 0 to 15 previous therapies (median, 4). Patients received one to six courses (mean, 3.3) of DAB389IL-2 over a range of 3 to 31 micrograms/kg/day. The dose-limiting toxicity was asthenia, establishing the maximum tolerated dose of 27 micrograms/kg/day. Approximately half of all patients had significant titers of antibody to diphtheria toxin or to DAB389IL-2 at the time of enrollment compared with 92% with titers at the end of treatment. The presence of antibody did not preclude clinical response. There were five complete (CR) and eight partial (PR) remissions in patients with CTCL with one CR and two PR occurring in NHL. The median time to response was 2 months and the duration of response was 2 to 39+ months. No responses were documented in patients with HD. DAB389IL-2 is well tolerated with an MTD of 27 micrograms/kg/day. This ligand fusion-protein showed antitumor effects in patients with IL-2 receptor expressing CTCL and NHL. Additional trials in these diseases are warranted. Publication Types: Clinical trial Clinical trial, phase i PMID: 9427692, UI: 98102419

To: RXGOLF who wrote (27957)	2/7/1999 12:52:00 PM
From: Henry Niman	Respond to of 32384

Here is the abstract from a peer reviewed journal suggesting that ONTAK could have applications for active inflammatory bowel disease: Dig Dis Sci 1997 Jul;42(7):1542-8 Interleukin-2 fusion protein (DAB389IL-2) selectively targets activated human peripheral blood and lamina propria lymphocytes. Bousvaros A, Stevens AC, Strom TB, Murphy J, Lamont JT Combined Program in Pediatric Gastroenterology and Nutrition, Children's Hospital, Boston, Massachusetts, USA. Activated mucosal T lymphocytes correlate with the intestinal inflammation of inflammatory bowel disease. Activated T cells elaborate interferon-gamma (IFN-gamma) and express high-affinity interleukin-2 (IL-2) receptors. The IL-2/diphtheria toxin fusion protein (DAB389IL-2) has been shown to specifically kill high affinity IL-2 receptor-bearing cells. We tested whether DAB389IL-2 could specifically target activated lamina propria lymphocytes. Lymphocytes were activated in vitro with phytohemagglutinin and IL-2 for 24-48 hr. Toxin efficacy was determined by the [14C]leucine incorporation, IFN-gamma ELISA, and flow cytometry. DAB389IL-2 (10(-11) M) inhibited protein synthesis by 80% in activated lamina propria lymphocytes. This inhibition was blocked by coculture of either excess IL-2 or a nonfunctional IL-2 diphtheria toxin mutant protein. DAB389IL-2 (10(-12) M) also significantly reduced the numbers of activated helper T cells and IFN-gamma levels in 24-hr cultures. DAB389IL-2 specifically targets activated IL-2 receptor-positive lamina propria lymphocytes and is a potential new therapeutic agent for patients with active inflammatory bowel disease. PMID: 9246061, UI: 97388828

To: RXGOLF who wrote (27957)	2/7/1999 12:56:00 PM
From: Henry Niman	Respond to of 32384

Here's an abstract of a peer reviewed journal showing that ONTAK had activity against the AIDS virus (HIV): J Infect Dis 1997 Apr;175(4):790-4 The interleukin-2 fusion protein, DAB389IL-2, inhibits the development of infectious virus in human immunodeficiency virus type 1-infected human peripheral blood mononuclear cells. Zhang LJ, Waters CA, Poisson LR, Estis LF, Crumpacker CS Division of Infectious Diseases, Beth Israel Hospital, Boston, Massachusetts 02215, USA. DAB389IL-2 is a genetically engineered fusion protein that reduces human immunodeficiency virus type 1 (HIV-1) replication in activated, interleukin (IL)-2 receptor (IL-2R)-expressing human peripheral blood mononuclear cells (PBMC). The level of infectious virus released by cultured PBMC after treatment with DAB389IL-2 was measured by a quantitative microculture assay. The inhibition of p24 antigen production was also evaluated in cultures that differed in duration of infection and activation state. Although the activation state of the cell and the time of DAB389IL-2 addition to the cultures influenced its anti-HIV activity, DAB389IL-2 treatment decreased levels of infectious HIV-1 to 0.1%-6.5% of untreated cell levels. DAB389IL-2 also decreased p24 antigen expression to 10%-48% of controls, even when added as late as 8 days after acute infection. Mutational variants of DAB389IL-2 that lack catalytic activity or IL-2R binding are without anti-HIV activity. PMID: 9086131, UI: 97240671

To: RXGOLF who wrote (27957)	2/7/1999 12:58:00 PM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

I have uploaded some abstracts showing potential applications of ONTAK. The NHL data was part of a clinical trial, which I am sure that Ligand sales reps can mention to doctors. I'm not sure about the pre-clinical publications.

To: RXGOLF who wrote (27957)	2/7/1999 1:03:00 PM
From: Henry Niman	Respond to of 32384

Here is a review by SRGN showing the status of some data for ONTAK in treating several tumor types. Although published in 1997, the last statement indicates that it was written in 1995: Eur J Cancer 1997 Jan;33 Suppl 1:S34-6 Interleukin-2 fusion protein: an investigational therapy for interleukin-2 receptor expressing malignancies. Nichols J, Foss F, Kuzel TM, LeMaistre CF, Platanias L, Ratain MJ, Rook A, Saleh M, Schwartz G Seragen Inc., Hopkinton, Massachusetts 01748, USA. DAB389IL-2 is an interleukin-2 receptor (IL-2R) specific fusion protein with a molecular weight of 58 kD containing the enzymatic and translocation domains of diphtheria toxin (DT) and human IL-2. This fusion protein is able to direct the cytocidal action of the DT enzymatic region only to cells which bear the IL-2R. The human IL-2R exists in three forms: low, intermediate and high affinity. The high-affinity form is believed to be the biologically relevant form on mature, activated T-lymphocytes, B-lymphocytes and monocytes. DAB389IL-2 is able to bind selectively to the high-affinity IL-2R in a concentration-dependent manner, and once bound is internalised via receptor-mediated endocytosis. Upon acidification of the formed vesicle, the enzymatic portion of the fusion protein is believed to pass into the cytosol where it ultimately inhibits protein synthesis by inactivation of elongation factor-2, resulting in cell death. The constitutive expression of the IL-2R on certain leukaemic and lymphomatous cells of T and B cell origin has been reported to occur in patients with chronic lymphocytic leukaemia, cutaneous T cell lymphoma (CTCL), Hodgkin's disease and non-Hodgkin's lymphomas (NHLs). A multicentre DAB389IL-2 dose-escalation study of patients with IL-2R expressing lymphomas has been conducted. A 10-fold range of doses were evaluated on a five-daily dose schedule. Patients received up to six courses, with an additional two courses permitted for patients with partial responses that appeared to be still improving after six courses. Most adverse experiences were transient and mild. Preliminary assessment of response indicated five complete responses (CR, duration ongoing at 20, 11, 7, 5 and 4 months) and seven partial responses (PR, duration 3-20 months) in the 35 patients with CTCL. One CR (duration > 20 months) in a patient with NHL (Lennett's lymphoma) and two PR (duration 9 and 2 months) in 17 patients with B-cell NHL have been observed. Based on the mode of action of DAB389IL-2, its safety profile, and the patient responses associated with the phase I/II clinical trials, a phase III programme in CTCL patients has been initiated and plans for additional trials in NHL patients are targeted for 1996. Publication Types: Review Review, tutorial PMID: 9166099, UI: 97308908

To: RXGOLF who wrote (27957)	2/7/1999 1:07:00 PM
From: Henry Niman	Respond to of 32384

Here's a peer review publication on the use of ONTAK for treating a disease that affects 200 million people worldwide: Cell Immunol 1995 Dec;166(2):217-26 Suppression of immunopathology in schistosomiasis by interleukin-2-targeted fusion toxin, DAB389IL-2. I. Studies of in vitro and in vivo efficacy. Ramadan MA, Gabr NS, Bacha P, Gunzler V, Phillips SM University of Pennsylvania, School of Medicine, Philadelphia 19104, USA. Schistosomiasis causes pathology in an estimated 200 million individuals. Clinical disease is caused by a complex immunopathologic response to the parasite ova, which are deposited in the host tissues. This immunopathologic response is caused by T lymphocytes which express the high-affinity IL-2 receptor (IL-2R). DAB389IL-2 is a diphtheria toxin-IL-2 fusion toxin protein which functionally inactivates or kills cells which bear the high-affinity IL-2R. DAB389IL-2 has been used in man to suppress IL-2R-dependent immune reactivity. Therefore, we reasoned that DAB389IL-2 might suppress immunopathology in schistosomiasis. In these studies we assessed the in vitro and in vivo effects of DAB389IL-2 on the development of immunopathology in murine schistosomiasis. DAB389IL-2 suppressed IL-2, lectin mitogen (Con A), and soluble Schistosoma mansoni egg antigen-induced lymphocyte proliferation and in vitro granuloma formation. In addition, DA-B389IL-2 suppressed in vitro IL-2R expression. DA-B389IL-2 also suppressed the development of granulomas and collagen deposition in vivo in the livers of infected animals. Therefore, DAB389IL-2 may have potential for the targeted reduction of immunopathology due to schistosomiasis in man. PMID: 7497523, UI: 96102269

To: RXGOLF who wrote (27957)	2/7/1999 1:10:00 PM
From: Henry Niman	Respond to of 32384

Here's a psoriasis trial indicating that ONTAK was too toxic at higher doses for the routine treatment of psoriasis: Am Acad Dermatol 1998 Jun;38(6 Pt 1):938-44 Administration of DAB389IL-2 to patients with recalcitrant psoriasis: a double-blind, phase II multicenter trial. Bagel J, Garland WT, Breneman D, Holick M, Littlejohn TW, Crosby D, Faust H, Fivenson D, Nichols J Psoriasis Treatment Center of Central New Jersey, East Windsor 08520, USA. BACKGROUND: Current therapies for recalcitrant psoriasis focus on immunoregulation and targeting of activated T-lymphocytes rather than keratinocytes. Previous studies with low doses of the lymphocyte-selective fusion protein DAB389IL-2 have shown benefit to patients with psoriasis. OBJECTIVE: We examined the safety and efficacy of DAB389IL-2 in 41 volunteers receiving more frequent and higher doses than in a previous trial. METHODS: Patients were randomized to receive either placebo or 5, 10, or 15 microg/kg daily of DAB389IL-2 intravenously for 3 consecutive days each week for 4 consecutive weeks with a subsequent 4-week observation period. RESULTS: Of the placebo group, 17% (2 of 12) exhibited at least 50% improvement from baseline Psoriasis Area and Severity Index scores at the end of the study, whereas 24% of all treated patients (7 of 29) showed the same improvement. Overall, 3 of 12 (25%) patients given placebo as opposed to 12 of 29 (41%) patients treated with DAB389IL-2 improved to this same extent at some point during the study. The rate of improvement for treated patients was significantly greater than for placebo patients (p = 0.04; repeated measures ANOVA). Among treated patients, decreases in Psoriasis Area and Severity Index scores were paralleled by changes in the Physician's Global Assessment and the Dermatology Life Quality Index. Treatment in ten patients was discontinued because of adverse events. Flu-like symptoms were the most common with severity increasing at the two higher doses. Only one serious adverse event was reported. This occurred in a patient receiving 5 microg/kg daily who experienced vasospasm and a coagulopathy resulting in arterial thrombosis. CONCLUSION: Our findings are consistent with the potential antipsoriatic activity of DAB389IL-2 demonstrated in an earlier study. However, DAB389IL-2 was less well tolerated at this dosing regimen, particularly at the highest dose, and it was too toxic at these doses and schedules to be considered in the routine treatment of psoriasis. Publication Types: Clinical trial Clinical trial, phase ii Multicenter study Randomized controlled trial PMID: 9632001, UI: 98293762