Replies to post #106900 on Biotech Values

[jq1234]

The TNF-alpha class will be a very big FoB payday for somebody, IMO.

Agree. One company I really like is PLX. It developed cerezyme copy (via BLA) pending at FDA. It is also developing Enbrel copy. The stock has run up a lot lately, so I am not saying it is a buy right now. But watch out. From PLX website:

We are developing pr-antiTNF, a biosimilar version of etanercept (Enbrel™) using the Company's proprietary ProCellEx™ technology. pr-antiTNF is a plant cell expressed recombinant fusion protein made from the soluble form of the human TNF receptor (TNFR), fused to the Fc component of a human antibody IgG1 domain. Pr-antiTNF has an identical amino acid sequence to Enbrel™. In vitro and preclinical animal studies have demonstrated that pr-antiTNF exhibits similar activity to Enbrel™. Specifically, pr-antiTNF binds TNF alpha thereby inhibiting it from binding to cellular surface TNF receptors and protects L929 cells from TNF-induced apoptosis in a dose-dependent manner. In a proof-of-concept in vivo study using an established arthritis animal model, pr-antiTNF administered intraperitoneally significantly improved the clinical arthritis parameters associated with this accepted arthritis mouse model including joint inflammation, swelling and tissue degradation. Data from the collagen induced arthritis animal model studies are expected to be presented at an upcoming scientific conference.

http://www.protalix.com/pipeline_products.html

[Preciouslife1]

TNF-Alpha: Tumor necrosis factor-alpha (TNF-A) is a pleiotropic inflammatory cytokine.
It was first isolated by Carswell et al. in 1975 in an attempt to identify tumor necrosis factors responsible for necrosis of the sarcoma Meth A (Carswell et al., 1975).
http://www.bio.davidson.edu/courses/immunology/Students/spring2000/wolf/tnfalpha.html

Most organs of the body appear to be affected by TNF-A, and the cytokine serves a variety of functions, many of which are not yet fully understood. The cytokine possesses both growth stimulating properties and growth inhibitory processes, and it appears to have self regulatory properties as well. For instance, TNF-A induces neutrophil proliferation during inflammation, but it also induces neutrophil apoptosis upon binding to the TNF-R55 receptor (Murray, et al., 1997). The cytokine is produced by several types of cells, but especially by macrophage. Tracey and Cerami suggest two beneficial functions of TNF-A which have lead to its continued expression (1990). First, the low levels of the cytokine may aid in maintaining homeostasis by regulating the body's circadian rhythm. Furthermore, low levels of TNF-A promote the remodeling or replacement of injured and senescent tissue by stimulating fibroblast growth.

Additional beneficial functions of TNF-A include its role in the immune response to bacterial, and certain fungal, viral, and parasitic invasions as well as its role in the necrosis of specific tumors. Lastly it acts as a key mediary in the local inflammatory immune response. TNF-A is an acute phase protein which initiates a cascade of cytokines and increases vascular permeability, thereby recruiting macrophage and neutrophils to a site of infection. TNF-A secreted by the macrophage causes blood clotting which serves to contain the infection. Without TNF-A, mice infected with gram negative bacteria experience septic shock (Janeway et al., 1999).

The pathological activities of TNF-A have attracted much attention. For instance, although TNF-A causes necrosis of some types of tumors, it promotes the growth of other types of tumor cells. High levels of TNF-A correlate with increased risk of mortality (Rink & Kirchner, 1996). TNF-A participates in both inflammatory disorders of inflammatory and non inflammatory origin (Strieter al., 1993). Originally sepsis was believed to result directly from the invading bacteria itself, but it was later recognized that host system proteins, such as TNF-A induced sepsis in response. Exogenous and endogenous factors from bacteria, viruses, and parasites stimulate production of TNF-A and other cytokines. Lipopolysaccharide from from bacteria cell walls is an especially potent stimulus for TNF-A synthesis (Tracey and Cerami, 1993). When cytokine production increases to such an extent that it escapes the local infection, or when infection enters the bloodstream, sepsis ensues. Systematic edema results in low blood volume, hypoproteinanemia, neutropenia and then neutrophilia (Janeway et al., 1999). Body organs fail and death may result. Victims of septic shock experience fever, falling blood pressure, myocardial suppression, dehydration, acute renal failure and then respiratory arrest (Tracey and Cerami, 1993).

TNF-A exhibits chronic effects as well as resulting in acute pathologies. To link to a diagram of cellular responses involved in chronic inflammation, please click here. [Continue scrolling through the slides to view illustrations of chronic inflammation]. If TNF-A remains in the body for a long time, it loses its anti tumor activity. This can occur due to polymerization of the cytokine, shedding of TNF receptors by tumor cells, excessive production of anti-TNF antibodies, found in patients with carcinomas or chronic infection, and disruptions in the alpha-2 makroglobulin proteinase system which may deregulate cytokines. Prolonged overproduction of TNF-A also results in a condition known as cachexia, which is characterized by anorexia, net catabolism, weight loss and anemia and which occurs in illnesses such as cancer and AIDS. Cachectin and TNF-A were once considered different proteins, but in 1985 researchers discovered that the two proteins were homologous (Beutler et al., 1985a).

TNF-alpha/tumor necrosis factor-alpha. ALTERNATIVE NAMES

http://www.copewithcytokines.de/cope.cgi?key=TNF-alpha
Cachectin:
CF (cytotoxic factor);
CTX (cytotoxin);
DIF (differentiation inducing factor);
EP (endogenous pyrogens);
Hemorrhagic factor;
Macrophage-derived cytotoxic factor;
J774-derived cytotoxic factor;
MCF (macrophage cytotoxic factor);
MCT (macrophage cytotoxin);
MD-FGF [monocyte-derived fibroblast growth factor]
PCF (peritoneal cytotoxic factor);
RCF (Released cytotoxic factor).
See also: individual entries for further information.

The new nomenclature is TNFSF2 [TNF ligand superfamily member 2], based on homology with other members of the TNF ligand superfamily of proteins.

SOURCES
TNF is secreted by macrophages, monocytes, neutrophils, T-cells, NK-cells following their stimulation by bacterial lipopolysaccharides. Cells expressing CD4 secrete TNF-alpha while CD8(+) cells secrete little or no TNF-alpha. Stimulated peripheral neutrophilic granulocytes but also unstimulated cells and also a number of transformed cell lines, astrocytes, microglial cells, smooth muscle cells, and fibroblasts also secrete TNF. Human milk also contains this factor (see: MGF, milk growth factor).

The synthesis of TNF-alpha is induced by many different stimuli including interferons (see: IFN), IL2, GM-CSF, SP (substance P; see also: Tachykinins), Bradykinin, Immune complexes, inhibitors of cyclooxygenase and PAF (platelet activating factor).

The release of TNF-alpha from isolated rat macrophages in culture is stimulated by Histogranin.

The production of TNF is inhibited by IL6, TGF-beta, vitamin D3, prostaglandin E2, dexamethasone, CsA (Cyclosporin A), and antagonists of PAF (platelet activating factor).

PROTEIN CHARACTERISTICS
Human TNF-alpha is a non-glycosylated protein of 17 kDa and a length of 157 amino acids. Murine TNF-alpha is N-glycosylated. Homology with TNF-beta is approximately 30 %. TNF-alpha forms dimers and trimers.

The 17 kDa form of the factor is produced by processing of a precursor protein of 233 amino acids. A TNF-alpha converting enzyme (see: TACA) has been shown to mediate this conversion.

A transmembrane form of 26 kDa has been described also.
TNF-alpha contains a single disulfide bond that can be destroyed without altering the biological activity of the factor. Mutations Ala84 to Val and Val91 to Ala reduce the cytotoxic activity of the factor almost completely. These sites are involved in receptor binding. The deletion of 7 N-terminal amino acids and the replacement of Pro8Ser9Asp10 by ArgLysArg yields a mutated factor with an approximately 10-fold enhanced antitumor activity and increased receptor binding, as demonstrated by the L-M cell assay, while at the same time reducing the toxicity. For other genetically engineered variants see: TNF-alpha muteins.

GENE STRUCTURE
The gene has a length of approximately 3.6 kb and contains four exons. The primary transcript has a length of 2762 nucleotides and encodes a precursor protein of 233 amino acids. The aminoterminal 78 amino acids function as a presequence (see also: gene expression).

The human gene maps to chromosome 6p23-6q12. It is located between class 1 HLA region for HLA-B and the gene encoding complement factor C. The gene encoding TNF-beta is approximately 1.2 kb downstream of the TNF-alpha gene. However, both genes are regulated independently. The two genes also lie close to each other on murine chromosome 17.

RECEPTORS
Two receptors of 55-60 kDa and 75-80 kDa have been described.

The 55-60 kDa has been given the designation CD120a in the nomenclature of CD antigens and is also referred to as TNFRSF1A [TNF receptor superfamily member 1A].

[mcbio]

Re: generic TNF-alpha biologics vs. RIGL/AZN's FosD

The TNF-alpha class will be a very big FoB payday for somebody, IMO.

Absolutely agree. What's the consensus timeframe for when these will start to hit the market? I'm thinking about this from the angle of potential RA competition down the road for RIGL and AZN's FosD, assuming the drug is successful in Phase 3 and makes it to market.

Notwithstanding the fact that the generic TNF-alpha biologics should be much cheaper by definition, I think FosD may be able to successfully compete against these drugs, because (1) RIGL thinks it may be able to differentiate FosD from the TNF biologics in Phase 3 by showing that the drug works quicker to prevent bone damage; (2) FosD is oral whereas the TNF biologics obviously are not; and (3) the price difference presumably won't be as great between FosD and the generic TNF biologics as it is with the branded TNF biologics because FosD is a pill and should by definition be much cheaper than a branded biologic.

Separately, I will say I'm curious as to why AZN is only running the Phase 3 trials for FosD in patients who have responded inadequately to DMARDs, including methotrexate, and in patients who have responded inadequately to anti-TNF therapy (http://www.astrazeneca.com/media/latest-press-releases/2010-new/fostamatinib_phase_III?itemId=11508115 ). Why wouldn't AZN run a head-to-head study to try to differentiate FosD from patients who have yet to try anti-TNF therapy? Is AZN afraid of a poor outcome on this front? Is this not a protocol that the FDA would approve? Does AZN assume if the FosD Phase 3 trials are successful, that doctors will extensively use FosD in patients who have yet to try anti-TNF therapy anyways, even if the FDA hasn't technically approved such a use?