NK1 receptor antagonist by Roche

DailyUpdates 23rd February, 2006: The tachykinins were first identified in 1931 however realization of the therapeutic potential of antagonists that block their action has only taken place over the last decade. Tachykinin receptor antagonists have been implicated in various conditions such as depression/anxiety, pain, airway disease, incontinence, nausea and bowel disorders.

The tachykinins are the products of two genes, preprotachykinin I which produces substance P (SP) and neurokinin (NK)A and preprotachykinin II which produces NKB. In 1986 the research community classified the tachykinin receptors into 3 subtypes, NK1, NK2 and NK3 receptors and one of the earliest examples of advanced development of the tachykinin antagonist class was in the field of depression and anxiety following pioneering work in a number of laboratories and especially those of Merck & Co.

Both the limbic system and the mesencephalic brain stem express high levels of SP-like immunoreactivity supporting their role in anxiety and depression. This is further evidenced by the anxiogenic effect of NK1 or NK2 agonists when administered into the CNS and the observation that SP levels are altered in experimental models of stress, anxiety and depression. On the basis of this data first generation NK1 receptor antagonists such as CP96345 were investigated for anxiolytic activity. Of ground breaking importance, MK-869 became the first NK1 antagonist to demonstrate therapeutic activity in patients with a cohort of depressed patients displaying significant improvement in both the level of depression and anxiety. The magnitude of this effect was similar to paroxetine while accompanied by fewer adverse effects.

As discussed in our recent feature The World Market for Antidepressants 2006, sales of antidepressant will crash over the next few years producing revenues in 2010 of only $7bn. This loss of almost 50% of total revenues is due to patent expirations. The lackluster pipeline is unlikely to halt this massive revenue loss in the near-term. This situation could have been different had the initial success of MK-869 been reproduced however this was not the case and in a subsequent study required for regulatory approval efficacy was not observed. Further development of MK-869 for the treatment of depression was subsequently terminated. Data later emerged to suggest that this failure was due to an elevated placebo effect opening the way for other NK1 receptor antagonists, however by that time MK-869 was on its way to becoming the first approved NK1 antagonist (launched as Emend; Aprepitant) but with the indication being nausea and vomiting.

A Roper Starch survey of chemotherapy patients found that prior to starting treatment, 32% reported surviving cancer as their biggest concern versus 40% who said side effects were their biggest concern. The most serious adverse effects of chemotherapeutic agents include anemia and related fatigue; neutropenia and associated risks of infection; and nausea and vomiting. Consequently the development of supportive care products to combat fatigue and neutropenia has played an important role in oncology research and development (see our feature Cancer Market Top 20 Drugs - Supportive Care Grows the Cancer Market).

According to the National Cancer Institute, over 500,000 Americans received chemotherapy in 2004. Patients receiving chemotherapy for cancer reported a greater degree of treatment-induced nausea and vomiting than generally recognized. An estimated 75% suffer from nausea or vomiting within 24 hours of treatment, and about 90% of all patients suffer from chemotherapy-induced nausea or vomiting 2-5 days after treatment (delayed onset chemotherapy-induced nausea and vomiting). If left untreated, chemotherapy-induced nausea and vomiting can result in a delay or discontinuation of chemotherapy and the majority of patients thus receive an antiemetic. The 5-HT3 receptor antagonists revolutionized the treatment of chemotherapy-induced nausea and vomiting and Zofran (Ondansetron), the market leader, generating annual US sales worth approximately $1.0 billion in 2003.

The vomiting reflex involves both central and peripheral components and the emetic response is integrated in the vomiting center a region including the nucleus tractus solitarius. SP and NKA are expressed in this region of the brain. The ferret has been extensively studied to determine the anti-emetic activity of tachykinin antagonists and prototypic antagonists were found to reduce retching in various animal models, including cisplatin-evoked emesis. Of importance the effects of NK1 and 5HT3 antagonism during the acute phase of emesis were additive. Perhaps even more important was the observation that NK1 receptor antagonism blocked both acute and delayed emesis; this finding was important since the control of delayed nausea and vomiting following cytotoxic administration has traditionally been a challenge.

Following the successful completion of two trials of over 1000 cancer patients receiving highly emetic chemotherapy, the FDA announced the approval of Emend (aprepitant) in 2003. In 2006, the FDA extended its approved indications to include the use of Emend in combination with other antiemetics, for the prevention of nausea and vomiting in cancer patients undergoing initial or repeat treatment with moderately or highly emetogenic chemotherapy

The trials and tribulations of Emend have been followed by a surge of activity from a number of other companies developing NK1 receptor antagonists including GSK who have vestipitant and casopitant in phase II development for depression, anxiety, and nausea & vomiting. Roche have also been involved in the development of NK1 receptor antagonists.

In their study due to be published in the March edition of Bioorg Med Chem Lett, Hoffmann and colleagues from Roche describe the design of two promising NK1 receptor antagonists, netupitant and befetupitant. These two molecules were optimized from a lead NK1 antagonist with nanomolar affinity identified during a random screen of Roche’s corporate library. Netupitant and befetupitant both displayed sub-nanomolar affinity at the NK1 receptor. Further in vivo study demonstrated that oral pretreatment with either of these compounds blocked NK1-induced foot tapping in gerbils with an efficacy approaching 0.1mg/kg.

The excellent potential of netupitant and befetupitant has resulted in the licensing of netupitant to the Swiss company, Helsinn Healthcare in 2006. Helsinn already has experience in the anti-emetic market having developed the 5HT3 antagonist Aloxi (palonosetron), which was launched in 2004. The improved pharmacokinetic properties of this compound mean that it is useful for the prevention of delayed nausea and vomiting, an indication for which it gained approval. Since 5HT3 and NK1 receptor antagonists exert additive effects there is considerable potential for the combined use of Aloxi and netupitant.

Befetupitant remains a licensing opportunity and deserves consideration from companies involved in the development of anti-emetics. Hopefully befetupitant may also strengthen the antidepressant pipeline and companies involved in the field of psychiatry may also be interested in contributing to the advance of befetupitant. Licensing-related inquiries should be directed to kurt.gathof@roche.com at Roche.

A novel therapeutic candidate for the treatment of lymphomas and other cancers

DailyUpdates 21th February: Regular visitors to this forum would have already realized that we don't post entries every day. Even though we try do so it is simply not possible with the work load imposed by our DailyUpdates service from which content on the forum is derived. Please feel free to register to our DailyUpdates service to keep up to date which breaking news & journal articles from the drug development sector (through today's edition if you wish).

Today's edition of DailyUpdates features work conducted by Imperial College researchers who have identified an aptamer able to reduce the proliferation of lymphoma cells by 40%. This work represents a licensing opportunity. The aptamer is of potential therapeutic use and may be of interest to companies with an interest in biologic approach to oncology. The aptamers also forms the basis of a HTS assay that should help identify small molecule therapeutics for the treatment of hematological cancers as well as breast and maybe pancreatic cancer.

Lymphoma is the fifth most common cancer in the US and represents over forty subtypes of cancers arising within the lymphatic system. The most prevalent type is non-Hodgkin's lymphoma (NHL) which accounted for 88% of the 63,700 estimated new cases of lymphoma diagnosed in the US in 2005, making this the most common hematological cancer. The incidence of NHL has increased, nearly doubling over the past 30 years, faster than any other type of cancer.

NHL can result from malignancies of either T- or B-cells however most are of the latter. B-cell NHLs can be further sub-divided according to stage of differentiation of cells from which they are derived. Large cell B-cell lymphoma tumors are amongst the most common accounting for 30% of newly diagnosed cases and emerge from either germinal center B-cells or activated B-cells.

Disease can be divided into two groups based on prognostic factors of tumor growth; indolent and aggressive. Large cell B-cell lymphomas are the most common malignancies found in patients presenting with aggressive disease. In this group, doxorubicin (Adriamycin)-based combination chemotherapy is the primary clinical approach and produces long-term disease-free survival in 35% to 45% of patients. The CHOP (cyclophosphamide, Adriamycin, vincristine, prednisone) regimen was among the first combinations to produce complete response rates and long-term survival. More recently, the addition of Rituxan to the CHOP regimen has been shown to increase the likelihood of a complete-response by 20% without a significant rise in the risk of a serious adverse event and this is now the standard regimen for newly diagnosed patients with diffuse large B-cell lymphoma.

Although NHL is highly treatable, significant unmet needs exist. Addressing these needs will in part involve the better definition of the various NHL subtypes, particularly with respect to molecular etiology. This should allow more targeted approaches which will in turn lead to a reduced rate of relapse and hopefully extended survival.

Targeting BAFF/APRIL is one highly promising approach to NHL as well as multiple myeloma. This target was recently evaluated in our report BAFF & APRIL: Emerging Targets for autoimmune disease & Cancer Therapeutics - Proof of concept, indications and development activity. Here we focus on another promising molecular target, BCL-6.

BCL-6 is a transcription factor which is normally expressed at high levels in lymph node germinal centers. Germinal centers are found in splenic or lymph node follicle and is the site where activated B-cells mature into memory and plasma cells. This reaction is important for immune memory and for the production of antibodies to pathogen however germinal center B-cells are also thought to be involved in the pathogenesis of most types of human B-cell malignancies. Targeting BCL-6 may therefore be a rational approach to both types of condition.

The BCL-6 gene was originally cloned from chromosomal translocations in diffuse large-cell lymphoma, and is expressed in other lymphoproliferative disorders. Approximately 40% of diffuse large cell lymphomas and 5-10% of follicular lymphomas are associated with chromosomal translocations that deregulate expression of BCL6 by juxtaposing heterologous promoters to the BCL-6 coding domain.

BCL-6 is a repressor of transcription that limits B-cell differentiation and cell death. Repression is quite specific, a selectivity afforded by its POZ domain and mediated by the recruitment of histone deacetylases (see Histone deacetylase inhibitors-Moving from the bench to a promising companion for classic and targeted cancer therapies for an overview of histone deactylases).

Inhibiting BCL-6 may therefore offer a novel approach to the treatment of lymphomas and other hematological malignancies. Here, we highlight a recent study published by Chattopadhyay et al in the journal, Oncogene that identifies a peptide aptamer targeted towards BCL-6.

Peptide aptamers are synthetic recognition molecules whose design was inspired by the structure of antibodies. They consist of a variable peptide loop attached at both ends to a protein scaffold (see inset after Aptanomics). This double structural constraint greatly increases the binding affinity of the peptide aptamer to levels comparable to an antibody's (nanomolar range). One advantage of aptamers is that they can be designed to target a peptide domain in the context of a specific protein. The highlighted Oncogene study screened 250,000 peptide aptamers and identified one, Apt48, that binds to BCL-6 POZ but not POZ domains of related proteins.

Further study demonstrated that Apt48 relieved the repression of BCL-6 target genes and restored the ability of IL-2 and IL-5 to block the proliferation of BCL-6 overexpressing cells. Perhaps most dramatic was the observation that Apt48 was able to reduce the proliferation of BCL-6 overexpressing lymphoma cells by 40%.

The highlighted study suggests that aptamers targeted against BCL-6 offer a highly attractive approach to lymphoma and other malignancies associated with BCL-6 overexpression. Further in vivo studies that demonstrate the efficacy of systemically administered aptamers or even cell therapy approaches that promote expression of Apt48 are eagerly awaited.

Although the study highlights the potential of Apt48 in the treatment of lymphomas, Bos et al, 2003 and Logarajah et al, 2003 have both suggested that BCL-6 plays a role in high grade breast cancer. Likewise in 2004 Holzmann et al, reported that BCL-6 was overexpressed in pancreatic cancer extending the potential indications of Apt48.

While the present study suggests that Apt48 may have therapeutic potential it also forms the basis of an HTS assay being developed by the authors for the identification of small molecule inhibitors of the Bcl-6 POZ domain. Molecules would be identified on the basis of their ability to compete with Apt48 for binding to the Bcl-6 POZ domain.

This work represents a licensing opportunity and interested parties should contact Dr Simon Wagner at simon.wagner@imperial.ac.uk

Gleevec: Improving it utility in exisiting indications; development for extended indications

DailyUpdates - February 10: A devastating disease with a poor prognosis for many patients, until recently CML has had few treatment options and, for the most part, these have succeeded only in delaying disease progression by up to a few years.

Chronic myeloid leukaemia (CML) is a myeloproliferative disorder affecting 1 to 2 people per 100,000 annually. These disorders arise from genetic defects in haematopoietic stem cells, and are associated with an increased production of mature and immature blood cells, which affects one or all cell lineages. CML, like most myeloproliferative disorders progresses through various stages of increasing aggressiveness until the bone marrow is no longer able to produce functional immunocytes. CML is also able to metastasize to other sites in the body.

In adults, CML represents about 15% of all cases of leukaemia and is most often diagnosed in individuals over 45 years of age. Radiation, the first treatment for CML, was introduced in the 1920s with limited results. Chemotherapeutic agents followed in the 1950s and 1960s and increased the survival rate among patients with CML to about 5 years. Bone marrow transplantation arrived in the 1970s, and interferon-alpha appeared in the 1980s.

The approval of Novartis’ Glivec in 2001 represents one of the real success stories in the treatment of CML. In addition this product was one of the first targeted anti-cancer agents to be approved, acting through the inhibition of Bcr-Abl, the oncogene responsible for CML (see Pipeline Insight: Hematological malignancies-Targeted treatments and immunotherapy infuse new blood). Glivec is also able to inhibit c-kit and PDGF protein kinase activity. Inhibition of c-kit led to the approval (2002) of Glivec as a treatment of gastrointestinal stromal cell tumors, a cancer type that overexpresses this oncogene. PDGF is overexpressed in a wide variety of tumors and the development of Glivec for other indication thus continues.

Already generating $2.2 billion in global sales (2005 figures), Glivec is Novartis’ second highest revenue generator and the continued development of this blockbuster seems certain to increase these figures still further.

The February 10^th (2006) edition of DailyUpdates highlights a clinical study evaluating Glivec as a treatment of small cell lung carcinoma (SCLC). This type of cancer commonly express c-kit and its ligand, stem cell factor, suggesting an autocrine loop promoting cell growth. SCLC cells treated with Glivec in vitro undergo cell cycle arrest supporting this proposal. In the January 2006 edition of the journal Cancer, Johnson et al report the results of two Phase I studies that enrolled patients with extensive disease. In both studies patients were treated with Glivec in combination with the cytotoxic agents cisplatin and irinotecan. Although partial responses were observed in nearly all patients, toxicity was considerable and suggested to result from decreased irinotecan clearance in the presence of Glivec treatment.

Of interest c-kit, one of the molecular targets of Glivec, is expressed by interstitial cells of cajal, cells which play an important role in intestinal motility. A recent study by Shimojima et al, reported that Glivec was able to block rhythmic contractions in the small intestine. Since a significant fraction of irinotecan is cleared in the feces it is possible that Glivec reduced this fecal disposal of irinotecan leading to greater exposure to the drug.

A maximum tolerated dose for this combination with granulocyte-colony-stimulating factor support was however identified and further study of this combination is awaited. Recruitment is currently underway for Phase II studies.

The February 10^th (2006) edition of DailyUpdates also highlights a press release from Genzyme announcing the availability of a new diagnostic test able to predict resistance of CML patients to Glivec.

Despite high response rates to Gleevec, approximately 5% of patients who were initially treated successfully will develop resistance during therapy. Genzyme's new BCR-ABL Mutation Analysis test will assist physicians in evaluating resistance to therapy and facilitate appropriate adjustments to treatment.

The development of Genzyme’s new test is in line with their commitment to personalized medicine (this fields is evaluated in Personalized Medicine - scientific & commercial aspects)

Ghrelin moves back into the limelight of obesity R&D

DailyUpdates: February 9, 2006: The prevalence of obesity has increased by 61% in the US during the period 1991-2001. According to Datamonitor’s report, Obesity - commercial opportunities and therapeutic pipeline analysis 127m people were classified obese in the seven major markets in 2003. Even though there is an increasing awareness of obesity in response to various advertising campaigns and educational programs, the prevalence of obesity is expected to reach 94m by 2012 in the US alone.

The two leading drugs Xenical and Meridia are both associated with unpleasant side effects, poor efficacy and high costs. Therefore, there is a huge demand in this market for drugs that can address the current unmet needs.

Obesity is an active area of R&D and numerous novel molecular targets are currently being evaluated. One target, ghrelin was the subject of a major target discovery report from LeadDiscovery published in 2003 Ghrelin: Pharmaceutical & Therapeutic Opportunities

Ghrelin is the endogenous ligand of the growth hormone secretagogue receptor (GHSR) which has been hypothesized to play an important role in signaling energy insufficiency. Ghrelin levels rise prior to meals and following food deprivation. Ghrelin administration potently stimulates feeding, while GHSR antagonists blunt feeding.

At the time of our report it appeared that GHSR antagonists may offer considerable benefit as anorectics. However, 3 recent loss-of-function studies threw this concept into doubt as ghrelin-knockout failed to alter body weight or food intake.

The February 9^th (2006) edition of DailyUpdates highlights a recent JCI paper that pushes ghrelin back into the limelight of obesity R&D. In this paper, Zigman and colleagues report on the effect of knocking-out the ghrelin receptor, GHSR. This genetic modification prevented food intake in response to exogenous ghrelin. Moreover the fat mass of mice maintained on a high fat diet was nearly half that of wild type mice. Likewise food intake was also considerably reduced while glucose homeostasis was improved.

These data therefore resurrect the ghrelin receptor as a candidate drug discovery target.

Flower power & Oncology

DailyUpdates 3rd Feb, 2006: The size of the cytotoxic market in the seven major pharmaceutical markets is estimated to be approximately $9.6 billion. Datamonitor expects it to reach a peak of $12.8 billion by 2009. However, mainly due to major patent expiries, it is expected to drop to $11.3 billion by 2014 (see Commercial Insight: Cytotoxics).

According to the ATC classification system there are 5 classes of cytotoxic agent. Topoisomerase inhibitors represent a subgroup of plant alkaloids, which also encompasses the vinca alkaloids such as vincristine and vinblastine, taxanes. Topoisomerase inhibitors act by preventing the unpackaging of DNA that must occur prior to transcription and replication. The earliest drugs in this class were inhibitors of topoisomerase II, however topoisomerase I inhibitors such as topotecan started entering the market in the mid-1990’s. DNA topoisomerase II inhibitors are among the most efficacious drugs for the treatment of cancer. Despite their widespread use, the use of topoisomerase II inhibitors is limited by severe adverse effects to normal tissues, including cardiotoxicity.

In addition to problems associated with toxicity, sensitivity of cancer cells to topoisomerase II targeting agents is also, like many other cancer therapeutics susceptible to resistance. The efficacy of this class is thought to depend on the expression of the topoisomerase IIalpha isoform, and drug resistance is often associated with loss or mutation of this isoform.

Considering the success of the alkaloids as cancer therapeutics, considerable effort is still being dedicated to the identification of new drug leads including novel topoisomerase II inhibitors. The plant Euphorbia kansui, a phytotherapy long used in Chinese medicine as a cancer treatment, represents a rich source of plant alkaloids and in particular terpenes. More recently researchers have evaluated the anticancer efficacy and mechanism of action of the terpenes.

Studies have shown E kansui terpenes to markedly reduce carcinogenesis in a skin tumor model and in 2002 Wang et al reported that representatives of this chemical class reduced the proliferation of Xenopus embryonic cells, an assay that has been used as an alternative to the study of cancer cell lines in the primary screening of anticancer drugs. More recently this antiproliferative effect has been shown to be related to an inhibition of cell cycle progression and similar effects have been observed with E kansui extracts using cancer cell lines.

In an upcoming issue of Bioorganic & Medicinal Chemistry highlighted in todays DailyUpdates, Miyata and colleagues investigate the mechanism of action of the diterpenes (a sub-class of terpenes that includes the retinoids), in greater detail. In this study a variety of different diterpenes inhibited human topoisomerase II activity however the potency of this effect did not appear to correlate with cell proliferation potency. This study therefore suggests that the anticancer activity of diterpene alkaloids may involve the inhibition of topoisomerase II activity as well as other components of the cell cycle.

The diterpenes have already been the subject of a clinical investigation with, for example Triptolide derivatives being developed by Fujisawa (now Astellas following the merger of Fujisawa with Yamanouchi). The present study highlights the lack of knowledge regarding the mechanism of the diterpenes and will hopefully prompt further investigation to resolve this issue and hopefully help optimize this promising therapeutic class.

Replidyne marches on in the development of novel antibiotics for the treatment of drug-resistant skin infections

The market for antibacterials, valued at $24 billion in the seven major markets, faces significant revenue loss in the period 2005-2007 due to major patent expiries (see Commercial Insight: Antibacterials).

Despite the problems faced by companies involved in antibacterials considerable success has been met by those targeting drug resistant infections such as MRSA. This is highlighted by the rapid uptake of products focused on drug-resistant infections, such as Pfizer's Zyvox (linezolid).

One company heavily involved in the development of antibacterials targeted against drug resistant microbes is Replidyne. Only last month (Jan, 2006) Replidyne announced that they had submitted an NDA for Orapem (faropenem medoxomil). Through this submission the company is seeking marketing approval for the use of Orapem against infection caused by multiple pathogens (click here for press release).

In addition to the development of Orapem, Replidyne has an active drug development program directed to inhibitors of bacterial DNA replication and it is the development of one candidate from this program, REP8839, that is the focus of today’s DailyUpdates (Feb 2^nd, 2006).

REP8839 has emerged from Replidyne’s methionyl tRNA synthetase program that it in-licensed from GlaxoSmithKline in 2003. The program includes multiple series of advanced leads that utilize a novel mechanism-of-action to inhibit bacterial protein synthesis. REP8839 targets methionyl tRNA synthetase, the enzyme responsible for the synthesis of methionine.

Methionine is unique among amino acids in that it is always the first amino acid to be incorporated into proteins. Thus, inhibitors of methionyl tRNA synthetase interfere with the initiation as well as the elongation phase of protein synthesis. Currently, only one anti-infective agent that inhibits a tRNA synthetase is on the market - mupirocin (Bactroban), an inhibitor of isoleucyl tRNA synthetase.

REP8839 has been selected by Replidyne as a lead methionyl tRNA synthetase inhibitor and is being developed as a new topical antibacterial agent. REP8839 is very active against major skin pathogens. The Antimicrob Agents Chemother paper featured in today’s DailyUpdates highlights this efficacy. Potent antibacterial activity was reported for clinical isolates of Staphylococcus aureus, Streptococcus pyogenes, Staphylococcus epidermidis and other clinically important gram-positive bacteria. All isolates of these bacteria were susceptible to REP8839 including multiple resistant strains.

Bacterial skin and skin structure infections are among the most common infections treated. There are a wide range of different types of infection, each with individual symptoms, epidemiology and etiology. However, the majority requires antibacterial treatment and, as a result, represent potential lucrative targets for novel product development (see Skin Infections - Where In The Antibacterial Lifecycle?). The efficacy of REP8839 against such a broad range of pathogens including resistant strains suggests that this therapeutic candidate should attract considerable success. Drug resistance underpins a high unmet need in the management of skin infections. This should increase the likelihood of compounds novel antibiotics gaining fast-track designation in the US. This has already been demonstrated by Cubist’s Cubicin (daptomycin) and Basilea’s novel cephalosporin, BAL5788. Hopefully REP8839 will follow a similar path as it moves out of preclinical development into the clinic bringing rewards to Replidyne and the patient sooner rather than later.