Vemurafenib

On August 17, 2011 the FDA announced that it had approved the oral targeted therapy vemurafenib (Daiichi Sankyo/Plexxikon/Roche’s Zelboraf; also known as PLX4032) for first-line treatment of metastatic and unresectable melanomas. The drug is indicated for use in patients whose tumors carry the BRAFV600E) mutation. Approximately 50% of melanoma patients have tumors that carry this mutation.

Vemurafenib  was approved together with a test called the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Diagnostics). This is a companion diagnostic designed to determine if a patient’s melanoma cells carry the BRAF(V600E) mutation and thus patients can benefit from therapy with the drug.

Vemurafenib and the companion BRAF(V600E) diagnostic test were approved earlier than scheduled. They had been reviewed under the FDA’s priority review program that provides for an expedited six-month review of drugs that may offer major advances in treatment or that provide a treatment when no adequate therapy exists. The original goal PDUFA (Prescription Drug User Fee Act) review dates for vemurafenib and the companion diagnostic were October 28, 2011 and November 12, 2011, respectively.

The Biopharmconsortium Blog has been following the veurafenib story since March 2010. See this January 23, 2011 article, and the links to earlier articles that it contains.

There are now two drugs approved for the treatment of advanced melanoma in 2011 that demonstrate an improvement in progression-free and overall survival, when before there were none. The other drug, the immunomodulator ipilimumab (Medarex/Bristol-Myers Squibb’s [BMS’s] Yervoy), was discussed in a March 30, 2011 article on our blog.

The FDA granted early approval for vemurafenib on the basis of the results of the pivotal Phase 3 trial known as BRIM-3. In a previous article on this blog, we discussed a report of an interim analysis of this trial in January 2011. The results of the trial were published in the June 30, 2011 issue of the New England Journal of Medicine. Earlier Phase 1 and 2 clinical trails of the drug had show response rates of over 50% in advanced melanoma patients whose tumors bore the BRAF(V600E) mutation.

In the BRIM-3 trial, researchers compared vemrafenib to dacarbazine (the previous standard of care) in 675 patients with previously untreated metastatic melanoma that had the BRAF(V600E) mutation. Patients were randomized to receive either vemurafenib or dacarbazine. Co-primary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety.

Patients receiving vemurafenib had a 74% reduction in the risk for progression (or death), compared with patients receiving dacarbazine. Mean progression-free survival was 5.3 months in the vemurafenib group, compared with 1.6 months in the dacarbazine group. At 6 months, estimated overall survival was 84% in the vemurafenib group and 64% in the dacarbazine group. The median survival of patients receiving vemurafenib has not been reached, while the median survival for those who received dacarbazine was 8 months.

Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse effects in patients receiving vemurafenib were joint pain, rash, hair loss, fatigue, nausea, and skin sensitivity to the sun. Approximately 26% of patients developed cutaneous squamous cell carcinoma, which was managed with surgery. Patients treated with vemurafenib should avoid sun exposure.

FDA approval of the cobas 4800 BRAF V600 mutation test was also based on data from the BRIM-3 trial. Patient tumor samples were tested with the diagnostic in order to select patients for the trial.

The complete response rate seen with vemurafenib has been only 0.9%. The great majority of patients experience tumor regrowth due to drug resistance. As we have discussed in previous article on this blog (for example, our January 23, 2011 article), researchers are hard at work developing combination therapies designed to overcome this resistance. As discussed in our June 8, 2011 blog article, research aimed at developing such combination therapies was extensively discussed at the 2011 ASCO meeting. We have also outlined strategies for overcoming vemurafenib resistance via design of multitargeted combination therapies in our June 2011 book-length report, Multitargeted Therapies: Promiscuous Drugs and Combination Therapies.

2011 has brought good news to patients who have or may develop late-stage melanoma, their families and friends, and to physicians who treat these patients. When previously there had been no FDA approved therapies that can produce improved survival in patients with this deadly disease, now there are two. We hope that research aimed at designing combination therapies to overcome drug resistance will result in even greater ability to control this disease, and that new therapies for still intractable forms of cancer will emerge in the next several years.

Two recent research reports may point the way to developing more effective, personalized therapies for two deadly women’s cancers for which their are currently few treatment options–triple-negative breast cancer and ovarian cancer. The approach followed in both reports is to use gene expression analysis to stratify each of the two diseases into subtypes. Researchers can then use gene expression and order aspects of the biology of each subtype to design subtype-specific targeted therapies, whether single drugs or drug combinations. If the drugs (whether approved or experimental) already exist, they can be tested in clinical trials, stratified by subtype. If no appropriate drugs exist, researchers can discover the drugs based on subtype-appropriate drug targets.

Triple-negative (TN) breast cancer refers to breast cancers that are negative for expression of estrogen receptor (ER), progesterone receptor (PR), and HER2. [HER2 is the target of trastuzumab (Roche/Genentech’s Herceptin) and lapatinib (GlaxoSmithKline’s Tykerb/Tyverb)]. Lacking all three receptors, it cannot be treated with standard receptor-targeting breast cancer therapeutics (e.g., tamoxifen, aromatase inhibitors, trastuzumab) but must be treated with cytotoxic chemotherapy. TN breast cancer is generally more aggressive than other types of breast cancer, and even treatment with aggressive chemotherapy regimens typically results in early relapse and metastasis.

TN breast cancers constitute approximately 25 percent of breast cancers. They are diagnosed most often in younger women, those who have recently given birth, women with BRCA1 mutations, and African-American and Hispanic women.

There is a Triple Negative Breast Cancer Foundation, which was founded in 2006 in honor of a mother in her mid-thirties who died of the disease.

Ovarian cancer, the ninth most common cancer in women, caused nearly 14,000 deaths in the U.S. in 2010. In its earliest stages, its symptoms are usually very subtle and mimic other, less serious diseases. As a result, it is usually detected at later stages in which treatment is more difficult and gives poorer outcomes. The 2001 five-year survival rate was 47%, up from 38% in the mid-1970s. This compared to an overall survival rate for cancer of 68% in 2001, up from 50% in the mid-1970s.

Treatment usually involves surgery and chemotherapy, and sometimes radiotherapy. Surgery (preferably by a gynecological oncologist) may be sufficient for earlier-stage tumors that are well-differentiated and confined to the ovary. In this early-stage disease (which represents about 19% of women presenting with ovarian cancer), the five-year survival rate is 92.7%. However, about 75% of women presenting with ovarian cancer already have stage III or stage IV disease, in which the cancer has spread beyond the ovaries. Then the prognosis is much poorer, and the vast majority of patients will have a recurrence.

The triple-negative breast cancer study

The TN breast cancer study was carried out by researchers at the Vanderbilt-Ingram Cancer Center (Vanderbilt University, Nashville, TN), and published in the 1 July 2011 issue of the Journal of Clinical Investigation. In this study, the researchers analyzed gene expression profiles from 21 publicly available breast cancer data sets, and identified  587 cases of TN breast cancer (by non-expression of mRNAs that encode ER, PR, and HER2). Using cluster analysis, they identified six TN breast cancer subtypes:

• two basal-like subtypes (BL1 and BL2),
• an immunomodulatory (IM) subtype (i.e., expressing genes involved in immune cell processes)
• a mesenchymal (M) subtype
• a mesenchymal stem–like (MSL) subtype
• a luminal androgen receptor (LAR) subtype.

Using gene expression analysis, the researchers identified TN breast cancer model cell lines that were representative of each of these subtypes. On the basis of their analysis, the researchers predicted “driver” signaling pathways, and targeted them pharmacologically as a proof-of-principle that analysis of gene expression signatures of cancer subtypes can inform selection of therapies.

BL1 and BL2 subtypes had higher expression of genes involved in the cell cycle and response to DNA damage, and model cell lines preferentially responded to cisplatin. M and MSL subtypes were enriched for expression of genes involved in the epithelial-mesenchymal transition (EMT), and growth factor-related pathways in model cell lines responded to the PI3K/mTOR inhibitor BEZ235 (Novartis, now in Phase 1 and 2 for solid tumors) and to the ABL/SRC inhibitor dasatinib [Bristol-Myers Squibb’s Sprycel, currently approved for treatment of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL), and under investigation for treatment of solid tumors). The LAR subtype was characterized by androgen receptor (AR) signaling, and included patients with decreased progression-free survival. LAR model cell lines were uniquely sensitive to the AR antagonist bicalutamide (AstraZeneca’s Casodex/Cosudex, currently approved for the treatment of prostate cancer and hirsutism, and under investigation for treatment of androgen receptor-positive, ER negative, PR negative breast cancer).

The researchers plan to use the TN breast cancer subtype-specific model cell lines for further molecular characterization, to identify new components of the “driver” signaling pathways for each subtype. These pathways can be targeted in further drug discovery efforts. The subtype-specific cell lines can also be used in preclinical studies with targeted agents, and in identification of subtype-specific biomarkers that can potentially be used in stratifying TN breast cancer patients so that they might be treated with the best agents for their disease.

The ovarian cancer study

The ovarian cancer study was carried out by the Cancer Genome Atlas Research Network [a consortium of academic researchers jointly funded and managed by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI)], and published in the 30 June 2011 issue of Nature. In this study, the researchers analyzed mRNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas, as well as the DNA sequences of exons from coding genes in 316 of these tumors. Serous adenocarcinoma is the most prevalent form of ovarian cancer, accounting for about 85 percent of all ovarian cancer deaths.

The researchers found that nearly all of the high-grade serous ovarian cancers (HGS-OvCa) studied had mutations in the TP53 gene, which encodes the p53 tumor suppressor protein. On the basis of their gene expression (mRNA) signatures, the researchers divided the population of HGS-OvCa into four subtypes:

• an immunoreactive subtype (i.e., expressing genes involved in immune cell processes)
• a differentiated subtype (high expression of markers of differentiated female reproductive tract epithelia)
• a proliferative subtype (high expression of markers of cell proliferation)
• a mesenchymal subtype (high expression of HOX genes and of markers of mesenchymal-derived cells)

The researchers also determined subtypes on the basis of microRNA expression and promoter methylation. microRNA subtype 1 overlapped the mRNA proliferative subtype and miRNA subtype 2 overlapped the mRNA mesenchymal subtype. Patients with miRNA subtype 1 tumors survived significantly longer that those with tumors of other microRNA subtypes.

Although the researchers found no significant difference in survival between the four transcriptional subtypes, they did identify a 193-gene expression signature that was predictive of overall survival. 108 genes were correlated with poor survival and 85 were correlated with good survival.

The researchers identified cancer-associated pathways in the HGS-OvCA population; this is equivalent to the prediction of “driver” signaling pathways in the TN breast cancer study. They found that 20% of the HGS-OvCA samples had germline or somatic mutations in BRCA1 or BRCA2, and that 11% lost BRCA1 expression through DNA hypermethylation. As we discussed in an earlier article on this blog, BRCA1- or BRCA2-negative tumor cells cannot repair their DNA via homologous recombination. They are dependent on an alternative pathway of DNA repair, which involves the enzyme poly(ADP) ribose polymerase (PARP). These tumors are thus sensitive to a class of drugs known as PARP inhibitors, such as KuDOS/AstraZenaca’s olaparib. There are now six PARP inhibitors, including olaparib, in clinical development.

The researchers found genetic alterations in several other genes involved in homologous recombination. Altogether, defects in homologous recombination may be present in approximately half of HGS-OvCa cases, and these tumors may be sensitive to PARP inhibitors. This provides a rationale for clinical trials of PARP inhibitors in women with ovarian cancers with defects in homologous recombination-related genes.

Olaparib and other PARP inhibitors are in clinical trials in women with advanced with BRCA-1 or -2 mutations and with other defects in homologous recombination. As discussed in the 2011 ASCO meeting, early Phase 2 results indicate that olaparib gives dramatic improvements in progression-free survival in these women. (See this article.) In these studies, in addition to tumors with genetic defects in homologous recombination, olaparib or another PARP inhibitor, Abbott’s ABT-888, appears to give improved progression-free survival in women who have previously been treated with chemotherapy drugs that result in DNA damage. This suggests that oncologists may be able to use a “one-two punch”, consisting of a DNA-damaging drug [such as the alkylating agent temozolomide [Merck’s Temodar]) followed by a PARP inhibitor, to treat advanced ovarian cancer.

In addition to BRCA-1 and BRCA-2 mutations and other genetic alterations that result in defects in homologous recombination, the HGS-OvCa population exhibited genetic changes that would result in deregulation of several other cancer related pathways. These pathways included the RB1 (67% of cases), RAS/PI3K (45% of cases), and NOTCH (22% of cases) pathways, as well as the FOXM1 transcription factor network (87% of cases). All of these pathways represent opportunities for target identification and drug discovery. FOXM1 (Forkhead box protein M1) was named the Molecule of the Year for 2010 by the International Society for Molecular and Cell Biology and Biotechnology Protocols and Research (ISMCBBPR) because of “its growing potential as a target for cancer therapies.” FOXM1 overexpression results in destabilization of the cell cycle, which can lead to a malignant phenotype.

The researchers also identified 22 genes that were frequently amplified or overexpressed in HGS-OvCA tumors (other than genes that are involved in homologous recombination). Inhibitors (including approved and experimental compounds) already exist for the products of these genes, and researchers might assess these compounds in HGS-OvCa cases in which target genes are amplified.

Can Verastem develop new therapeutics for triple negative breast cancer?

The private biotechnology company Verastem (Cambridge, MA) focuses on discovery and development of drugs to target cancer stem cells. The company was founded in 2010, and is based on a strategy for screening for compounds that specifically target cancer stem cells. This strategy, published in the journal Cell in 2009, was developed by Drs. Robert Weinberg (MIT Whtehead Institute), Eric Lander (Broad Institute of MIT and Harvard University), and Piyush Gupta (MIT and Broad Institute) and their colleagues. Drs. Weinberg, Lander, and Gupta are on the Scientific Advisory Board of Verastem.

On July 14, 2011, Verstem announced that it had raised $32 million in a Series B financing. Verastem had previously raised $16 million from a group led by former Christoph Westphal’s Longwood Founders Fund. Dr. Westphal (formerly of Sirtris) is now Chairman of Verastem.

Cancer stem cells are best known in acute myeloid leukemia (AML), but their existence in other cancers (especially solid tumors) is controversial. The cancer stem cell hypothesis asserts that a small subpopulations of cells in a leukemia or solid tumor have characteristics that resemble normal adult stem cells, such as self renewal, the ability to give rise to all the cell types found in the leukemia or cancer, and stem cell markers. The hypothesis further asserts that most cancer treatments fail to knock out cancer stem cells, which can repopulate a tumor cell population, resulting in treatment relapses. Cancer stem cell researchers therefore propose developing cancer stem-cell specific therapeutics that can be used to eliminate these cells, which can block these relapses.

Whether cancer stem cells are involved in the pathobiology of solid tumors or not, the biology of the putative cancer stem cell phenotype can be important in certain subtypes of cancer. Cancer stem cells are characterized by the epithelial-mesenchymal transition (EMT), and in the Cell paper the researchers screened for compounds that specifically targeted breast cancer cells that had been experimentally induced into an EMT, and which as a result exhibited an increased resistance to standard chemotherapy drugs.   They identified the compound salinomycin as a drug that specifically targeted these cells, as well as putative cancer stem cells from patients.

As discussed earlier in this article, TN breast cancer includes two subtypes that have gene expression signatures related to the EMT: the mesenchymal (M) subtype and the mesenchymal stem–like (MSL) subtype. One or both of these subtypes might be sensitive to compounds that specifically target putative breast cancer stem cells. This may be true whether the cancer stem cell hypothesis applies to TN breast cancer or not. Verastem recognizes this, and is thus focusing on TN breast cancer as its first therapeutic target. The Vanderbilt TN breast cancer study suggests that trials of any “cancer stem cell-specific” therapeutics for TN breast cancer should be guided by subtype-specific biomarkers.

Hope for treatment of TN breast cancer and advanced ovarian cancer

Researchers and oncologists have made great strides in increasing the percentage of breast cancers that are treatable or even curable in recent years. For example, prior to the FDA approval of trastuzumab in 1998, HER2 positive breast cancer carried a grim prognosis. But the advent of trastuzumab (and later, lapatinib) has had a major impact on treatment of this once uniformly deadly type of breast cancer.

We hope that the new, personalized medicine-based approach to TN breast cancer and advanced serous ovarian adenocarcinoma will also result in successful new therapeutic strategies for these deadly women’s cancers.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

Huntington’s disease. Dr. Steven Finkbeiner. http://bit.ly/q48xdX

In the June 10, 2011 edition of Cell, there is a Leading Edge Preview (short review) and a research Article on a surprising new potential therapeutic strategy for neurodegenerative disease. The Preview is by Peter H Reinhart (Proteostasis Therapeutics, Cambridge MA) and Jeffery W Kelly (Skaggs Institute and Scripps Research Institute, La Jolla CA), and the the Article (Zwilling et al.) is by Paul J Muchowski (Gladstone Institute of Neurological Disease, University of California at San Francisco) and his colleagues. In addition to Dr. Muchowski’s academic collaborators, researchers from the Novartis Institutes for BioMedical Research in Basel, Switzerland participated in that work.

In previous studies, the kynurenine pathway (KP) of tryptophan degradation has been linked to such neurodegenerative diseases as Huntington’s disease (HD) and Alzheimer’s disease (AD). The kynurenine pathway (KP) is the most important pathway for degradation of the amino acid tryptophan in humans. Patients with HD and AD have elevated levels of two metabolites in the KP–quinolinic acid (QUIN) and 3-hydroxykynurenine (3-HK)–in their blood and brains. Studies in rodents have implicated both of these metabolites in pathophysiological processes in the brain. QUIN, which is a selective N-methyl-D-aspartate (NMDA) agonist, has been implicated in excitotoxicity, which is a mechanism by which excessive stimulation of glutamate receptors causes neuronal dysfunction and cell death. (NMDA receptors constitute a major type of glutamate receptor.) 3-HK is a free radical generator that can mediate neuronal cell death. Intrastriatal injection of QUIN in experimental animals duplicated many of the pathological features of HD. Administration of QUIN to other areas of the brain of experimental animals also duplicated features of AD, such as destruction of  basal forebrain cholinergic neurons projecting to the cortex and memory deficits.

In contrast, kynurenic acid (KYNA), which is formed in a side arm of the KP by conversion of kynurenine by the enzyme kynurenine aminotransferase, appears to be neuroprotective. KYNA is an antagonist of ionotropic excitatory amino acid receptors. In particular, KYNA blocks the neuropathological effects of QUIN. Kynurenine aminotransferase is found in the brain, and is thus capable of transforming kynurenine (which is actively transported into the brain by a neutral amino acid transporter) to KYNA in that organ. The concentration of brain KYNA is often decreased in HD and AD.

All of these studies in rodents were done in the 1980s or 1990s. However, no therapies based on that research have yet been advanced into the clinic.

Studies with JM6, a prodrug small-molecule inhibitor of kynurenine 3-monooxygenase, in wild type mice

In the Zwilling et al. study, researchers studied inhibition of  kynurenine 3-monooxygenase (KMO) as a strategy for inducing a more favorable ratio of KYNA to QUIN in vivo. KMO is the enzyme in the KP that converts kynurenine to 3-hydroxykynurenine, which is further converted in three steps to QUIN. KMO is found at high levels in peripheral blood macrophages and other immune cells in the blood. Inhibition of  KMO results in elevation of kynurenine levels in the blood. This kynurenine can then enter the CNS, where it is converted to the neuroprotective metabolite KYNA.

In 1996, researchers at Roche published the synthesis and characterization of a KMO inhibitor, 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide, known as Ro 61-8048. Subsequent studies showed that Ro 61-8048 was neuroprotective in rodent models of brain ischemia and cerebral malaria, and in a model of levodopa-induced dyskinesias (movement disorders) in parkinsonian monkeys.

However, Zwilling et al found that Ro 61-8048 was metabolically unstable. They therefore developed an orally bioavailable “slow-release” prodrug of Ro 61-8048, 2-(3,4-dimethoxybenzenesulfonylamino)-4-(3-nitrophenyl)-5-(piperidin-1-yl)methylthiazole (JM6). JM6 was designed to be converted to Ro 61-8048 in the gut. However, when JM6 was administered orally to wild type mice, the researchers found high levels of both JM6 and Ro 61-8048 in the blood. However, neither JM6 nor Ro 61-8048 accumulated to any great extent in the brain, and the brain concentration of both drugs was insufficient to inhibit KMO. Thus neither JM6 nor Ro 61-8048 appeared to cross the blood-brain barrier.

Despite the failure of JM6 and Ro 61-8048 to cross the blood-brain barrier, oral administration of JM6 results in increased brain levels of KYNA. Administration of an inhibitor of kynurenine aminotransferase to the brain inhibits the increase in levels of KYNA in that organ. This is consistent with the hypothesis that Ro 61-8048 inhibition of KMO in the blood results in elevated blood levels of kynurenine, which is transported into the brain. Kynurenine aminotransferase in the brain converts the kynurenine to KYNA. In addition, elevation of KNYA levels in the brain coincides with a decrease in extracellular concentrations of brain glutamate. This is consistent with earlier studies that showed that increases in brain KYNA, via inhibition of presynaptic α7 nicotinic receptors, reduce extracellular brain glutamate levels. Blocking of presynaptic α7 nicotinic receptors results in inhibition of glutamate release from neurons that bear these receptors. Reduction in extracellular brain glutamate levels may be responsible for KYNA’s neuroprotective effects, via reduction of excitotoxicity. However, at high local concentrations of KYNA, this metabolite may also block glutamate receptors directly.

Studies with JM6 in mouse models of Alzheimer’s and Huntington’s disease

After performing these studies in wild type mice, the researchers then tested the effects of JM6 in mouse models of AD and HD. Transgenic J20 mice that express a mutant form of the human amyloid precursor protein (hAPP) develop spatial memory deficits and synaptic loss starting at 4-5 months of age. Oral administration of JM6 starting at 2 months of age gave significant improvement in spatial memory in mice tested at 6 months of age, as compared to untreated J20 APPtg (transgenic APP) mice. JM6 treatment also prevented synaptic loss in J20 APPtg mice. However, JM6 treatment had no effect on beta amyloid (Aβ) plaque load, which was increased in the hippocampus and cortex of JM6-treated and untreated J20 mice. Under the amyloid hypothesis of AD pathogenesis, Aβ plaques are central to the causation of AD.

J20 APPtg mice had lower brain KYNA levels than wild type littermate controls, consistent with findings in AD patients. Treatment of J20 APPtg mice with oral JM6 (over a 120 day period) increased brain and plasma levels of KYNA. KMO activity, and 3-HK and QUIN levels in the brains and QUIN levels in the plasma of J20 APPtg mice treated with JM6 were not significantly different from levels in wild type controls.

The researchers also tested the effects of oral JM6 administration in R6/2 mice, the best characterized mouse model of HD. HD is a trinucleotide repeat disorder in which a cytosine-adenine-guanine (CAG) repeat segment in exon one of the huntingtin gene (HTT) (encoded in the germline of the individual) exceeds a normal range. The HD CAG repeat region encodes 36 or greater repeated glutamines in the polyQ region of the huntingtin protein (Htt); people without the disease have fewer than 36 glutamines. The disease-associated huntingtin protein is neurotoxic.

In the R6/2 mouse model, mice are transgenic for the 5′ end of the human HD gene carrying a large CAG repeat expansion. These mice develop a progressive neurologic disease, including motor deficits, weight loss, and premature death. The researchers started oral JM6 administration at 4 weeks of age, which is an early symptomatic stage in R6/2 mice. JM6 administration had a dramatic dose-dependent effect on survival. JM6 treatment did not affect the weight of the mice, but it did modestly improve performance on an accelerating rotarod (a measure of motor performance). JM6 treatment also prevented synaptic loss and reduced CNS inflammation in R6/2 mice.

JM6 treatment of R6/2 mice did not influence the size or abundance of neuronal inclusion bodies in these mice. These inclusion bodes are related to those seen in HD in humans. Thus in mouse models of both AD and HD, JM6 treatment did not affect the aggregated proteins (Aβ plaques and mutated Htt inclusion bodies, respectively) that are thought to cause the diseases; nevertheless, they ameliorated disease symptoms.

In chronically JM6-treated J20 APPtg (AD model) and R6/2 (HD model) mice, although JM6 and Ro 61-8048 accumulated in plasma, brain levels of these compounds were nil. Thus JM6 treatment of both neurodegenerative disease models resulted in increased brain levels of KYNA and neurodegenerative disease amelioration, despite the inability of JM6 and R0 61-8048 to cross the blood-brain barrier.

JM6 treatment is a surprising therapeutic strategy for neurodegenerative diseases for three reasons.

• JM6 cannot cross the blood-brain barrier, which is almost always a sine qua non of CNS disease therapy.
• JM6 ameliorates disease without affecting the protein aggregates that are usually thought to cause the diseases.
• JM6 ameliorates multiple neurodegenerative diseases.

How might this novel therapeutic strategy be moved into the clinic?

Clinical trials in AD are notoriously long and expensive. Therefore, Drs. Reinhart and Kelly in their Preview suggest that it might be best to first conduct clinical trials in HD, since the cause of HD is much better understood than for AD, and disease progression in placebo controls is better characterized than for AD.

The results of the mouse model studies suggest that JM6 will ameliorate, but not cure, HD and AD. However, since there are no disease-modifying therapies for either disease, demonstrating amelioration of HD comparable to that seen in the mouse models (provided the drug is proven to be safe in humans) will almost certainly gain approval for the drug. However, in the long run JM6 would need to be combined with other disease-modifying drugs to more effectively treat diseases such as HD and AD. Since other drugs  developed for neurodegenerative diseases will almost always act directly in the brain, combining them with JM6, which does not enter the brain, may help maximize the clinical benefit of a combination therapy. It may also aid in minimizing the toxicity of combination therapies (since the two drugs would not interact in the brain).

Lennart Mucke, MD, the director of the Gladstone Institute, suggested that Dr. Muchowski and his colleagues might begin testing JM6 in patients within the next two years.

The ability of JM6/Ro 61-8048 to ameliorate neurodegenerative diseases in animal models also raises questions as to the mechanisms by which it does so, and how these mechanisms might interact with mechanisms thought to be central to the pathobiology of neurodegenerative diseases (e.g., the amyloid and Tau pathways in AD, huntingtin inclusions, inflammatory pathways, apoptotic pathways, etc.). What are the molecular mechanisms downstream from KYNA elevation? Is JM6 treatment prophylactic, or is it efficacious in animals (and in humans) that are already suffering disease symptoms and that have pathogenic protein aggregates?

Research to answer these questions may lead to still newer therapeutic strategies, including potentially more effective combination therapies for neurodegenerative diseases that include JM6.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

The time for the July 2011 World Drug Targets Summit in Cambridge MA is looming closer and closer! Registration for the conference is still open, however.

I will lead a workshop entitled “Developing Improved Animal Models in Oncology and CNS Diseases to Increase Drug Discovery and Development Capabilities” at the Summit on July 19.  A workshop on addressing kinase signaling in drug discovery and development will take place later that day. The main conference follows on July 20-21. I am planning to attend the entire conference.

Our workshop will be a discussion of four case studies involving development of novel animal models in oncology and CNS diseases, aimed at more closely modeling human disease than current models. Drug discovery and development in these therapeutic areas has been severely hampered by animal models that are  poorly predictive of efficacy. This is a major cause of clinical attrition in these areas.

There will be one case study on a zebrafish cancer model, two on mouse cancer models, and one on a mouse CNS disease model. The case studies will include applications of these animal models to understanding disease biology, developing new therapeutic strategies, overcoming resistance to breakthrough targeted cancer therapeutics, and identifying drug candidates and advancing them into the clinic.

The main conference will focus on developing improved target discovery and validation strategies that are capable of meeting the challenges of drug discovery and development in the early 21st century–minimizing drug attrition in the clinic, and delivering commercially differentiated products that address unmet medical needs to the market. Speakers will include target discovery and validation leaders from leading pharmaceutical companies, biotechnology companies, and academic institutions.

On June 1, 2011, Cambridge Healthtech Institute’s (CHI’s) Insight Pharma Reports announced the publication of our new book-length report, Multitargeted Therapies: Promiscuous Drugs and Combination Therapies.

In the past 20 years or so, pharmaceutical and biotechnology industry R&D has been increasingly aimed at developing drugs to treat complex diseases such as cancer, cardiovascular disease, type 2 diabetes, and Alzheimer’s disease. However, the one drug-one target-one disease paradigm that has become dominant in the post-genomic era has proven to be inadequate to address complex diseases, which have multiple “causes”, and each of which may be more than one disease. This has been a major cause of clinical failure and the low productivity of the pharmaceutical industry.

Moreover, researchers have found that most of the successful, FDA-approved small-molecule drugs that were developed prior to the year 2000 are promiscuous, i.e., they are single drugs that address multiple targets. In addition, the great majority of kinase inhibitors, one of the most successful drug classes of the early 21st century, are also promiscuous.

The study of small-molecule drug promiscuity has spawned the emerging field of network pharmacology, which can be applied both to study drug promiscuity and to rationally design small-molecule multitargeted drugs. (Researchers can discover or design multitargeted kinase inhibitors without the use of network pharmacology, however.)

Meanwhile, the development of targeted drugs such as kinase inhibitors and monoclonal antibodies has resulted in the need to develop multitargeted combination therapies. This has been especially true in cancer, where disease causation may involve multiple signaling pathways. In particular, the development of resistance to targeted antitumor drugs has spawned the need to develop second-generation treatments, many of which are multitargeted combination therapies.

Our report covers both discovery and design of small-molecule promiscuous/multitargeted drugs, and of multitargeted combination therapies.

The design of multitargeted combination therapies is one of the hottest areas of cancer R&D today, especially with respect to developing means to overcome resistance to targeted therapies. This area was the focus of many key presentations at the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting, which was held in Chicago on June 3-7. For example, treatment with vemurafenib (PLX4032) of metastatic melanoma patients whose tumors carry the B-Raf(V600E) mutation has produced spectacular overall response rates and increased survival. However, in nearly all cases, the tumors relapse. The latest results with vemurafenib were discussed at ASCO 2011, as well as strategies to overcome resistance to therapy. Our new report also discusses strategies for overcoming vemurafenib resistance, all of which involve design of multitargeted combination therapies.

Another topic discussed at ASCO 2011 was antitumor strategies based on synthetic lethality. We discussed this strategy in an earlier article on this blog, especially with respect to poly(ADP) ribose polymerase (PARP) inhibitors such as KuDOS/AstraZenaca’s olaparib. At a session at the ASCO meeting entitled “PARP Inhibitors, DNA Repair, and Beyond: Theory Meets Reality in the Clinic”, speakers reviewed current progress in developing PARP inhibitors, of which six are now in clinical development.

This session also included a presentation by Michael B. Kastan, MD, PhD (St. Jude Children’s Research Hospital, Memphis TN) on other ways of using the synthetic lethally strategy, for example by targeting kinases involved in DNA repair pathways such as ATM (Ataxia-Telangiectasia Mutated) or Chk1 checkpoint kinase, or even utilizing features of the tumor microenviroment such as hypoxia. Such strategies might be used to design multitargeted combination therapies that specifically target cancer cells with defects in DNA repair and/or in hypoxic solid tumors, and/or to sensitize cancer cells to radiation.

Our new report includes a chapter on using the synthetic lethality strategy to design combination therapies of a cytotoxic drug with a chemosensitizing agent, and to develop therapies for p53-negative cancers. (The key tumor suppressor p53 is deleted, mutated, or inactivated in the majority of human cancers).

Although design of multitargeted combination therapies, as well as discovery and design of kinase inhibitors, are of key importance for current oncology R&D and are also being applied to other diseases, design of single small-molecule multitargeted drugs via network pharmacology is an early-stage, and perhaps a premature, technology. Nevertheless, given the current pharmaceutical company R&D business model that emphasizes outsourcing early-stage R&D, academic research groups and biotechnology companies that are active in this area may be able to forge partnerships with pharmaceutical companies.

For more information on Multitargeted Therapies: Promiscuous Drugs and Combination Therapies, or to order it, see the Insight Pharma Reports website.