Synta announces results from ganetespib Phase 2b trial on NSCLC

In continuation of my update on Ganetespib....

"The preliminary results from GALAXY indicate that the addition of ganetespib to docetaxel is well tolerated and may improve outcomes in patients compared to docetaxel alone," said Dr. Ramalingam, a Principal Investigator of the study. "This includes promising improvements in survival seen across the broad adenocarcinoma population as well as in key predefined patient populations. A well-tolerated combination regimen that extends survival associated with salvage therapy in NSCLC will meet a much awaited need to improve the current standard of care."

As per the CEO's statement "the objective of the interim analysis was to identify the best choice of patient population and trial design for transitioning to the Phase 3 stage of the study. The broad-based activity seen in the results presented  support advancing into the Phase 3 stage in alladenocarcinoma patients. The results have yielded a rich data set which we are using to optimize and de-risk the Phase 3 stage of the program. We are hopeful that this next stage of development will lead to a new treatment option for patients fighting this devastating disease."

Enrollment completion of the Phase 2b stage of the GALAXY trial and the transition to the Phase 3 stage are expected later this year. Based on current assumptions, the Company anticipates that Phase 3 will enroll approximately 500 adenocarcinoma patients, with overall survival as a primary endpoint. Biomarker findings and other patient selection and treatment experience from the Phase 2b stage will be incorporated into the design of the Phase 3 stage. An announcement with additional Phase 3 details is anticipated later this year, following discussion with regulatory agencies.  

Ref : http://www.syntapharma.com/documents/Ganetespib_GALAXY_ESMO_2012_Poster.pdf

Synta announces results from ganetespib Phase 2b trial on NSCLC

Drug combinations show promise against metastatic melanoma

In continuation of my update on Vemurafenib..

A Phase I study in 44 patients shows that the combination of the MEK inhibitor GDC-0973  (see structure) and vemurafenib can be delivered safely, Dr Rene Gonzalez of the University of Colorado Cancer Center, Denver, and colleagues report.

"BRAF inhibition has resulted in high response rates and improved survival in patients with BRAF mutated melanoma," Dr Gonzalez said. "One of several mechanisms of resistance has been reactivation of the MAPK pathway. Preclinical models show that combined inhibition of BRAF and MEK can delay the acqusition of resistance compared to BRAF inhibitor monotherapy. Inhibition of the pathway downstream from BRAF with the MEK inhibitor GDC-0973 could theoretically overcome or delay this resistance mechanism and improve outcomes."

The study was not designed to evalate efficacy. "While early data in a small number of patients did show tumor reduction, it would be premature to comment on efficacy based on these preliminary results and further research is warranted," Dr Gonzalez said.

Drug combinations show promise against metastatic melanoma

ARIAD announces initial results from AP26113 Phase 1/2 trial on non-small cell lung cancer

We know that, AP26113 (see structure) is a highly potent ALK inhibitor with IC50 of 0.62 nM. As an ALK inhibitor, AP26113 overcomes mutation-based resistance in NSCLC models. Multiple mutations in ALK were identified that conferred resistance to crizotinib, but not AP26113, including the L1196M "gatekeeper" mutation which has now been observed clinically in patients who initially responded to crizotinib and then relapsed. AP26113 also inhibits activated EGFR in preclinical models, including the T790M "gatekeeper" mutant that confers resistance to current EGFR inhibitors. Constitutive EGFR activity due to activating mutation is a key feature of certain non-small cell lung cancers, and the T790M mutation causes resistance to inhibitor therapy in approximately 50 percent of these cases. In preclinical studies, AP26113 was shown to be specific for mutated EGFR and avoids inhibition of native (endogenous or unmutated) EGFR; such inhibition is thought to be associated with the toxicity of other EGFR inhibitors.

ARIAD announces initial results from AP26113 Phase 1/2 trial on non-small cell lung cancer

Combination of targeted treatment drugs delays resistance in melanoma patients

In continuation of my update on dabrafenib and trametinib.....

Combination of targeted treatment drugs delays resistance in melanoma patients

Beating Drug-Resistant TB.....

An antibiotic produced naturally by common soil bacteria kills Mycobacterium species that cause various human diseases, including tuberculosis (TB), according to a report published Monday (September 17) in EMBO Molecular Medicine. The antibiotic even kills drug-resistant strains that escape current TB treatments.

“I seldom get so tickled when I read a paper,” said William Jacobs, a microbiologist and immunologist at the Albert Einstein College of Medicine in New York, who did not participate in the research. The emergence of multidrug resistant strains of Mycobacterium tuberculosis “is a big problem,” he said. “This could be a godsend.”

Tuberculosis infections are commonly treated with a mixture of antibiotics, including one called isoniazid, which Jacobs described as “the cornerstone of TB therapy.”  Unfortunately, the most common drug-resistant strains of M. tuberculosis are isoniazid-resistant, he said.

Many researchers, including Stewart Cole, chair of the microbial pathogenesis department at the École Polytechnique Fédérale de Lausanne in Switzerland, have thus been searching for new M. tuberculosis-killing drugs. “In the past we’ve been working a lot on TB drug discovery using target-based approaches… [but] this has been spectacularly unsuccessful,” said Cole. So instead, he and his colleagues looked back over decades of academic literature searching for reports of natural compounds with M. tuberculosis-killing activity.

They found pyridomycin (see above structure). First described in the 1950s, the drug was reportedly produced by the bacteria Streptomyces pyridomyceticus and Dactylosporangium fulvum. Surprisingly, little was known about pyridomycin—perhaps, Cole suggested, because isoniazid was discovered around the same time and simply stole the limelight.

Cole’s team grew cultures of D. fulvum bacteria, figured out how to isolate and purify pyridomycin, and then showed that the drug was indeed capable of killing M. tuberculosis, as well as many otherMycobacterium species, in culture.

This indiscriminate Mycobacterium-killing ability is a bonus, said Cole. “One of the problems with isoniazid is that it only works against TB,” he said. “If pyridomycin makes it into the clinic, it could have applications in leprosy or Buruli ulcer or atypical mycobacterial infections that can occur in cystic fibrosis patients.”

The team went on to identify the bactericidal target of pyridomycin—a protein called inhA, which is involved in synthesis of bacterial cell wall components. As it happens, inhA is the same protein targeted by isoniazid, but there is a difference in the two drugs’ mechanisms. While isoniazid is a pro-drug that requires activation by an intracellular enzyme called KatG before it can bind to inhA, pyridomycin binds inhA directly.

This is an important distinction, explained Valerie Mizrahi, director of the Institute of Infectious Disease and Molecular Medicine at Cape Town University, South Africa, who was not involved in the study. The overwhelming majority of drug resistance mutations in M. tuberculosis occur in the KatGgene, she explained, and such mutant strains should not be resistant to pyridomycin. Indeed, the team showed that clinical isolates of isoniazid-resistant M. tuberculosis carrying KatG mutations were killed effectively by pyridomycin. “The efficacy against drug resistant forms of M. tuberculosis is particularly encouraging,” Mizrahi said.

There is, however, much to be done before pyridomycin can be used in the clinic. “We would [need to] test that it works in animal models and that it is safe and doesn’t have any side effects,” said Cole. “That will take a couple of years.”

“It’s a long journey,” agreed Mizrahi, “but the big plus is that they don’t really need to validate inhA as a drug target because inhA is already the most well validated drug target out there… [so] it has got a good head start.”

Ref : http://onlinelibrary.wiley.com/doi/10.1002/emmm.201201689/abstract

FDA approves Enzalutamide (XTANDI Capsules)

Enzalutamide (marketed as Xtandi and formerly known as MDV3100) is an androgen receptor antagonist drug developed by the pharmaceutical company Medivation for the treatment of castration-resistant prostate cancer  currently in phase 3 clinical trials. Medivation has reported up to an 89% decrease in prostate specific antigen serum levels after a month of taking the medicine. Early preclinical studies also suggest that enzalutamide inhibits breast cancer cell growth. In August of 2012, the U.S. Food and Drug Administration approved enzalutamide (see structure) for the treatment of castration-resistant prostate cancer......

 
Approved Drugs > Enzalutamide (XTANDI Capsules)

GenSpera plans to initiate G-202 Phase II trial in prostate cancer

 We know that, a Mediterranean plant (see pic), Thapsia garganica, a simple weed, is the original source of G202. For millennia, the plant has been known to be poisonous to animals; in the days of desert caravans, it was called the “death carrot” for the unfortunate fate awaiting any camel that ingested it. Researchers at the Johns Hopkins Kimmel Cancer Center in the US and their Danish collaborators hoped to harness the toxicity of the plant in a controlled way that could be used to treat cancer in people.

They did so by taking apart the toxic compound, thapsigargin, produced by the plant and altering its chemical structure. The resulting prodrug, G202, is not active until it comes into contact with a particular protein produced by certain tumors. This prostate-specific membrane antigen (PMSA) is released by cells lining the outside of prostate and other tumors. Samuel Denmeade, the study’s lead author, uses the image of a hand grenade. The presence of PMSA essentially “pulls the pin” of the G202 grenade. In its active form, the drug is able to kill not only the tumor, but the blood vessels that provide it with nutrients.

A recent study of  G202,  looked at the effects of the drug on human prostate tumors grown in mice, and compared it to docetaxel, a chemotherapy drug already in use. G202 clearly came out on top, reducing by half the size of seven out of nine tumors; docetaxel achieved the same effect on only one out of eight tumors. Similar results for G202 were also seen in experiments with human breast, kidney and bladder cancer.

These promising results encouraged doctors to test the safety of G202 in a phase I clinical trial, involving 29 cancer patients at advanced stages of the disease.  

Now its  good news that,......

GenSpera plans to initiate G-202 Phase II trial in prostate cancer

Potential new COPD drug

 

A study led by researchers at Boston University School of Medicine (BUSM) has shown that a compound used in some skin creams may halt the progression of emphysema and reverse some of the damage caused by the disease. When the compound Gly-His-Lys (GHK) was applied to lung cells from patients with emphysema, normal gene activity in altered cells was restored and damaged aspects of cellular function were repaired. 

Researchers took cells from lungs donated by patients undergoing a double lung transplant because their lungs were irrevocably damaged by COPD and found 127 genes had changes in activity as disease severity increased within the lung. The genes that showed increased activity included several that are associated with inflammation, such as those involved in signalling to B-cells (the immune system cells that make antibodies).

In contrast, the genes involved in maintaining cellular structure and normal cellular function, along with the growth factors TGFβ and VEGF, were down-regulated and showed decreased activity. Genes that control the ability of the cells to stick together (cell adhesion), produce the protein matrix that normally surrounds the cells and promote the normal association between lung cells and blood vessels were among the genes in this category. 

Using genomic technologies and computational methods, the researchers identified genetic activity defects that occur as emphysema progresses and matched these defects with compounds that could reverse the damage.

"Our study results showed that the way genes were affected by the compound GHK, a drug identified in the 1970s, was the complete opposite of the pattern we had seen in the cells damaged by emphysema," said Marc Lenburg, PhD, associate professor in computational biomedicine and bioinformatics at BUSM and one of the study's senior authors.

Potential new COPD drug

Potential drug for treatement of Alzheimer's disease investigated

Cannabinoid type 2 (CB₂) agonists are neuroprotective and appear to play modulatory roles in neurodegenerative processes in Alzheimer's disease. We have studied the effect of 1-((3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl) carbonyl) piperidine (MDA7 see below structure), a novel selective CB₂ agonist that lacks psychoactivity—on ameliorating the neuroinflammatory process, synaptic dysfunction, and cognitive impairment induced by bilateral microinjection of amyloid-β (Aβ)_1–40 fibrils into the hippocampal CA1 area of rats. In rats injected with Aβ_1–40 fibrils, compared with the administration of intraperitoneal saline for 14 days, treatment with 15 mg/kg of intraperitoneal MDA7 daily for 14 days (1) ameliorated the expression of CD11b (microglia marker) and glial fibrillary acidic protein (astrocyte marker), (2) decreased the secretion of interleukin-1β, (3) decreased the upsurge of CB₂ receptors, (4) promoted Aβ clearance, and (5) restored synaptic plasticity, cognition, and memory. Our findings suggest that MDA7 is an innovative therapeutic approach for the treatment of Alzheimer's disease.

Potential drug for treatement of Alzheimer's disease investigated

Carboranes Increase the Potency of Small Molecule Inhibitors of Nicotinamide Phosphoribosyltranferase - Journal of Medicinal Chemistry (ACS Publications)

We know that,  carborane is a cluster composed of boron and carbon atoms. Like many of the related boranes, these clusters are polyhedra and are similarly classified as closo-, nido-, arachno-, hypho-, etc. based on whether they represent a complete (closo-) polyhedron, or a polyhedron that is missing one (nido-), two (arachno-), or more vertices. Interesting examples of carboranes are the extremely stable icosahedral closo-carboranes.

A prominent example is the charge-neutral C₂B₁₀H₁₂ or o-carborane with the prefix o derived from ortho, which has been explored for use in a wide range of applications from heat-resistant polymers to medical applications.  

Now researchers lead by Dr. Lee of University of Missouri used carboranes to build new drugs designed to shut off a cancer cell's energy production, which is vital for the cell's survival. All cells produce energy through complex, multi-step processes. The key to an effective drug is targeting the process that cancer cells depend on more than healthy cells. By increasing the binding strength of a drug, a smaller dose is required, minimizing side effects and increasing the effectiveness of the therapy. With carboranes, Lee found that the drug is able to bind 10 times more powerfully.

"The reason why these drugs bind stronger to their target is because carboranes exploit a unique and very strong form of hydrogen bonding, the strongest form of interactions for drugs," Lee said.

Lee said that this discovery also will lead to further uses for the drug.

"Too often, after radiation or chemotherapy, cancer cells repair themselves and reinvade the body," Lee said. "This drug not only selectively shuts off the energy production for the cancer cells, but it also inhibits the processes that allow those cancer cells to repair themselves. When we tested our carborane-based drugs, we found that they were unimaginably potent. So far, we have tested this on breast, lung and colon cancer, all with exceptional results."

According to Lee, this is the first study to show systematically how carboranes can improve the activity of a drug. Lee believes this discovery will open additional possibilities of improving drugs that are used to treat other diseases, not just cancer.

"The end result is that these new drugs could be many thousands of times more potent than the drugs that are used in the clinics today," Lee said.

 Carboranes Increase the Potency of Small Molecule Inhibitors of Nicotinamide Phosphoribosyltranferase - Journal of Medicinal Chemistry (ACS Publications)