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Category → Small Molecules

Liveblogging First-Time Disclosures of Drug Structures from #ACSNOLA

Bookmark this page now, folks. On Wednesday, April 10, I will be here, liveblogging the public debut of five drug candidates’ structures. The “First Time Disclosures” Session at the ACS National Meeting in New Orleans runs from 2PM-4:55PM Central time. I am not able to conjure up a permalink to the session program, so here’s a screengrab instead.
NOLAblog-program
1:20PM I’m in hall R02, where the session’s set to begin in about 40 minutes. Found a seat with a power outlet nearby, so I’m good to go!
2:29PM
IMG_3813
BMS-906024
Company: Bristol-Myers Squibb
Meant to treat: cancers including breast, lung, colon, and leukemia
Mode of action: pan-Notch inhibitor
Medicinal chemistry tidbit: The BMS team used an oxidative enolate heterocoupling en route to the candidate– a procedure from Phil Baran’s lab at Scripps Research Institute. JACS 130, 11546
Status in the pipeline: Phase I
Relevant documents: WO 2012/129353
3:02PM
IMG_3810
LGX818
Company: Novartis Institutes for Biomedical Research and Genomics Institute of the Novartis Research Foundation
Meant to treat: melanoma with a specific mutation in B-RAF kinase: V600E
Mode of action: selective mutant B-RAF kinase inhibitor
Status in the pipeline: Phase Ib/II
Relevant documents: WO 2011/023773 ; WO 2011/025927
3:47PM
IMG_3812
AZD5423
Company: AstraZeneca
Meant to treat: respiratory diseases, in particular chronic obstructive pulmonary disease
Mode of action: non-steroidal glucocorticoid receptor modulators
Medicinal chemistry tidbit: This compound originated in part from a collaboration with Bayer Pharma.
Status in the pipeline: Phase II
Relevant documents: WO 2011/061527 ; WO 2010/008341 ; WO 2009/142568
4:17PM
IMG_3811
Birinapant (formerly known as TL32711)
Company: TetraLogic Pharmaceuticals
Meant to treat: cancer
Mode of action: blocks the inhibitor of apoptosis proteins to reinstate cancer cell death
Status in the pipeline: Phase II
Relevant documents: US 8,283,372
5:00PM
IMG_3814
MGL-3196 (previously VIA-3196)
Company: Madrigal Pharmaceuticals, acquired from VIA Pharmaceuticals, licensed from Roche
Meant to treat: high cholesterol/high triglycerides
Mode of action: mimics thyroid hormone, targeted to thyroid hormone receptor beta in the liver
Medicinal chemistry tidbit: this molecule was discovered at Roche’s now-shuttered Nutley site.
Status in the pipeline: completed Phase I trials
Relevant documents: WO 2007/009913 ; WO 2009/037172

And that’s it, folks! Watch the April 22nd issue of C&EN for more on this session.

New developments in Advanced Pancreatic Cancer from ASCO GI 2013 – Part 2

The following is a guest post from Sally Church (known to many in the twittersphere as @MaverickNY), from the Pharma Strategy Blog.

In my last post on The Haystack, we discussed the phase III data from the Abraxane MPACT trial in advanced pancreatic cancer that was presented at the recent ASCO GI meeting in San Francisco. Two other late-stage studies in pancreatic cancer caught my eye—fresh data for AB Science’s kinase inhibitor masitinib and Sanofi’s multidrug pill S1.

Masitinib is an oral tyrosine kinase inhibitor from AB Science that targets KIT, PDGFR, FGFR3 and has shown activity in gastrointestinal stromal tumours (GIST). A different version of the drug (Masivet, Kinavet) is also approved in France and the US for the treatment of a dog mast cell (skin) cancers, which are also known to be KIT-driven.

S1 is multidrug pill from Sanofi and Taiho that consists of tegafur (a prodrug of 5FU), gimeracil (5-chloro-2,4 dihydropyridine, CDHP) which inhibits dihydropyrimidine dehydrogenase (DPD) enzyme, and oteracil (potassium oxonate, Oxo), which reduces gastrointestinal toxicity. Previous Japanese studies have demonstrated effectiveness of this agent in gastric and colorectal cancers, so a big unaswered question is whether it is effective in pancreatic cancer.

So what was interesting about the latest data at this meeting?

At the ASCO GI conference in 2009, French oncologist Emmanuel Mitry presented data from a small Phase II study of the effect of combining masitinib and Eli Lilly’s Gemzar in advanced pancreatic cancer. The study had just 22 patients, but the median overall survival of 7.1 months in was not a large improvement over what is often seen with the standard of care, Gemzar given alone, or with a combination of Gemzar and Genentech’s Tarceva. Over the years, many combination therapies based on Gemzar have failed to show superiority over single agent therapy. It’s both a high unmet medical need and a high barrier to beat.  Thus, the phase III data for the combination of masitnib and Gemzar was highly anticipated at this year’s ASCO GI meeting.

Gael Deplanque and colleagues compared masitinib plus Gemzar to Gemzar plus placebo.  Although the overall trial results for median overall survival were slightly higher than in the phase II study, they were not significant (7.7 versus 7.0 months, P=0.74; HR=0.90).

Some promising data was observed, however, in a subset of the population identified by a profile of biomarkers that the authors vaguely described as, “a specific deleterious genomic biomarker (GBM) consisting of a limited number of genes.” No other details on the actual genes or biomarkers were was provided, but the subset was described as having an improved MOS to 11.0 months compared to the Gemzar and placebo arm.

They also noted that patients with high pain, who usually do poorly on standard chemotherapy, also saw improvement with the masitinib combination. AB Science might have found a particularly aggressive subset that respond to masitinib, in which case, a biomarker would be useful in selecting those patients most likely to respond, as opposed to a catch-all approach where everyone is treated regardless of the predictive value.

AB Science has asked European regulatory authorities for approval, but the Phase III data will not be sufficient for US approval. The company will need to validate the biomarker panel in a large-scale randomized study, and a new phase III trial is now recruiting patients. The outcome of that study won’t be known for awhile, but the hope is for more insight into how to choose the right patients to respond to masitinib in combination with Gemzar.

The other compound featuring late-stage results in pancreatic cancer was Sanofi’s S1. The compound is interesting, but so far its development has been limited to Asian patients, particularly people of Japanese origin. Studies in caucasians have not seen any benefit over standard 5FU therapy.

Katsuhiko Uesaka, medical deputy director at Shizuoka Cancer Center Hospital in Japan, presented encouraging data for the use of S1 as adjuvant therapy in combination with Gemzar after surgical resection (relevant in stage I-III pancreatic cancer). They compared S1 and Gemzar in a head to head non-inferiority trial (with 385 patients. In the interim analysis reported at this year’s ASCO GI meeting, the hazard ratio for S-1 to Gemzar was 0.56, while the 2-year survival rates were 53% for Gemzar and 70% for S-1. The percentage of serious side effects were similar to previously reported studies with Gemzar and S-1, including fatigue (4.7/5.4), anorexia (5.8/8.0), leukopenia (38.7/8.6), thrombocytopenia (9.4/4.3), anemia (17.3/13.4), and elevated AST (5.2/1.1).

Overall, the authors concluded that S-1 adjuvant chemotherapy was shown to be as good as, perhaps even better than Gemzar, even suggesting that S-1 could be considered the new standard treatment for resected pancreatic cancer. It should be noted, however, that this data is only applicable to patients of Japanese origin since no caucasian data was included in this analysis.

 

New Developments in Advanced Pancreatic Cancer from ASCO GI 2013 – Part 1

The following is a guest post from Sally Church (known to many in the twittersphere as @MaverickNY), from the Pharma Strategy Blog.

The cancer research conference season kicked off in earnest in 2013 with the American Society of Clinical Oncology (ASCO)’s Gastrointestinal Symposium, held in San Francisco in late January. Some of the most anticipated data to be presented at ASCO GI was for drugs that treat pancreatic cancer, with three drugs—Celgene’s Abraxane, AB Science’s masitinib, and Sanofi’s S1, generating the most interest.

With this post, we’ll take a closer look at the most advanced of the three agents, Abraxane, which generated encouraging results in a Phase III study. Later this week, we’ll tackle masitinib and S1.

Abraxane is a nanoparticle albumin-bound form of the breast cancer drug paclitaxel, and is designed to improve the activity of the active ingredient. Abraxane is already approved in the US for advanced breast and lung cancers, and recently showed signs of activity in metastatic melanoma.

At ASCO GI, Daniel Von Hoff, director of the Translational Genomics Research Institute, presented data from a randomized phase III study called MPACT that compared the effects of Lilly’s Gemzar, the current standard of care, to a once weekly combination of Gemzar and Abraxane in patients with metastatic adenocarcinoma of the pancreas. With 861 patients, this was a large global study that sought to determine whether the combination would outdo the regulatory standard of care.

A note on the trial design: Although this study uses Gemzar as the standard of care, in practice, many leading oncologists prescribe FOLFIRINOX (fluorouracil, leucovorin, irinotecan and oxaliplatin) for advanced pancreatic patients. But because FOLFIRINOX is generic, and is not formally approved by FDA for advanced pancreatic cancer, Phase III studies tend to match new drug candidates up against Gemzar.

As Hedy Kindler, director of gastrointestinal oncology at the University of Chicago, explained, FOLFIRINOX is widely used because the regimen has “the higher response rate, and that has the longer median survival.”

However, FOLFIRINOX also has unpleasant side effects, and in private practice settings, oncologists prefer to use less toxic combinations based on Gemzar—namely, Gemzar alone, GemOx (with oxaliplatin), or GemErlotinib (with Tarceva, an EGFR TKI). To provide context, FOLFIRINOX typically has an improved survival of approximately 11 months, while gemcitabine or gemcitabine plus erlotinib elicit a 6-7 month improvement in median overall survival (MOS).  Erlotinib added 12 days of extra survival over gemcitabine alone, but unfortunately we have no way of selecting those advanced pancreatic patients most likely to respond to EGFR therapy.

Celgene is exploring the combination of Abraxane and Gemzar based on preclinical work that suggests Abraxane can knock out the protective stroma surrounding the tumor, thereby providing better penetration of the tumor.  The phase II data led to a promising 12.2 months improvement in median overall survival.

In general, results from randomized phase III trials tends to be lower than that reported in the smaller studies. This is exactly what happened in the MPACT trial, with the Abraxane combination showing a MOS of 8.7 months versus 6.7 months for Gemzar alone, a highly statistical significant finding (P<0.000015). The hazard ratio (HR) was 0.72, suggesting that the combination gave a 28% reduction in the risk of death versus gemcitabine.

Kindler is eager to use and learn more about the combination and notes that it will be another option for oncologists rather than a new standard of care.

This is encouraging data and met the primary endpoint. Celgene is expected to file for approval for Abraxane in advanced pancreatic adenocarcinoma in the second half of the year. Data on a previously identified biomarker (SPARC expression) was not yet available and is expected to be presented at the annual ASCO meeting in June.  The audience at the GI meeting were clearly expecting survival to be higher in those patients with high SPARC expression, but we will see what happens.

Advanced pancreatic cancer is a particularly devastating disease – the incidence and prevalence are approximately equal, with patients typically having a year of life left.  The symptoms are vague and insidious plus there are no useful screening approaches approved for earlier detection, so the emergence of potential biomarkers for selecting patients most likely to respond to Abraxane or Tarceva in combination with gemcitabine would be a most welcome advance, especially given the toxicities associated with FOLFIRINOX.

 

 

Rigged Reactions: Biocatalysis Meets 13C NMR

When you think of reaction screening, what comes to mind? Most would say LC-MS, the pharma workhorse, which shows changes in molecular polarity, mass, and purity with a single injection. Some reactions provide conversion clues, like evolved light or heat. In rare cases, we can hook up an in-line NMR analysis – proton (1H) usually works best due to its high natural abundance (99.9%).

Please welcome a new screening technique: 13C NMR. How can that work, given the low, low natural abundance of ~1.1% Carbon-13?

Researchers at UT-Southwestern Medical Center have the answer: rig the system. Jamie Rogers and John MacMillan report in JACS ASAP 13C-labeled versions of several common drug fragments, which they use to screen new biocatalyzed reactions.

Biocatalysis = big business for the pharma world. The recent Codexis / Merck partnership for HCV drug boceprevir brought forth an enzyme capable of asymmetric amine oxidation. Directed evolution of an enzyme made sense here, since they knew their target structure, but what if we just want to see if microbes will alter our molecules?

Enter the labeled substrates: the researchers remark that they provide an “unbiased approach to biocatalysis discovery.” They’re not looking to

13C Proof-of-Concept

Credit: JACS | UT-Southwestern, 2012

accelerate a certain reaction per se, but rather searching for any useful modifications using the 13C “detector” readout. One such labeled substrate, N-(13C)methylindole, shows proof-of-concept with their bacterial library, producing two different products (2-oxindole and 3-hydroxyindole) depending on the amount of oxygen dissolved in the broth. NMR autosamplers make reaction monitoring a snap, and in short order, the scientists show biotransformations of ten more indole substrates.

This paper scratches multiple itches for various chem disciplines. Tracking single peaks to test reactions feels spookily close to 31P monitoring of metal-ligand catalysis. Organickers, no strangers to medicinally-relevant indole natural products, now have another stir-and-forget oxidation method. Biochemists will no doubt wish to tinker with each bacterial strain to improve conversion or expand scope. The real question will be how easily we can incorporate 13C labels into aromatic rings and carbon chains, which would greatly increase the overall utility.

J&J Could Score Priority Review Voucher with Bedaquiline NDA

Janssen Research and Development, part of J&J, has asked the FDA to approve bedaquiline, a diarylquinoline to treat multi-drug resistant tuberculosis. If given the green light, bedaquiline would be the first drug with a new mechanism of action to be approved for tuberculosis in over four decades. Janssen points out that the pill would also be the first drug approved for multi-drug resistant TB.

If approved, Johnson & Johnson will score a Priority Review Voucher, an incentive created in 2007 to prompt more R&D in neglected disease. A PRV, given to a company that wins U.S. approval for a new drug for neglected disease, is a coupon good for shaving the review time for another new drug application. The value of that coupon depends on the drug its applied to—in theory, if a drug has lofty sales potential, gaining a few extra months (as we’ve written, it could shorten the FDA’s decision time by anywhere from four to 12 months) could translate into hundreds of millions of dollars.

To date, Novartis has been the only company to be granted a PRV, which it gained through the U.S. approval of the malaria drug Coartem. But that first test of the incentive had some questioning its value, as Novartis cashed in its PRV for a supplemental new drug application for Ilaris, an antibody for auto-inflammatory disorders that brought in just $48 million last year.

So, readers, any thoughts on how J&J might cash in its PRV if granted?

 

Tetrodotoxin: Why Toxic Is Complicated

(This post was written for the “Our Favorite Toxic Chemicals” blog carnival hosted by Sciencegeist.)

It was a meal Captain James Cook would just as soon have forgotten. The fish, an unfamiliar species, seemed harmless enough. But after just a small taste of its liver, he and two shipmates regretted it.

“We were seized with an extraordinary weakness in all our limbs attended with a numness [sic]…We each of us took a Vomet and after that a Sweat which gave great relief. One of the pigs which had eat the entrails was found dead… When the Natives came on board and saw the fish hanging up, they immidiately [sic] gave us to understand it was by no means to be eat.”

Cook had a rather more dramatic introduction to the lethal chemical tetrodotoxin than I did. I learned about it from a lecture in a windowless room. (Yes, I’ve linked to the original slides, still online after eight years.) That presentation had plenty to make my ears perk up. Highly poisonous. No antidote. Still kills today, because pufferfish, one of the web of creatures that makes tetrodotoxin, gets carved into a delicacy called fugu, and sometimes those knives miss a little bit of the animal’s toxic innards.

We weren’t learning about tetrodotoxin because of its deadliness. Tetrodotoxin, to the organic chemist, is a case study. The lab where I earned my Ph.D. is in the business of making the toughest molecules it can. The lessons teams learned by forging tetrodotoxin from scratch, the idea goes, will be useful in other endeavors. Chemists for decades have argued about whether this is an appropriate way to train students, but suffice to say it’s still the way that most medicinal chemists in pharma get their start.

Tetrodotoxin is different things to different people. To biochemists and neurobiologists, tetrodotoxin, or TTX for short, is a tool for unraveling how pain works. Researchers today know that TTX binds to sodium channel proteins involved with pain pathways in the nervous system.

To those who study the cultures of Haiti, tetrodotoxin evokes something else entirely– the zombie of Haitian tradition.

In the 1980s, ethnobotanist Wade Davis fingered tetrodotoxin as a key ingredient in a powder witch doctors use in voodoo zombie-making rituals. His doctoral thesis, as well as his bestselling book the “The Serpent and the Rainbow”, about the topic eventually became the basis for a movie of the same name.

Davis’s results came under fire from the medical and scientific community. Another team’s measurements of tetrodotoxin levels in the powder detected amounts too low to have any relevant effects, though Davis and another set of researchers have countered that fluctuations in pH dramatically affect those levels.

Tetrodotoxin levels aside, “the main criticism of Wade’s hypothesis is that tetrodotoxin does not confer the long term fugue that would be necessary to keep someone in a wakeful but zombified state,” says Frank Swain, a science writer currently working on a book about zombies. Swain also points to clinical examinations of three purported zombies, where each was diagnosed with a mental illness. “It seems zombies are just normal people with learning difficulties, who become pawns in various feuds as one family accuses another zombifying their children,” Swain says.

Davis, today an explorer-in-residence at the National Geographic Society, defends his work, saying that examining zombies with a purely chemical lens ignores their cultural context. “The zombie definition in Haiti has nothing to do with the poison,” he says. “Of course tetrodotoxin cannot make a zombie, but it can make someone appear to be dead.” From there, the belief system takes over and makes tetrodotoxin “the obvious culprit,” he adds.

Whether or not you adhere to the Haitian belief system, tetrodotoxin is a chemical that’s not to be messed with. Yet somehow fugu emerged as a delicacy. Customers line up, as the BBC puts it, to “play Russian roulette at the dinner table”. Consuming fugu is a much bigger gamble than consuming a burger made with the infamous meat product “pink slime”. But it was the slime that got the outrage.

It all comes down to information and choice. According to economist Robin Hanson, America is much more paternalistic when it comes to regulating foods consumed by the poor and by children, presumably because people feel those groups are unable to obtain or act on the information they’d need to make informed food choices.

Preserved pufferfish at the Heard Natural Science Center, Fairview, Texas (Flickr/gurdonark)

With fugu, folks know what they’re in for. They’re aware of the risk, though they may be less aware of the black-market trade in pufferfish, or of Tokyo’s recent move to ease strict regulations about who can serve it. And it doesn’t end with food. Hairstylists and consumers didn’t know that the cancer-causing chemical formaldehyde was in the hair-straightener Brazilian Blowout, because of the company’s deceptive marketing. Now that they do, some people beg for it anyway, and drop hundreds of dollars a pop to do it.

Our relationship with toxic chemicals is complicated. It isn’t always Nick Kristof’s “Big Chem” that’s out to obscure dangers or cloud our judgement. Sometimes, it’s human nature. We know smoking’s bad for us, and we do it anyway. But we don’t always know what lurks in, for example, a trailer provided by FEMA. Painting chemicals as “evil” or “good” is too simplistic- it’s all about their doses and their context. Instead of op-eds “teaching nothing more than a generalized chemical anxiety”, as Deborah Blum eloquently wrote, the world would be better served by op-eds that call for better information on what chemicals’ danger thresholds are. It’s a nuanced mission, but I’d venture a paper of the New York Times’ caliber is up to it.

TEDMED: Andrew Read’s Five Tips For Keeping Superbugs At Bay

Read (TEDMED)

Researchers may like to think they’re pretty smart, but you could argue that bacteria have also got some bragging rights. Every day, microbes develop resistance to even the most powerful antibiotics scientists have developed.

Andrew Read thinks evolution is the best lens for staring down the superbugs. He took the stage Thursday at TEDMED, where he warned, “we’re picking a fight with natural selection.”

“Picking a fight without Darwin is like going to the moon without Newton,” Read added. “We are in the dark ages when it comes to evolutionary management.”

Read, director of Penn State University’s Center for Infectious Disease Dynamics, sat down with me on Thursday and shared a few principles he thinks the scientific community should keep in mind in order to keep antibiotic resistance in check. Here are his five tips for would-be superbug slayers. Continue reading →

TEDMED and Alzheimer’s: Gregory Petsko, Reisa Sperling, and the next Al Gore

Petsko (TEDMED)

Gregory Petsko knows why he came to TEDMED. “I’m looking for Al Gore,” he told me flat-out over lunch. Folks who know Petskoknow the former Brandeis University biochemistry department chair isn’t one to mince words. And he’s nailed the reason why an academic might want to look outside traditional conferences and soak up some of the TEDMED aura. He’s looking for a charismatic champion to take up a biomedical cause: in Petsko’s case, it’s support for research in Alzheimer’s disease.

Petsko and Reisa Sperling, director of the Center for Alzheimer’s Research and Treatment at Brigham and Women’s Hospital, talked about Alzheimer’s at TEDMED on Wednesday. Both talks were cast as calls to action. Just consider the introduction Petsko got from TEDMED chair and Priceline.com founder Jay S. Walker: “This is a man who hears a bomb ticking.”

Alzheimer’s statistics are sobering and Petsko used them to dramatic effect. People who will reach 80 by the year 2050 have a 1 in 3 chance of developing the disease if nothing is done, he told the audience. “And yet I hear no clamor,” he said. “I hear no sense of urgency.”

Petsko shared some not-yet-published work with TEDMED’s audience. Continue reading →