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Trouble Brewing for New HCV Meds

In a blow to the Hepatitic C drug development arena, Bristol-Myers Squibb last night pulled the plug on BMS-986094, an NS5B inhibitor in mid-stage trials. The decision comes just weeks after the company reported a patient suffered from heart failure during a Phase II study of the compound. Nine patients were eventually hospitalized, with varying symptoms of kidney and heart toxicity, according to BMS’s release (See more coverage by Adam Feuerstein at

The Street and by Andrew Pollack at the NYT)

BMS-986094? You might know this molecule better as Inhibitex’s former nucleoside INX-089. The molecule came to BMS through its $2.5 billion purchase of Inhibitex in 2011, as we wrote last year here at the Haystack.

The molecule belongs to a family of new nucleosides with fairly common structural motifs: a central sugar appended to a nitrogen heterocycle (usually purine- or uracil-based) and an elaborate phosphoramidate prodrug. These new drugs’ similarities may also prove to be their Achilles heel – Idenix Pharmaceuticals announced an FDA-requested partial clinical hold on their IDX-184 lead. This cautious approach aims to protect patients; though the drugs are similar, 184’s main structural difference – a thioester-based, slightly more-polar prodrug – seems to be enough to distance it from the cardiac side-effects seen with BMS-986094.

For a fairly in-depth look at the chemistry behind these inhibitors, as well as dozens of other analogues that never made it to prime time, check out US Patent 7,951,789 B2, issued to Idenix just last year.

The HCV Combo Race Just Got Hotter

BMS is shelling out $2.5 billion dollars for Inhibitex, a small pharma company with a Phase II molecule for treatment of Hepatitis C (HCV). The deal adds to the scramble for HCV assets in recent months, with Gilead agreeing to pay almost $11 billion for Pharmasset in November, and Roche’s recent purchase of Anadys. While much has been written about the merits (and price tags) of each deal, the Haystack thought it was worth taking a closer look at the chemical composition of the multi-million dollar molecules.

So what did BMS get for their money?

INX-089, Inhibitex’s lead molecule, has a common antiviral motif: a nucleoside core (the 5-membered ring sugar attached to a nitrogen heterocycle) with an amino acid based prodrug hanging off the left-hand side. Clinically-tested antivirals sharing this basic setup include IDX-184 and NM-283, both from Idenix, and PSI-352938, from Pharmasset  (For an overview of the varied structures currently in development for HCV, see Lisa’s 2010 C&EN story).

INX-089 bears a close resemblance to Pharmasset’s lead nucleotide inhibitor PSI-7977. That’s not a mistake, believes ‘089 discoverer Chris McGuigan, of the Welsh School of Pharmacy. In a recent article (J. Med. Chem. 2010, 53, 4949), McGuigan himself comments “The Pharmasset nucleoside [is] rather parallel to our early work on anti-HIV ProTides.”

Wait, what are ProTides?

Both INX-089 and PSI-7977 aren’t themselves the active viral inhibitor, but phosphoramidate “ProTide” prodrugs: compounds broken down by the body into the active drug (Chem Note: PSI-7977 has single-enantiomer Sp chirality at phosphorus, while INX-189 is a mixture of diastereomers).

Once in the body, enzymes cleave the phosphoramidate group to a phosphate (PO42-). Kinases attach two more phosphate groups, and viruses let this dressed-up molecule inside, where the nucleotide warhead inhibits HCV by interfering with RNA replication (Antimicrob. Agents Chemother. 2011, 55, 1843).

A few comments on the drug itself: The similarity of the ProTide portion (left-hand side) of the molecule to PSI-7977 really is striking: swap in an isobutyl ester and a phenyl, and it’s the same beast! The more interesting switch comes on the upper-right (“eastern”) part of the structure: a protected guanosine ring. This ring harks back to guanine, one of the four common nucleic acids found in DNA.

Source: J. Med. Chem., Pharmasset

PSI-7977, meanwhile, shows off a uracil, a nucleic acid found in RNA, not DNA.

Although it’s tempting to think such similar compounds all dock into the NS5B polymerase at the active site (in the yellow “palm” of the hand-shaped enzyme), don’t be too sure – a recent paper by Pharmasset scientists (J. Med. Chem. 2012, Just Accepted) shows quite a few “Finger,” “Palm,” and “Thumb” sites.  It’s not yet clear whether all nucleoside drugs bind to the active site in the same way. The authors also remark that, due to fast replication and mutation, potentially resistant strains of HCV pop up daily.

Haystack 2011 Year-in-Review

Well, 2011 is in the books, and we here at The Haystack felt nostalgic for all the great chemistry coverage over this past year, both here and farther afield. Let’s hit the high points:

1. HCV Takes Off – New treatments for Hepatitis C have really gained momentum. An amazing race has broken out to bring orally available, non-interferon therapies to market. In October, we saw Roche acquire Anadys for setrobuvir, and then watched Pharmasset’s success with PSI-7977 prompt Gilead’s $11 billion November buyout.  And both these deals came hot on the heels of Merck and Vertex each garnering FDA approval for Victrelis and Incivek, respectively, late last spring.

2. Employment Outlook: Mixed – The Haystack brought bad employment tidings a few times in 2011, as Lisa reported. The “patent cliff” faced by blockbuster drugs, combined with relatively sparse pharma pipelines, had companies tightening their belts more than normal. Traffic also increased for Chemjobber Daily Pump Trap updates, which cover current job openings for chemists of all stripes. The highlight, though, might be his Layoff Project.  He collects oral histories from those who’ve lost their jobs over the past few years due to the pervasive recession and (slowly) recovering US economy.. The result is a touching, direct, and sometimes painful collection of stories from scientists trying to reconstruct their careers, enduring salary cuts, moves, and emotional battles just to get back to work.

3. For Cancer, Targeted Therapies – It’s also been quite a year for targeted cancer drugs. A small subset of myeloma patients (those with a rare mutation) gained hope from vemurafenib approval. This molecule, developed initially by Plexxikon and later by Roche / Daiichi Sankyo, represents the first success of fragment-based lead discovery, where a chunk of the core structure is built up into a drug with help from computer screening.From Ariad’s promising  ponatinib P2 data for chronic myeloid leukemia, to Novartis’s Afinitor working in combination with aromasin to combat resistant breast cancer. Lisa became ‘xcited for Xalkori, a protein-driven lung cancer therapeutic from Pfizer. Researchers at Stanford Medical School used GLUT1 inhibitors to starve renal carcinomas of precious glucose, Genentech pushed ahead MEK-P31K inhibitor combinations for resistant tumors, and Incyte’s new drug Jakifi (ruxolitinib), a Janus kinase inhibitor, gave hope to those suffering from the rare blood cancer myelofibrosis.

4. Sirtuins, and “Stuff I Won’t Work With  – Over at In the Pipeline, Derek continued to chase high-profile pharma stories. We wanted to especially mention his Sirtris / GSK coverage (we had touched on this issue in Dec 2010). He kept up with the “sirtuin saga” throughout 2011, from trouble with duplicating life extension in model organisms to the Science wrap-up at years’ end. Derek also left us with a tantalizing tidbit for 2012 – the long-awaited “Things I Won’t Work With” book may finally be coming out!

5. Active Antibacterial Development – In the middle of 2011, several high-profile and deadly bacterial infections (Germany, Colorado, among others) shined a spotlight on those companies developing novel antibacterials. We explored front -line antibiotics for nasty Gram-negative E.coli, saw FDA approval for Optimer’s new drug Fidiclir (fidaxomicin) show promise against C. difficile  and watched Anacor’s boron-based therapeutics advance into clinical testing for acne, and a multi-year BARDA grant awarded to GSK and Anacor to develop antibacterials against bioterrorism microorganisms like Y. pestis.

6. Obesity, Diabetes, and IBS – Drugs for metabolic disorders have been well-represented in Haystack coverage since 2010. Both Carmen and See Arr Oh explored the vagaries of Zafgen’s ZGN-433 structure, as the Contrave failure threatened to sink obesity drug development around the industry. Diabetes drugs tackled some novel mechanisms and moved a lot of therapies forward, such as Pfizer’s SGLT2 inhibitors, and Takeda’s pancreatic GPCR agonist. Ironwood and Forest, meanwhile, scored an NDA for their macrocyclic peptide drug, linaclotide.

7. The Medicine Show: Pharma’s Creativity Conundrum – In this piece from October, after Steve Jobs’ passing, Forbes columnist Matt Herper both eulogizes Jobs and confronts a real ideological break between computer designers and drug developers. His emphasis? In biology and medical fields, “magical thinking” does not always fix situations as it might in computer development.

We hope you’ve enjoyed wading through the dense forest of drug development with Carmen, Aaron, Lisa, and See Arr Oh this past year. We here at The Haystack wish you a prosperous and healthy 2012, and we invite you to come back for more posts in the New Year!

ARIAD Presents PACE Data; Provides Potential Gleevec Backup

Sufferers of chronic myeloid leukemia (CML), a rare and tough-to-treat blood cancer, received some good news at the 2011 Americanponatinib Society of Hematology meeting in San Diego this week. On Monday, ARIAD Pharmaceuticals disclosed new results from the Phase 2 PACE trial of its lead drug ponatinib (AP24534). The data (covered by FierceBiotech, Xconomy, and TheStreet), indicate major responses to the drug in ~40% of recipients, even in advanced or refractory (resistant to treatment) CML .

With these numbers in hand, ARIAD enters a tight race, already populated by headliners like Gleevec (imatinib), which in 2001 made a splash as a first-line CML therapy. Drugs such as Gleevec and ponatinib belong to the family of tyrosine kinase (TK) inhibitors, which dock with a mutated protein called Bcr-Abl. This protein (actually a fusion of two distinct proteins via a chromosomal mishap) triggers disease by accelerating blood cell creation, leading to uncontrolled growth and eventually CML.

imatinibSince cancers constantly evolve, new mutations in the TK active site had rendered Gleevec ineffective for certain variations of CML. Many of the PACE trial patients had previously tried newer TK inhibitors, such as Sprycel (dasatinib, BMS) and Tasigna (nilotinib, Novartis), and found that their CML had become resistant due to a single amino acid mutation in the kinase active site, which swapped a polar residue (threonine) for a carbon chain (isoleucine). So, ARIAD chemists decided to develop a drug that borrowed the best points from the earlier therapies, but capitalized on this mutation (A pertinent review in Nature Chemical Biology covers early examples of “personalized” cancer drugs developed for disease variants).

So, how did they accomplish this particular act of molecular kung-fu?  For that, we hit up the literature and go all the way back to . . . 2010. As explained in a development round-up (J. Med. Chem., 2010, 53, 4701), most approved Bcr-Abl inhibitors share several traits: densely-packed nitrogen heterocycles linked to a toluyl (methyl-phenyl) amide, then a highly polar end group, such as piperazine or imidazole. Since the mutation axed a threonine residue, the hydrogen-bond donor adjacent to the ring in earlier drugs was no longer necessary. So, chemists replaced it with a vinyl group.

A computer analysis designed to achieve better binding and drug-like properties suggested an alkyne linker might fit into the mutated active site even better than a vinyl group, so that’s ultimately what ARIAD installed. The program also suggested moving an exocyclic amino group into the aromatic (forming an uncommon imiadzo-[1,2-b]-pyridazine, green in picture). Borrowing the best stuff from other therapies, ARIAD’s chemists also wove in the “flipped” amide and -CF3 motifs (both blue) from nilotinib, as well as the methylpiperazine (red) from imatinib.Binding overlay

With computational rendering (Cancer Cell, 2009, 16, 401) ARIAD scientists could overlay both imatinib and ponatinib in the mutated enzyme’s active site (see picture, right). Notice that unlike imatinib, ponatinib avoids bumping into isoleucine 315. Ponatinib also gets a little extra binding oomph by poking its CF3 group into a hydrophobic pocket near the bottom of the active site.

HCV Followup: Anadys Acquired for Active Antiviral

It’s been a busy six months for new Hepatitis C (HCV) meds: first, Merck and Vertex have their drugs approved in May, and then Pharmasset leaks PSI-7977 clinical data. Now, Anadys Pharmaceuticals has just announced Phase IIb results for its clinical candidate setrobuvir (ANA-598). The pill lowered virus levels to undetectable limits in 78% of patients after 12 weeks of combination treatment with either ribavirin or pegylated interferon. Anadys notes only one major side effect, a rash occurring in 1/3 of the ‘598-treated patients. The therapy targets patients in tough-to-treat HCV genotype 1 (gen1), unlike PSI-7977, which targets gen2 and gen3.

The data seems to have convinced Roche, which acquired Anadys last Monday in all-cash deal analysts say represented a 260% premium over Anadys’s Friday stock closing price. Roche, no stranger to the HCV battle, hopes to integrate setrobuvir into a potential oral drug cocktail with its current suite of polymerase and protease inhibitors.

Setrobuvir interacts with N5SB polymerase at the allosteric “palm” binding site, located in the center of the baseball-mitt shaped enzyme. The drug’s sulfur-nitrogen heterocycle – a benzothiadiazine – is the key to virus inhibition; Anadys has installed the motif in all their HCV inhibitors, going back to their 2005 patents.

Chemists have known about the virus-targeting properties of this heterocycle for a while, but most derivatives have been culled in pre-clinical testing (see J. Antimicrob. Chemoth. 2004, 54, 14-16 for a brief review). Interestingly, chemists initially prepared benzodiathiazines, such as those in Merck’s chlorothiazide (c. 1957, according to the Merck Index), as diuretics, which found use in diabetic treatment. Over the next 40 years, modified medicines treated conditions ranging from epilepsy and cognitive therapy to hypertension and transcriptase regulation. Tweaked benzodiathiazines first showed anti-HIV and anti-CMV activity in the mid-1990s.

One final advantageous wrinkle in this structure: unlike PSI-7977, setrobuvir is not nucleoside-derived. This feature changes its binding behavior, pharmacokinetics, and even its intellectual property strategies, since many current antiviral therapies mimic the nucleosides found in RNA and DNA chains.


Two HCV Meds are Better than One for Pharmasset

An announcement hinting at the possibility of an all-oral hepatitis C treatment had researchers abuzz last week. Pharmasset, a Princeton, NJ company specializing in antiviral discovery, alluded to upcoming conference data that suggested a combination of ribavirin (a generic antiviral) and Pharmasset’s experimental pill PSI-7977 lowered viral counts to near-undetectable levels in a ten-patient trial (kudos to Adam Feuerstein of The Street for initial reports. . . here at The Haystack, editor Lisa Jarvis has also tracked HCV drug development for some time now).

Hepatitis C virus (HCV) is a chronic liver virus with an estimated 180 million infected worldwide. Two relatively new extermination options are available: Merck’s Victrelis (boceprevir) and Vertex’s Incivek (telaprevir), approved by the FDA ten days apart last year. Unfortunately, though both drugs are administered orally, each requires co-administration of injected interferon, which can cause severe fatigue and flu-like symptoms. Both oral drugs inhibit the same enzyme: the NS3 protease, which drags down a patient’s immunity and helps the virus to produce new copies of its proteins.

In contrast, the ribavirin and PSI-7977 combination involves no injections, making it easier for patients to follow the appropriate medication schedule, and lessening side effects. The PSI compound also clips a different target: NS5B polymerase, an RNA enzyme that helps viral genetic replication. In addition, the PSI-7977 is “pan-genotypic,” meaning it inhibits several genetically different strains of HCV.

 A 2010 article (J. Med. Chem. 2010, 53, 7202) details the full story of PSI-7977’s synthesis. Notice anything interesting? It’s really a nucleotide strapped on to a P-chiral prodrug, a “protected” substance the body later converts to the active drug species. This P-chiral motif is seen more often in asymmetric phosphine ligands (compounds that stick to metal catalysts during reactions to modify catalyst activity) than in drug development – often chemists install drug chirality at carbon or sulfur instead. The initial drug lead was actually a mixture of both phosphorus enantiomers (“Sp” and “Rp”), until process chemists realized they could selectively crystallize out the more potent “Sp” product.

In the meantime, Pharmasset scientists haven’t stopped pushing their HCV portfolio forward: a recent paper (J. Org. Chem., 2011, 76, 3782) details a new lead: PSI-352938, a cyclic phosphate prodrug attached to a purine-fluororibose nucleotide warhead. The team credits this new prodrug design with a 10-100-fold increase in potency over the “naked” adenine drug for NS5B RNA polymerase inhibition. PSI-352938 recently completed a multiple ascending dose Phase I trial, in which a daily 200 mg dose brought HCV titres down below the detection limit in 5 of 8 patients. 




Novartis’s Afinitor helps Pfizer’s Aromasin to Delay Breast Cancer

Looks like Afinitor (everolimus), a drug marketed by Novartis for various cancers, may soon have a new indication. Already approved for a variety of diseases – kidney cancer, pancreatic tumors, and organ rejection prevention – Afinitor shows new promise for breast cancer patients. Clinical data released Monday demonstrate marked improvement for hormone-resistant breast cancer patients when Afinitor, an mTOR inhibitor, is used in combination with the aromatase inhibitor Aromasin (exemestane). Patients receiving both drugs delayed disease progression an average of 7 months, versus 3 months for Aromasin alone.

Standard therapy for breast cancer includes treatment with estrogen receptor antagonists, such as Aromasin and tamoxifen, which bind in the estrogen receptor pocket of cancer cells, slowing proliferation (see the excellent NCI website for more information on breast cancer treatment). Aromasin itself has a very similar structure to estrone (a natural body hormone that binds to estrogen receptors) except that it irreversibly modifies the receptor pocket upon binding, making Aromasin a so-called “covalent” or “suicide” inhibitor (see Lila Guterman’s article from Sept. 5, 2011 issue of C&EN for more on drugs that bind for keeps).

Like Aromasin, Afinitor follows the trend of being structurally related to a natural binder of a key cancer target protein. mTOR (mammalian target of rapamycin), the protein target of Afinitor and related macrolides, was first discovered through binding studies using rapamycin, a polyketide natural product found in a soil bacterium from Easter Island (its Polynesian name is Rapa Nui, hence, rapamycin). Rapamycin also goes by the generic name sirolimus, of which so many analogues have been prepared that all go by the catch-all “limus drugs.” The attachment of a hydroxyethyl (CH2CH2OH) tail to rapamycin produces everolimus, which compared to sirolimus demonstrates better pharmacokinetic properties, including higher bioavailability (greater proportion of drug reaching target sites) and a shorter plasma half-life (meaning the drug doesn’t stick around as long, which can help curb toxicity or other side effects).

Note: Please see Sally Church’s post on Pharma Strategy Blog for more info on mTOR pathway biology and coverage of ECCO 2011 conference information regarding everolimus.

Mergers’ Latest Stint In The Hot Seat

Anyone who reads the comments at Derek Lowe’s In the Pipeline knows that drug company mergers are far from favorites among industry researchers. Mergers also took the heat at a pair of high-profile events this month.

At this month’s ACS/Société de Chimie Industrielle panel discussion, former Pfizer Global R&D President John LaMattina laid the blame for ailing pharma pipelines largely on mergers.
From today’s C&EN editorial by Rudy Baum:

LaMattina’s comments focused on the negative impact of mergers and acquisitions on pharmaceutical R&D (Nature, DOI: 10.1038/nrd3514) calling them “a major factor in the decline in R&D productivity.” He pointed out that the Pharmaceutical Research & Manufacturers of America had 42 members in 1988, of which only 11 exist today as independent companies. While there are more than 11 current members of PhRMA, “the fact is , due to industry consolidation as well as some companies dropping their pharmaceutical R&D, there is far less competition in this industry than there was a decade ago.”

“Lilly has announced that they are going to be growing organically, and not through M&A,” Baum says. At the Société event both LaMattina and fellow panelist Ron Breslow of Columbia wished the company well in this strategy, he adds.

LaMattina confirms this, adding via Twitter “I would hope that Pharmas can succeed without the devastating effects of mergers.”

It wasn’t just LaMattina and Breslow calling out mergers. Last Friday, at the Pharmaceutical Strategic Alliances Conference, Bristol Myers Squibb CEO Lamberto Andreotti said that avoiding mergers was part of what’s made his company successful. As tweeted by Pearl Freier, founder of advisory firm Cambridge BioPartners:
PearlF: #PSA11 BMS transform, CEO credits continuity in R+D team working together for 7,8 years + No big mergers in 15 yrs, no disruptions

You can read more about Andreotti’s remarks at Reuters.