The HCV Combo Race Just Got Hotter
Jan13

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. 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...

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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...

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HCV Followup: Anadys Acquired for Active Antiviral
Oct24

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....

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Two HCV Meds are Better than One for Pharmasset
Oct05

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.     ...

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HCV News Extravaganza

Apparently everybody in the hepatitis C race was busy over the holiday weekend, as Tuesday brought a flood of news from the sector. There was good news, bad news, and an acquisition. Last things first: the acquisition. Bristol-Myers Squibb announced it will fork over $885 million for Zymogenetics, its partner in the development of pegylated interferon-lambda, in Phase II trials to treat hepatitis C (HCV). If you’ll recall, last year BMS paid $85 million upfront and a $20 million licensing fee for access to the drug. Under that arrangement, the Seattle-based biotech would have scored up to $430 million in milestones if the therapy actually made it to patients. Given Zymogenetics product pipeline and its one marketed product, Recothrom, the $885 million price tag doesn’t sound so outlandish. Interferon-lambda uses the same cell-signaling pathway as interferon-alfa, one of the two cornerstones of current HCV therapy. But as we wrote earlier this year, because interferon-lambda has fewer functions in the body than interferon-alfa, it is expected to be as effective with milder side effects. Onto the bad news: Idenix Pharmaceuticals said FDA put a clinical hold on two of its hepatitis C drugs, IDX184 and IDX320, due to liver toxicities in a small trial testing the safety of giving both drugs to healthy people. The company’s stock took a beating on the news, with shares falling by 47% to close at $3.18 yesterday. The question now is which of the molecules is causing the elevated liver enzymes. Leerink Swann analyst Howard Liang commented on the issue in a note to investors this morning: “The lack of association between the liver toxicity signals and IDX184 exposure and more extensive safety data on IDX184 would suggest us to that IDX320 is more likely the culprit than IDX184, which is the more important asset in our view.” And the good news (part 1): Vertex Pharmaceuticals released more positive Phase III data for telaprevir, its much-anticipated protease inhibitor for HCV. The drug candidate was tested in some of the toughest patients—those who didn’t respond to or had only a partial response to the standard of care (pegylated interferon and ribavirin) or whose disease relapsed after standard of care. Vertex said 65% of those HCV patients were “cured” when adding telaprevir to the treatment regimen, compared to 17% in the control arm, which was given just the standard of care. Take a look at the company’s press release for more details on each segment of patients, but the relapsers had the most success with treatment, with a smaller portion (31%) of the folks that didn’t respond at all to interferon and ribavirin seeing complete suppression of...

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