Trouble Brewing for New HCV Meds
Aug24

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...

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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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BMS-AstraZeneca Dapagliflozin Diabetes Drug Falls Short; Pfizer’s Answer on the Horizon?
Jul29

BMS-AstraZeneca Dapagliflozin Diabetes Drug Falls Short; Pfizer’s Answer on the Horizon?

As reported by Nature News and Forbes’ The Medicine Show  on July 20, dapagliflozin, a BMS-developed diabetes drug marketed with partner AstraZeneca, was given a “thumbs-down” by an FDA review panel on July 19. After the 9-6 final vote, panel members commented favorably on the drug’s new mechanism, but evidently felt that the safety profile could not be overlooked: the FDA committee meeting statement mentions increased risk of breast and bladder cancer, increased genital infections, and perhaps most seriously, potential for drug-induced liver injury (DILI). Dapagliflozin has been one of the rising stars of the new class of Sodium-Glucose cotransporter 2 (SGLT2) inhibitors for diabetes treatment, whose development roster includes Johnson & Johnson, Astellas, Boehringer Ingelheim, Roche, GSK, and Lexicon (Note: see Nat. Rev. Drug Disc. 2010, 551 for a full recap).  The excitement behind these drugs comes from a relatively new idea for diabetes treatment: inhibition of the SGLT2 enzyme stops the kidney from reabsorbing sugar, leading to excretion of the excess glucose in the urine, which in turn lowers blood sugar. Dapagliflozin, like most SGLT2 inhibitors, is a glucose molecule with a large aromatic group attached to the carbon atom in the spot chemists call the anomeric position. Such so-called C-glycosides are thought to have improved staying power in the bloodstream relative to O-glycosides (where the linkage point is at an oxygen atom, a more common scenario in sugars), since they are less susceptible to enzymatic breakdown. So, how do you improve these compounds? A paper Pfizer published last March (J. Med. Chem. 2011, 2952) may offer some hope.  Pfizer noted that some of the C-glycoside SGLT2 inhibitors gave a positive micronucleus test, indicating their potential to damage chromosomes. To work around this liability, their chemists  designed an analog of dapagliflozin where a second hydroxymethyl (CH2-OH) group is “tied” underneath the ring, forming a bicyclic compound that advantageously rigidifies the compound, increasing potency, while at the same time blocking a potential site of reactive metabolite formation (which might contribute to further DILI). The improved compound shows high potency for SGLT2 (~920 pm), a negative micronucleus test, and is now in Phase II  trials. Want to hear more? The lead author of Pfizer's paper, Dr. Vincent Mascitti, will speak about the study as part of the Organic Division program at the ACS National Meeting in Denver - Sunday, August 28, 8:00 AM-8:30AM, Four Seasons...

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This Week in Pharma Job Cuts…
Sep24

This Week in Pharma Job Cuts…

As we know, its tough out there for scientists working in the pharmaceutical and biotech industries. This week brought yet another spate of drug industry cutbacks that seemed worth chronicling. For those keeping track: Abbott Laboratories is getting rid of 3% of its workforce, or about 3,000 jobs, as it folds Solvay’s pharmaceuticals business into its operations. Most of the cuts will come from Europe: 300 jobs will be trimmed in Hannover, Germany; 500 in Weesp, the Netherlands; and Solvay’s U.S. headquarters in Marietta, Ga., will be shuttered. According to SEC filings, certain R&D programs will be discontinued (perhaps they can be auctioned off?). Alnylam Pharmaceuticals, a leader in RNAi technology, is shedding 25-30% of its employees after Novartis decided not to opt-in to a technology licensing clause worth $100 million at the end of a five-year pact between the companies. The biotech raked in $125 million in funding during the lifetime of the pact, and had 25 full-time employees working on projects for Novartis. An interesting tidbit from a conference call held this morning from Alnylam: According to Alnylam’s CEO John Maraganore, Novartis now has 100 people working on RNAi technology at its site in Cambridge, Mass. Clearly they made a commitment to the field with their five-year pact with Alnylam, but somehow the sheer numbers were surprising. Alnylam expects to end the year with $320 million in cash on hand. Bristol-Myers Squibb is cutting 3% of its workforce, estimated at around 800 jobs, as generic competition on its blood thinner Plavix looms. The company had already unveiled plans in 2008 to eliminate about 10% of its workforce, or about 3,700 jobs, by the end of this year. A 2007 cost-savings program had separately targeted 4,350 jobs. Genzyme said last week it would eliminate 1,000 jobs over the next 15 months as it tries to right its manufacturing operations and combat takeover attempts. Lundbeck is shedding 50 R&D jobs amid a reorganization of its R&D operations in Denmark and the U.S. The specialty pharma firm is shifting its focus to three main areas of biology-- neurodegeneration, neuroinflammation and synaptic transmission—related to brain diseases, and will rely more on external partnerships. Merck, meanwhile, appears to be having a tough time making cuts in the Netherlands, where it is essentially ridding itself of Organon’s R&D operations. According to Radio Netherlands, the big pharma firm is now negotiating with the Dutch government over the thousands of jobs slated to be lost in the...

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HCV News Extravaganza
Sep08

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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