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Posts Tagged → Idenix

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.

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 the virus. In other words: there’s still room for at least some of the many compounds in development to treat the infection.

In other potentially good news for a biotech developing HCV drugs, Leerink Swann’s Liang also noted that Roche appears poised to start a Phase III trial for RG7128, a polymerase inhibitor discovered by Pharmasset, by the end of the year. The earlier-than-expected start to the late-stage trial would put the compound in a strong position to be the first polymerase inhibitor approved for HCV.

The Race For the Next Big Thing in HCV

All spring, biotech watchers have been anxiously awaiting Phase III data for two new drugs to treat Hepatitis C, Vertex Pharmaceutical’s telaprevir and Merck’s boceprevir. Both drugs are expected to be approved next year, ushering in a new era in the treatment of HCV. This week’s cover story takes a look beyond that first wave of new drugs for HCV to assess the pipeline of second-generation compounds. After all, improving cure rates by adding a direct-acting antiviral like telaprevir or boceprevir to the current standard of care (PEG-interferon/ribavirn) will be great, but creating a cocktail of small molecules that work on their own would be even better.

As the article notes, everybody wants to be the Gilead Sciences of the HCV market. Gilead has cornered the HIV market with a pill that combines three antivirals in one, and is hoping to unroll a four-in-one pill soon. Only there’s a catch: unlike in HIV, where there is a steady stream of new infections each year, the rate of new infections in HCV has slowed considerably. As such, there will be a flood of patients seeking treatment–and ideally be cured of the disease–over the next decade, after which industry observers expect the patient pool to shrink.

Industry observers expect to see more licensing and M&A activity in the HCV world as companies with antivirals in the late stages of development seek partners with compounds with complementary activity to their own drugs. “Larger companies cannot afford to wait five to six years for clinical development,” says Decision Resources analyst Alexandra Makarova. “Its not even a choice of saving money—either you are late for the bus or not. You have to partner with someobody developing drugs in phase II or late phase I.”

Some deals have already been made, enabling the first studies of combinations of small molecules in the absence of interferon and ribavirin:

-Roche, which has a vested interested in maintaining its leading position in the HCV market, partnered with Pharmasset in 2004 for PSI-6130, a nucleoside polymerase inhibitor that the companies later turned into the prodrug R-7128. Two years later, it snagged InterMune’s ITMN-191, for $60 million upfront and up to $470 million in milestones. The companies will split sales of ITMN-191 down the middle. Roche has already conducted a small clinical trial in New Zealand testing the efficacy of using a combination of R-7128 and ITMN-191 together.

-Gilead has had mixed luck in its deal-making: the company entered into a HCV development with Achillion Pharmaceuticals in 2004, but later killed development of GS-9132 after it had unwanted side effects. In 2008, Gilead ended a four-year HCV collaboration with Genelabs.

-Last year, Vertex bought Virochem for $375 million, giving it access to what is now called VX-222, a non-nucleoside polymerase inhibitor. Vertex recently announced plans to conduct a four-arm trial, with two arms testing the addition of telaprevir and VTX-722 to the standard of care, and two arms testing the effectiveness of giving telaprevir and VX-222 on their own.

-In February, Novartis licensed Debio-025, Swiss biotech Debiopharm’s cyclophilin inhibitor in Phase II trials.

So what’s left? Some companies that have already sold off drug candidates are back with what they say are even better compounds, and other biotechs are trying to jump into the ring. Continue reading →