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Posts Tagged → Pharmasset

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!

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. 

 

 

 

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 →