The Right Kinase, Part II – Roche and Daiichi’s Vemurafenib Approved
Aug24

The Right Kinase, Part II – Roche and Daiichi’s Vemurafenib Approved

Last week, the FDA approved Zelboraf (vemurafenib), co-marketed by Roche and Daiichi Sankyo, for the treatment of melanoma characterized by genetic mutation BRAF V600E, which occurs in a subset of the overall patient population. Treatment of late-stage melanoma patients with Zelboraf increases their survival around five months longer than traditional chemotherapy. Cancer-stricken families believe this extra time justifies the $9400 / month price tag for the treatment, considering the dearth of treatments currently available for these near-terminal patients  (for a more detailed look into the people who brought vemurafenib to market, read Amy Harmon’s New York Times article series from 2010). Vemurafenib went from concept to approval in just six years, lightning-fast for pharma, which usually takes decades to bring a drug to market. So, what’s the secret behind its success? Vemurafenib, developed initially by San Francisco pharma company Plexxikon (acquired in 2011 by Daiichi Sankyo) shows all the hallmarks of rational drug design. Initial screening of a 20,000-member compound library against the ATP-binding site of 3 kinases (Pim-1, CSK, and p38) yielded a 7-azaindole lead structure. This approach, known as fragment-based lead discovery (FBLD) - the concept that a drug can be built up from a tiny piece as opposed to a high-potency binder -  may represent a first for the industry, as pointed out by Dan Erlanson of blog Practical Fragments. Further synthetic modification of this azaindole fragment, supported by computer binding studies, showed that a hydrophobic (nonpolar) pocket on the enzyme surface could best be filled by a difluoro-phenylsulfonamide group. Biochemical assays confirmed that a ketone linker (in place of the 3-aminophenyl group shown above) between the azaindole and the sulfonamide increased potency. Additionally, a 5-chloro residue on the azaindole eventually became a 4-chlorophenyl group; it’s unclear how this relatively non-polar group helps improve binding, since early active-site models suggest it faces out towards the watery cell cytoplasm. How is Zelboraf halting melanoma growth? It all comes down to kinase inhibition, a topic covered with both a story and a Haystack post here at C&EN last year. B-RAF, a common gene overexpressed in melanoma cells, produces a protein kinase that is selectively inhibited by Zelboraf. Once shut off, this pathway reinstates a “lost” negative feedback loop for the BRAF V600E tumor cells, resulting in a cascade failure of growth factors further down the line. Cell growth arrest or apoptosis (cell death) follows, but only for the targeted melanoma cells, with no effect on non-cancerous cells. In an interesting twist, a review published in July shows that inhibitors of Raf kinases (the family of kinases that includes the product of the B-RAF gene) can be developed for...

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Merck Seals Hepatitis C Pact with Roche
May17

Merck Seals Hepatitis C Pact with Roche

Merck is going bare knuckles in the marketing battle for Hepatitis C patients. Just days after receiving FDA approval to market its protease inhibitor boceprevir, now known as Victrelis, it revealed Roche has signed on to co-promote the drug alongside its pegylated interferon drug Pegasys, a cornerstone of HCV treatment. Competition in the HCV arena is expected to be fierce, as Vertex Pharmaceuticals is expected to get the FDA nod to market its own protease inhibitor for HCV telaprevir, to be marketed as Incivek, no later than Monday. Both the Merck and Vertex drugs will need to be taken in combination with the current standard of care, pegylated interferon and ribavirin. Although the two drugs have never gone head to head in the clinic, telaprevir is widely considered to have a better dosing regimen and a slight safety and efficacy edge over Victrelis. As such, analysts have believed that Merck’s main advantage in the HCV market would be its ability to promote Victrelis alongside its own pegylated interferon PegIntron. Now, it will also have Roche’s sales force out there hawking Victrelis with Pegasys, as well. No financials for the deal were announced, so its hard to say at this point how much Merck is giving up in its quest for a bigger piece of the HCV market. It’s also important to note that this is a non-exclusive pact, so time will tell whether Roche and Vertex establish a similar alliance. The deal also allows Merck and Roche to “explore new combinations of investigational and marketed medicines.” As readers will recall, the ultimate goal is to eliminate the need for interferon and ribavirin, which have harsh side effects, and treat HCV using only a cocktail of pills. Roche and Merck each have promising small molecules against HCV in their pipelines: Merck has vaniprevir, an NS3/4a protease inhibitor in Phase II trials, while Roche has the polymerase inhibitor RG7128, the protease inhibitor RG7227, and the earlier-phase polymerase inhibitor RG7432. Read here for past coverage of the race to get new HCV drugs to...

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Roche Cuts Back RNAi Research
Nov17

Roche Cuts Back RNAi Research

As part of sweeping job cuts announced this morning, Roche said it would close down RNAi research at three sites: Kulmbach, Germany; Madison, Wis.; and Nutley, NJ. It seemed worth taking a look at how much money Roche has sunk into RNAi research so far, and where it means for the overall RNAi landscape. Let’s start with the Kulmbach site. Back in 2007, Roche paid Alnylam $331 million in cash and equity for the site, as part of a broad pact covering RNAi drugs for oncology, respiratory diseases, metabolic diseases, and certain liver diseases. The 40 Alnylam employees working at Kulmbach were transferred over to Roche as it made the site its “center of excellence” for RNAi. According to Alnylam’s financial statements, Roche was its largest research collaborator, contributing $14 million last quarter. In 2009, Alnylam recorded $57 million in research revenues from Roche. In a statement this morning, Alnylam said that Roche’s RNAi overhaul “does not fundamentally impact Alnylalm’s financial position nor current or future plans in building its pipeline and advancing RNAi therapeutics as a whole new class of medicines.” Now onto the Madison, Wis., site. In 2008, Roche agreed to pay $125 million for Mirus Bio, which brought the Madison site along with 20 employees. As we described in an earlier article, Mirus had devised an siRNA delivery system called dynamic polyconjugate technology. Which brings us to 2009, when Roche said it would fork over $18.4 million upfront to use Tekmira’s lipid nanoparticle deliver technology to put its RNAi products into the clinic. Mirus' technology was not quite ready for prime time, and Roche wanted to look at another delivery strategy to accelerate product development. When Roche signed that deal, it said the goal was to put its first RNAi-based product into human trials by the end of 2010. In a statement today, Tekmira noted that most of its revenues comes from a manufacturing deal with Alnylam, and it still has broad partnerships with Pfizer, Takeda, and Bristol-Myers. The tally? Upfront payments and the Mirus acquisition bring Roche's investment in RNAi to nearly half a billion dollars in the last three years. That's not taking into account whatever it was spending on development in Nutley, along with research support to Alnylam and, more modestly, to...

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The Right Kinase
Sep09

The Right Kinase

Today I posted a news story about the debut of the structure of PLX4032, a promising melanoma drug developed by Berkeley, California startup Plexxikon. This drug's story has already been given the narrative treatment courtesy of the New York Times. And when the results of a Phase I clinical trial of PLX4032 came out, it got covered in many other news outlets as well. But we here at The Haystack are most interested in PLX4032's chemical backstory. And when I contacted kinase expert Kevan M. Shokat for his opinion on the work, he said the story has another dimension- clues about how to pick the right kinase targets to treat diseases. The kinase enzyme that Plexxikon's experimental drug targets is called B-RAF. It's part of a critical signaling pathway that also includes the kinases MEK and ERK. What's interesting about Plexxikon's stunningly successful early trial (81% of patients taking PLX4032 saw their tumors shrink) is just how well people tolerate the drug, Shokat says. The patients in that 81% success group were taking almost a gram of the stuff, twice daily. This is despite the obvious central importance of the RAF-MEK-ERK pathway, and in contrast to what happens when you block MEK, just one step down the pathway, Shokat says. Compounds that block MEK tend to have what's called a narrow therapeutic index- there's a small window between giving an effective dose and giving a toxic one, he says. So if researchers could understand why such a dramatic difference exists, it could help them make the right kinase choices for other diseases as well, he says. When I spoke with Plexxikon's senior VP of research, Gideon Bollag, he too had interesting things to say about kinases, but our discussion was less about choosing one kinase out of many and more about making the commitment to choosing one at all. "Over the last 10 years or so many of the drugs for cancer have been multitargeted kinase inhibitors, and I think our compound is changing that paradigm," he says. "More selective compounds can be more effective because you can dose higher levels safely," he...

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Aileron & Roche in Stapled Peptides Pact
Aug24

Aileron & Roche in Stapled Peptides Pact

Roche has agreed to pay up to $1.1 billion for access to technology at Aileron Therapeutics, a tiny Cambridge, Mass.-based biotech focused on developing stapled peptides. As part of the deal, Roche and Aileron will develop drug candidates against five targets. Stapled peptides make intriguing drug candidates for their ability to access previously intractable targets. As we’ve described: Protein-embedded α-helices mediate key protein handshakes in cancer, HIV, and other diseases. But actually using an α-helix as a drug has proven tricky. So-called stapled α-helices, boasting sturdy cross-links between nonnatural amino acid side chains, just might change that. This class of stabilized peptides can regulate signaling pathways to subvert cancer. They also appear to overcome several of the usual problems that have hampered the development of peptide drugs. Stapled peptides are locked into the biologically active shape, enabling the drug to penetrate the cell and bind tightly to protein surfaces. Last fall, Harvard chemical biologist and Aileron’s scientific founder Gregory L. Verdine and colleagues showed the helix-stabilizing strategy could be used to turn off the Notch transcription factor complex, a master cell regulator in cancer that has gone awry in over half of patients with a certain type of leukemia. It was the first direct inhibitor of the Notch complex. Aileron gets $25 million upfront and R&D funding, but could score a bounty in milestones if drug candidates against all five targets reach the market. Roche was clearly keeping close tabs on the technology. The Swiss pharma firm’s corporate venture fund was one of several big pharma funds to invest in the $40 million round raised by Aileron last...

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