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Merck Jumps into Antibody-Drug Conjugates With Ambrx Deal

Merck today has jumped into what has become one of the hottest areas in oncology, antibody-drug conjugates, through a deal with San Diego-based Ambrx. Merck will pay $15 million upfront and up to $288 million in milestones for access to Ambrx’s site-specific protein conjugation technology.

Coincidentally, on the cover of today’s magazine, we take a look at the future of antibody-drug conjugate technology. Although people have been working on ADCs for three decades, interest in the approach has reached fever pitch after last year’s approval Seattle Genetics’ lymphoma drug Adcetris and the recent hubbub at ASCO over positive interim Phase III data for Genentech’s T-DM1.

The idea behind ADCs is simple: use a targeted antibody to deliver a highly potent chemotherapeutic to a cancer cell, sparing healthy cells. But current ADC technology has limitations. This week’s cover story looks at efforts to improve upon each component—the antibody, the small molecule, and the “linker” that connects the two.

Ambrx is focused on the antibody, using site specific protein conjugation technology to better control how many and where small molecules are placed on an antibody. Currently, companies manufacturing ADCs (most using technology from Seattle Genetics or ImmunoGen) wind up with a heterogenous product—each ADC has anywhere from zero to eight small molecules attached to the protein, but on average, 3.5 to four small molecule “payloads” linked. The placement of the payloads on the antibody also varies, leading to families of conjugates. As I explain in today’s story, even among the ADCs with four small molecules attached, some have all the cytotoxins clustered in one region, but they might be spread out on others.

Ambrx incorporates a nonnatural amino acid into the antibody to allow precise placement of the drug payload. As I explain:

Ambrx can insert p-acetyl-phenylalanine onto two sites of the antibody. The phenyl- alanine derivative has been modified to include a ketone that acts as a functional group for conjugation to the linker and small molecule.

Although Ambrx can attach more than two chemistry “handles” to the antibody, its studies have shown that two small molecules make the most sense. “You really want to be mindful about preserving the native structures and function of the antibody, while trying to optimize therapeutic activity,” says Chief Technology Officer Ho Cho. “The more you stray away from that, the more risks there are in drug development.”

The beauty of site-specific conjugation, researchers say, is that it allows them to me- thodically determine which ADC variety is the most active. “We can specifically attach whatever payload-linker combo we wish and do quantitative experiments to find out how it works,” Cho says. His team tests biophysical stability, pharmacokinetics, and efficacy to understand how much of the drug can be given before toxicity kicks in.

The ADCs in the current clinical pipeline are all to combat cancer, but Ambrx believes its site-specific conjugation technology will open the door to using ADCs in other therapeutic areas. As Cho told me, the heterogeneous nature of current ADCs has limited their use. “What we’re excited about is taking this into non-oncology indications,” Cho says. “We’ve started to generate some interesting pre-clinical data sets…This is where Ambrx really thinks the field is moving.”

It’s worth noting is that Ambrx was founded by Scripps Research Institute’s Peter Schultz, who Merck recently appointed head of Calibr, a San Diego-based non-profit funded by the big pharma firm that will act as a vehicle for academic scientists to turn their ideas into drug candidates. For more on Calibr, click here.




Epizyme & Celgene to Develop Epigenetics-Based Cancer Drugs

Cambridge, Mass.-based Epizyme has scored $90 million upfront as part of a broad cancer drug development pact with Celgene. The deal adds to a spate of lucrative pacts to find compounds to modulate epigenetic targets, or enzymes that control gene expression without altering the underlying DNA.

As we wrote in last week’s cover story, DNA carries the instructions for assembling all of life’s essential building blocks, but epigenetics dictates how and when that DNA is put to work. Recently, companies have made significant process in understanding the complex biology behind epigenetic processes, while also figuring out how to design compounds that can potently block epigenetic enzymes. With the science and business rationale for pursuing epigenetic targets dovetailing, big pharma and big biotech alike are forging deep ties with the handful of companies with expertise in the field.

Under the three-year deal announced today, Celgene has the right to opt-in to the ex-U.S. rights for any unencumbered histone methyl transferase program at Epizyme. Eisai currently has the rights to Epizyme’s EZH2 inhibitor, while GlaxoSmithKline has a deep collaboration with Epizyme against undisclosed targets that would be excluded from today’s pact with Celgene.

Epizyme says the partnership makes sense because Celgene shares “our vision in oncology and epigenetics,” says Epizyme’s president and CEO Robert J. Gould. “That’s been a fundamental bedrock of our partnering strategy–to partner with people who share our enthusiasm for this space.”

Indeed, Celgene has long played in the epigenetics space, boasting two of the four currently marketed drugs that act on epigenetic targets. However, Celgene’s drugs, Istadax and Vidaza, hit first-generation epigenetic targets. Epizyme’s activities, meanwhile, center on one of the next waves of epigenetic targets: a family of enzymes called histone methyltransferases (HMTs). Of the 96 members of that family, Epizyme has identified roughly 20 HMTs for which there is a clear link to a specific form of cancer, Gould says.  To date, the company has two compounds—the EZH2 inhibitor partnered with Eisai, and a DOT1L inhibitor—in preclinical studies. (Check out last week’s cover story on epigenetics for more on how Epizyme went about discovering those two compounds.)

Celgene is kicking off the pact by opting into the inhibitor of DOT1L, an HMT that is implicated in mixed lineage leukemia, a rare subtype of the blood cancer that the Leukemia and Lymphoma Society says affects about 1,500 new patients in the U.S. each year.

With each program thereafter that Celgene buys into, Epizyme could score up to $160 million in milestone payments.

The cash influx, coupled with the U.S. rights to the programs, “positions us nicely to maintain our independence, but also control our own future as a company,” Gould says. “We now have the runway to go pretty far with these programs.”

That independence is important aspect of Epizyme’s strategy of commercializing its cancer therapies in the U.S., a goal Gould says is attainable because HMT inhibitors will be used in highly specific, genetically-defined patient populations.

The Celgene deal also broadens Epizyme’s scientific horizons, Gould says. “This expands the depth of research we can do around histone methyl transferases specifically…but also gives us the opportunity to imagine what other approaches we might take that might be synergistic or additive to the HMT family.”

Gould is quick to note that in the near term, the company is focused on HMTs “until we prove these compounds are effective in these patients with genetically-defined cancer.”

Between its deals with GSK, Eisai, and Celgene, and its burgeoning pipeline, Epizyme will need to expand its operations. The current headcount stands at about 48, but Gould notes that going forward the small biotech will need to grow out its clinical development organization and, more modestly, its basic research activities.




TEDMED: Andrew Read’s Five Tips For Keeping Superbugs At Bay


Researchers may like to think they’re pretty smart, but you could argue that bacteria have also got some bragging rights. Every day, microbes develop resistance to even the most powerful antibiotics scientists have developed.

Andrew Read thinks evolution is the best lens for staring down the superbugs. He took the stage Thursday at TEDMED, where he warned, “we’re picking a fight with natural selection.”

“Picking a fight without Darwin is like going to the moon without Newton,” Read added. “We are in the dark ages when it comes to evolutionary management.”

Read, director of Penn State University’s Center for Infectious Disease Dynamics, sat down with me on Thursday and shared a few principles he thinks the scientific community should keep in mind in order to keep antibiotic resistance in check. Here are his five tips for would-be superbug slayers. Continue reading →

TEDMED and Alzheimer’s: Gregory Petsko, Reisa Sperling, and the next Al Gore

Petsko (TEDMED)

Gregory Petsko knows why he came to TEDMED. “I’m looking for Al Gore,” he told me flat-out over lunch. Folks who know Petskoknow the former Brandeis University biochemistry department chair isn’t one to mince words. And he’s nailed the reason why an academic might want to look outside traditional conferences and soak up some of the TEDMED aura. He’s looking for a charismatic champion to take up a biomedical cause: in Petsko’s case, it’s support for research in Alzheimer’s disease.

Petsko and Reisa Sperling, director of the Center for Alzheimer’s Research and Treatment at Brigham and Women’s Hospital, talked about Alzheimer’s at TEDMED on Wednesday. Both talks were cast as calls to action. Just consider the introduction Petsko got from TEDMED chair and Priceline.com founder Jay S. Walker: “This is a man who hears a bomb ticking.”

Alzheimer’s statistics are sobering and Petsko used them to dramatic effect. People who will reach 80 by the year 2050 have a 1 in 3 chance of developing the disease if nothing is done, he told the audience. “And yet I hear no clamor,” he said. “I hear no sense of urgency.”

Petsko shared some not-yet-published work with TEDMED’s audience. Continue reading →

Exploring Rational Drug Design

Medicinal chemists strive to optimize molecules that fit snugly into their proposed targets. But in the quest for potency, we often overlook the local physics that govern drugs’ binding to these receptors. What if we could rationally predict which drugs bind well to their targets?

A new review, currently out on J. Med. Chem. ASAP, lays out all the computational backing behind this venture. Three computational chemists (David Huggins, Woody Sherman, and Bruce Tidor) break down five binding events from the point-of-view of the drug target: Shape Complementarity, Electrostatics, Protein Flexibility, Explicit Water Displacement, and Allosteric Modulation….whew!

Selectivity Strategies

Selectivity Strategies for Rational Design | Credit: Huggins, Sherman, Tidor; J. Med. Chem.

Note: Before we dive into this article, let’s clarify a few terms computational drug-hunters use that bench chemists think of differently: ‘decoy’ – a test receptor used to perform virtual screens; ‘ligand’ – the drug docking into the protein; ‘affinity / selectivity’ – a balance of characteristics, or how tightly something binds vs. which proteins it binds to; ‘allosteric’ – binding of a drug molecule to a different site on an enzyme than the normal active site. Regular readers and fans of compu-centric chem blogs such as The Curious Wavefunction and Practical Fragments will feel right at home!

We’ll start at the top. Shape complementarity modeling uses small differences in a binding pocket, such as a methylene spacer in a residue (say, from a Val to Ile swap) to dial-in tighter binding between a target and its decoy. The authors point out that selectivity can often be enhanced by considering a drug that’s literally too big to fit into a related enzymatic cavity. They provide several other examples with a ROCK-1 or MAP kinase flavor, and consider software packages designed to dock drugs into the “biologically active” conformation of the protein.

Electrostatic considerations use polar surface maps, the “reds” and “blues” of a receptor’s electronic distribution, to show how

Affinity Optimization

Affinity Optimization - Black dot represents the optimal minimum energy between Coulombic forces (green) and desolvation penalty (blue) | Credit: Huggins, Sherman, Tidor; J. Med. Chem.

molecular contacts can help binding to overcome the desolvation penalty (the energy cost involved in moving water out and the drug molecule in). An extension of this basic tactic, charge optimization screening, can be used to test whole panels of drugs against dummy receptors to determine how mutations might influence drug binding.

Because target proteins move and shift constantly, protein flexibility, the ability of the protein to adapt to a binding event, is another factor worth considering. The authors point out that many kinases possess a “DFG loop” region that can shift and move to reveal a deeper binding cavity in the kinase, which can help when designing binders (for a collection of several receptors with notoriously shifty binding pockets – sialidase, MMPs, cholinesterase – see p. 534 of Teague’s NRDD review).

But these shifting proteins also swim in a sea of water and other cytoplasmic goodies. This means that drug designers, whether they like it or not, must account for explicit water molecules. The authors even suggest a sort of “on-off” switch for including the bound water molecules, but contend that more efforts should be directed to accurate modeling of water in these protein settings.

Finally, the authors weigh the effects of allosteric binding, the potential for a modeled molecule to be highly selective for a site apart from where the protein binds its native ligand. The authors consider the case of a PTP1B ligand that binds 20Å away from the normal active site, at the previously mentioned “DFG loop.” Since this binding hadn’t been seen for related phosphatases, it could then be used to control selectivity for PTP1B.

In each section, the authors provide examples of modeling studies that led to the design of a molecule. Two target classes recur oftenCOX and HIV inhibitors throughout the review: HIV protease inhibitors (saquinavir, lopinavir, darunavir) and COX-2 inhibitors (celecoxib), which have all been extensively modeled.

Two higher-level modeling problems are also introduced: the substrate-envelope hypothesis, which deals with rapidly mutating targets, and tailoring molecules to take rides in and out of the cell using influx and efflux pumps in the membrane. Since different cell types overexpress certain receptors, we can use this feature to our advantage. This strategy has been especially successful in the development of several cancer and CNS drugs.

Overall, the review feels quite thorough, though I suspect regular Haystack readers may experience the same learning curve I did when adapting to the field-specific language that permeates each section. Since pictures are worth a thousand words, I found that glancing through the docking graphics that accompany each section helped me gain a crucial foothold into the text.

GSK’s R&D Review: Successes & Lessons Learned

Three years after reorganizing its discovery research activities into small, multi-disciplinary units, GlaxoSmithKline is providing a first peek at how its new approach to R&D is faring. A healthy chunk of its year-end earnings presentation yesterday was devoted to discussing the productivity of its research engine, and what can be expected out of its labs in the next three years.

As we described, the goal of its 2008 revamp was to create a biotech-like, entrepreneurial feel within the walls of a big pharma firm:

After being one of the first drug companies to create research hubs, or what it calls “centers of excellence in drug discovery,” GSK last year created “discovery performance units” (DPUs) within each hub. Each of the 38 DPUs operating now has a multidisciplinary team of up to 60 scientists focusing on a therapeutic area, a disease pathway, or some aspect of basic biology.

GSK also formed a “discovery investment board” that makes funding decisions for the research projects in each DPU. The idea is to bring diverse perspectives on the merits of each project: In addition to [GSK R&D head] Slaoui, the board includes a biotech company CEO, a senior public health official, and GSK’s heads of drug discovery, late-stage development, and business development.

DPUs are intended to operate like a biotech company housed in a big pharma firm. Much as a biotech gets funded by venture capitalists, a DPU receives an initial bolus of money and then extra cash when certain project goals are met. Each DPU had an initial review after a year of operation and will undergo another review this month, the 18-month check point. The board meets a last time at the three-year mark.

GSK says there are clear signs that the DPU approach is working. Although the company is spending less on R&D and has raised the bar for moving a drug candidate into late-stage development, it has increased the number of molecules in its late-stage pipeline, Patrick Vallance, GSK’s president of R&D told the Haystack. Under the new R&D regime, 22 molecules have moved into late-stage development, and Vallance wants to see 30 molecules pushed forward in the next three years.

And in what Vallance believes is a sign that scientists are becoming more ambitious and attempting to do genuinely novel early research, roughly 17 publications in came out of GSK’s labs last year. Prior to the DPU approach, basically no papers were being submitted to prestigious journals, he says.

The board, which had its final review in November, decided to shut down three DPUs, and create four new DPUs. Funding for six existing DPUs was upped by more than 20%, while five units saw funding decrease by more than 20%. Overall, 40 DPUs were funded for the next three-year cycle, with a budget that has remained unchanged.

So what has GSK learned at the end of three years? On a practical level, reviewing all projects on the same schedule “is just too complicated,” Vallance says.

And the largest DPUs, which had 60 to 70 scientists, need scaling back in order to maintain their focus, he says. “What some of those units did was filled the activity to meet the number of people rather than the size of the opportunity,” he says. And the number of scientists needed for a DPU is entirely project dependent, “I do think there is an upper limit, beyond which the returns become diminishing,” he adds. “When you get above 60, I don’t think you see more, I think you see less.”

The review process also brought some surprises. Some DPU heads told the board “we don’t think you should reinvest,” either because the project didn’t get as far as originally planned or the scientific problem turned out to be different than they expected, Vallance says. “The confidence of people to say, ‘This isn’t right, cut it and move on to something else,’ was a positive surprise.”

Leaders also came from unexpected places. Vallance points to the case of a bench chemist who came before the board with a proposal for a DPU that was so strong that not only did the project get funded, but the chemist is now heading it up.

Other big phama firms surely keeping a close watch on how GSK fares—and how investors respond to their pipeline progress. Since GSK unveiled the model in 2008, several others have adopted similar strategies.

*story amended on 2/9/12: Patrick Vallance is currently president of R&D for GSK.

Pharma & Biotech Job Cuts Mount in 2012

For those keeping track, yesterday’s layoffs at AstraZeneca add to an already substantial list of cuts in the pharma and biotech industries since the beginning of the year. By our tally, nearly 13,000 job cuts, many in R&D, have been announced so far–and we’re barely into February. Here’s where we’re at (and do let us know if we’ve missed any):

–AstraZeneca is chopping 7,300 jobs, including 2,200 R&D positions, by 2014. Neuroscience research is being revamped and focused on external partnerships; the company’s Montreal R&D site will be shuttered, and research activities ended at its Södertälje site in Sweden.

–Genzyme gave the pink slip to an unspecified number of R&D scientists this week. The layoffs come as Sanofi integrates its big biotech acquisition.

–Alnylam is trimming 61 jobs, or 33% of its workforce, in order to save roughly $20 million this year.

–BioSante Pharmaceuticals is shedding 25% of its staff, or 21 employees and contractors, after disappointing Phase III results for its female sexual dysfunction treatment LibiGel.

–Takeda is axing 2,800 jobs, or 9% of its workforce, following its acquisition of Swiss drugmaker Nycomed. The bulk of the layoffs, which cut across R&D, commercial, operations, and administrative positions, will occur in Europe.

–Novartis unveiled plans to shed some 1,960 positions in the U.S. as it braces for generic competition for Diovan, a blood pressure medicine that brought in more than $6 billion in 2010, and an expected drop in demand for its renin inhibitor Rasilez following questions about the drug’s safety.

–Human Genome Sciences said it would cut 150 jobs, or about 14% of its workforce, in a move that affects manufacturing, R&D, and administrative activities.

–Xoma is shedding 84 workers, or 34% of its staff, as it shifts to outsourcing late-stage and commercial manufacturing, as well as some research.

–SkyePharma is cutting 20% of the 101 employees at its site in Muttenz, Switzerland.

–Sanofi plans to layoff 100 workers at its Monteal site as part of an overhaul of its Canadian operations.

–J&J will trim 126 workers as it closes its Monreal R&D center.

Celgene & Avila Forge Permanent Ties

Today brought a spate of M&A activity in the biotech space, with Amgen unveiling a $1.2 billion bid for Micromet, and Celgene agreeing to pay up to $925 million for Avila Therapeutics. Both deals brought the acquirer a drug in development to treat blood cancers, while also adding a platform technology to their research engines.

Being all about the chemistry, The Haystack is particularly interested in the Celgene/Avila deal, which involves covalent drug development technology. Celgene is paying $350 million upfront, with the promise of up to $195 million more if Avila’s lead covalent drug candidate, AVL-292, reaches the market. Pushing other covalent drugs through the pipeline could garner Avila shareholders another $380 million.

So what is a covalent drug, anyway? As C&EN’s Lila Guterman described last fall, covalent drugs form a permanent link with their target. By comparison, most conventional drugs are designed to reversibly bind to their targets—in other words, they can stick and “un-stick” to a protein.

The beauty of a covalent drug is that its specificity and potency means it can be given in low doses. As Guterman explains, patients only be given enough of the drug for molecule to reach each target protein molecule, and then another dose only when the body has generated more of that target protein. The low dose means less potential for drug-drug interactions and off-target effects.

Indeed, for years, scientists avoided developing covalent drugs out of fear that serious toxicity will arise if a covalent drug happens to permanently stick itself to the wrong protein. Check out Guterman’s piece for a cautionary toxicity tale from none other than “Rule-of-Five” inventor (and former Pfizer researcher) Christopher Lipinski.

The current generation of covalent drugs, however, is designed to assuage those fears through their highly selective and weakly reactive nature. Avila isn’t the only one banking on better molecular design leading to successful drugs: Zafgen’s obesity drug candidate ZGN433 also covalently binds to its target, an approach that—if it works—could enable it to sidestep the side effect issues that have plagued the obesity drug space.

So are these covalent drugs worth the price tag? Avila’s pipeline is relatively young, meaning there isn’t a lot of data to go on: AVL-292 is in Phase I studies in lymphomas; a compound targeting mutant EGFR is also in Phase I trials; meanwhile, two Hepatitis C drug candidates in preclinical studies. The company has also made public preclinical date on its PI3Kα-selective inhibitor (the same target as Intellikine’s INK1117, one of the drivers behind Takeda’s $190 million acquisition of Intellikine.).

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.