Category → Deals
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.
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.
You know you’re at an interesting conference when the director of the NIH starts off his presentation with a guitar duet, and shares a session with Cookie Monster.
But the organizers of TEDMED made a very deliberate decision in opening this year’s conference with Francis Collins. This is the first year that the gathering of medical luminaries, artists, and design gurus (TED stands for Technology, Entertainment, Design) is taking place in Washington, DC, after moving from San Diego. It marks a philosophical shift for the organization, from TEDMED as idea incubator to TEDMED as inserting itself into the national conversation on health and medicine. What better way to do that then bringing in the head of the biggest biomedical funding agency?
Collins wants to compress the time it takes to get a drug development pipeline, and make the pipeline less leaky. This isn’t news to folks around the pharma blogosphere, including here at the Haystack, Ash at Curious Wavefunction and Derek Lowe, who’ve followed last year’s announcement of NIH’s venture for drug discovery, the National Center for Advancing Translational Sciences.
Folks have expressed some concerns about the concept, and its emphasis on the promise of gene-based drug discovery. But, as Derek noted, the fact of the matter is that everyone in drug discovery wants the things Collins wants, so there’s a measure of goodwill for the venture too.
Collins spent his time on the TEDMED stage emphasizing two things: drug repurposing and developing high-tech cellular solutions to supplement and replace often-imperfect animal models.
On the tech side, Collins showcased the Harvard-based Wyss Institute’s lung-on-a-chip, which combines tissue engineering and electronics to mimic the interface between the lung’s air sacs and capillaries (Science, DOI: 10.1126/science.1188302). He said that technologies like this suggest viable alternatives to animal testing are possible.
When New Scientist reported on the lung-on-a-chip in 2010, researchers praised it as a step in the right direction, but cautioned that immortalized cell lines, such as those on the chip, don’t neccesarily behave like primary cells from patients. Collins also noted that it might be possible to use such devices with patients’ own cells someday.
On the repurposing side, Collins cited an article on the topic in Nature Reviews Drug Discovery (DOI: 10.1038/nrd3473), and alluded to lonafarnib (SCH 66336), a farnesyltransferase inhibitor that was originally designed to be part of cancer-treatment cocktails. It didn’t pan out as a cancer drug, Collins said, but now clinical trials are underway to test whether the drug is effective at countering a rare mutation that causes Hutchinson-Guilford progeria, an ailment that leads to rapid aging in children. Collins shared the stage with 15-year-old Sam, a progeria patient.
To bridge the massive gap between ideas and applications in medicine “we need resources, we need new kinds of partnerships, and we need talent,” he told the audience.
In a conversation with reporters after his talk, Collins provided another repurposing story published last month– bexarotene, a retinoid X receptor agonist intended for lymphoma that was just shown to clear amyloid-beta and reverse cognitive deficits in a mouse model of Alzheimer’s (Science, DOI: 10.1126/science.1217697)
At that chat, I asked Collins how the repurposing effort and his call for talent squares with massive layoffs in industry and flat or declining funding.
“It would help if we had a strong foundation of support,” Collins said. He said his agency’s purchasing power has decreased 20% over the last 8 years.
Another reporter asked what was the main obstacle to getting repurposing become habit. “IP,” Collins said. He told reporters that a model intellectual property sharing agreement with pharmaceutical companies has been drafted. Asked if companies had signed on to it, Collins said “we’re working on it.”
Yesterday brought word of a new partnership between Merck & Co. and Scripps Research Institute chemist and biotech entrepreneur Peter Schultz. The two have launched the California Institute for Biomedical Research (Calibr), a San Diego-based not-for-profit that will collaborate with academic investigators to bring drug discovery ideas to the point of proof-of-concept in animals. Merck has kicked in $90 million over seven years to help fund the venture, and will have an option to license any molecule that comes out of it.
C&EN’s news story with all the nitty-gritty details can be found here, but we wanted to follow up with some more insights into the formation of the institute gleaned from talks yesterday with Schultz and Merck’s R&D head Peter Kim.
A burning question I had was how the individual collaborations with academic researchers would be structured. Throughout my coverage of pharma-academia collaborations over the years (see here and here), I’ve repeatedly heard from big pharma that a major hang-up in doing more and better deals is the difference of opinion between the company and the university tech transfer office in the value of an early stage project. Drug companies will say a discovery needs a lot of work, done on their dime, and a university wants to ensure it gets its fair share of the potential sales of a drug.
One benefit of the not-for-profit as intermediary model is that the set up sidesteps what can quickly become contentious negotiations between universities and potential industry partners, Schultz says. “When it gets to a discussion between a university tech transfer office and big pharma, all of a sudden it’s ‘who’s taking advantage of whom’,” Schultz says. Conversely, “it’s really easy for people at, say, UCSF and Berkeley to collaborate.”
At Calibr, the collaboration begins at such an early stage in the discovery process that it offers a straightforward 50/50 split in any gains made down the road. “The whole idea of two not-for-profits with complementary skill sets in a collaboration is to make it simple and move things forward,” Schultz says.
Based on early conversations Schultz and others involved with Calibr have had with potential collaborators, that model seems satisfactory. “People get it,” he adds.
Another question was how quickly Calibr will move forward. Despite a lot of talk of eliminating red tape in some of the more ambitious pharma-academia collaborations, getting things up and running when two different flavors of bureaucracy are involved is no small task.
Schultz says that the first projects to come through Calibr will likely be a result of networking by the institute, its scientific advisory board, and Merck. He expects they will have the capacity to take on 15-20 projects within the first two years. Down the road, Schultz anticipates a more formal proposal process will be put in place.
Merck, meanwhile, believes this model will provide access to the best scientific discoveries out there. Many companies have formed broad collaborations with academic institutions: for example, Pfizer has a network of deep partnerships through its Centers for Therapeutic Innovation; J&J has an oncology pact with MIT’s David H. Koch Institute of Integrative Cancer Research; and AstraZeneca has a close relationship with several departments at Columbia University Medical Center.
That approach is not for Merck, Kim says. “We’re not interested in doing collaborations with entire institutions or departments, but rather we ask ‘Who is the best person in the world who we should be working with?’” he notes. “Calibr enhances that strategy and moves it to the next level. Essentially, any scientist anywhere in the world can tap into Calibr.”
As a side note, Merck’s participation in Calibr was made possible in no small part to the two scientists long-standing mutual admiration. They have known each other since the early 1980s, when Kim was a graduate student at Stanford and Schultz was an assistant professor at UC Berkeley. “There’s a very deep respect here and deep trust,” Kim says. “We’ve been friends–and competitors-for many years.”
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!
GlaxoSmithKline recently announced a contract with the Biomedical Advanced Research and Development Authority (BARDA), a US government preparedness organization (Note: it’s not often pharma-relevant press releases come from the Public Health Emergency website!). The award guarantees GSK $38.5 million over 2 years towards development of GSK2251052, a molecule co-developed with Anacor Pharma a few years back, as a counter-bioterrorism agent. The full funding amount may later increase to $94 million, pending BARDA’s future option.
The goal here is to develop “GSK ‘052”, as it’s nicknamed among med-chemists, into a new antibiotic against especially vicious and virulent Gram negative bacteria, such as the classic foes plague (Yersinia pestis) or anthrax (Bacillus anthracis).
So what’s so special about this molecule? Usually, med-chemists “color” with the same atomic “crayons”: some carbon, sulfur, nitrogen, oxygen, and hydrogen, with a few halogens or transition metals every now and then (luckily, the golden age of mercury and arsenic therapies has largely passed on!). But seeing boron ensconced in a lead molecule rings alarm bells . . . you don’t usually see boron in pharmaceutical scaffolds!
Look closely at GSK’052 (shown above): that’s a boron heterocycle there! Anacor, a company specializing in boron based lead compounds, first partnered with GSK in 2007 to develop novel benzoxaborole scaffolds. This isn’t the first company to try the boron approach to target proteins; Myogenics (which, after several acquisitions, became Millennium Pharma) first synthesized bortezomib, a boronic acid peptide, in 1995.
Stephen Benkovic (a former Anacor scientific board member) and coworkers at Penn State first discovered Anacor’s early boron lead molecules in 2001, with a screening assay. The molecules bust bacteria by inhibiting leucyl-tRNA synthetase, an enzyme that helps bacterial cells to correctly tag tRNA with the amino acid leucine. Compounds with cyclic boronic acids “stick” to one end of the tRNA, rendering the tRNA unable to cycle through the enzyme’s editing domain. As a result, mislabeled tRNAs pile up, eventually killing the bacterial cell.
Inhibition of synthetase function turns out to be a useful mechanism to conquer all sorts of diseases. Similar benzoxaborozoles to GSK ‘052 show activity against sleeping sickness (see Trypanosoma post by fellow Haystack contributor Aaron Rowe), malaria, and various fungi.
Today biopharmaceutical company Anacor announced a partnership with Medicis to discover and develop small molecules to fight acne. Medicis brings its expertise in dermatology and aesthetics treatments to the table (it’s the company behind Juvederm, an injectable wrinkle filler). Meanwhile, Anacor’s mission is developing boron-containing drugs.
Now, you don’t see boron in drugs very often. The first boron-containing drug- Millenium’s Velcade, for multiple myeloma- was approved less than ten years ago. Derek Lowe has mused about why medicinal chemists may have been reticent to check out boron compounds.
But Anacor has built its company on boron chemistry. From its website:
Boron based compounds have a unique geometry that allows them to have two distinct shapes, giving boron based drugs the ability to interact with biological targets in novel ways and can address targets not amenable to intervention by traditional carbon based compounds.
So what’s this mean, exactly? It goes back to general chemistry. Boron has unusual bonding properties. Its outer electron shell, the most important one for chemical bonding, has only three electrons. If it makes three bonds to other atoms, it then has three pairs of electrons in its outer shell. That’s one pair short of what chemists typically consider stable. Still, these electron-deficient boron compounds tend to be pretty stable anyway. They have a flat shape to them chemists call trigonal planar.
But these flat boron compounds have the potential to take in two more electrons. When they come into contact with, say, an oxygen or nitrogen-containing compound rich in electrons, the boron compound forms a new bond, called a dative or coordinate covalent bond. And the molecule changes its shape from flat (trigonal planar) to tetrahedral. Those are the two distinct shapes Anacor is talking about. And the company has made a few chemical tweaks to control this type of boron reactivity.
What’s this have to do with acne? Well, the entire story’s not exactly clear. But we do know that enzymes often use electron rich oxygen, nitrogen, and sulfur motifs to do their business. And we know that Anacor’s antifungal in clinical trials, AN2690, gums up protein production with its distinctive bonding properties.
We also know acne isn’t a completely new area for Anacor. At a 2006 American Academy of Dermatology Conference Anacor presented a compound designed to kill Propionibacterium acnes, a rod-shaped bacterium linked to zits. These bacteria normally dwell on human skin but clogged pores swell their ranks, and the chemicals they secrete (like propionic acid, hence their name) lead to the inflammation and irritation typical of acne.
Antibacterials are already a common acne treatment. But the press release announcing the partnership doesn’t say whether the Anacor/Medicis acne target has to do with bacteria. We’ll surely hear more as the partnership progresses.
More reading: WebMD acne center
Boron-containing inhibitors of synthetases. Chem. Soc. Rev. DOI: 10.1039/c0cs00131g