Posts Tagged → Pfizer
Today’s issue examines the surge of interest in rare disease drugs, which in the past few years have attracted significant interest from biotech firms, big pharma, and venture capitalists alike. In addition to exploring the business and policy drivers behind increased investment in orphan drugs, the multi-part story looks at the critical role patient organizations play in drawing attention to rare diseases. As such, it seemed worth highlighting advice from various stakeholders on what patient groups can do to entice drug developers to work on their disease:
–Organize yourselves. Find as many patients as possible, and establish a registry that will make it easy for a drug firm to begin a clinical trial. “Beginning to identify people, getting them into a registry, and collecting natural history data is one of the most valuable things a developer can have when they’re thinking about a program,” says Genzyme’s CEO David Meeker. “Among the most helful things that patient advocates can do is to help us to understand the natural history of disease,” agrees Kevin Lee, CSO of Pfizer’s rare disease unit. “Without that understanding of how the disease progresses, and what the endpoints can be, its almost impossible to do drug development.”
–Find a way to collaborate with one another. In even the smallest of diseases, patient groups tend to proliferate. And while its natural and understandable for advocates to want to do all they can to help their own child or family member, it can lead to duplicative efforts. The disparate groups can also make it tougher for drug developers to access. “We all need to give everybody a lot of space here to do what they think is best, but in an optimal world, there are tremendous advantages to being coordinated,” Meeker says.
–Be connectors. Patient organizations have the amazing ability to bring together academics who had previous not collaborated. “What I have found over and over again is that patient advocates know the investigators in their field far better than the investigators themselves do,” says Christopher Austin, director of NIH’s National Center for Advancing Translational Science (NCATS). “They can be instrumental there.”
–Get the right researchers interested. Often only a handful of academic researchers are working on a given rare disease, and drug developers say attracting new scientists into the field, while also giving careful consideration about who to fund is key. Patient groups should look for someone who can use advocacy funds to attract larger grants. “If they can get some grant support, you’ll get more done,” says Emil Kakkis, CEO of Ultragenyx. “If they can’t get any grant support, you’ll have to wonder if it was just because the disease is rare, or another reason.”
–Don’t cut corners. As more patient groups directly fund and organize natural history studies and early clinical trials, they need to make sure the work they support is of the same caliber as that done by biotechs or pharma. “Every data point they generate may some day be helpful in getting a drug approved,” says Philip Reilly, venture partner at Third Rock Ventures.
–Take the reins. With the passage of FDASIA last year, FDA committed to allowing patients more of a seat at the table during regulatory discussions. But the role patient groups will play—how they will be allowed to particulate and how much influence they have—is still to be determined. Ritu Baral, analyst at Canaccord Genuity, thinks there’s opportunity in that vagueness. “Give an inch, take a mile. If they’re going to define it, then we can define it as a patient group,” Baral, who also sits on the board of a disease foundation, says. “We can set the markers where we want to set them.”
–Help drug developers understand your needs. Drug companies are partnering with patient organizations earlier on in the drug process than in the past, convening patient advisory boards to understand how best to design a clinical trial, says Amy Waterhouse, vice president of regulatory affairs at Biomarin. That design ins’t just about regulatory practicalities, but about what families need out of the design in order to participate—a three day visit to a hospital instead of four, for example, can make all the difference. “We learn so much from discussions [with patient groups] that we wouldn’t get from the literature,” Waterhouse says.
As drug companies forge closer ties with academic researchers, the value of pharma-academia partnerships continues to be cause for much debate (see here, here, here, and here for more on that). We’ve watched the evolution of these collaborations with interest, and as part of our ongoing coverage, this week’s issue brings an in-depth look at the mechanics of Pfizer’s Centers for Therapeutic Innovation, its network of academic partners centered on hubs in San Francisco, New York, Boston, and San Diego.
But much of our focus has been on what drug companies can gain from deeper ties with academia. There’s another side to the coin: what the academic lab gains from teaming up with industry. While visiting Pfizer’s Boston CTI, I was glad to have a long chat with Harvard’s Lewis Cantley, known in cancer research circles for the discovery of the PI3K pathway, about why it made sense to link up with Pfizer.
Cantley has had many pharma partnerships, was a founder of Agios Pharmaceuticals, and has sat on the boards of other start-ups. As such, I was curious what made him want to turn to Pfizer for this particular project—developing a drug against a cancer target discovered in his lab–rather than go at it alone, or try to spin out another company.
Cantley conceded that his lab could have plugged away at the target for several years and eventually come up with something promising. But the target requires an antibody, and his lab is more experienced at discovering small molecules. Pfizer, meanwhile, could step in with expertise and technology that they otherwise would never have access to, significantly speeding up the drug discovery process.
Further, Pfizer made teaming up easy. “The legalities of conflict of interest issues and IP issues had all been addressed with negotiations between Harvard and Pfizer before they even solicited proposals,” Cantley says. “To me, this was huge.” He notes that past partnerships with industry have involved at least a year of negotiating before anyone gets down to doing business—or, as it may be, science.
Another positive was that working with Pfizer meant researchers in his lab could continue to be involved with the project. When Cantley became a founder of Agios, which focuses on developing drugs that interrupt cancer cell metabolism, he could no longer ethically allow students in his lab work on that aspect of the science. But under the Pfizer pact, post-docs can continue to explore the drug development as well as any basic biological questions that may arise.
Lastly, Cantley was attracted by the facility with which Pfizer and academic scientists could interact. As it turns out, Cantley’s labs are in the same building as Pfizer’s Boston CTI. “It’s literally two minutes to get from my lab to theirs,” he notes. The seamless exchange of reagents and technologies occurs at a “speed which just doesn’t happen with other industry collaborations,” he says.
Indeed, as the story discusses, Pfizer is banking on that proximity to enable good targets or lead molecules to be quickly moved from the bench to the bedside. The goal is to have three to four compounds in human trials in the next 18 months—a swift turnaround considering the first CTI, a partnership with UCSF and labs in San Francisco, was announced just two years ago.
The evolution of the model for academic-pharma collaboration has been a topic of much discussion as more companies try to tap into university talent for early-stage research (recent examples of collaborations can be found here and here). Industry observers question whether anything tangible will come out of the efforts (see here for a recent critique), believing the divergent missions and cultural differences of each organization inevitably sidelines these pacts.
Pfizer is making one of the more aggressive pushes through its Centers for Therapeutic Innovation. Under the CTI model, Pfizer has set up labs in research hotbeds like Boston and San Francisco, where, through partnerships with various academic institutions, its scientists work side-by-side with university scientists to discover new biologics-based drugs. This week at BIO, I sat down with Tony Coyle, CTI’s chief scientific officer, to talk about CTI’s progress. A more in-depth look at the CTI model will come in the pages of the magazine, but in the meantime, I wanted to share some facts and figures that came out of our chat:
Number of CTIs formed: Four (San Francisco, San Diego, New York, Boston)
Number of academic centers involved: 20
Number of Pfizer scientists across each of its dedicated labs: roughly 100 (Coyle says about 75% were hired from the outside, coming from biotech, academia, with a few from big pharma)
Number of proposals reviewed in the last year: 400
Percentage of proposals overlapping with internal Pfizer efforts: <5%
Number of proposals funded so far: 23
Number of therapeutic areas being studied: 4 (rare diseases, inflammation, cardiovascular disease, and oncology)
Facts and figures aside, Pfizer is trying to move as quickly as possible given the learning curve of teaming with academia. Coyle said he’s promised his bosses that by the third year of the effort, at least four drugs will be in human studies across multiple therapeutic areas. “We’re well on our way to identifying a number of candidates, and I have no doubt that in the next 18 months, we’ll be in our first patient studies,” he added.
Those numbers could change in 2013, when Pfizer potentially expands its CTI outside the U.S. “Ex-U.S is still our ambition,” Coyle says. “2012 has been a period of ‘lets build the group, get the programs and start executing on the pipeline.’ For 2013, we will be and are looking at opportunities ex-U.S., and have had some pretty good discussions to date externally.”
In this week’s issue, I look at the perceived exodus by pharma companies from neuroscience R&D. Between AstraZeneca’s recent cutbacks, the closure of Novartis’ neuroscience research facility in Basel, and earlier moves by GSK and Merck, industry watchers are understandably worried that the neuroscience pipeline will dry up.
One person who isn’t worried is Michael Ehlers, Pfizer’s chief scientific officer for neuroscience research. Ehlers came to Pfizer a year and a half ago from Duke, with the explicit mission to revamp how the company finds and develops drugs for brain diseases. The scientist is convinced that the field is ripe for new and better drugs, and that by staying in the game, Pfizer will be in a good position to capitalize on what he believes will be a healthy flow of new discoveries.
Many drug companies argue that the risk in neuroscience simply doesn’t justify the investment. The overarching sentiment is that the brain is still a black box: good targets are few and far between; clinical trials are long and unpredictable; regulatory approval is tough; and generic competition is plentiful. For many big pharma firms, the math just doesn’t add up.
“I personally don’t find that calculus to give you the total picture,” Ehlers says. Shifting resources away from neuroscience to focus on areas like oncology, where the environment looks favorable—clear clinical trial endpoints, the opportunity for fast-track approval, an easier chance for reimbursement from payors—only makes sense in the short term, Ehlers says. But that thinking “is short sighted as to where the fundamental state of biology is in neuroscience,” he says.
Why is Ehlers so encouraged about a field that so many are walking away from? He believes that neuroscience is poised to benefit from the kind of genetic links that generated so many targets—and eventually so many targeted-drugs—in oncology. “There is going to be kind of a revolution in the next five years—it’s not going to be tomorrow…but you have to think about that inflection of opportunity over the five-to-ten year time horizon.”
To take advantage of each new genetic clue, Ehlers has revamped Pfizer’s approach to neuroscience R&D. As this week’s story explains:
In the past, big pharma often gave its scientists a mandate to work in areas such as Alzheimer’s or schizophrenia, regardless of tractable drug targets. Now at Pfizer, Ehlers says, his team is “indication agnostic.” Any program that Pfizer undertakes must have a critical mass of biological knowledge—for example, human genetics, human phenotyping, and evidence of dysfunctional neurocircuits—to convince Ehlers it’s worth pursuing. “We start there,” he says. “That hasn’t always been the case.”
Moreover, Pfizer no longer relies on mouse models as predictors for responses in humans. “We’ve for the most part stopped all rodent behavior as a model for disease and are much more about what’s happening in the brain,” he says. Scientists measure human responses to prove experimentally that a drug works.
Pfizer’s goal, according to Ehlers, is to tackle fewer projects but have more confidence in their potential for success. The result should be a drug pipeline “rooted in something more than optimism.”
He cites Huntington’s disease as one area that, even before coming to Pfizer, he saw as a prime scientific opportunity. “You know the gene, you know a fair bit about what’s going on, you have a wealth of data, tons of models, a clear clinical course, and an identifiable patient population,” he says. “If we can’t deal with that, we’re in trouble.”
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!
Looks like Afinitor (everolimus), a drug marketed by Novartis for various cancers, may soon have a new indication. Already approved for a variety of diseases – kidney cancer, pancreatic tumors, and organ rejection prevention – Afinitor shows new promise for breast cancer patients. Clinical data released Monday demonstrate marked improvement for hormone-resistant breast cancer patients when Afinitor, an mTOR inhibitor, is used in combination with the aromatase inhibitor Aromasin (exemestane). Patients receiving both drugs delayed disease progression an average of 7 months, versus 3 months for Aromasin alone.
Standard therapy for breast cancer includes treatment with estrogen receptor antagonists, such as Aromasin and tamoxifen, which bind in the estrogen receptor pocket of cancer cells, slowing proliferation (see the excellent NCI website for more information on breast cancer treatment). Aromasin itself has a very similar structure to estrone (a natural body hormone that binds to estrogen receptors) except that it irreversibly modifies the receptor pocket upon binding, making Aromasin a so-called “covalent” or “suicide” inhibitor (see Lila Guterman’s article from Sept. 5, 2011 issue of C&EN for more on drugs that bind for keeps).
Like Aromasin, Afinitor follows the trend of being structurally related to a natural binder of a key cancer target protein. mTOR (mammalian target of rapamycin), the protein target of Afinitor and related macrolides, was first discovered through binding studies using rapamycin, a polyketide natural product found in a soil bacterium from Easter Island (its Polynesian name is Rapa Nui, hence, rapamycin). Rapamycin also goes by the generic name sirolimus, of which so many analogues have been prepared that all go by the catch-all “limus drugs.” The attachment of a hydroxyethyl (CH2CH2OH) tail to rapamycin produces everolimus, which compared to sirolimus demonstrates better pharmacokinetic properties, including higher bioavailability (greater proportion of drug reaching target sites) and a shorter plasma half-life (meaning the drug doesn’t stick around as long, which can help curb toxicity or other side effects).
Note: Please see Sally Church’s post on Pharma Strategy Blog for more info on mTOR pathway biology and coverage of ECCO 2011 conference information regarding everolimus.
Over the weekend Bristol-Myers Squibb and Pfizer announced that their blood-clot-preventing drug candidate, Eliquis (apixaban), bested the workhorse anticoagulant Coumadin (warfarin) in a large clinical trial. The results were announced at the European Society of Cardiology congress and simultaneously published in the New England Journal of Medicine. This is the first time that one of the cadre of anticoagulants seeking to replace warfarin has been shown to be superior to warfarin at preventing dangerous blood clots that can lead to strokes while also having a lower rate of bleeding compared to warfarin.
In the 18,201 patient Phase III clinical trial, called ARISTOTLE, apixaban reduced the risk of stroke in patients with an abnormal heart rhythm called atrial fibrillation by 21 percent, major bleeding by 31 percent, and mortality by 11 percent.
More statistics are available in the announcement, the journal article, and in this Forbes report, which plucks out these illustrative numbers:
The investigators calculated that for every 1000 patients treated with apixaban instead of warfarin for 1.8 years
•stroke would be avoided in 6 patients,
•major bleeding would be avoided in 15 patients, and
•death would be avoided in 8 patients.
Analysts reacted positively to the data, with Leerink Swann analyst Seamus Fernandez raising his 2017 sales estimate for apixaban by $1.1 billion to $4.1 billion in a note to investors.
We’ve previously explained how apixaban works– briefly, it blocks Factor Xa, a protease enzyme near the end of the complex biochemical pathway that regulates blood clotting. Another Factor Xa inhibitor, rivaroxaban, has been approved in Europe but awaits FDA approval. Pradaxa (dabigatran), which blocks the enzyme thrombin, has been approved by FDA for reducing the risk of stroke associated with atrial fibrillation.
So what’s the secret of apixaban’s success? Continue reading →
FDA has given the regulatory nod to crizotinib, Pfizer’s ALK inhibitor that has proven very effective in the small portion of the population whose lung cancer is driven by the protein.
Pfizer says the drug, to be sold under the brand name Xalkori, will cost $9,600 per month, and it will provide assistance so that patient co-pays will not exceed $100. It’s the first in a handful of new drugs Pfizer is counting on to help offset the sales drain when the patent expires this fall on its blockbuster cholesterol drug Lipitor.
The approval is notable as the second drug/diagnostic combo to get the FDA green light in recent weeks—Plexxikon/Roche’s melanoma treatment Zelboraf is the other.
Also notable? We call the compound an ALK-inhibitor, but scientists didn’t start out looking for an ALK-inhibitor. Work on crizotinib originated at Sugen, a South San Francisco-based biotech first bought by Pharmacia, which was later acquired by Pfizer. Sugen chemists were intent on finding a molecule that blocked c-Met, a protein implicated in tumor metastasis. They had already struck upon a promising amino pyridine scaffold by the time their activities were moved into Pfizer’s La Jolla site, where lead optimization took place.
An optimized molecule, billed as a c-Met inhibitor, was put into clinical trials. Then, as we wrote last year, scientific discovery and serendipity converged to change the course of the drug’s development:
Researchers led by Hiroyuki Mano, a professor of functional genomics at Japan’s Jichi Medical University, found that when a certain chromosome inverted, a fusion occurred in lung cancer cells between the echinoderm microtubule-associated proteinlike 4 (EML4) gene and the ALK gene. The researchers found that the fusion caused tumor formation in mice. A subsequent test determined that about 7% of lung cancer patients had this fusion gene. In a paper published in Nature, the researchers concluded that ALK would make a good drug target (Nature 2007, 448, 561).
As it happened, Pfizer had just learned it had an ALK inhibitor on its hands. The company and Massachusetts General Hospital had evaluated results from large biochemical and cell-based screens to see whether crizotinib was hitting targets other than c-Met, says James Christensen, director of translational research in Pfizer’s oncology unit. Upon characterizing the hits, the collaborators found that it was blocking ALK’s activity.
Better, crizotinib was just as good at blocking ALK as it was at shutting down c-Met. Pfizer scientists believe the dual activity is due to a similarity in a residue on each protein. Specifically, both c-Met and ALK have a particular tyrosine within one of the three phosphorylation sites, called the activation loop, which seems to be responsible for the compound’s activity.
All in all, pretty cool science that has translated into a very promising treatment for some lung cancer patients.
As reported by Nature News and Forbes’ The Medicine Show on July 20, dapagliflozin, a BMS-developed diabetes drug marketed with partner AstraZeneca, was given a “thumbs-down” by an FDA review panel on July 19. After the 9-6 final vote, panel members commented favorably on the drug’s new mechanism, but evidently felt that the safety profile could not be overlooked: the FDA committee meeting statement mentions increased risk of breast and bladder cancer, increased genital infections, and perhaps most seriously, potential for drug-induced liver injury (DILI).
Dapagliflozin has been one of the rising stars of the new class of Sodium-Glucose cotransporter 2 (SGLT2) inhibitors for diabetes treatment, whose development roster includes Johnson & Johnson, Astellas, Boehringer Ingelheim, Roche, GSK, and Lexicon (Note: see Nat. Rev. Drug Disc. 2010, 551 for a full recap). The excitement behind these drugs comes from a relatively new idea for diabetes treatment: inhibition of the SGLT2 enzyme stops the kidney from reabsorbing sugar, leading to excretion of the excess glucose in the urine, which in turn lowers blood sugar. Dapagliflozin, like most SGLT2 inhibitors, is a glucose molecule with a large aromatic group attached to the carbon atom in the spot chemists call the anomeric position. Such so-called C-glycosides are thought to have improved staying power in the bloodstream relative to O-glycosides (where the linkage point is at an oxygen atom, a more common scenario in sugars), since they are less susceptible to enzymatic breakdown.
Genentech this week unveiled promising results from a Phase I study suggesting it is possible to safely combine two cancer drug candidates, its MEK inhibitor GDC0973 and its PI3K inhibitor GDC0941. In addition to a relatively clean safety profile, there were also early signs that the combination is combating cancer.
Genentech is one of several companies running a trial to test the safety of combining inhibitors of the lipid kinase PI3K, part of the PI3K/AKT/mTor pathway, and drugs blocking the protein kinase MEK, part of the KRas/MAP signalling pathway. As we discuss in our upcoming April 11th cover story on PI3K inhibitors, the rationale for knocking down both pathways is compelling: both are considered to be crucial in cancer cells’ survival, and blocking only one pathway has more often than not proven ineffective.
As Robert Abraham, CSO of Pfizer’s oncology research unit, explains in Monday’s story:
“KRas mutations are associated with many of the deadliest cancers,” including colorectal and pancreatic, Pfizer’s Abraham says. Yet they are incredibly resistant to conventional chemotherapy, and based on preclinical studies of the mutations, are expected to be resistant to the new batch of mTor/PI3K inhibitors as well, he adds. The working hypothesis is that knocking out two of the major drivers of cancer—the KRas and PI3K pathways—could have a significant effect on the most recalcitrant tumors.
To date, there are at least six Phase I trials planned or ongoing that combine MEK inhibitors with compounds that block some aspect of the mTor/PI3K pathway. Merck and AstraZeneca made headlines in 2009 when they said they would partner to test Merck’s AKT inhibitor with AstraZeneca’s MEK inhibitor. Sanofi-Aventis has meanwhile teamed with Merck Serono to explore the potential of combining two of its PI3K inhibitors in combination with Merck Serono’s MEK inhibitor. GlaxoSmithKline has two of its own drugs in a combination trial, and its MEK inhibitor GSK1120212 is also being tested in combination with Novartis’ PI3K inhibitor BKM120. And while Pfizer has yet to initiate such a study, Abraham said the company is “keeping two eyes on that combination.”
We go into much more detail in Monday’s cover story about the efforts to match PI3K inhibitors with other drugs, and the rationale behind different flavors of compounds (mTor/PI3K inhibitors vs. pan-PI3K inhibitors vs. single-isoform inhibitors). Stay tuned!