Deals Of The Week: Kicking The Tires

Apparently, virtually by the time it became “news,” it transformed into “non-news.” News reports of Roche’s interest in acquiring ultra-rare disease focused Alexion Pharmaceuticals surfaced suddenly July 12 and just as rapidly evaporated the following week, as Wall Street analysts noted the prohibitive premium price and lack of cost-saving synergies.

That doesn’t mean that “tire-kicking” season is over in biopharma, if indeed it ever ends. During a steamy summer season highlighted by the running of the bulls in Spain, the jockeying for position of the bikers in France, and world-class tennis being followed quickly by world-class golf in the U.K., renewed speculation about the fate of cancer specialist Onyx Pharmaceuticals after it it put itself up for sale in in late June surfaced just as the Roche/Alexion story sputtered to an end.

Recall that Amgen got the ball rolling on Onyx speculation with a $120-per-share bid confirmed by Onyx on June 30. Onyx declined the offer but also put itself on the auction block, hoping to attract an even greater price tag. Now, perhaps four or more companies are interested in the oncology firm, possibly including its long-time partner Bayer and competitors in the multiple myeloma space such as Celgene and Takeda.

Media reports also cited Bristol-Myers Squibb and Gilead Sciences as possible suitors, while Pfizer was mentioned as a player, then backed off due reportedly to the price premium. Also not in the running, according to speculation, are Sanofi, GlaxoSmithKline, Novartisand Biogen Idec.

Roche’s reputed interest in Alexion, while understandable because of the Connecticut biotech’s all-out success with Soliris (eculizumab), the highest-priced drug in the world, also is puzzling because of questions about how the Swiss pharma would derive value from such a pricey acquisition. The company has only one commercial product – for a pair of ultra-orphan diseases – albeit a rapidly growing, billion-dollar product, bolstered by an up-and-coming robust pipeline. Reports – unconfirmed – had Roche looking over financing vehicles in order to make a purchase in the range of $25 billion for Alexion.

Deutsche Bank analyst Robyn Karnauskas wrote July 15 that while many European large pharma companies might be able to afford Alexion, they would balk at the price. Roche likely would be better off pursuing “a product/company with more strategic fit or transformational potential,” she said. Projecting Alexion total revenues of $1.7 billion in 2014 and $2.6 billion in 2015, the reported Roche bid would translate into multiples of 15x next year and 10x in 2015, she estimated.

An analyst at UBS Investment Research, Matthew Roden, who covers Alexion, wrote July 15 that the company is an attractive and likely take-out target but would offer few points of potential synergy with Roche. It would be more of a “bolt-on” transaction than a “fold-in” acquisition, he suggested.

“Since the Alexion business model requires a high degree of patient touch and very specialized sales force to reach idiosyncratic PNH (paroxysmal nocturnal hemoglobinuria) and aHUS (atypical hemolytic uremic syndrome) markets, we see limited capability for SG&A cost savings through a deal beyond regulatory structure,” Roden said.

His U.K.-based colleague Andrew Whitney, who covers Roche, noted July 15 that an offer of about $130-per-share for Alexion would represent 35 times the UBS projections for 2014 earnings by the biotech.
So, while Roche/Alexion apparently is not happening and Onyx could end up in the hands of a big pharma, a big biotech or some business model in between, DOTW can offer these transactions that reached the point of signatures along the dotted line …

Spectrum/Talon: Spectrum Pharmaceuticals acquired Talon Therapeutics in the hopes of expanding the indications for Marqibo. The liposomal form of vincristine received accelerated approval from FDA in August 2012 to treat third-line patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL). Spectrum hopes Phase III data to treat newly diagnosed, elderly non-Hodgkin’s lymphoma patients will pan out and lead to an approval in NHL, thereby significantly expanding the potential market for Marqibo. A Phase III trial of Marquibo in newly diagnosed ALL patients also is ongoing. This trial is intended to serve as a confirmatory trial for the accelerated approval. Disclosed on July 17, the deal was slated to close a day later. Spectrum paid $11.3 million in cash, in addition to 3 million of its shares. Spectrum shares closed at $8.77 on July 17. At that price, Spectrum paid $37.6 million in cash and stock, plus contingent value rights (CVRs) worth up to $195 million. CVRs are tied to Marqibo sales milestones and an approval for Menadione, a Phase II topical lotion for the treatment of the skin toxicity associated with epidermal growth factor receptor anti-cancer (anti-EGFR) agents. Spectrum plans to launch Marqibo before early December, with a price point similar to other improved formulations of oncology treatments, like Abraxane, a long-acting, nanotech formulation of paclitaxel, or Doxil, a liposome-encapsulated doxorubicin. Private equity firm Warburg Pincus and hedge fund Deerfield Management recapitalized Talon in 2010, buying at least $69 million in equity in the last three years. - Stacy Lawrence

Pfizer/Sequella: Anti-infective drug specialist Sequella has licensed a mid-stage tuberculosis antibiotic from Pfizer. The privately held Rockville, MD, company acquired worldwide rights to sutezolid, previously known as PNU-100480, for an undisclosed amount. Pfizer previously investigated the oxazolidinone antibiotic in both drug-sensitive and multi-drug resistant tuberculosis, conducting Phase II and pivotal trials in Africa and Russia respectively. Sutezolid complements the Phase II drug SQ109, Sequella’s lead program in Mycobacterium tuberculosis; the company plans to investigate pairing the two in a combination therapy. The 16-year-old company has another TB drug, SQ609, as well as programs in Helicobacter pylori, Clostridium difficile and M. avium paratuberculosis. Sequella traditionally has supported itself by raising capital from hedge funds and other private investors as well as government grants. It also completed a partnership with Maxwell Biotech Venture Fund in 2011, giving the Russian investor territorial rights to SQ109. Pfizer said it is shifting its anti-infective focus from treatment to prevention, and has been seeking to partner drug candidates such as sutezolid. The drug also could be studied in Gram-positive infections such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus, as well as other forms of tuberculosis. – Paul Bonanos

Medtronic/Amgen: Medtronic reps who sell the firm’s interventional spine devices will need to expand their skill set to include drug sales beginning this month. Under a three-year strategic partnership with Amgen, announced July 15, Medtronic will start promoting the biotech's Prolia (denuosumab) to U.S. spine specialists by July 31. Prolia is an FDA-approved biologic for the treatment of postmenopausal women with osteoporosis at high risk for fracture. For Amgen, the deal offers access to Medtronic’s expansive customer base of spine physicians, “who are at the forefront of evaluating and treating women with fractures caused by [postmenopausal osteoporosis],” said Marion McCourt, a VP with Amgen, in a July 15 press release. “This partnership allows us to intervene shortly after an osteoporosis-related fracture has occurred, and encourage therapeutic interventional to help reduce the risk of a subsequent fracture.” The upshot for Medtronic is not as clear cut. Financial terms of the agreement were not disclosed. “This new agreement increases awareness and access to our current base of orthopedic and spine physicians already treating patients with osteoporotic vertebral compression fractures,” said Doug King, president of Medtronic Spine. “Identifying successful treatment options and access to care at the site of service for the growing number of women with osteoporosis at high risk for fracture is our primary objective.” - David Filmore

Royalty/Quest: Quest Diagnostics has divested its stake in the highly-anticipated cancer drug ibrutinib as it continues to refocus its business on information services and simplify its operations. Quest sold the single-digit royalty stream to Royalty Pharma for $485 million, the companies announced July 18. Ibrutinib, an oral Bruton’s tyrosine kinase inhibitor (BTK), is being developed by Pharmacyclics and Johnson & Johnson for the treatment of chronic lymphocytic leukemia, small lymphocytic lymphoma and mantle cell lymphoma. Pharmacyclics submitted an NDA for the drug to FDA on July 10. Earlier this year, the regulatory agency granted the drug its new breakthrough designation, a means of pushing highly-effective drugs through regulatory approval more quickly. The drug is expected to receive a fast track review and could be on the market by early next year. Analysts estimate worldwide peak sales between $2 billion and $3.5 billion. Royalty Pharma buys up royalty streams from other companies – the investment firm has stakes in several of the largest drugs on the market, including AbbVie’s blockbuster rheumatoid arthritis drug Humira (adalimumab), Pfizer’s fibromyalgia pill Lyrica (preagbalin), J&J’s RA drug Remicade (infliximab), Biogen Idec’s recently approved multiple sclerosis pill Tecfidera (dimethyl fumarate), and Merck’s diabetes blockbuster Januvia (sitagliptin). - Lisa LaMotta

Auxilium/Sobi: Auxilium Pharmaceuticals has found a new partner to take over commercialization of its treatment for Dupuytren’s contracture and Peyronie’s disease, Xiapex (collagenase clostridium histolyticum), in Europe after its prior partnership fell through due to slow sales of the drug. Swedish Orphan Biovitrum (Sobi) will take over where Pfizer left off, taking on commercialization of the drug in the 28 EU member countries, Switzerland, Norway, Iceland, 18 Central Eastern Europe/Commonwealth of Independent countries, including Russia and Turkey, and 22 Middle Eastern & North African countries. In exchange for the commercialization rights, Auxilium will receive tiered double-digit royalties on all sales and will be eligible for up to $40 million in milestone payments that are tied to undisclosed sales benchmarks. Pfizer originally signed on to commercialize Xiapex in Europe in 2009. At the time, Pfizer paid Auxilium $75 million upfront, and agreed to pay $150 million in regulatory milestones and $260 million based on undisclosed sales milestones. In addition, Auxilium was to receive increasing tiered royalties based on sales in Pfizer's territories. Pfizer to pull out of the partnership in November 2012, but did not stop promoting the product until the end of March. It will continue supplying the product to physicians until mid-October. - L.L.

Rexahn/University of Maryland, Baltimore: Rexahn Pharmaceuticals has in-licensed a novel drug delivery platform, Nano-Polymer-Drug Conjugate Systems (NPDCS), from the University of Maryland, Baltimore, the company announced July 17. The technology delivers chemotherapeutics directly into tumors, potentially increasing efficacy and reducing toxicity. Rexahn plans to use the technology to develop RX-21101, a preclinical-stage polymer conjugated form of docetaxel. By minimizing the circulating concentration of docetaxel in the blood and maximizing the concentration in the cancer tumor, RX-21101 may increase anti-tumor activity while lowering adverse events. The financials were not disclosed. Rexahn, based in Rockville, Md., has three oncology candidates in clinical development, the lead of which is Archexin, an akt1 inhibitor partnered with Teva Pharmaceutical Industries. - Jessica Merrill

Bausch & Lomb/Mimetogen: Eye-care company Bausch & Lomb has acquired the option to license a Phase II compound for dry eye syndrome from Mimetogen Pharmaceuticals. The compound, MIM-D3, stimulates the production of mucin, which is essential for lubrication of the eye. The drug was shown to be effective and safe in Phase II studies and a late-stage trial is expected to begin before the end of the year. B&L paid Mimetogen an undisclosed option fee and will have the opportunity to pursue development upon Phase III results. At that time, B&L will assume all development costs and will pay Mimetogen development and sales milestones, as well as royalties. Dry eye affects 25 million people in the U.S. alone and tends to affect more people as they age. The global market is currently worth $2.5 billion and is growing at a rate of 10% annually. - L.L.

Alexion/Ensemble: Bringing to a close a week highlighted by Roche’s apparent buyout interest, Alexion signed a drug-discovery collaboration July 18 with Ensemble Therapeutics. Financial terms were not disclosed, but Ensemble gets an upfront payment and research funding, along with potential for development and commercial milestones under the agreement. Ensemble, whose Ensemblin technology platform can produce novel small-molecule candidates to address targets normally addressed by biologic therapies, will screen more than 10 million macrocyles against undisclosed disease drug targets specified by Alexion. Alexion, which focuses on life-threatening, ultra-rare disorders, will have exclusive worldwide rights to develop and commercialize any candidates emerging from the collaboration. Recently hired Executive VP and Head of Global R&D Martin Mackay said this transaction is meant to expand Alexion’s product portfolio. “We seek to broaden the number of pathways toward developing potentially transformative first-in-class drug candidates for patients with selected severe and life-threatening ultra-rare disorders,” he said in a release. - Joseph Haas

Ocera/Tranzyme: Ocera Therapeutics has made its way to the public markets through a reverse merger with the publicly-traded biotech Tranzyme. The new company will focus on developing Ocera’s lead drug, an ammonia scavenger OCR-002 in development for hyperammonemia, the ammonia build-up in the blood when the liver is no longer able to remove toxic substances from the blood. That build-up can cause hepatic encephalopathy, marked by worsening brain function, which eventually can lead to brain swelling, coma and death. Ocera’s investors also committed $20 million in a private placement financing, cash that will see the company through most of a Phase IIb trial testing OCR-002. Becoming a publicly-traded company wasn’t the impetus for the transaction, however, CEO Linda Grais said. “The strategic rationale was really the strength of the combined management team, particularly bringing the clinical development team from Tranzyme together with the program from Ocera,” said Grais. “We realized that this was a team that would take us a long time to build from scratch.” Though Tranzyme’s research was focused in gastrointestinal disease, its Research Triangle Park, NC, team led by Chief Medical Officer Franck Rousseau has extensive experience in liver disease. Before joining Tranzyme, he worked at Gilead asTherapeutic Area Head, Hepatic Diseases and VP Clinical Development. Tranzyme ran into trouble in 2012 when a Phaes III trial in postoperative ileus on lead drug TZP102 failed to meet its primary and secondary endpoints. It began reviewing strategic options early this year. - J.M.

Photo credit: Wikimedia Commons

Deals Of The Week Wonders Whether Heated Competition To Buy Ache Laboratorios Will Muddy The Brazilian Waters

Could a bidding war for Brazil’s privately held Ache Laboratorios do for Latin America what Abbott Laboratories’ gargantuan purchase of part of India’s Piramal Healthcare did for biopharma M&A in India?

Call it the “Piramal effect,” if you will. Abbott reset expectations among India’s domestic pharma world with its $3.72 billion purchase in 2010 of Piramal’s branded generics business. Brazil hasn’t yet seen the kind of blockbuster deal that would raise prices across the board; the highest value deal in that market to date is Sanofi’s $662 million buyout of Brazilian generics firm Medley Pharmaceuticals in 2009.

Sanofi got in early – staking its claim before big pharma’s buying spree in emerging markets generated significant deal inflation – but the deal hardly lifted the value of Brazilian companies across the board. That transaction was followed by smaller deals, such as Takeda’s $251.5 million (BRL 500 million) buyout of Brazilian branded generics specialist Multilab Indústria e Comércio de Produtos Farma about one year ago, which also included potential for up to BRL 40 million in earn-outs.

But, now comes word that could blow all previous Brazilian deals out of the water – Abbott and two of its big pharma competitors, Pfizer and Novartis, are preparing a second round of bids to buy Ache, Brazil’s leader in the sale of prescription drugs. The rumored price tag for Ache, fourth overall domestically in drug sales when over-the-counter products are included, ranges between $4 billion and $5 billion, a matter complicated by talk that at least one of three ownership families does not wish to sell. Ache’s public stance is that it is not up for acquisition.

Ache reported net earnings of $270 million for the 12 months ending Sept. 30, 2012. Nonetheless, a source familiar with the company told Deals of the Week that Ache remains an appealing investment for big pharma due to higher gross margins than its domestic competition, high top-line growth and strong relationships with distributors. In an emerging-markets competition where it is difficult to acquire worthy assets without overpaying, the three pharmas are facing a reality that a price tag above $5 billion – about 20 times EBITDA (earnings before interest, taxes, depreciation and amortization) – may be required just to get a foot in the door.

One pharma executive who asked not to be named told DOTW that his company is so discouraged by prices for assets in the primary emerging markets that it already is looking to next-generation possibilities such as Nigeria and Colombia.

As an article in The Atlantic notes, for overall business climate, Brazil recently has been viewed as the shining jewel of the so-called BRICS nations (Brazil, Russia, India, China, South Africa), with an average real gross domestic product growth rate of 4% between 2004 and 2010, including an eye-opening 7.5% in 2010. Add in low unemployment and a fairly industry-friendly regulatory environment, and Brazil perhaps was positioned to join China as the top emerging market for biopharma.

An early 2013 Business Monitor International report states that total pharmaceutical expenditure in Brazil in 2011 was more than $28.7 billion, and that total was expected to grow by 7.6% in local currency terms in 2012 (while declining in U.S. dollar spending due to exchange-rate fluctuations.) However, the biopharma opportunity in Brazil is being diminished by drug rebates, which are increasing both in total numbers and in size.

Meanwhile, GDP declined 0.9% in Brazil last year, combining with a 6% inflation rate to tarnish the South American giant’s emergence. Outside investment hoping to tap Brazil’s huge population, highlighted by a rising consumer class, faces what is known as “the Brazil cost” – a combination of high tariffs, poor infrastructure and red tape that increase the cost of doing business, the Atlantic reported.

But industry interest in tapping the Brazilian market cannot be denied. A review of Elsevier Business Intelligence’s Strategic Transactions database reveals six major equity investments in Brazilian biopharma holdings this decade. Beside last May’s Takeda/Multilab transaction, these include:

• Valeant Pharmaceuticals paying $28 million in May 2010 for Instituto Terapeutico Delta, a private branded generics and OTC company focused largely on dermatology;
• Pfizer anteing $240 million plus performance-based earn-outs to acquire 40% of generics firm Laboratorio Teuto Brasileiro in October 2010;
• Amgen ponying up $215 million in cash for Bergamo, a hospital-focused company with an emphasis on oncology, in April 2011;
• Merck investing an undisclosed amount in February 2012 to create and own a 51% stake in a Brazilian joint venture with Supera Farma Laboratorios, Cristalia Produtos Quimicos Farmaceuticos and Eurofarma Laboratorios; and
• UCB Group paying an undisclosed sum with potential for performance-based earn-outs to acquire 51% of specialty pharma Meizler Biopharma. The May 2012 deal included an option for UCB to buy out the remainder of the company.

While we await the outcome of the multi-company pursuit of Ache – GlaxoSmithKline reportedly dropped out of the bidding a while back – other biopharma deal-making was completed in the past week as we tally up …

AstraZeneca/AlphaCore: Following through on CEO Pascal Soriot’s promise to rebuild the company’s cardiovascular pipeline, AstraZeneca announced its third cardiovascular deal in two weeks. In the latest tie up, announced April 3, AstraZeneca’s biologics unit MedImmune acquired private biotech AlphaCore Pharma for an undisclosed sum. The big pharma gains ACP-501, a recombinant human lecithin-cholesterol acyltransferase (LCAT) enzyme that is believed to play a major role in removing cholesterol from the body and also may increase levels of high-density lipoprotein (HDL) cholesterol, better known as “good cholesterol.” A Phase I trial testing the drug met its primary safety and tolerability endpoint and also showed that ACP-501 raised HDL cholesterol in patients taking it. The cholesterol space is a high-risk, high-reward area of drug development, given the growing regulatory and commercial hurdles. But Soriot vowed AstraZeneca would embrace risk as a key to unlocking success in the drug-development process during an overview March 21 in which he unveiled his turnaround plan for the company. Cardiovascular disease is one of three core therapeutic areas the company has committed to. In March, the company signed two deals in the field: an option agreement with messenger RNA developer Moderna Therapeutics for up to 40 programs in exchange for $240 million upfront and a research partnership with Sweden’s Karolinska Institute. - Jessica Merrill

Bind Therapeutics/Pfizer: Nanotech company Bind Therapeutics has inked its second deal with a major player this year, signing a collaboration with Pfizer on April 3. Pfizer will pay Bind to combine its Accurins technology with small molecules provided by the big pharma. Pfizer will pay $50 million in upfront and near-term development expenses per molecule and Bind is eligible for $160 million in regulatory and commercial milestones for each product that reaches the market. Bind did not retain any commercialization rights, but will receive tiered royalties on worldwide sales. The company would not reveal the number or kinds of molecules covered by the deal or the therapeutic area of focus, but did say the agreement covers more than one molecule. The Accurins technology has been explored in the areas of oncology, inflammatory diseases like arthritis and cardiovascular indications. In January, Bind announced a similarly sized agreement with Amgen to develop and commercialize kinase inhibitor nanomedicines to treat solid tumors. - Lisa LaMotta

Ra Pharma/Merck: Less than a year after exiting stealth mode, Ra Pharmaceuticals has landed its first partnership, aligning with Merck to help the pharma discover and develop drugs for difficult-to-hit protein targets. Under the agreement announced April 1, Ra will use its proprietary Extreme Diversity platform to find and develop cyclomimetic candidates that can address intracellular protein-protein reactions in multiple undisclosed therapeutic areas. Ra will receive an undisclosed upfront payment and research funding; discovery, development, regulatory and commercialization milestones could bring its full remuneration to $200 million. While the deal stemmed from early conversations between Ra executives and Reid Leonard, head of Merck Research Ventures Fund, it does not include an equity component for the pharma, Ra President and CEO Doug Treco said. It also includes no risk-sharing, such as a co-promotion option down the road. Ra is developing what it terms a new class of drugs, peptide-like molecules offering the diversity and specificity of antibodies along with the attributes of small molecules, such as oral bioavailability. Cyclomimetics, the cyclic polymer drug candidates produced with Ra’s technology, are characterized by their cyclic structure and backbone as well as side-chain modifications that can provide beneficial properties not offered by natural peptides, the company says. It claims that Ra’s platform produces molecules that are highly specific and stable, offering improved cell permeability and potential for increased bioavailability as well as longer half-lives. - Joseph Haas

Astellas/Ambrx: In its latest tie-up with a major pharmaceutical player, Ambrx announced April 5 that it will collaborate with Japanese pharma Astellas Pharma on a series of antibody-drug conjugates (ADCs) in the oncology setting. Astellas will pay the biotech $15 million upfront, as well as $285 million in potential development, regulatory and sales-based milestones to discover and develop an undisclosed number of molecules that use its site-specific ADC technology. Last June, Ambrx inked a deal with almost identical financials with Merck. While details of the targets the companies intended to focus on were not disclosed, it was revealed that they would focus on areas “beyond oncology.” Ambrx also has tie-ups with Eli Lilly and Bristol-Myers Squibb. Previously it had arrangements with Wyeth, Roche and Merck Serono. ADC technology, which allows drugs to be targeted to a specific site carrying a therapeutic payload, have become a hot space since Seattle Genetics got approval of its ADC lymphoma drug Adcetris (brentuximab vedotin) in August 2011. - L.L.

Agios/Foundation Medicine: Agios Pharmaceuticals and Foundation Medicine signed a pact April 4 to use the latter’s clinical assay, FoundationOne, to create diagnostics which could identify ideal patients for Agios’ compounds aimed at cancer metabolism. No financial terms were disclosed. The diagnostic-discovery collaboration will focus on Agios candidates intended to inhibit tumors that carry mutations in the IDH1 and IDH2 metabolic enzymes. The work will seek to identify tumor genomic alterations that would be most likely to respond to Agios’ candidates, and to potentially develop and commercialize companion diagnostics for Agios compounds. Foundation, which developed the FoundationOne genome analysis profiling system for personalized cancer treatment decision-making, raised a $42.5 million Series B financing in 2012 with a syndicate of venture capital and corporate venture outfits. The round was topped off with an additional $13.5 million this past January from individual investors including Bill Gates, Yuri Millner and new board member Evan Jones. Agios, partnered since 2010 with Celgene on cancer metabolism R&D efforts, raised a $78 million Series C round in 2011 and announced plans to branch out therapeutically into rare genetic disorders. - J.A.H.

Novartis/ImmunoGen: ImmunoGen on April 4 updated the status of its 2010 licensing agreement with Novartis to apply the biotech’s Targeted Antibody Payload (TAP) technology platform to create cancer-fighting antibodies for undisclosed targets chosen by the multinational pharma. Under an amendment to the agreement, Novartis has exclusively licensed one compound against a still-undisclosed target, while taking a non-exclusive license to a second compound which can be converted later to an exclusive license. ImmunoGen will receive $4.5 million upfront under the amendment and could earn between $200 million and $238 million in milestones pegged to the two compounds, plus potential sales royalties. Of the upfront money, $1 million is an option exercise fee, while the remaining $3.5 million, which could be credited against future milestone payments, will be paid if Novartis terminates development of one or both compounds. In a same-day note, Cowen & Company analyst Simos Simeonidis called the developments “an incremental positive for ImmunoGen” that helps to validate the TAP platform. In October 2010, Novartis paid $45 million upfront for the license, intended to help it create antibody-drug conjugate (ADC) therapeutics for cancer. The deal offered the potential for up to $200.5 million in milestones for each target leading to development of an ADC, as well as sales royalties on any products reaching market. - J.A.H.

ArQule/Daiichi Sankyo: In our “No-Deal” of the week, collaborators ArQule and Daiichi Sankyo have decided to terminate an early-stage collaboration around Phase I oncology compound ARQ-092. The news comes just months after a Phase III setback of the companies’ later-stage oncology compound tivantinib, which the two companies will continue developing together. Daiichi opted to license ARQ-092 in November 2011 and paid $10 million upfront at the time, as well as Phase I development expenses. ArQule stood to gain $255 million in milestone payments and the deal included development of multiple compounds; the program now has been returned to the Woburn, Mass.-based company. Meanwhile, tivantinib failed to show overall survival in a late-stage trial in non-small cell lung cancer. The drug’s development focus now has been shifted to liver cancer. The partners signed their initial agreement for tivantinib (known then as ARQ-197) in November 2008. Daiichi agreed to pay $60 million upfront, as well as $560 million in milestones to license the c-Met receptor tyrosine kinase inhibitor. - L.L.

Photo Credit: Muddy Amazonia

Deals Of The Week: Vaxxas To Help Shape The Next Generation Of Vaccines

Australian/U.S. biotech Vaxxas came out of stealth mode Oct. 8, announcing a deal with Merck & Co. in which the biotech’s proprietary Nanopatch technology will be tested with Merck vaccines as a delivery vehicle offering potential advantages for ease of administration and potency.

Based on technology developed in the lab of Dr. Mark Kendall at Australia’s University of Queensland, Nanopatch, a patch delivery system said to induce robust immune system activation by targeting vaccine to immunological cells just below the patient’s skin surface, may offer Vaxxas a string of licensing deals, including milestone payments and royalties, similar to a biotech offering small- or large-molecule drug candidates to bigger companies.

“As a vaccine-delivery mode, Nanopatch is capable of delivering a very potent immunogenic response that in some respects is akin to what you’d see in using an adjuvant. We call it a physical adjuvant,” Vaxxas CEO David Hoey told Deals of the Week. “Even though our business model is to partner with companies that are producing vaccines, we believe that use of the patch actually can provide a lot more than simply a delivery vehicle can by making vaccines more potent and perhaps opening new windows for use of vaccines in development.”

Merck and Vaxxas are not disclosing which vaccine will be tested with the technology. The agreement calls for Merck to make an undisclosed upfront payment and R&D funding and then pay potential development and approval milestones plus royalties on commercial sales for a vaccine which Vaxxas will test with the Nanopatch system. Merck gets an option to an exclusive license to produce a vaccine using Nanopatch, meaning that Vaxxas will not partner its technology with another company selling or developing a vaccine for the same indication.

The pharma also gets the option to expand the agreement to two additional vaccine types, although Hoey said exclusivity for additional indications will have to be negotiated between the two companies. “The structure of the initial vaccine candidate agreement is exclusive and has been defined, and the subsequent vaccine candidates have the potential to be exclusive but have not been defined yet,” he said. “At present, we have a landscape of opportunity minus the vaccine field that we’ve licensed under this arrangement with Merck.”

While R&D will continue in Australia at Kendall’s labs, Vaxxas also has opened an 18-person office in Cambridge, Mass., which  will focus on business development. The Boston area was chosen because it offers numerous potential licensing partners for the Nanopatch technology, added Hoey, previously the VP of business development at PathoGenetix.

Vaxxas raised a $15 million Australian (about $16 million) Series A in August 2011 backed by Australian venture capital firms OneVentures and Brandon Capital, U.S. VC firm HealthCare Ventures LLC and an Australian non-profit, Medical Research Commercialisation Fund. It was the largest venture round for an Australian company since anti-infectives biotech Avexa raised $12 million Australian in 2004.

Nanopatch is a stamp-sized device designed for painless vaccination over a period of two minutes. Providing direct access to immune cells in the skin, the self-administered, needle-free vaccine delivery system contains a nano-projection array patch to which the drug is dry-coated, so there is no need for refrigeration. It was tested in animals to deliver a flu vaccine at 1/150 the dose compared with syringe administration and also has been evaluated for vaccines for human papillomavirus, human simplex virus, Chikungunya disease and West Nile virus.

The patches are produced in the same facilities that manufacture chips for cell phones and computers, Hoey said. They are coated with projections a micron in length using a high-density array that can apply thousands to tens of thousands of projections to a single patch. A dry, needle-free delivery system, Hoey said he is confident the technology can work with many different companies’ vaccines without great formulation challenges.

“Most vaccines today are derived as liquids because needles and syringes are the predominant delivery method, however, the work that has been done by Kendall shows that by a pretty standard set of steps you can prepare a vaccine to be deposited and dried down on a patch,” he explained. “There’s a series of excipients that can be added to existing vaccines to make them adaptable in a format suitable for use in conjunction with the patch. So there’s no specific formulation required of the vaccine provider.”

In searching for partners, Vaxxas is not prioritizing certain indications but trying to position itself by sharing data with vaccine makers showing the technology’s potential to increase vaccine potency and offer the possibility of easier dosing, possibly even self-administration. And Vaxxas will not compete with its partners, Hoey said; the firm has no plans to develop its own vaccines using the Nanopatch technology.

Elsewhere, it was a busy week in biopharma deal-making, as we detail in our latest edition of  …

AstraZeneca/Ardelyx: In its first deal under new CEO Pascal Soriot, AstraZeneca is licensing a Phase IIb-ready kidney drug from privately held Ardelyx. Announced Oct. 7, the deal brings AstraZeneca worldwide rights to oral NHE sodium transport inhibitor RDX5791, as well as other compounds in Ardelyx’s NHE3 inhibitor program. The Fremont, Calif.-based biotech receives an upfront payment of $35 million and can earn up to $237.5 million in development and commercial milestones, along with potential double-digit royalties on product sales. NHE3 is sodium-hydrogen antiporter 3, a protein essential to absorption of sodium by the intestines. The two companies believe these compounds can address end-stage renal disease, chronic kidney disease and other disorders related to sodium and fluid overload. Ardelyx has evaluated ‘5791 in a Phase IIa trial in constipation-predominant irritable bowel syndrome as well as a pair of Phase I studies in healthy subjects to determine the compound’s ability to divert sodium absorption from the gastrointestinal tract. The deal gives Ardelyx an option to co-promote ‘5791 in the U.S. AstraZeneca will assume development costs for the drug, while the biotech will conduct Phase IIb studies. - Joseph Haas

Roche/Inception: A drug-hunting venture borne out of the Bristol-Myers Squibb/Amira Pharmaceuticals buyout in 2011 has resulted in a new opportunity for Roche. Under a novel collaboration structure involving big pharma, venture capital and biotech, Inception Science will create a third company – called Inception 3 – to discover and develop small molecule drug candidates for sensorineural hearing loss based on technology licensed from Stanford University. Roche, which will fund Inception 3’s work with milestone-based R&D payments, will hold an option to acquire the program upon the filing of the first IND based on the Stanford technology. Inception’s backer Versant Ventures, meanwhile, will provide the equity financing for the new company, under an agreement announced Oct. 10. Inception, which consists of two current small biotechs (Inception 1 and Inception 2) focused on neurology and oncology, arose from assets spun out by Bristol after it acquired Amira for $325 million upfront in July 2011. Bristol’s focus was on idiopathic pulmonary fibrosis candidate AM152, and it spun out much of Amira’s remaining intellectual property into Inception, backed by Versant and led by former Amira CEO Peppi Prasit, known around the biopharma industry for his “drug-hunting” acumen. The various parties are not disclosing any financial details about the collaboration nor providing a timeline to the potential IND filing at FDA. However, Clare Ozawa, chief business officer at Inception and a former officer at Versant, said the combined capabilities of Inception and Roche should result in rapid progress toward a clinical candidate. “Because we’re combining capabilities across both Roche and Inception, we think we have the fastest ability possible to get to IND stage as quickly as possible,” she said in an interview. - JAH

GlaxoSmithKline/Aeras: The joint development of a tuberculosis vaccine, expected to be of use in addition to BCG vaccine to prevent pulmonary TB, is the aim of a collaboration also announced Oct. 10 between GlaxoSmithKline and Aeras Global TB Vaccine Foundation, the Rockville, Md.-based non-profit TB vaccine development organization. BCG vaccine prevents some forms of TB in infants, but does not prevent pulmonary TB, which accounts for the majority of infections and deaths among adolescents and adults. A new TB antigen, M72, a fusion protein which is compatible with adjuvant containing Agenus Inc.’s QS-21 Stimulon adjuvant, has been developed by GSK, and found in initial clinical trials to induce an immune response and offer an acceptable safety profile. GSK and Aeras have agreed to each provide resources in order for a Phase IIb clinical study to be conducted in Kenya, India and South Africa next year, in healthy adults aged between 18 and 50. Aeras is supporting the development of half a dozen TB vaccine candidates, the most advanced of which is Oxford University’s MVA85A, a candidate vaccine using a modified vaccinia virus as a vaccine delivery system and two other candidates initially developed by Crucell (now Johnson & Johnson) and Sanofi. Aeras is funded by the Bill & Melinda Gates Foundation and other private foundations and governments. - John Davis

UCB/Harvard University: In the third research collaboration to be set up under an alliance forged in 2011, the Belgian mid-sized pharma UCB is to work with Harvard University researchers on exploiting the human intestinal microbiome for therapeutic molecules. The microbiome comprises the 100 trillion bacteria found in each person’s gastrointestinal tract. These bacteria influence the well-being of individuals and their immune systems, and UCB will provide up to $4.5 million to fund the microbiome-related research of three professors of immunology at Harvard: Christophe Benoist, Dennis Kasper and Diane Mathis. They will systematically mine and classify any new species they find in the microbiome, evaluate the impact of the microbiome on the immune system, and look for new immune-modulating molecules with potential therapeutic applications, UCB announced Oct. 10. Several companies, including VC-backed start-ups, already are looking to exploit the microbiome to develop new therapies. In total, UCB expects to spend $6 million in a multi-year agreement to fund specific research projects at Harvard in the fields of central nervous system disorders and immunology. The first project funded was with Prof. Gokhan Hotamisligil, to identify antibodies against an undisclosed target in metabolic diseases. The second, concluded in June 2012, was with cell biology professor Junying Yuan, who was to develop small molecules which induce autophagy. This is the process in which cells ingest intracellular components and offers potential in the treatment of neurodegenerative diseases. - JD

Sanofi/Massachusetts General Hospital: Sanofi is expanding its presence in the Boston research community through a translational medicine collaboration with Massachusetts General Hospital. MGH will work with Sanofi’s oncology division on two preclinical molecules that were discovered in Sanofi’s labs. The teams will include scientists from both organizations and will be “highly collaborative.” Financial terms of the deal were not disclosed, but it will encompass a two-year period during which the compounds are expected to enter the clinic. The deal terms are flexible enough that other molecules may be added to the collaboration in the future and the timeframe of the collaboration may be extended. The focus of the collaboration will be on translational medicine solutions in oncology. “Sanofi Oncology takes a dedicated and integrated translational medicine approach by understanding the problems that doctors and patients are facing, both from the perspective of a pharmaceutical company and that of a diagnostic company,” said Donald Bergstrom, head of translational and experimental medicine at Sanofi Oncology. Bergstrom added that finding biomarkers will be a key part of the collaboration. The researchers will be focusing on which patient groups will benefit best from the drugs being developed and how to design the clinical program to achieve successful results. - Lisa LaMotta

Roche/Lilly/Washington University: Roche and Eli Lilly will see their investigational drugs tested in a large-scale Alzheimer’s disease trial run by Washington University in St. Louis. Roche’s amyloid beta antibody gantenerumab and Lilly’s solanezumab have been chosen by the university’s School of Medicine for testing in a clinical trial to study if the drugs can prevent the loss of cognitive function in people with inherited mutations that cause early-onset Alzheimer’s disease, the university announced Oct. 10. A third drug, a beta secretase inhibitor also developed by Lilly, is under consideration as well. The trial, expected to begin in early 2013, will be conducted by the university's  Dominantly Inherited Alzheimer’s Network Trials Unit , which is funded in part by NIH, the Alzheimer’s Association, and the DIAN Pharma Consortium composed of 10 pharmaceutical companies. The Roche and Lilly drugs were selected from more than a dozen nominations, with each offering a unique approach to counter the effects of amyloid beta, which builds up in the brains of patients with Alzheimer’s disease. All three drugs have been tested in earlier clinical trials to evaluate safety and efficacy. Gantenerumab is in a Phase III trial testing the drug in early-stage Alzheimer’s patients who have not yet experienced symptoms of dementia. Solanezumab has been making headlines recently; it failed in two high-profile Phase III trials in patients with Alzheimer’s disease, but did show signs of efficacy for slowing cognitive decline in a secondary analysis of pooled data. Roche and Lilly will make the treatments available at no cost and provide supporting grants. The Alzheimer’s Association provided a $4.2 million grant. The trial will enroll 160 people with inherited mutations for Alzheimer’s at a point when they would be within 10 to 15 years of the anticipated age when symptoms of cognitive decline and dementia would appear. An additional 80 participants who did not inherit the mutations also will be monitored. - Jessica Merrill

MedImmune/Cancer Research Institute/Ludwig Institute for Cancer Research: MedImmune, the biologics arm of AstraZeneca, has set up a collaboration with two non-profit research organizations, the Cancer Research Institute and the Ludwig Institute for Cancer Research, to collaborate on clinical trials to test combinations of three novel monoclonal antibodies from MedImmune’s pipeline. The partners also said they are open to including promising non-MedImmune novel compounds in the trials. The agreement, announced Oct. 9, calls for Ludwig and CRI, with input from MedImmune, to conduct the trials using yet-to-be determined combinations of the three compounds, and/or other compounds the partners are working on, or other potential partners might offer up. One of the compounds is tremelimumab, which Pfizer gave up on several years ago and which belongs to the same class as Bristol’s successful melanoma treatment Yervoy (ipilimumab), but MedImmune and its collaborators insist that the problem with tremelimumab was due to the clinical trial design, not the compound itself. CRI’s Cancer Vaccine Acceleration Fund, a two-year-old venture philanthropy group set up to invest in and facilitate innovative cancer immunotherapy trials, is funding the trials. MedImmune is supplying the drugs and, depending on results of the clinical trials, plans to commercialize them and make milestone payments to its backers. The biotech also is continuing to develop the compounds separately, based on its original plans. - Wendy Diller

Picture credit: Nano-structure geometry

2010 M&A DOTY Nominee: Celgene/Abraxis Bioscience

It's time for the IN VIVO Blog's Third Annual Deal of the Year! competition. This year we're presenting awards in three categories to highlight the most interesting and creative deal making solutions of the year. The categories are M&A Deal of the Year, Alliance Deal of the Year, and Exit/Financing Deal of the Year. We'll supply the nominations (four or five in each category throughout December) and you, the voting public, will decide the winners (by voting early and often, commencing once we've announced all the nominees). Strap yourselves in, it's The Race for the Roger™.


As we noted a week ago, Celgene hasn't been shy about striking creative deals. The $2.9 billion cash and stock acquisition of Abraxis Bioscience fits the mold, for reasons we'll explain in a minute, but the creativity isn't what makes this deal worthy of a DOTY nomination.

It's actually Celgene's bet itself that intrigues us: after building its bona fides in liquid tumors with Thalomid (thalidomide) and the now-blockbuster Revlimid (lenalidomide), the New Jersey firm is spending nearly $3 billion to expand into solid tumors, an aggressive move at a time when retrenchment (Biogen Idec), reorganization (Genentech, via its parent Roche), desperate defense (Genzyme) and urgent reinvention (Amgen) are the main trends for big biotechs. In late 2007, Celgene's dealmakers high-stepped into the spotlight after years of relative silence, and they haven't relinquished the stage. The Abraxis deal, dollar-wise, is Celgene's largest yet.

For what, exactly? Abraxis' only marketed product is Abraxane, a reformulation of the generic chemotherapy paclitaxel using albumin nanoparticles that's been approved for metastatic breast cancer. It's a modest seller so far -- $360 million in 2009 revenue -- but Celgene sees promise in other solid tumor indications, including a potential submission for use in non-small cell lung cancer in the first half of 2011. Abraxis owns the "nab" nanoparticle delivery technology; whether Celgene puts it to use to reformulate other drugs remains to be seen. Investors at first were befuddled at the June 30 deal announcement, driving Celgene's stock below $50 from a high of $56.58, but they've since come round. Celgene ended trading Thursday, Dec. 16 at $58.79.

Terms of the acquisition were complicated and suggest this was a product Celgene had to have. In the end, Celgene paid $2.5 billion in cash and issued 10.7 million shares of common stock worth $58.21 each, or about $620 million, on Octo. 15, the day the acquisition finally closed.

In addition, Celgene has promised significant earn-outs, or contingent value rights (CVRs), to Abraxis shareholders -- most especially founder Patrick Soon-Shiong (pictured, right). The CVRs include a $250 million cash payment upon approval of Abraxane by FDA for NSCLC with a progression-free survival claim; either a $300 million or $400 million cash payment upon approval of Abraxane by FDA for pancreatic cancer with an overall survival claim; and potential cash royalty payments if Abraxane and certain pipeline drugs reach established sales thresholds.

It's hard to say CVRs are creative deal-making when so many acquisitions these days require them, though in the public markets, unlike the private side, they're still the exception, not the rule. There was an added twist, as well. To get the deal past the finish line, Celgene agreed to make the CVRs tradeable -- in essence, a tracking stock that follows the value of one product, Abraxane. Very few CVRs have ever been converted into tradeable securities, and Soon-Shiong has been involved in two of the most prominent examples as we discuss here.

Industry pundits continue to opine about the wisdom of spending billions for a single asset, but this diversification into solid tumors makes sense for Celgene. Data released at ASH suggests Revlimid may face headwinds in the maintenance setting for multiple myeloma. That could stymie the product's growth, a worrisome fact since it now accounts for 70% of Celgene's total revenue. Celgene wants to be one of the leaders in the increasingly competitive oncology space and it's not afraid to spend money or meet the deal requirements of the companies its courting. That chutzpah deserves your vote for DOTY, if nothing else.

Photo courtesy flickr user health2con.

FDA Thinks Small: Next Steps for Nanotech

When it comes to drug development, the Food & Drug Administration is starting to think small. Really small.

Nanotechnology—the manipulation of matter on the scale of a billionth of a meter—has gotten the attention of FDA regulators. And while nanotech has been mostly used for cosmetics and OTC drugs like high-tech sunscreens, the science is starting to move in the direction of pharmaceutical and biotechnology applications.

As Ellen Licking wrote in a recent issue of START UP, there are a handful of nano-based prescription drug products out on the market, like the aprepitant nanocrystals Merck markets as the antiemetic Emend, and the albumin-coated molecules used in Abraxis Biosciences’ breast cancer drug Abraxane.

And while none of the marketed nano drug products are exactly blockbusters, there are a few drug delivery companies with dreams to change all that by producing next-generation, “me-better” therapies that are safer or more efficacious than existing products. These young upstarts include BIND Biosciences, Tempo Pharmaceuticals and Liquidia Technologies.

Those invested in nanotech have great expectations for the science. Noubar Afeyan, PhD, a managing director with the Boston-based VC firm Flagship Ventures, told START-UP that nanotechnology is a “whole new way of thinking about designing a drug…that hasn’t been available before.” And talk about bullish: David Sarphie, PhD, CEO of Bio Nano Consulting, predicts that by 2015 nanotechnology will play a critical role in the delivery process or development of up to 60% of biopharma products.

Regardless of whether one buys into the nanotechnology hype, FDA sees it as significant enough to take a closer look. An internal task force released a report on nanotech last year, the findings of which will be discussed September 8 at the latest in a series of public meetings on nanotech-y issues. Topics for discussion will include:

(1) The type of information and data that may be needed to demonstrate the safety and effectiveness of FDA-regulated products containing nanoscale materials and;

(2) The circumstances under which a product's regulatory status might change due to the presence or use of nanoscale materials (for example, making a device no longer exempt from 510(k) submission requirements).

Expect some controversy at the meeting. Like other new-tech areas like genetically modified foods, not everyone is thrilled about the prospects for nanotechnology. Do a Google search of “nanotechnology” and “safe,” and you’ll come up with a whole host of organizations that question whether FDA should be keeping tighter control over nanotech.

But there is some concern about whether FDA even has the authority and resources to regulate nanotechnology. Plus, nanotechnology extends into other sectors, like clothing and consumer goods, which raises still more questions. If the agency can regulate some nano products, but not others, will that ultimately damage the prospects for the entire science?

Those questions certainly won’t be resolved anytime soon, but given the interest in really, really small things—as well as new ways to improve upon existing products—the meeting is worth checking out. We'll certainly be there.

A Note on Nanotech and Cancer Diagnostics

Does anyone else sense an increase in the rate at which nanotechnology is being rationally applied to cancer diagnostics? More and more, it seems, researchers are aligning new instrumentation with existing sample preparation and analysis, which should help accelerate commercialization.

In this month’s START-UP, for example, we wrote about a way to differentiate tumors cells from normal cells based on nanomechanical measurements of cell stiffness—a technique that could improve the accuracy of traditional cytology using standard tissue sample prep and may have an immediate opportunity to diagnose mesothelioma, which is not now possible using visual analysis. Now comes a report in the December 20 issue of Nature describing a nanofluidics chip-based method for identifying circulating tumor cells (CTCs).

To be able to capture and preserve the rare and fragile CTCs, the researchers, from Massachusetts General Hospital, fine-tuned the speed and force at which a blood sample passes through their CTC-chip. By so doing, they could consistently extract up to 1000 CTCs from a 10ml blood sample from a cancer patient (other methods max out at one to five CTCs, and can only do that 50% of the time).

The CTC-chip can measure whether the number of circulating tumor cells is rising or falling after therapy, to monitor drug response, and could make monitoring of blood for tumor cells a routine part of a medical exam. And because the analysis is done by placing whole blood onto the chip without the need for any labeling or processing, the chip preserves live intact cells for subsequent analysis, which could help select the best therapy based on the molecular characteristics of the tumor.

“It’s almost like a viral load measure,” says senior author Mehmet Toner of MGH’s Bioelectromechanical Systems (BioMEMS) Resource Center. “We’re always looking at ways to put cells through chips for different purposes. This application was within reach of the technology.” MGH is continuing to demonstrate the chip’s clinical utility. It has also licensed the technology to a California company, Cellpoint Diagnostics.