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Top 5 Game-Changing Drug Delivery Technologies

October 26, 2010 10:14am ET | By Howard Lovy

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It is not enough to invent a potential new miracle drug. If there is no efficient way to get the therapeutic to exactly where it is needed, without harming healthy cells, then the drug is no "miracle" at all. If the drug produces so many unpleasant side effects that patient compliance becomes an issue, development is far from over. This remains true not only with drugs that are in development, but even those that are already on the market. Just because it has been approved by the FDA and is being successfully and safely used by consumers does not mean development of that drug is over. What new delivery methods bring to the table are not only unique ways to continue innovating even after the therapeutic goes off patent, but the ability to give relief to patients who may be suffering from drug side effects. Drug delivery is not just about getting a therapeutic to its target. It's also about finding new materials that can make the journey without interfering with the drug. One of the major problems facing the pharmaceutical industry today is the poor solubility of drugs. So, drugmakers tack on compounds to make it more soluble. Unfortunately, patients read about the side-effects of those soluble

compounds in the often-mocked, ubiquitous "fine print" that drug companies are forced to include in their commercials. The challenge is to find materials that make those side effects disappear. The drug delivery industry is not only alive and well, but could be booming in the near future. Here are the top five technologies catching drugmakers' attention. 1. Oral Thin Films 2. Microneedles 3. Slow release/extended release for addiction 4. Aerosol 5. Liposomes

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Oral Thin Films: Game-Chaning Drug Delivery Technologies


October 26, 2010 10:12am ET | By Howard Lovy

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What are they? Oral thin films are postage-stamp-sized versions of existing drugs that dissolve under the tongue or against the cheek-sort of a high-tech version of the breath strips you can buy at your local convenience store. They can carry very low doses of prescription that are highly uniform and larger doses up to 80 mg. They are emerging as a trend in drug delivery in treatments for everything from Alzheimer's disease to diabetes to erectile dysfunction. What makes it groundbreaking? Oral thin films are easy to swallow without water, especially for pediatric, geriatric and neurodegenerative disease patients where proper dosing can be difficult. In chronic care, thin films give caregivers the ability to medicate regularly without injections. They are also a means of differentiated marketing for offpatent drugs. Who's working on it: Monosol Rx markets PharmFilm, which the FDA has given the goahead for an opioid-dependence drug, Suboxone, which is expected to hit the market after October. The drug was developed jointly by MonoSol Rx and Reckitt Benckiser Pharmaceuticals. MonoSol Rx has a continuing mission to take existing drugs and formulate thin-film versions of them. MonoSol RX has also collaborated, since 2008, with Midatech Group, a UK-based company that designs and synthesizes nanoparticlebased proteins and peptides for therapeutic delivery using pharmaceutical films. Report | Report Applied Pharma Research (APR) and its development partner Labtec have entered into an exclusive licensing agreement with Ferrer Internacional, which will promote and distribute Donepezil Oral Dispersible Film (ODF) in Spain, Portugal and Germany. Donepezil ODF is a thin film formulation for symptomatic treatment of Alzheimer's disease and other types of dementia. Report IntelGenx is developing a thin oral film that delivers INT007, which is the bioequivalent to phosphodiesterase type 5 that is found in leading ED tablets Viagra and Cialis. IntelGenx has announced that it's finished a study that indicates its thin film, called VersaFilm might actually work faster than those leading ED tablets. Report

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Microneedles - Game-Changing Drug Delivery Technologies


October 26, 2010 10:10am ET | By Howard Lovy

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What are they? Microneedles have been highly touted in the drug delivery industry as of late. Hundreds of them can be placed on a single patch. They show promise in delivering flu shots, with other applications in diabetes, pain relief and, in the case of one Chinese company, the eradication of zits using microneedles to unclog pores. They could even deliver quantum dots to deeper layers of skin--useful for diagnosis and treatment of skin cancers, Why is it groundbreaking? They're pain-free because they're so small and do not hit nerve endings, but can still deliver precise amounts of a drug or vaccine. They're great for needle-phobics, since the needles are too small to be seen with the naked eye. As easy to apply as a Band-Aid, microneedles should help improve patient compliance. They help avoid problems like GI irritation and variations in delivery rates due to the presence of food. And they also help

protect health-care workers who would run less of a risk of accidentally poking themselves with larger needles. Who's working on it: China-based Suzhou Natong Bionanotechnology is developing a 5 mm-square "MicroArray" patch that contains about 400 tiny needles with possible applications in diabetes and pain relief in addition to the eradication of zits. A product, LiteClear, is available in China that uses the microneedles to unclog pores. Report Researchers from North Carolina State University think they've found a way to deliver quantum dots into the body using tiny, specially fabricated, hollow microneedles. Report Researchers at Purdue University have developed a pump that can fit in 20-micron-diameter needles, which would go on patches to deliver a wider range of medication than is now possible. Report Georgia Tech and Emory University have tested on laboratory animals a vaccine-delivery patch containing hundreds of microneedles. Report And one imaging company is developing technology that it believes microneedle researchers need. Michelson Diagnostics, based in the U.K., is reporting that its VivoSight OCT imaging system was used to evaluate the performance of a new microneedle drug delivery technology by researchers at Queen's University Belfast. The research by Ryan Donnelly, published in the Journal of Controlled Release, shows how the VivoSight system was used to directly image the microneedles penetrating the skin. Those results helped evaluate how far apart the needles were spaced and how much force is required. Report
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Slow release/extended release for addiction - Game-Changing Drug

Delivery Technologies
October 26, 2010 10:09am ET | By Howard Lovy

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What is it? This is really an extension of older technology, but new materials are opening up new applications to enable sustained release over long periods of time. There are many applications to slow-release technology, but one prominent one is for addiction treatment and prevention. Why is it groundbreaking? All you have to do is follow the news, from your local crime report to celebrities who continuously get in trouble with the law for failing to remain drug-free. Part of the problem is that drugs that begin as painkillers are too easily abused and become gateways to illegal drugs like heroin. The solution? Better drug delivery for painkillers that get the right amount into the system to do the job, but avoid user temptation for abuse. Opioid addicts--including abusers of prescription drugs such as OxyContin--do not get a chance to backslide because they do not have to think about taking the treatment every day. Who's working on it: A drug called Vivitrol has received separate FDA approvals to treat alcohol and opioid addictions through drug-delivery technology by Alkermes called Medisorb, which enables sustained releases over long periods of time. The company says the technology allows us it to encapsulate small molecules, peptides and

proteins in microspheres made of biodegradable polymers with extended-release profiles lasting from days to months. Report Titan Pharmaceuticals' implanted drug-delivery device helped people fight addiction to heroin and prescription painkillers better than a placebo, a company-funded study found. Study participants who used Titan's Probuphine implant had significantly less illicit opioid use, experienced fewer symptoms of withdrawal and craving, stayed in treatment longer and had greater overall improvement. Report
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Aerosol - Game-Changing Drug Delivery Technologies


October 26, 2010 10:07am ET | By Howard Lovy

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What is it? This is not your father's nebulizer. A new range of materials--and nanomaterials--are being developed for pulminary delivery via aerosols, metered dose inhaler systems, dry powder

inhalers or nebulizers. Research into lung delivery is driven by the potential for successful gene therapy for respiratory diseases such as cystic fibrosis. Why is it groundbreaking? Aerosol delivery offers alternative technologies to meds going off patent. According to a recent report in in-PharmaTechnologist, Big Pharma is biting. Recently, "three of the world's largest industry companies" expressed interest in using a platform developed by one company, Stirling, to create inhalable formulations of their drugs. Studies are ongoing on the benefits of aerosol vs. oral for treatment of TB. Who's working on it? Stirling is one of many companies offering alternative delivery technologies to meds going off patent. What Stirling offers is its high density aerosol technology, which promises to provide the same efficacy as drugs taken orally, but with far less active drug content, according to the company. That, the company adds, means fewer side effects. Report Savara Pharmaceuticals, based in Austin, Texas, has caught the attention of investors for its nanoscale powders--called NanoClusters--to take the place of propellants for delivery via oral pulmonary or nasal routes. Report
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Liposomes - Game-Changing Drug Delivery Technologies


October 26, 2010 10:06am ET | By Howard Lovy

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What it is: Artificially made microscopic drug delivery device consisting of a fatty membrane over a hollow "bubble." What make it groundbreaking: This class of drug delivery device is not new. However, recent years have seen such big improvements in these drug-carrying "bubbles" that they might as well be considered as new. Who's working on them: ThermoDox, by drug developer Celsion, was recently granted fasttrack status by the FDA for treatment of primary liver cancer. Celsion's technology involves low heat-activated liposomes, which the company says enables delivery of drugs directly to cancer sites. They call them lysolipid thermally sensitive liposomes (LTSL), and they're being billed by Celsion as "the first in a new generation of liposomes." Report Marina Biotech recently acquired the rights to "Smarticles" technology from Germany's Novosom in exchange for $5 million in common stock. "Smarticles," involve liposomes that can cross cell membranes to deliver to the target and engage the RNA interference pathway. They can also change its surface electric charge to drop off its payload. Report
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Celsion's ThermoDox liver cancer trials

get fast-tracked
August 25, 2010 1:02am ET | By Howard Lovy

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Drug developer Celsion and sufferers of primary liver cancer received some good news from the FDA this week as the Columbia, MD-based company's first drug, ThermoDox, was granted fast-track status. Developed in partnership with Duke University, Celsion's technology involves low heat-activated liposomes, which the company says enables delivery of drugs directly to cancer sites. They call them lysolipid thermally sensitive liposomes (LTSL), and they're being billed by Celsion as "the first in a new generation of liposomes." ThermoDox, enhanced with LTSL, treats primary liver cancer and recurrent chest wall breast cancer. The specially treated liposomes concentrate at the tumor as an external microwave device gently heats the tumor tissue to 42 degrees Celsius over the course of 40 minutes. ThermoDox circulates through the bloodstream, penetrating tumors through vascular leaks. The microwave heat accentuates this leaking, opening the tumor door to more ThermoDox. According to the company, the liposome "melts" only when the microwave heat is present and releases the oncology drug doxorubicin only into the tumor in high concentrations. Celsion says its goal is to improve standard treatment options for difficult-to-treat cancers, including non-resectable hepatocellular carcinoma (HCC), commonly referred to as primary liver cancer. For

liver cancer, the technique is used in conjunction with radio frequency ablation (RFA), which uses uses extremely high temperatures of 80 to 100 degrees Celsius to ablate tumors. RFA may fail to treat the outer margins of larger tumors since temperatures in the periphery are not high enough to destroy the cancer cells. That's where ThermoDox comes in. "We are very pleased to receive the Agency's Fast-Track Designation for ThermoDox," says CEO Michael Tardugno, in a statement. "Fast Track Designation is an acknowledgement that HCC is a significant unmet medical need representing a life threatening disorder. It also recognizes the challenges facing pharmaceutical companies to develop effective new treatments for this difficult disease." ThermoDox is currently being evaluated under a Special Protocol Assessment agreement with the FDA in a 600-patient global Phase III trial in patients with primary liver cancer. Celsion hopes to complete patient enrollment by the end of the year. - read the Celsion release - take a look at more info at clinicaltrials.gov - and see a video of ThermoDox in action

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ProNAi tests 'Smarticles' delivery tech in trials


September 22, 2010 1:40am ET | By Howard Lovy

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Kalamazoo-MI-based ProNAi Therapeutics has launched Phase I clinical trials in Texas for its anti-tumor drug candidate, PNT2258, using a drug delivery technology licensed by Marina Biotech. "We are pleased to move PNT2258 into the clinic and to be able to gain insights into the safety and promise of this novel delivery technology," Dr. Wendi Rodrigueza, vice president of product development at ProNAi, says in a statement. The company says this clinical trial will test the drug on patients with advanced solid tumors for which there are no standard therapies. The drug-delivery technology it uses, called "Smarticles," involves liposomes that can cross cell membranes to deliver to the target and engage the RNA interference pathway. It can also change its surface electric charge to drop off its payload. As we reported at the beginning of August, Marina Biotech acquired the rights to the Smarticles technology from Germany's Novosom in exchange for $5 million in common stock.

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Marina Biotech acquires RNAi delivery technology


August 4, 2010 2:22am ET | By Howard Lovy

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Marina Biotech of Bothell, WA, has added more siRNA IP to its toybox by acquiring the rights to technology from Germany's Novosom in exchange for $5 million in common stock. Development of gene-silencing RNA therapeutics has been delayed for years because of difficulties in finding a delivery device that can slip inside a cell, precisely deliver the therapeutics, then go away harmlessly. In-PharmaTechnologist reports that Novosom has applied its technology to the delivery of antisense, siRNA, LNA and other oligonucleotides. The technology, called "Smarticles," involves liposomes that can cross cell membranes to deliver to the target and engage the RNA interference pathway. It can also change its surface electric charge to drop off its payload. - see the Marina Biotech release - read the in-PharmaTechnologist report - a more technical description can be found on the RNAi therapeutics blog

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Marina Biotech Acquires RNA Delivery Assets of Novosom AG


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Marina Biotech Acquires RNA Delivery Assets of Novosom AG Patent Rights to SMARTICLES(R) Technology Strengthens Marina's Intellectual Property Position and Further Expands Its siRNA Delivery Technologies BOTHELL, WA, Jul 28, 2010 (MARKETWIRE via COMTEX) -- Marina Biotech, Inc. (NASDAQ: MRNAD) announced today that the Company has acquired the intellectual property of Novosom AG of Halle, Germany for its SMARTICLES(R) liposomal-based delivery system in an all-stock transaction. The transaction further expands Marina's RNA delivery platform IP estate, which now includes DiLA2 delivery platform, tkRNAi (bacterial delivery platform), peptide nanoparticle delivery platform, and the SMARTICLES(R) liposomal delivery platform. This acquisition significantly broadens the number of approaches Marina may take for systemic and local delivery of its proprietary UsiRNA therapeutics. The assets were acquired by Marina for approximately $5 million in unregistered Marina common stock. Additional terms of the agreement were not disclosed. "We are pleased to have acquired the SMARTICLES(R) intellectual property estate of Novosom," stated J. Michael French, President and CEO of Marina Biotech. "We believe that this technology and intellectual property estate, resulting from years of hard work and diligent IP prosecution on the part of Novosom, is a significant addition to our existing RNA delivery platforms and the IP estate of Marina Biotech. We plan to take full advantage of our new IP position by expanding our existing delivery capability to develop additional novel formulations for safe and effective systemic and local delivery of RNAibased therapeutics."
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The acquired Novosom patent estate represents a global portfolio

including 42 issued or allowed patents and 31 pending patent applications providing broad coverage for liposomal delivery formulations, lipid compounds and nucleic acid chemistry. "We believe the team at Marina Biotech is best positioned to further develop and exploit the advantages of the SMARTICLES(R) siRNA delivery platform," stated Elias Papatheodorou, Chief Executive Officer of Novosom, AG. "The addition of this technology to the expanding capability of Marina provides a truly unique opportunity in the sector to advance multiple RNAi-based therapeutics to the market." Novosom's SMARTICLES(R) define a novel class of liposomes: fully charge-reversible particles. Novosom's liposomal vectors allow delivery of active substance (siRNA, antisense, decoy, etc.) inside the cell either by local or systemic administration. SMARTICLES(R) are designed to ensure: (1) stable passage through the bloodstream and (2) release of the nucleic acid payload within the target cell where it can engage the RNA interference pathway and exert its therapeutic effect. Canaccord Genuity served as Marina's financial advisor on this transaction and Ferghana Partners Group served as Novosom's financial advisor. About Marina Biotech, Inc. Marina Biotech (formerly known as MDRNA, Inc.) is a biotechnology company, focused on the development and commercialization of therapeutic products based on RNA interference (RNAi). Marina's pipeline currently includes a clinical program in Familial Adenomatous Polyposis (a precancerous syndrome) and two preclinical programs -in hepatocellular carcinoma and bladder cancer. Marina's goal is to improve human health through the development of RNAi-based compounds and drug delivery technologies that together provide superior therapeutic options for patients. Additional information about Marina Biotech is available at http://www.marinabio.com.
Forward-Looking Statements Statements made in this news release may be forward-looking statements within the meaning of Federal Securities laws that are subject to certain risks and uncertainties and involve factors that may cause actual results to differ materially from those projected or suggested. Factors that could cause actual results to differ materially from those in forward-looking statements include, but are not limited to: (i) the

ability of Marina Biotech to obtain additional funding; (ii) the ability of Marina Biotech to attract and/or maintain manufacturing, research, development and commercialization partners; (iii) the ability of Marina Biotech and/or a partner to successfully complete product research and development, including preclinical and clinical studies and commercialization; (iv) the ability of Marina Biotech and/or a partner to obtain required governmental approvals; and (v) the ability of Marina Biotech and/or a partner to develop and commercialize products that can compete favorably with those of competitors. Additional factors that could cause actual results to differ materially from those projected or suggested in any forward-looking statements are contained in Marina Biotech's most recent periodic reports on Form 10-K and Form 10-Q that are filed with the Securities and Exchange Commission under MDRNA Inc. Marina Biotech assumes no obligation to update and supplement forward-looking statements because of subsequent events. Contacts: Pete Garcia Chief Financial Officer 3603 pgarcia@marinabio.com (425) 908-

Westwicke Partners (Investors): Stefan Loren, Ph.D. (443) 2130507 sloren@westwicke.com John Woolford (443) 2130506 john.woolford@westwicke.com McKinney|Chicago (Media): Alan Zachary (312) 944-6784 316 or 707-6834 azachary@mckinneychicago.com SOURCE: Marina Biotech, Inc. (708)

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THURSDAY, JULY 29, 2010

Marina Biotech Continues to Drive Sector Consolidation, Acquires

Novosoms Liposomal Delivery IP


Marina Biotech, formerly known as mdRNA, continues to snap up assets in the oligonucleotide therapeutics and diagnostics space, this time acquiring the liposomal delivery IP from Novosom, a privately held drug delivery company based in Germany. This comes only a week after shareholders approved mdRNAs merger with tkRNAi company Cequent Pharmaceuticals to form Marina Biotech. It will be curious to see whether Marinas strategy of challenging Alnylam's industryleading position by taking advantage of the depressed market for oligonucleotide therapeutics will succeed in luring Big Pharma and pay off for shareholders. The investment this time: $5M in newly issued stock. Similar to Silence Therapeutics, Marina acts on the premise that in order to capture those lucrative partnerships, being able to provide a choice of delivery technologies, plus some claims in RNAi triggers, too, is key. This, of course, is in contrast to Tekmiras so far quite successful strategy of doing one thing very well, meaning clinically maturing and expanding the applicability of its industry-leading SNALP delivery technology and avoid some of the deal frenzy and dilution of effort. By the looks of it, Novosom has to be considered one of the more bona fide delivery companies. Similar to Tekmiras SNALP, Novosoms SMARTICLES can change their surface electrical charge and therefore reconcile (serum and storage) stability with endosomal release functionality. Unlike SNALPs, however, these liposomes also contain anionic lipids, in addition to cationic and

neutral lipids, and do not employ PEG stabilizers. This stability can be attributed to the negative charge of SMARTICLES at phyisiologic pH which ought to avoid various interactions with host factors and resulting toxicities often associated with positively charged lipids. However, as the pH acidifies upon endosomal uptake of these particles, they become positively charged and competent for membrane disruption and cytoplasmic release. For similar reasons, ionizable SNALPs as practiced by Tekmira not only employ PEGylation, but are also essentially uncharged at physiologic pH. In terms of IP, from the looks of it, Novosom has assembled a respectable IP estate with various fairly broad patents granted also in the important US market. This should provide Marina with considerable options to leverage its other liposomal assets, trp-cage targeting technology and amino acid-derived lipids, that I have felt lacked robust patent protection when used in liposomal formulations similar in composition to Tekmiras SNALPs. Theory and IP, of course, are only part of the equation. In terms of actual data, the literature bears out the tolerability of these liposomes. In terms of in vivo knockdown efficacy, I havent really seen much for liposomal delivery of siRNA in the peerreviewed literature. There was, however, a paper on the liposomal delivery of a CD40 antisense oligo (under license from ISIS) in a rodent inflammatory disease model and that supported specific CD40 knockdown and disease amelioration while the unformulated antisense oligo appeared to be inactive. In general, based on the literature and also Novosoms website, their technology seems to be in the late rodent stage and yet to be

validated in larger mammals including non-human primates and Man. There should, however, be an open IND for the delivery of a DNAi compound (no mis-spelling) by PRONAI which makes use of Novosoms technology. However, it appears that PRONAIs funding situation may have delayed actual dosing. Novosom also entered into at least 2 collaborations with RNAi companies. One with (now defunct) DNA-directed RNAi company Nucleonics for treating hepatitis viral infections, and one with Boehringer-Ingelheim for the validation of drug targets in the liver and lung. Again, because Novosom is a private company I can only speculate whether the lipids used by Nucleonics in their soon aborted phase I study stemmed from the Novosom collaboration. Similarly, the status of the Boehringer-Ingelheim collaboration is unclear to me. Who knows, but maybe Boehringer-Ingelheim is actively looking for (liposomal) delivery and triggers for the development of RNAi Therapeutics, which raises another point: although the press release did not specify this, but selling what looks like the entire IP estate would appear to be tantamount to selling the entire company, existing partnerships and programs included. But back to the fundamental question: Consolidating into a onestop-shop, almost an anti-Alnylam, a la Marina and Silence versus technological deep-dive a la Tekmira- which strategy will create more shareholder value? The next 3 months should provide for some of the answers.

Please let your voice be heard and vote on the right.

Posted by Dirk Haussecker at Thursday, July 29, 2010 Labels: Alnylam, Boehringer-Ingelheim, ISIS, liposomal delivery, Marina Biotech, Novosom, Nucleonics, Smarticles, SNALP, Tekmira

9 comments:
Anonymous said... Dirk, Thanks for the new blog entry re; Marina Biotech. That was much more than I had expected. I will post a link to your blog over at yahoo. Hope you don't mind. Joe/Miami Beach July 29, 2010 10:28 AM Dirk Haussecker said... Joe, That's fine. The reason though I did not respond to your earlier inquiry is that in some cases such inquiries don't come from retail investors or other generally interested people like you appear to be one, but in disguise from those that write reports on RNAi Therapeutics companies that are then sold for good money to 'traders', often of the short/parasitic type. Especially with broad questions it can be difficult to tell. July 29, 2010 11:56 AM Anonymous said... Dirk, There is an saying, "You can learn more about a person from what he asks, than from what he says." I found the question you posted on the survey, telling. Most recently, you appear to be a strong proponent of the technologies and general investment prospects of Alnylam and Tekmira; however, clearly you are debating the value proposition of the one-stop-shop business model, also. I am very curious, for companies that you categorize as one-stop-

shops, which specfic companies would you rank #1 and #2 for technology and investment prospects? Further, if I now asked you to rank Alnylam, Tekmira and these two other companies - what ranking order would you come up with. I know I am posing a challenging question as I haven't provided specific definitions of "good technology" or "good investment" prospects... and I know a good investment for one person, might be a terrible choice for another; however, consider the same investment thesis you have used to arrive at the value proposition of Alnylam and Tekmira, and apply to all four companies. Thank you in advance. July 29, 2010 8:56 PM Dirk Haussecker said... I believe all 4 companies deserve a look here. Clearly, as most readers here will know very well, my favorite company both investment and technology-wise is Tekmira- and it has been like this for the last 2 years. With the industry's most advanced delivery technology, essentially allowing for knocking down genes at will in the liver and increasingly also in other tissues and disease states, Tekmira is in an excellent strategic position in most regards. If you have read the papers and patents by Tekmira and their collaborators, I don't know how one cannot be excited about the future of the company and what it could do for human health. Couple this with one of the most attractive financial gearing in the small biotech space, an $80M market cap is very attractive to me. Alnylam at $15 is clearly attractive, too, but probably with a more limited upside than Tekmira near to midterm. Simple gravity. Although Alnylam also practices SNALP quite extensively and is getting better and better at target picking, the business model is more capital intensive/aggressive than Tekmira's which is something that Alnylam ought to look out for. The prospects for clear clinical knockdown results from their TTR and PCS programs plus Novartis and maybe another $100M+ deal should put the share price back on track. Silence and Marina...probably worth wetting the feet at this

point. I've personally been adding Silence Therapeutics over the last couple of weeks because of progress on the IP front which should increase their leverage in partnership negotiations and contentious relationship with Alnylam. The lipoplex delivery data looks promising although by far not as extensively validated as Tekmira's SNALP. So before increasing my position, I will wait for more scientific validation in the literature. The risk is clearly very high, but so should be the upside. A $10M upfront deal should probably more than double its share price (market cap only $20M with about a year of cash runway). I think it is not totally out of the question. I treat it as an attractive LEAP option, or a hedge on Alnylam because all these companies are vying for collaborators. In the case of Marina, I'd need some more time to digest the recent deal flurry, its impact on its financials and scientific strategy. July 30, 2010 8:26 AM
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Dicerna Gets Glaxos SR One to Join Investor Syndicate


Ryan McBride 10/21/10

[Corrected---10/22/10 at 6:25 am ET. See editor's note] Watertown, MAbased Dicerna Pharmaceuticals said this morning it has brought in $4 million from SR One, the venture capital arm of London-based drug giant GlaxoSmithKline. The funding makes Glaxos SR One the latest big-name investor to buy into Dicernas new approach to silencing disease-related genes to treat cancer and other diseases. SR Ones investment brings Dicernas Series B fundingwhich was initially announced as a $25 million financing in Augustto $29 million. Dicerna has now raised a total of $50.4 million from a syndicate that includes Abingworth Management, Domain Associates, Oxford Bioscience Partners, Skyline Ventures, and SR One. Dicerna, founded in 2007, is a relatively new entrant in the field of RNA interference (RNAi), which uses short pieces of RNA to knock down

expression of disease genes. The firms molecules are slightly longer than earlier RNAi drugs under development at companies such as Cambridge, MA-based Alnylam Pharmaceuticals (NASDAQ:ALNM). Dicerna, which is focused on treating cancer, says that its RNAi drugs are more potent and offer a greater duration of gene-silencing activity than previous RNAi molecules. This is because its drugs work at an early point in the genesilencing pathway. [RNAi drugs are made with short pieces of RNA, not DNA, as was initially reported in this story. We regret the error.] Brian Gallagher, a partner at SR One, is joining Dicernas board as an observer. He and Christoph Westphalthe former CEO of Cambridges Sirtris Pharmaceuticals who became president of SR One this yearare based in Boston. Westphal knows the RNAi field well; he co-founded and served as the early CEO of Alnylam. We are very excited about the broad potential for RNAi therapeutics to treat diseases caused by a large number of gene targets that are considered undruggable with todays pharmacologic treatments, Gallagher stated in a press release. Dicerna is working on advancing its first internal drug candidate into clinical trials for cancer, but the firm isnt saying what type. Doug Fambrough, the firms CEO, said yesterday at Xconomys Bostons War on Cancer forum in Cambridge, that its lead candidate is being developed in partnership with Japan-based drug maker Kyowa Hakko Kirin. Ryan McBride is Xconomy's correspondent. You can reach him at rmcbride@xconomy.com, or follow him on Twitter at http://twitter.com/Ryan_McBride.

Dicerna Snags Deal With Japans Kyowa Hakko Kirin to Develop RNAi Cancer Treatments
Luke Timmerman 1/4/10

Dicerna Pharmaceuticals has found some deep pockets to support its approach to creating RNA interference drugs. The Watertown, MA-based company is announcing today that it has formed an alliance with Japanbased Kyowa Hakko Kirin. Under the deal, Kyowa Hakko Kirin will get access to Dicernas proprietary RNAi drug technology against one undisclosed target on cancer cells. In

exchange, Dicerna will get $4 million in upfront cash, plus $120 million in milestone payments for success in development and commercialization, as well as royalties on future product sales. The partnership can be broadened over time to include as many as 10 more drug targets for cancer and other diseases, each with the same financial terms. Dicerna also has an option to co-promote and equally split the profits in the U.S. on the initial cancer drug. This is the first significant partnership for Dicerna, a company founded in 2007 on the idea that it had found a second doorway of RNA interference. Like Cambridge, MA-based Alnylam Pharmaceuticals and others, Dicerna is seeking to specifically silence disease-related genes. One key difference is that Dicernas drugs are a little longer than so-called small interfering RNA molecules, and they interact with an enzyme called dicer thats involved at an earlier step in the RNAi process. Kyowa Hakko Kirin has a long history of manufacturing and marketing biotech drugs in Japan, and it has its own internal teams devoted to RNAi research and development. They looked carefully at different siRNA opportunities for some time, and they chose this one, says Dicerna CEO Jim Jenson. They are committed to biotech, and they are a strong player in Japan. Dicerna still has a lot to prove about its method, as none of its treatments are yet in clinical trials. The partnership does provide cash that will enable Dicerna to add a few new faces to its staff of 23 employees, Jenson says. It also helps provide outside validation that should enable the company to raise a Series B venture round in 2010, which he expects will be worth
NEXT PAGE

Luke Timmerman is the National Biotech Editor of Xconomy, and the Editor of Xconomy Seattle. You can e-mail him at ltimmerman@xconomy.com, or follow him at twitter.com/ldtimmerman.

Dicerna Snags Deal With Japans Kyowa Hakko Kirin to Develop RNAi Cancer Treatments
Luke Timmerman 1/4/10

(Page 2 of 2)

about $25 million, he says. Dicerna is hopeful that its drugs will be more potent than other RNAi therapies, and that they will last longer in the body. If that can be proven, it could translate into fewer injections for patients, lower manufacturing costs, and higher profit margins. But delivery is the major challenge in RNAi today, because most treatments given directly through injection get filtered out by the kidneys before they can have the desired effect on the target. Lots of energy is being poured into new ways to deliver the RNAi drugs in the body, and that is one important feature of the Kyowa Hakko Kirin collaboration with Dicerna. The Japanese company has its own technology for using liposomes to deliver the RNAi drugs. Dicerna is developing its own lipid nanoparticle delivery technology in house, Jenson says, although it is trying a variety of approaches, like using antibodies, peptides, small molecules, or other ways of getting an RNAi drug where its supposed to go. Dicerna doesnt envision itself becoming a research wing for Kyowa Hakko Kirin. Rather, this partnership will lead to more alliances and help the small company build up its own pipeline of wholly owned drug candidates, Jenson says. Already, he says the company has commitments from its existing investorsOxford Bioscience Partners, Abingworth, and Skyline Venturesto invest in a Series B venture round that just needs a new investor to join the syndicate. That round of investment will go toward building up the Dicerna pipeline, he says. While the Japanese partnership will focus in the beginning on a novel target for a cancer drug, Dicernas own program will concentrate instead on a less-risky target that has been validated by other drugs, Jenson says. The strategy is that by silencing a validated target, theres less chance of an unexpected safety problem emerging, which could cast a cloud over the whole RNAi field, he says. Clinical successes in this field are badly needed, Jenson says. Jenson wouldnt say which target Dicerna is going to pursue first, but he did offer some clues. Dicernas ideal target will be measured by a validated biomarker, he says, so the company will be able to take a biopsy from patients and determine whether its RNAi drug is getting to where it is

supposed to be in the body, and silencing the intended target. Ideally, the company wont have to wait very long for this sort of scientific validation. Dicerna has already been working on a clinical trial design, and expects to bring that drug into human testing in 2011, Jenson says.

Luke Timmerman is the National Biotech Editor of Xconomy, and the Editor of Xconomy Seattle. You can e-mail him at ltimmerman@xconomy.com, or follow him at twitter.com/ldtimmerman.

Dicerna, Archemix Team Up to Make Souped Up RNAi Combo Drugs


Luke Timmerman 7/21/09

Dicerna Pharmaceuticals has set its sights on silencing problematic genes using what it calls the second doorway of RNA interferencean approach to the burgeoning field that other RNAi companies arent pursuing. But to get its drugs over the transom and where they need to go in the body, the Watertown, MA-based company will need a little help, and for that it has turned to Cambridge, MA-based Archemix. The two firms have partnered up to develop combination treatments that will merge Archemixs proprietary aptamer treatments with Dicernas gene-silencing drugs. Both companies hope the alliance will yield drugs that can preciselyand potentlyhome in on the molecular roots of disease. Specific financial terms of the deal arent being disclosed, although Dicerna and Archemix will split the early development costs, and Dicerna has an option to get exclusive rights to take the new drugs through development, leaving the usual milestone payments and product royalties to Archemix if the collaboration bears fruit. The idea behind RNAi-based drug development is to create specially engineered RNA molecules that selectively turn off disease-causing genes. Entrants to the field typically have to pay some sort of toll to Cambridge, MA-based Alnylam Pharmaceuticals (NASDAQ: ALNY), which has an extensive RNAi IP estate, but Dicerna insists it has found a second doorway. Simply put, its designing drugs that are a little longer than socalled small interfering RNA molecules being developed by Alnylam and othersand which are therefore not covered by Alnylams patents. Dicerna says its drugs may have the added advantage of being more

potent that other RNAi-based treatments. Importantly, these slightly longer RNAi drugs can be made with a handle on them that allows them to be welded together with other drug compounds that could give them extra kick. NEXT PAGE

Dicerna, Archemix Team Up to Make Souped Up RNAi Combo Drugs


Luke Timmerman 7/21/09

(Page 2 of 2) In this case, they hope to combine the Dicerna molecules with Archemixs aptamersshort synthetic molecules designed to bind very specifically and tightly to certain protein targets. This provides a double-punch with one molecule, says Jim Jenson, Dicernas CEO. This deal is important to Dicerna and to the RNAi field. This will change the game. There isnt any proof yet such drugs will work in people, so these treatments have a long way to go and a lot of high hurdles to clear. Dicerna is also hedging its bets with a number of partners who bring expertise with antibody fragments and peptides, which also might be used to soup up its RNAi drugs. Dicerna already has established a couple of research collaborations (which it hasnt disclosed) over the past six months, and has several more discussions underway that it hopes will lead to a partnership with a Big Pharma company this year, Jenson says. This is an area of great interest in the Big Pharma world, Jenson says. Archemix, for its part, gets to align itself with a glamorous niche within biotech and keep itself busy as an independent company, a little more than six months after it got dumped at the altar by Lexington, MA-based NitroMed, which was looking to merge. Two months ago, Archemix named Kenneth Bate, the former NitroMed CEO, as its new top executive. This is the first significant R&D deal at Archemix since he came on board. This collaboration showcases how our proprietary aptamer technology can be used in conjunction with other therapeutic modalities and we look forward to beginning this exciting work with Dicerna, Bate said in a

statement. Dicerna wasnt about to say when it will enter clinical trials with one of these new RNAi-aptamer drugs, although it is most interested in treatments for cancer and metabolic diseases like diabetes, Jenson says. Dicerna, which closed the last bit of its $21.4 million Series A venture round last Julyright before the economy tankedis still doing well with its cash balance, Jenson says. But even so, pushing new drugs through development will take more money. Dicerna plans to start raising more money before the end of this year, Jenson says. Luke Timmerman is the National Biotech Editor of Xconomy, and the Editor of Xconomy Seattle. You can e-mail him at ltimmerman@xconomy.com, or follow him at twitter.com/ldtimmerman. Luke Timmerman is the National Biotech Editor of Xconomy, and the Editor of Xconomy Seattle. You can e-mail him at ltimmerman@xconomy.com, or follow him at twitter.com/ldtimmerman.

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Read more: Marina Biotech Acquires RNA Delivery Assets of Novosom AG FierceBiotech http://www.fiercebiotech.com/press-releases/marina-biotechacquires-rna-delivery-assets-novosom-ag-0#ixzz13fzTLgjt Subscribe: http://www.fiercebiotech.com/signup?sourceform=Viral-TyntFierceBiotech-FierceBiotech

NitroMed and Archemix to Merge


Robert Buderi 11/18/08

Last month, when Lexington, MA-based biotech company NitroMed announced it was selling off all the assets related to its only drug product, CEO Kenneth M. Bate said the company would concentrate on combining, through one or more strategic transactions, with companies that have significant unrealized value or growth potential. Apparently it didnt take long for Bate to find that partner: the publicly traded NitroMed (NASDAQ:NTMD) today announced it plans to merge

with Archemix, a private Cambridge biotech company exploring new ways to treat cancer, inflammatory conditions, and other illnesses with short pieces of RNA or DNA known as aptamers. Completion of the deal would mean that Archemixwhich pulled a planned IPO when the market for such offerings went sour early this yearhad found an alternative path to the public market. Ryan took a look at Archemix last month, just a few days before NitroMeds asset sale announcement, when the company signed a licensing and options deal with Eli Lilly (NYSE:LLY) that gave the Indianapolis-based drugmaker options to evaluate Archemixs technology and gain exclusive licenses to aptamers for up to two disease targets. Archemix itself has not yet received FDA approval for any of its treatments, but is focused initially on developing drugs to treat blood disorders. Under the all-stock deal announced today, the merged company will retain the Archemix name and will be based in Archemixs current offices, but NitroMeds Bate will become president and CEO. Archemix shareholders will own about 70 percent of the new company, while NitroMeds stockholder will hold 30 percent. The firm plans to apply to relist its shares of the combined company on NASDAQ, under the symbol ARCH, the symbol Archemix planned to use when it filed for an IPO worth up to $69 million in July of 2007. Assuming the previously announced sale of NitroMeds assets goes through, it is estimated that cash and cash equivalents for the combined company will be approximately $50-60 million at closing, according to the statement. Bob is Xconomy's founder and editor in chief. You can e-mail him at bbuderi@xconomy.com, call him at 617.500.5926, or follow him on Twitter at http://twitter.com/bbuderi.

NitroMed Takes Buyout Offer from Deerfield, Dumps Archemix at the Altar
Ryan McBride 1/27/09

NitroMed (NASDAQ:NTMD), the Lexington, MA-based drug developer that struggled to market a heart failure drug for African-Americans, says it has agreed to be acquired for 80 cents per share in cash by investment firm Deerfield Management. This means NitroMed bailed out of previous

agreements to sell BiDil to specialty drugmaker JHP Pharmaceuticals and to merge with Cambridge, MA-based biotech firm Archemix. Archemix issued a separate statement confirming the terminated deal with NitroMed, and the associated fallout. Now that its planning to be independent again, Archemix said CEO Errol De Souza, who negotiated the deal with NitroMed, is resigning from the top job and will remain on the board of directors. Duncan Higgons, who was previously executive vice president of business operations, is replacing him as interim president and CEO of Archemix. De Souza had planned to step down after the merger with NitroMed. Deerfields buyout offer, which is subject to NitroMed shareholder approval and other conditions, came last month after NitroMed announced the previous month that it agreed to an all-stock merger with privately held Archemix. The offer represents a 25 percent premium above NitroMeds closing stock price yesterday of 64 cents. The Deerfield bid puts NitroMeds value at about $36.8 million. In October, before Deerfield made its bid, NitroMed said it would sell all assets related to BiDil (isosorbide dinitrate/hydralazine hydrochloride), its heart failure drug approved by the FDA for self-identified African Americans in 2005, for about $26 million. Now Deerfields acquisition of NitroMed is expected to close in April. Archemixs and JHPs breakup fees with NitroMed provide some degree of a silver lining. As part of the firms agreements with NitroMed, Archemix is due to get a $1.5 million termination fee from NitroMed and JHP is expected to receive $900,000. Archemix continues to land lucrative deals related to its drugs called aptamers, which use short pieces of DNA or RNA to bind with diseaserelated proteins. Last month Archemix received $27.5 million in upfront money in a deal to develop aptamer treatments for London-based drug giant GlaxoSmithKline. Two months before landing the GSK deal, former Archemix CEO De Souza told me that his firm had enough cash to support operations through the middle of 2010. Also, Archemix says that it has just started mid-stage clinical trials of its lead aptamer drug for treating a rare blood disorder known as thrombotic microangiopathiesement.

Ryan McBride is Xconomy's correspondent. You can reach him at rmcbride@xconomy.com, or follow him on Twitter at http://twitter.com/Ryan_McBride.

NitroMed to Get $2.6M in NO Deal


Ryan McBride 4/23/09

[[Updated: see editor's note below]]NitroMed, a Lexington, MA-based drug development firm, says it has struck a deal with French biotech firm NicOx to sell and license nitric oxide-based technology to NicOx. NicOx will pay NitroMed an initial fee of $2.6 million, and NitroMed is eligible for future payments of $5.2 million from NicOx based on certain terms. NitroMed (NASDAQ:NTMD), which makes heart failure drug isosorbide dinitrate/hydralazine hydrochloride (BiDil) for self-identified Black patients, says that the initial fee from NicOx would be distributed to shareholders if the payment is received before NitroMed closes its merger with entities affiliated with investment group Deerfield Management. The merger was approved at a stockholders meeting this week and is expected to close as soon as practical. [[Editor's note: this story was updated with the amount of future payments NitroMed could receive in this licensing deal with NicOx.]] Ryan McBride is Xconomy's correspondent. You can reach him at rmcbride@xconomy.com, or follow him on Twitter at http://twitter.com/Ryan_McBride.