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Japanese group to take induced pluripotent stem (iPS) cell-derived retinal cells into the clinic

Published by on March 14, 2013 | Leave a response

 

Stem cells. Source: http://bit.ly/ZnYuFS

Stem cells. Source: http://bit.ly/ZnYuFS

As reported in Nature News on 27 February 2013 ophthalmologist Masayo Takahashi M.D., Ph.D. and her colleagues at the RIKEN Center for Developmental Biology (Kobe, Japan), plan to submit an application to the Japanese health ministry for a clinical study of induced pluripotent stem cell (iPS)-derived cells. The researchers planned to submit their application in March 2013; if approved, they could begin recruiting patients as early as September.

The author of the Nature News article is Nature‘s Asian-Pacific Correspondent, David Cyranoski, who is based in Tokyo.

The researchers plan to treat approximately six people with severe age-related macular degeneration (AMD). Specifically, the researchers are targeting “wet” AMD, in which angiogenic blood vessels invade the retina, destroying the retinal pigment epithelium (RPE) that supports the light-sensitive photoreceptors.

AMD is a common cause of blindness that affects at least 1% of adults over 50. Wet AMD can be treated with anti-vascular endothelial growth factor (anti-VEGF) agents such as ranibizumab (Genentech/Novartis’ Lucentis), pegaptanib (Gilead/OSI/Pfizer’s Macugen), aflibercept (Sanofi/Regeneron’s Eylea), and–off-label–small doses of the anticancer agent bevacizumab (Genentech/Roche’s Avastin). However, the use of these agents requires that they be injected repeatedly into the eye.

According to the Nature News article, Dr. Takahashi and her colleagues will take an upper arm skin sample the size of a peppercorn, and transform the cells from this sample into iPS cells by using specific proteins. They will then add other factors that will induce differentiation of the iPS cells into retinal cells. Then a small sheet of these retinal cells will be placed under the damaged area of the retina, where they are expected to grow and repair the damaged RPE.

Although the researchers would like to demonstrate efficacy of this treatment in ameliorating the disease, the main focus of these studies will be on safety. Safety concerns include immunogenicity of the transplanted cells, and formation of tumors if the transplanted cells multiply uncontrollably. Another concern is that the transplanted cells might fail to engraft, and to integrate with the host tissue. It is also possible that the RPE identity of the transplanted and differentiated cells might not be stable over time.

With respect to these concerns, studies published by Japanese researchers in 2013 (Araki et al.) and reviewed in a recent Nature News article contradicted the original mouse studies that suggested that syngeneic or autologous iPS cells might be immunogenic.

With respect to tumor formation, Dr. Takahashi’s proposed studies will involve using only a few iPS cells, thus reducing the probability of forming tumors. Moreover, since the eye is relatively accessible, any tumors would be relatively easy to remove.

In addition, Dr, Takahashi has presented preclinical studies at conferences, which indicate that her iPS cells do not form tumors in mice and are safe in non-human primates. (Dr. Takahashi’s preclinical studies have also been submitted for publication.) The studies have provided reassurance of the cells’ safety to at least some leading researchers, such as Martin Pera (University of Melbourne, Australia) and George Daley (Harvard Medical School, Boston MA).

However, other researchers believe that to take iPS cell-derived tissue into the clinic at this time is premature. Robert Lanza, M.D., the chief scientific officer at Advanced Cell Technology (ACT) (Santa Monica CA) says that he cannot imagine regulatory agencies permitting studies such as Dr. Takahashi’s without years of preclinical testing.

As mentioned in the Nature News article, ACT has a program involving human embryonic stem cell (hES cell) and iPS-derived platelets for transfusion. This program is in the preclinical stage. Since platelets lack a nucleus and cannot form tumors, it is inherently less risky that clinical programs of stem-cell (and especially iPS cell) derived differentiated cells that have nuclei.

Dr. Takahashi’s proposed study of her therapy in humans is considered a “clinical study”, not a clinical trial. In Japan’s regulatory system, clinical studies are less tightly regulated than clinical trials. However, a clinical study cannot by itself lead to approval of a potential therapeutic for clinical use as a treatment. If Dr. Takahashi’s clinical study data is positive, that might attract investors or help her to get approval for a formal clinical trial. As in the U.S. or Europe, successful clinical trials will be required if Dr. Takahashi’s cellular therapy is ever to be used to treat patients.

Dr. Takahashi’s clinical study was approved by institutional review boards at both the natural sciences institute RIKEN in Wako and the Institute of Biomedical Research and Innovation in Kobe, where the surgical procedures will be carried out. Final approval will depend on the action of a committee of the Japanese Ministry of Health, Labour and Welfare. If Dr. Takahashi wins approval by September 2013 as expected, it will take another eight months to produce the tissue implants needed for her clinical study.

Other retinal repair programs involving human embryonic stem cell-derived RPE cells

Dr. Takahashi’s research does not represent the only RPE cell-based retinal repair program now being developed. There are at least two others, both of which are based on hES cells, not iPS cells.

As was not mentioned in the Nature News article, ACT has Phase 1 trials underway in its own RPE retinal repair program. ACT’s RPE cells are derived from human embryonic stem cells (hES cells). The company’s Phase 1 safety studies are in Stargardt’s Macular Dystrophy (SMD) and in dry AMD (which results from atrophy of the RPE layer, and causes vision loss through loss of photoreceptors in the central part of the eye. Dry AMD does not involve angiogenesis.). SMG is a rare inherited juvenile macular degeneration.

In February 2012, Dr. Lanza and his academic collaborators at the University of California at Los Angeles published a preliminary report of their clinical studies in dry AMD and SMG. In this study, one patient with each of the two conditions was treated with hES cell-derived RPE cells. The hES cell-derived RPE cells showed no signs of hyperproliferation, tumorigenicity, ectopic tissue formation, or apparent rejection after 4 months. Neither patient showed loss of vision, and there were signs of improvement of vision. As a result of this very preliminary study, the researchers decided in the design of future clinical studies to treat patients earlier in the disease processes, potentially increasing the likelihood of improvement of vision.

The other RPE-based retinal repair program is a collaborative effort between Neusentis (A Cambridge U.K. and Durham NC-based Pfizer research unit) and “The London Project” which was formed by Professor Pete Coffey [Institute of Ophthalmology, University College London (UCL)] and his collaborator Lyndon da Cruz (Moorfields Eye Hospital) to develop cellular therapies for all types of AMD. The London Project began collaborating with Pfizer in 2008; this collaboration was brought under the aegis of Neusentis when it was formed in 2011. Research is based on RPE cells derived from hES cells.

The Neusentis/London Project group claims to have developed a deep understanding of the biology of hEC cell-derived RPE cells, and to have worked out methods of producing enough RPE cells under GMP conditions to support clinical studies. They also claim to have developed a clear approach to establishing the safety of the therapy via preclinical studies. The collaborative group is now moving towards clinical studies of their therapies, which they “hope to achieve in the not too distant future”.

As we discussed in our February 15, 2011 article on this blog, Pfizer–as of February 1, 2011–closed its Memorial Drive laboratory in Cambridge, MA. This laboratory housed most of Pfizer’s regenerative medicine research, as well as the company’s RNAi therapeutics research group. However, as we said in this article, Pfizer was folding its Cambridge, UK regenerative medicine group–”which had been focusing on development of preclinical embryonic stem (ES) cell-based ophthalmology therapies, in collaboration with the University of London”–into a “new pain and sensory disorder research unit”. According to its website, Neusentis, which was formed in 2011, has “a particular focus on pain and sensory disorders”.

Japanese government backing for iPS cell research and commercialization

Japan has been a hotbed of iPS cell research, since these cells were first produced by Shinya Yamanaka, M.D. Ph.D. (Kyoto University) in 2006. He received The Nobel Prize in Physiology or Medicine in 2012 for his work on iPS cells. The co-recipient of the Prize, Sir John B. Gurdon, successfully cloned a frog using intact nuclei from the somatic cells of a Xenopus tadpole back in 1958. The two scientists received the 2012 Prize “for the discovery that mature cells can be reprogrammed to become pluripotent”. Since their discovery, iPS cells have been employed in such areas as basic research, disease modeling, and drug screening. (Follow this link for a recently-published example of the potential use of iPS cells in designing personalized treatments for Alzheimer’s disease.)

In 2013, as part of its stimulus package, the Japanese government has been providing generous funding for iPS research. This funding includes ¥700 million for a cell-processing centre at the Foundation for Biomedical Research and Innovation in Kobe, mainly to support Dr. Takahashi’s regenerative medicine research. In general, the iPS funding under the stimulus is aimed at moving university research on iPS cells into commercial and medical applications.

Moreover, according to Mr. Cyranoski’s 27 February 2013 Nature News article, the Japanese parliament is expected to rule by late June 2013 on a provision of a revised drug law, which would fast-track iPS-based therapies that appear to be effective in phase 2 or phase 3 trials. However, the success of the Japanese government’s efforts to accelerate commercialization of iPS-based therapies may depend in part on the success of Dr. Takahashi’s clinical research.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or an initial one-to-one consultation on an issue that is key to your company’s success, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

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Is gene therapy emerging from technological prematurity?

Published by on October 11, 2012 | Leave a response

 


The idea of gene therapy has been around since at least the early 1970s. In 1972, an article by Theodore Friedmann and Richard Roblin advanced the concept of treating genetic diseases by replacing defective endogenous DNA with exogenous “good” DNA. However, these authors concluded that it was premature to begin gene therapy studies in humans because of lack of basic knowledge of genetic regulation and of genetic diseases, and for ethical reasons. They did, however, propose that studies in cell cultures and in animal models aimed at development of gene therapies be undertaken. Such studies–as well as abortive gene therapy studies in humans–had already begun as of 1972.

In the 1970s and 1980s, researchers applied such technologies as recombinant DNA and development of viral vectors for transfer of genes to cells and animals to the study and development of gene therapies. In the 1990s, several research groups conducted FDA-approved human studies of gene therapies, based on this technological development and increased knowledge of genetic diseases. However, several notable failures put a damper on development of gene therapies.

The most notorious case was the 1999 death of 18-year-old Jesse Gelsinger, who had ornithine transcarbamylase deficiency. In a clinical trial at the University of Pennsylvania, he was injected with an adenoviral vector carrying a corrected gene to test the safety of use of this procedure. He suffered a massive immune response triggered by the use of the viral vector, and died four days later. As a result of this incident, the FDA suspended several gene therapy clinical trials pending review of ethical and scientific/medical practices.

This incident, as well as the failure of other clinical studies put a severe damper on the gene therapy field, especially attempts at commercialization of gene therapies and of building biotech companies specializing in this field. Nevertheless, between 2003 and 2012, researchers have been quietly developing more advanced gene therapy technologies and conducting clinical studies, with some success. Entrepreneurs have also been building gene therapy specialty companies to commercialize this research.

Now comes the July 20, 2012 ruling by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) that recommends marketing of a gene therapy known as Glybera (alipogene tiparvovec) as a treatment for the ultra-rare genetic disease lipoprotein lipase deficiency (LPLD) under exceptional circumstances. LPLD affects no more than two people per million in the general population. People with LPLD cannot break down fat, and must manage their disease with a restricted diet. However, dietary management is difficult, and a high proportion of patients suffer life-threatening pancreatitis.

Glybera is being developed by a small Dutch biotech called uniQure biopharma. Glybera consists of an adeno-associated virus (AAV) vector that carries the gene for LPL. Therapy consist of multiple intramuscular injections of the product, resulting in the delivery of functional LPL genes to muscle cells.

The European Commission (EC) generally follows the recommendations of the CHMP. At the time of the CHMP ruling, uniQure expected initial approval from the EC within 3 months of that decision. Articles published in Nature and Nature Biotechnology in the late September/early October 2012 period anticipate EC approval in a mater of days or a week or two.

If it is approved in the European Union (EU) as expected, that approval will require that Glybera be offered through dedicated centers of excellence with expertise in treating LPLD, and by specially trained doctors to ensure ongoing safety of the therapy. uniQure is now preparing to apply for approval in the U.S., Canada, and other markets.

uniQure is also using its AAVvector platform as the basis of a series of gene therapies for other rare diseases, including porphyria and Sanfilippo B, as well as what it calls “disruptive innovation” products for such diseases with established treatments as Parkinson’s disease and Hemophilia B.

Does the expected approval of Glybera herald the beginning of a new era of gene therapy?

Jörn Aldag, the CEO of uniQure, believes that “just like antibodies, gene therapy will one day be a mainstay in clinical practice.” Although uniQure is concentrating its development efforts in the area of rare diseases, Mr Aldag believes that “the potential of gene therapy stretches far beyond rare diseases.” He cites a December 2011 publication in the New England Journal of Medicine, which describes a study in which 6 patients with hemophilia B were treated (via peripheral-vein infusion) with an AAV vector carrying a proprietary (codon-optimized) human factor IX (FIX) transgene. This treatment resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype, with few side effects, all of which were easily treatable. Hemophilia B, the second most common form of hemophilia, is nowhere as rare as the ultra-rare disease LPLD. Some of the patients treated with this gene therapy were able to discontinue prophylactic treatment with FIX. uniQure’s program in gene therapy for Parkinson’s disease exemplifies the companies efforts to move beyond the rare disease area.

However, others are not so sure that the approval of Glybera will usher in a new era of gene therapy, at least not in the near future. In particular, Fulvio Mavilio, Ph.D., Scientific Director of Genethon (Evry, France) (a non-profit center for development of gene therapies), does not believe that a large number of patients will be treated with gene therapies in the near future.

Dr. Mavilio cites the “relatively rich pipeline of gene therapy candidates already in human trials,” which  “suggests there may be a surge in the number of gene therapies approved over the next few years.” However, most of the gene therapy clinical candidates are for ultra-rare single Mendelian genetic deficiencies, with similar frequencies in the population to LPLD. The hemophilias (hemophilia A, 1 in every 5,000 male babies diagnosed per year in the US; hemophilia B, 1 in every 30,000 male babies per year) are the most common diseases to be addressed by gene therapies now in clinical development, according to Dr. Mavilio’s article. Moreover, Dr. Mavilio–as well as others–expects safety issues to thwart or slow the development of at least some gene therapies, which will also face competition from existing enzyme replacement therapies similar to those developed by Genzyme.

No gene therapy has yet been approved in the U.S. However, the FDA has established a system that facilitates faster reporting of adverse events in human gene transfer trials and that tracks such trials that are taking place. And uniQure has been planning to work with the FDA to seek U.S. approval of Glybera.

Gene therapy as a “premature technology”

Gene therapy fits the model of a “premature technology”. A field of biomedical science is said to be scientifically or technologically premature when despite the great science and exciting potential of the field, any practicable therapeutic applications are in the distant future, due to difficult hurdles in applying the technology. Moving a premature technology up the development curve requires the development of enabling technologies that can allow researchers and product developers to overcome the hurdles.

The classic case of a premature technology that has moved up the development curve and become successful is the field of therapeutic monoclonal antibodies (MAbs). We discussed the history of MAbs in detail in our September 28, 2009 blog article. The first ever MAb to enter the market, Johnson & Johnson’s Orthoclone OKT3 was approved in 1986 for use in transplant rejection. However, this drug can only be used once in a patient due to its immunogenicity. There were not any further approvals of MAb drugs until 1994. The numerous MAbs that have entered the market since then were made possible by the development of enabling technologies that overcame the immunogenicity problem. Several of these products are highly successful, and there is a rich pipeline of MAb therapeutics now in development.

Commentators on recent developments in gene therapies, including the ones we cited earlier, compare Glybera to Orthoclone OKT3. Given the limited number of patients for whom Glybera is appropriate, and especially given the exceptional circumstances under which Glybera may be prescribed and used, they are likely to be right.

bluebird bio

Among the many companies that are developing gene therapies, one has been singled our for special attention lately. That is bluebird bio (Cambridge, MA). On September 19, 2012, bluebird bio was named to FierceBiotech’s 2012 “Fierce 15″. By naming bluebird bio to the Fierce 15, FierceBiotech is designating the company as “one of the most promising private biotechnology companies in the industry”. “The Fierce 15 celebrates the spirit of being ‘fierce’ – championing innovation and creativity, even in the face of intense competition.” bluebird bio was formerly known as Genetix Pharmaceuticals.

bluebird bio has developed a novel gene therapy platform, in which a wild-type version of a patient’s disease-causing gene, carried in a lentiviral vector, is inserted into autologous CD34+ bone marrow-derived stem cells. These transformed autologous stem cells are then transfused into the patient. This eliminates potential complications associated with donor cell transplantation, or with systemic administration of gene therapy vectors.

bluebird bio’s platform thus represents both a gene therapy technology and an adoptive cellular transfer (ACT) technology. We have discussed ACT technologies (in this case, for immunotherapy for cancer) in the previous article on this blog. Since some of these technologies involve genetically-engineered autologous T cells, they may also be thought of as representing both ACT and a kind gene therapy. (However, the “gene therapy” in these cases is not directed toward repairing a genetic disease, as  in classic gene therapy.)

For a list of links to bluebird bio publications using this and other gene therapy technologies, see the publications page of the company’s website.

bluebird bio is preparing a pivotal Phase 2/Phase 3 study of its lead treatment, for childhood cerebral adrenoleukodystrophy (ALD). The company is also in Phase 1/2 trials for its beta-thalassemia therapy, and in Phase 1 for its sickle cell disease program.

ALD is a rare, inherited neurological disorder that affects one in every 21,000 boys worldwide. It can cause damage to neural myelin sheaths in the brain, and progressive dysfunction of the adrenal glands. ALD is the disease that was featured in the 1992 movie Lorenzo’s Oil. Beta-thalassemias affect one in every 100,000 people throughout the world, with the greatest prevalence in the Mediterranean basin and in South Asia. Sickle cell disease mainly affects sub-Saharan Africans and their decedents, as well as residents of other areas with a high prevalence of malaria. Its prevalence in the U.S. is around 1 in 5,000, in France one in 2,415, and in the U.K. 1 in 2,000.

Thus the diseases that constitute the current focus of bluebird bio are much more common than is LPLD, the target of Glybera. The prevalence of the diseases that are the current targets of bluebird bio resemble the prevalence of “rare diseases” targeted by current Genzyme therapies–Gaucher’s disease (1 in 40,000 in the U.S.), and lysosomal storage disorders (individual diseases, an incidence of less than 1:100,000; total lysosomal storage diseases, an incidence of about 1 in 5,000 to 1 in 10,000).

bluebird bio’s business thus lies in the intersection between gene therapy and the “rare diseases” that are the main targets of an increasing number of biotechs and Big Pharmas.

bluebird bio is backed by several venture capital firms, notably TVM Capital, Third Rock Ventures, and Forbion Capital Partners, as well as by Genzyme (which is now part of Sanofi) and Shire. According to the Fierce 15 press release, bluebird bio is also “exploring a potential set of partnerships”.

Conclusions

In the long history of gene therapy, the expected approval in Europe of Glybera represents a key milestone–if indeed the EC approves the therapy as expected. However, given the very limited number of patients for whom Glybera is appropriate, and the exceptional circumstances under which Glybera may be prescribed and used, this milestone may be analogous to the approval of Orthoclone OKT3. Thus there may be a lag between the approval of the first gene therapy and the beginning of a more steady stream of gene therapy approvals.

However, bluebird bio’s cellular approach may enable it to circumvent many of the pitfalls of gene therapy. Other gene therapy companies may also possess enabling technologies that can help drive the gene therapy field up the technology development curve.

________________________________

As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or an initial one-to-one consultation on an issue that is key to your company’s success, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

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Obesity therapeutics revisited

Published by on May 23, 2012 | 2 Responses

 

Brown fat in humans

The CNS-targeting “Class of 2010″ drugs

We have not had an article on obesity therapeutics on this blog since February 1, 2011. At that time, we had an article entitled “That’s all, folks!”, complete with the old Warner Brothers Porky Pig graphic. As of that date, all three of the obesity drug candidates that came up for FDA review in 2010-–Vivus’ Qnexa, Arena’s lorcaserin, and Orexigen’s Contrave–were rejected for approval by the FDA, and sent back for further studies. Also in 2010, the then-marketed antiobesity drug sibutramine (Abbott’s Meridia) was withdrawn from the market at the FDA’s request. All of these agents targeted the central nervous system (CNS).

Concern about long-term safety was the major consideration in the rejection of the NDAs for Qnexa, lorcaserin, and Contrave, and safety issues were also the reason for the withdrawal of sibutramine. That left only one anti-obesity drug approved by the FDA for long term use– orlistat (Roche’s Xenical), with no new drugs In sight. The outlook for obesity drugs was gloomy indeed.

However, as of May 2012, after the further studies prescribed by the FDA in 2010, two of the obesity drug Class of 2010–Qnexa and lorcaserin have received positive votes by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, and are awaiting final FDA action later this year. Contrave, after a February 6, 2012 agreement with the FDA, appears to be on track for possible NDA resubmission in 2014.

We shall continue to follow progress with the consideration of the resubmitted NDAs for Qnexa and lorcaserin in 2012.

Novel approaches based on the physiology of brown fat

Meanwhile, there is renewed interest in earlier-stage, alternative obesity therapies based on the physiology of brown fat, also known as brown adipose tissue (BAT). The May 1, 2012 issue of The Scientist has an article by the publication’s associate editor Edyta Zielinska entitled “Treating Fat with Fat: Is brown fat ready for therapeutic prime time?”  This article focuses on new discoveries in brown fat physiology, and on entrepreneurial companies that are attempting to develop these discoveries into therapeutics.

On the Biopharmconsortium Blog, we also have an article on brown fat physiology and companies attempting to develop therapeutics based on these findings. The article is dated November 17, 2010. As we state in that article, brown fat researchers and companies are seeking to develop therapeutics that work by increasing energy expenditure, rather than the usual approaches of decreasing appetite (as with the Class of 2010 CNS-targeting antiobesity drugs) or blocking absorption of fat in the gut (as with orlistat).

More specifically, these researchers and companies intend to discover and develop drugs that increase the amount and/or activity of BAT, which is a type of mitochondria-rich adipose tissue that oxidizes fat and dissipates the resulting energy as heat rather than storing it. The mitochondrial protein UCP1 (uncoupling protein 1) is the key biomolecule that makes this process possible. BAT has long been known to be central to non-shivering thermogenesis in rodents, for example to maintain body temperature when they are exposed to cold.

Until recently, researchers believed that in humans, significant populations of BAT cells were found only in infants. However, in recent years researchers found that adult humans possess reservoirs of brown fat in the neck region and other areas of the upper body as well as in skeletal muscle. Adult human BAT can be stimulated by acute exposure to cold and via the sympathetic nervous system, and by various pharmacological agents.

Energesis’ autologous brown adipose tissue transplantation program

Our November 17, 2010 article in particular focused on the Boston-based early-stage company Energesis Pharmaceuticals. Energesis was confounded by Olivier Boss, PhD (formerly of Sirtris Pharmaceuticals), Brian Freeman, MD (former Venture Partner at GreatPoint Ventures), and Jean-Paul Giacobino, MD (Professor Emeritus, University of Geneva Medical School, Switzerland). Dr. Boss serves as Energesis’ Chief Scientific Officer, and Dr. Freeman as its Chief Operating Officer.

Energesis is also mentioned in the new article in The Scientist. According to that article, Energesis is using brown fat “stem cells” (which are precursor cells found in skeletal muscle that can differentiate into either muscle or brown fat) to identify novel targets that activate brown fat. Energesis researchers then work to discover new drugs that address these targets. They are also investigating transplantation of brown fat “stem cells” as an obesity therapy.  According to the article, Energesis is planning to initiate clinical trials of their therapies within 2 to 3 years.

In October 2011, Energesis was awarded a U.S. Department of Defense Small Business Technology Transfer (STTR) grant to develop therapeutics based on autologous BAT transplantation. The project is a feasibility study to define a source and culture system for the generation of human BAT for autologous transplantation therapy. It will involve isolating and characterizing the best brown adipocyte progenitor sub-population from human muscle biopsies, expanding these cells, and establishing the optimal culture conditions for in vitro differentiation to generate approximately 50 grams of BAT cells for transplantation. This project is being conducted in collaboration with Dr. Stephen R. Farmer of the Boston University School of Medicine; Boston University is Energesis’ academic partner on the STTR grant.

According to a January 31, 2012 article in Wired magazine, the U.S. Army’s interest in Energesis’ technology is the result of the growing incidence of overweight and obesity in the Army’s recruit pool, as in young Americans in general. The Army is funding the Energesis/Boston University researchers in the hopes of using autologous BAT transplantation to boost weight loss in military personnel.

According to Brian Freeman, an autologous cell transplantation therapy might also be commercialized for treatment of severely obese individuals in lieu of bariatric surgery. Such an autologous cellular therapy would be analogous to the FDA-approved Genzyme cell transplantation therapy products Carticel and Epicel. It may be easier and faster for Energesis to gain FDA approval for an autologous BAT transplantation product than to develop and gain approval for a drug based on the company’s BAT research. Energesis will therefore pursue both drug discovery and autologous cell transplantation programs, with the strategy to gain early approval and revenues for a transplantation product while it continues to pursue drug discovery and development. Success in development of an autologous transplantation product should also boost the company’s prospects for funding, which would enable its wider R&D programs.

Other approaches to brown adipose tissue-based therapies

The May 1 2012 Edyta Zielinska article begins with a discussion of metabolic diseases start-up Ember Therapeutics. As stated in the article, Ember was founded by Third Rock Ventures partner Lou Tartaglia, a scientist by background who was formerly the Vice President of Metabolic Diseases at Millennium Pharmaceuticals. Ember was launched with $34 million in financing from Third Rock. The company plans to work both on therapeutics based on BAT biology, and on developing a new generation of safer insulin sensitizers for treatment of type 2 diabetes. The latter area of focus is based on studies by Ember scientific founders Dr. Bruce Spiegelman (Dana-Farber Cancer Institute and Harvard Medical School, Boston MA) and Patrick R. Griffin (Scripps Research Institute, Scripps FL) We discussed that work on our blog in an August 29, 2010 article, which was followed by two additional articles on September 16, 2010 and September 21, 2011.

In the January 11 2012 issue of Nature, Dr. Spiegelman’s group reported the discovery of a myokine hormone (i.e., a cytokine produced by muscle cells), which the researchers named irisin. Irisin is named after the Greek goddess Iris, the messenger of the gods. It acts on white adipose cells in culture and in vivo to stimulate what appears to be development into brown fat-like cells. Specifically, irisin stimulates expression of UCP1 and an array of other brown fat genes. Mildly increased blood levels of irisin results in an increase in energy expenditure in mice with no changes in movement or food intake, as would be expected with an increase in brown fat levels. This results in improvements in obesity and glucose homeostasis. Exercise increases levels of blood irisin in mice and humans, leading to the hypothesis that irisin is an “exercise hormone” that mediates at least some of the beneficial metabolic effects of exercise. Irisin is therefore a potential therapeutic for metabolic diseases such as type 2 diabetes and obesity. Ember entered into an exclusive license agreement with Dana-Farber Cancer Institute for the irisin technology, and is optimizing and developing a proprietary molecule based on this technology. This molecule is designed to augment and activate the body’s brown fat. This research constitutes the company’s lead BAT biology program.

On March 28, 2012, Ember also exclusively licensed technology from the Joslin Diabetes Center (Boston, MA) covering bone morphogenetic protein 7 (BMP7), and its role in BAT development. The role of BMP7 in BAT biology was discovered by Ember scientific co-founder C Ronald Kahn, M.D. and his colleagues, who published their findings in Nature in 2008.

In addition to its lead irisin program, Ember is developing a pipeline of biologics (including those based on BMP7) and small molecules designed to increase BAT levels and to activate BAT-specific pathways. According to the article in The Scientist, among the pathways being investigated by Ember are those involving the PRDM-16 transcription factor and FoxC2.

Zafgen’s beloranib (ZGN-433)

Meanwhile, the other obesity start-up founded by Brian Freeman, Zafgen (Cambridge, MA) has been making progress in developing its lead drug candidate, beloranib (ZGN-433). Beloranib, a methionine aminopeptidase 2 (MetAP2) inhibitor, was originally discovered by the Korean company CKD Pharmaceuticals, and was being developed as an angiogenesis inhibitor for treatment of solid tumors. However, the drug was poorly efficacious for this indication in animal models. At much lower concentrations, however, beloranib exerts an antlobesity effect. Zafgen therefore licensed the compound from CKD, and has been developing it as an agent to induce weight loss in severely obese patients.

Beloranib targeting of MetAP2 in vivo results in downregulation of signal transduction pathways within the liver that are involved in the biosynthesis of fat. Animals or humans treated with the drug oxidize fat to form ketone bodies, which can be used as energy or are excreted from the body. The result is breakdown of fat cells and weight loss. Obese individuals do not usually have the ability to form ketone bodies.

In January 2011, Zafgen reported top-line data from a Phase Ib multiple-ascending dose study in which 24 obese women were given 0.9 milligrams/meter(2) of belanorib twice-weekly intravenous. The subjects had a median reduction in body weight of 1 kg/week or 3.1% over 26 days. Treatment with beloranib also reduced triglycerides by 38% and LDL cholesterol (“bad cholesterol”) by 23% from baseline. These results were statistically significant  (p<0.05).

Patients (who were given no instructions regarding diet or exercise) also showed a decline in hunger, and showed no treatment-related serious adverse effects. If sustained (e.g., over a 6-9 month course of treatment in individuals requiring a 20-40 percent reduction in weight) the degree of weight loss seen in this study would be comparable to bariatric surgery.

On July 7, 2011, Zafgen secured a $33 million Series C financing, which was led by the company’s original investor syndicate, including Atlas Venture and Third Rock Ventures. Proceeds from the financing were to be used to support development of Zafgen’s pipeline and especially to advance its lead compound beloranib for the treatment of severe obesity into Phase 2 clinical studies. Zafgen, like Energesis, is operated as a lean virtual company, with only 5 employees. Thus Zafgen should have sufficient cash to advance its beloranib program to the next stage.

Inducing brown fat via modulation of TGFβ signaling

In our November 17, 2010 article, we also mentioned Acceleron Pharma (Cambridge, MA), and its R&D program aimed at brown fat induction via inhibition of signaling by members of the TGFβ (transforming growth factor beta) superfamily. Acceleron is continuing to investigate this approach, and has published a report on this research in the online version of the journal Endocrinology in May 2012. Novartis researchers also published a report on their studies in this area in the online version of the journal Molecular and Cellular Biology.

Conclusions

Despite the doom-and-gloom atmosphere of the obesity drug field in late 2010 and early 2011, with investment bank and business press analysts declaring the field to be “dead”, obesity drug R&D has shown definite signs of life in recent months. NDAs for two of the “Class of 2010″ CNS-targeting antiobesity drugs, Qnexa and lorcaserin, have been resubmitted and are up for reconsideration by the FDA later this year. Meanwhile, R&D efforts aimed at producing therapeutics to increase energy expenditure via brown fat induction are progressing, mainly in small entrepreneurial biotech companies. The latter approach, if confirmed by future clinical trials, appears to have a greater likelihood of inducing the degree of weight loss needed to reverse even severe obesity.

Regulatory hurdles–especially safety concerns–were the most significant factor in the failure of the initial NDA submissions of the “Class of 2010″ CNS-targeting drugs. The developers of these drugs are working to overcome these hurdles via performing the additional studies mandated by the FDA followed by NDA resubmission. We shall see how well this approach is working when the FDA rules on marketing approval of Qnexa and lorcaserin later this year. Meanwhile, developers of brown-fat targeting therapies are attempting to target severe obesity rather than the general obese population. They are positioning their therapeutics as alternatives to bariatric surgery. They expect that the regulatory hurdles to treating this population will be lower than for the general obese population.

As discussed in several articles on the Biopharmconsortium Blog, the need for antiobesity agents is great, and with the fast accelerating incidence of obesity and its complications, the need is also accelerating. Moreover, our understanding of the pathogenesis of obesity is limited. Thus both continuing basic research and development of agents with novel mechanisms are sorely needed.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

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“It’s not junk”–RaNA Therapeutics emerges from stealth mode with $20.7 million in venture funding-Part 2

Published by on March 30, 2012 | Leave a response

 

Atlas!

This is Part 2 of the article on RaNA Therapeutics that we began on March 29, 2012.

Jeannie Lee’s research and RaNA’s technology platform

Jeannie Lee’s laboratory focuses on the study of the mechanism of X-chromosome inactivation in mammals. In X-chromosome inactivation, one of the two copies of the X chromosome present in the cells of female mammals is inactivated. The inactive X chromosome is silenced by packaging into transcriptionally inactive heterochromatin.  X-chromosome inactivation results in dosage compensation, the process by which cells of males and females have the same level of expression of X-chromosome genes, even though female cells have two X chromosomes and male cells have only one. In placental mammals such as mice and humans, the choice of which X chromosome will be inactivated is random, but once an X chromosome is inactivated it will remain inactive throughout the lifetime of the cell and its descendants.

The Lee laboratory has focused on genes encoded by the X-chromosome whose actions coordinate X-chromosome inactivation. These genes  are contained in the 100 kilobase long X-inactivation center (Xic). One of these genes, Xist, encodes the lncRNA XIST, which as discussed in Part 1 of this article inactivates an X-chromosome by spreading along the X chromosome and recruiting the silencing factor PRC2. XIST is regulated in cis by TSIX, an antisense version of XIST which works to keep the active X-chromosome active. Tsix is in turn regulated by Xite (X-Inactivation intergenic transcription element), an upstream locus that harbors an enhancer that enables the persistence of TSIX expression on the active X chromosome. The mechanism by which Xite acts (including whether it acts via its RNA transcripts) is not clear. Xite and Tsix appear to regulate pairing between the two X chromosomes in a female cell, and determine which X chromosome will be chosen for inactivation. Several other recently discovered genes in the region of the Xic, which work via lncRNAs, also serve as regulators of XIST function. For example, the Rep A and Jpx genes, work via lncRNA transcripts to induce Xist. Thus Xist is controlled by positive and negative lncRNA-based switches–TSIX for the active X chromosome and JPX and REPA for the inactive X. Of these lncRNAs, REPA, XIST, and TSIX bind to and control PRC2.

In late 2010, the Lee laboratory published an article in Molecular Cell in which the researchers identified a genome-wide pool of over 9000 lncRNA transcripts that interact with PRC2 in mouse ES cells. Many of these transcripts have sequences that correspond to potentially medically-important loci, including dozens of imprinted loci (i.e., loci that are epigenetically modified such that only the paternal or maternal allele is expressed), hundreds of oncogene and tumor suppressor loci, and multiple genes that are important in development and show differential chromatin regulation in stem cells and in differentiated cells. The researchers obtained evidence that at least in one case, an RNAs works to recruit PRC2 to a disease-relevant genes, similar to PRC2 recruitment by XIST and HOTAIR. This case of specific PRC2 recruitment has not been previously known, suggesting that the researchers’ methodology could be used to discover new examples of PRC2 recruitment by lncRNAs.

Some of the PRC2-associated lncRNAs identified in the Molecular Cell report may be potential therapeutic targets and/or biomarkers. Overexpression of PCR2 proteins have been linked to various types of cancer, including metastatic prostate and breast cancer, and cancers  of the colon, breast, and liver. Pharmacological inhibition of PRC2-mediated gene repression was found to induce apoptosis in several cancer cell lines in vitro, but not in various types of normal cells. Induction of apoptosis in this system is dependent on reactivation of genes that had been repressed by PRC2. There is also evidence that PRC2-mediated gene repression may be linked to the maintenance of the stem-cell properties of cancer stem cells. These results suggest that at least in some cases, inhibition of PRC2-mediated gene repression–including via targeting lncRNAs that recruit PRC2 to critical genes–is a potential strategy for treating various types of cancer.

RaNA’s R&D strategy

Not much information is available about RaNA’s strategy.  However, according to the January 2012 Mass High Tech article, RaNA Therapeutics has licensed technology from Mass General Hospital based on Dr. Lee’s research. The company has also filed several patent applications, some of which are described as being very broad. This includes patent applications on the existence and method of use of thousands of lncRNA targets. However, Dr. Lee’s published patent applications currently include only three items involving the X-chromosome inactivation system or TERC. Presumably, the patent applications mentioned in the Mass High Tech article will be published at the end of the 18-month publication period for U.S. patent applications.

According to the Mass High Tech article, RaNA is in the process of narrowing down the diseases it will initially focus on. Likely areas will include genetic diseases, including diseases that result from haploinsufficiency. In haploinsufficiency, one allele of a gene is nonfunctional, so all of the protein coded by the gene is made from the other allele. However, this results in insufficient levels of the protein to produce a normal phenotype. RaNA intends to use its technology to increase expression of the functional gene, resulting in a adequate dosage of the protein for a normal phenotype.

RaNA intends to choose one indication out of a short list of 20 diseases for internal R&D, and to seek collaborations for other indications. Dr. Krieg says that he hopes to have a collaboration by the end of 2012, and also to have Investigational New Drug (IND)-enabling safety studies on its internal drug candidate by the end of the year as well.

As one might expect, RaNA will target the appropriate lncRNAs using oligonucleotides, similar to how RNAi companies target mRNAs. Dr. Krieg, an oligonucleotide therapeutic development veteran, recruited some of his old oligonucleotide team from Pfizer into RaNA, according to a Fierce Biotech article. Thus Dr. Krieg and his team can quickly get up and running in designing and testing oligonucleotide therapeutics, once RaNA selects the targets for its initial focus.

In the Mass High Tech article, Dr. Krieg says that he believes that “oligonucleotides are on the cusp of being recognized as the third leg of drug development,” along with small-molecule and protein therapeutics. However, as we discussed in our August 22, 2011 article on this blog, oligonucleotide drug development, as exemplified by RNAi and microRNA-based therapeutics, has run into several technological hurdles, especially those involving drug delivery. The August 2011 article cites an editorial by Dr. Krieg, in which he voices his optimism despite these hurdles.

Nevertheless, large pharmaceutical companies and investors have been moving away from the oligonucleotide field. This is exemplified by Alnylam’s January 20, 2012 restructuring, which cut one-third of its work force and focused the company on two of its Phase 1 programs. Having exhausted its ability to capture major Big Phama licensing and R&D deals, Alnylam has had to become a normal early-2012 biotech company and focus its strategy. (However, Alnylam did a $86.9 million public offering in February 2012.)

The emergence of RaNA, and its $20.7 million funding, thus swims against the tide of the general pessimism about oligonucleotide therapeutics of Big Pharmas, investors, and stock analysts. However, at least some oligonucleotide therapeutics will eventually emerge onto the market, and lncRNA regulation is likely to be crucial to many disease pathways. RaNA is thus the pioneering company in this field.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

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“It’s not junk”–RaNA Therapeutics emerges from stealth mode with $20.7 million in venture funding-Part 1

Published by on March 29, 2012 | Leave a response

 

XIST Source: Alexbateman http://bit.ly/GZNTZg

 

On January 18, 2012, start-up company RaNA Therapeutics (Cambridge, MA) emerged from stealth mode with 20.7 million in cash. The Series A venture funding was co-led by Atlas Venture, SR One, and Monsanto, with participation of Partners Innovation Fund.

RaNA will work on developing a technology platform that involves targeting long noncoding RNA (lncRNA), in order to selectively upregulate gene expression.

Arthur Krieg, M.D. will serve as RaNA’s President and CEO. He is the former Chief Scientific Officer of the now-closed Pfizer Oligonucleotide Therapeutics Unit, who later became an Entrepreneur in Residence at Atlas Venture (Cambridge, MA). Dr. Krieg was mentioned in two of our previous Bippharmconsortium Blog articles, dated February 15, 2011 and August 22, 2011.

Atlas quietly nurtured RaNA while working to complete the Series A venture round. According to a January 18, 2012 article in Mass High Tech, the company plans to move into about 9,000 square feet of space “somewhere in Cambridge” in early 2012.  RaNA has approximately a dozen employees.

According to the Mass High Tech article, RaNA’s platform is based on technology developed by scientific founder Dr. Jeannie Lee (Massachusetts General Hospital/Howard Hughes Medical Institute, Boston MA).  Drs. Lee and Krieg and Atlas Ventures are cofounders of RaNA.

This is Part 1 of our discussion of RaNA Therapeutics.

RaNA and “junk DNA”

RaNA’s focus is related to what has traditionally been called “junk DNA”. As shown by work on the Human Genome Project and other genomics studies, only about 2-3 percent of the human genome consists of protein-encoding genes. Genomics researchers had not been able to identify a function for most of the remaining 97-98% of the human genome. This gave rise to the idea that these sequences consisted of parasitic DNA sequences that had no function whatsoever. Most researchers thus called these sequences “junk DNA”. Some of the leading lights of the genomics field gave presentations in which they dismissed this DNA as “junk”, and they even proposed models for how this “junk DNA” might accumulate during evolution. Then they would go on to discuss the “interesting” 2-3 percent.

However, the “junk DNA” concept was not really established science, but a hypothesis. I–among a few others–would call these sequences “DNA of unknown function”.

In more recent years, many researchers showed that at least the vast majority of DNA of unknown function was transcribed. Then researchers found a function for a relatively small percentage of these sequences–they are precursors of microRNAs and other small regulatory RNAs. These RNAs are related to the phenomenon of RNA interference (RNAi), which has been the subject of much basic research, including the Nobel Prize-winning research of Drs. Andrew Fire and Craig Mello. RNAi is the basis for various therapeutic RNAi drug discovery and development efforts at such companies as Alnylam, Silence Therapeutics, Quark Phamaceuticals, Dicerna, and Santaris, as well as several large pharmaceutical companies.

The majority of DNA sequences of unknown function, however, are transcribed into lncRNA. As exemplified by the first article ["Quantity or quality?", by Monika S. Kowalczyk and Douglas R. Higgs (University of Oxford)] in a point/counterpoint Forum published in the 16 February 2012 issue of Nature, many researchers postulate that at least most of these transcripts are nonfunctional. Transcription of these sequences might be, for example, at a low level, as the result of experimental artifacts or of exposure of sequences to the transcriptional machinery due to changes in chromatin during such processes as cell division or expression of nearby genes. This point of view moves the “junk DNA” hypothesis to the RNA level–now one might speak of “junk RNA”.

However, in the second article in the Nature Forum ["Patience is a virtue", by Thomas R. Gingeras (Cold Spring Harbor Laboratory)], the author counsels “patience” in carefully unraveling the function, one by one, of each noncoding RNA (ncRNA) transcript. According to Dr. Gingeras’ article, there are currently some 161,000 human transcripts, 53% of which are ncRNAs. About 2% of these ncRNAs are precursors to microRNAs. Approximately 10% of the transcripts are lncRNAs that map to intergenic and intronic regions, and many of these transcripts have been implicated in regulation — both of locally and at a distance— of developmentally important genes. Another 16% of the ncRNAs are transcripts of pseudogenes — genes that appear to have lost their original functions during evolution. Some of the pseudogene transcripts have been shown to regulate gene expression by acting as decoys for microRNAs. Despite this progress in assigning functions to ncRNAs, no function has yet been found for the majority of these transcripts. However, these are early days in the ncRNA field, so patience and openness to new discoveries is advisable.

The same 16 February 2012 issue of Nature contains a “Nature Insight” supplement on “Regulatory RNA”. Of particular interest with respect to the functions of lncRNAs is the review by Mitchell Guttman (Broad Institute and MIT, Cambridge MA) and John Rinn (Broad Institute and Harvard, Cambridge MA), entitled “Modular regulatory principles of large non-coding RNAs”. Among the lncRNAs discussed in that review are the X-inactive specific transcript (XIST) (see the figure above) and the telomerase RNA component (TERC). Both of these lncRNAs were identified and their functions determined in the 1990s–XIST in 1991  and TERC in 1995. XIST is expressed exclusively from inactive X chromosomes and is required for X inactivation in mammals. TERC is an essential RNA component of telomerase, the enzyme that replicates chromosome ends (telomeres). At the same time as the functions of XIST and TERC were beginning to be unraveled, most researchers were continuing to dismiss ncDNA as “junk”. Should they have known better?

The Guttman and Rinn review discusses several other lncRNAs with known, important functions, all of which were discovered since the pioneering work on XIST and TERC. Among the genes that encode these lncRNAs are HOTAIR and HOTTIP, which affect expression of the HOXD and HOXA gene family, respectively. HOX genes are a superfamily of evolutionarily conserved genes that are involved the determination of the basic structure of an organism. They encode transcription factors that regulate target genes by binding to specific DNA sequences in enhancers. The large intergenic non-coding RNA-RoR (lincRNA-RoR) modulates reprogramming of human induced pluripotent stem cells (iPS cells, which were discussed in earlier articles on this blog). The lncRNA NRON regulates transcription factors of the NFAT (nuclear factor of activated T-cells) family, which are involved in regulating the immune response, as well as in the development of cardiac and skeletal muscle, and of the nervous system. These genes have also been implicated in breast cancer, especially in tumor cell invasion and metastasis.

A common theme in the function of several lncRNAs, as highlighted in the Guttman and Rinn review, is association of the lncRNA with a chromatin-regulatory protein complex. The lncRNA serves to guide the regulatory protein complex to specific regions of chromatin. The protein complex then modifies specific histones in the chromatin regions, resulting in silencing of target genes.

In particular, HOTAIR serves as a molecular scaffold that binds to two protein complexes. A 5′ domain of HOTAIR binds polycomb repressive complex 2 (PRC2), and a 3′ domain of HOTAIR binds the CoREST–LSD1 complex. This enables the targeting of PRC2 and LSD1 to chromatin for coupled histone H3 lysine 27 methylation by PRC2 and histone H3 lysine 4 demethylation by LSD1. Both are required for proper repression of HOX genes.

XIST has at least two discrete domains, one involved in silencing (RepA) and the other in localization (RepC) of the XIST molecule on the X chromosome. The silencing domain RepA binds to PRC2, and the localization domain RepC binds to the YY1 protein and heterogeneous nuclear ribonucleoprotein U (hnRNP U).

The cases of HOTAIR and XIST are examples of how lncRNAs may function as molecular scaffolds of regulatory protein complexes. This may be general phenomenon, since a recent study by Drs. Guttman and Rinn and their colleagues indicates that about 30% of lincRNAs in mouse embryonic stem (ES) cells are associated with multiple regulatory complexes. In this study, the researchers found that RNAi knockdown of dozens of lincRNAs causes either exit from the pluripotent state or upregulation of specific differentiation programs. Thus lincRNAs appear to have important roles in the circuitry controlling the pluripotent state of ES cells, and in commitment to differentiation into specific lineages.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

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Preclinical-stage biotech Verastem goes public. Really‽

Published by on January 31, 2012 | Leave a response

 

Salinomycin

On November 3, 2011, Cambridge MA biotech firm Verastem announced that it was filing a prospectus for an initial public offering (IPO). At that time, the company was 15 months old.

Verastem is led by Christoph Westphal, MD, PhD, a founder and the former CEO of Sirtris and a veteran entrepreneur and venture capitalist. The IPO has been underwritten by UBS, Leerink Swann, Lazard Capital Markets, Oppenheimer & Co., and Rodman & Renshaw.

On January 27, 2012, Fierce Biotech reported that Verastem had announced the previous night that its IPO raised $55 million from the sale of 5.5 million shares at $10 apiece. This price fell exactly in the middle of its expected $9 to $11 price range, and the company had even increased the offering by a million shares over what had originally been planned.

On the same day, Verastem’s stock opened at $11 a share on the NASDAQ, up from its initial public offering price of $10.

Verastem not only has Christoph Westphal as its Chairman and CEO, but is also based on science from eminent MIT researchers Robert Weinberg, Ph.D. and Eric Lander, Ph.D., and has several other well-respected academic researchers (including Nobelist Phillip Sharp, Ph.D.) plus biotech industry drug discoverers Julian Adams, Ph.D. (MIllennium’s Velcade) and Roger Tung, Ph.D. (Vertex’ Lexiva and Agenerase) on its Scientific Advisory Board. The company has had considerable fundraising success prior to its IPO, including raising $32 million in venture capital  in July 2011.

However, Verastem has not one lone drug in human clinical trials, its most advanced compounds are in the preclinical stage, and the company does not plan to file an IND until 2013! Thus Verastem has successfully gone public, in an era in which even most private biotech companies with drugs in late-stage clinical trials are finding it very difficult to do so, despite its lack of any clinical-stage drugs.

As noted in the Fierce Biotech article, Dr. Westphal as well as other venture capital funders of Verastem agreed to buy up to $16.3 million of the IPO. This in part explains the success of the IPO. As also noted by Fierce Biotech, with over 19 million common shares outstanding, the offering valued Verastem at $192 million.

We discussed Verastem in our August 2, 2011 Biopharmonsortium Blog article entitled “Development of personalized therapies for deadly women’s cancers”. Verastem focuses on discovery and development of drugs to target cancer stem cells. Its technology is based on a strategy for screening for compounds that specifically target cancer stem cells, developed by Drs. Weinberg, Lander, Piyush Gupta (MIT and Broad Institute) and their colleagues.

Cancer stem cells are best known in acute myeloid leukemia (AML), but their existence in other cancers (especially solid tumors) is controversial, as discussed in our article. Whether cancer stem cells are involved in the pathobiology of solid tumors (or a particular type of solid tumor) or not, the biology of the putative cancer stem cell phenotype can be important in certain subtypes of cancer. Cancer stem cells are characterized by the epithelial-mesenchymal transition (EMT). In the Cell paper, the researchers screened for compounds that specifically targeted breast cancer cells that had been experimentally induced into an EMT, and which as a result exhibited an increased resistance to standard chemotherapy drugs.   They identified the compound salinomycin (now being marketed as a generic veterinary antibiotic) as a drug that specifically targeted these cells, as well as putative cancer stem cells from patients.

As we discussed in our article, triple-negative (TN) breast cancer cannot be treated with standard receptor-targeting breast cancer therapeutics (e.g., tamoxifen, aromatase inhibitors, trastuzumab) but must be treated with cytotoxic chemotherapy. It is generally more aggressive than other types of breast cancer, and even treatment with aggressive chemotherapy typically results in early relapse and metastasis. However, TN breast cancer includes two experimentally defined subtypes that have gene expression signatures related to the EMT. One or both of these subtypes might therefore be expected to be sensitive to compounds that specifically target putative breast cancer stem cells. This may be true whether the cancer stem cell hypothesis applies to TN breast cancer or not. Verastem is focusing on TN breast cancer as its first therapeutic target.

Verastem’s VS-507, a proprietary formulation of salinomycin, is being developed to treat TN breast cancer. The company is also screening for additional compounds, including New Chemical Entities (NCE) that can achieve stronger intellectual property protection than a salinomycin formulation. Verastem had not chosen a lead compound as of the middle of 2011. The company is now reported to be doing preclinical studies on three of its compounds, and also plans to create diagnostic tests to identify patients that could benefit from its treatments. (As we discussed in our article, biomarker-based tests will be critical in making such therapies work.)

As one can discern from our blog article, we are intrigued by Verastem’s approach to cancer treatment, and especially its approach to TN breast cancer. The science behind Verastem’s drug discovery strategy, developed by 2011 ASCO award-winning oncogene and cancer stem-cell pioneer Bob Weinberg, is very compelling. We would love to see Verastem’s therapeutic strategy succeed.

However, as virtually all pharmaceutical and biotechnology R&D researchers well know, it is difficult to translate even the most compelling science developed by the most brilliant researchers into the clinic. Even therapeutic strategies with an excellent scientific rationale that have achieved proof of principle in the best animal models can result in clinical failure, especially with the first compound tested in proof-of-concept studies in human patients. The cancer stem cell hypothesis remains controversial. Moreover, diseases such as TN breast cancer are complicated, they may have mechanisms of resistance to a new experiential therapy that no one knows about, and our understanding of disease biology is limited.

Thus at least until Verastem’s therapies achieve proof of concept in human studies, purchase of Verastem stock is risky indeed. Moreover, there are other risks involved other than technical and clinical risk–especially competition for developing cancer stem cell-based therapies by other biotech/pharma companies. Venture capitalists (and certain knowledgeable individual investors and funds) are in the business of taking on high-risk investments for the sake of potential large rewards, but ordinary retail investors in the public markets are not. Therefore, it seems too early for Verastem to go public, even if it has founders and investors with enough clout to make an IPO successful.

Expert analysts in the IPO field, as stated in the Fierce Biotech article, are puzzled by the rationale for Verastem going public at this time. The financial news and services website “TheStreet.com” agrees. Our own sense of puzzlement is symbolized by the interobang (‽) in the title of this article.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

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The Big Pharma retreat from RNAi therapeutics continues

Published by on August 22, 2011 | Leave a response

 

Source: Narayanese. http://bit.ly/oi10H1

On July 29, 2011, Merck announced that It was shutting down the San Francisco research laboratory that it had acquired as part of its $1.1 billion acquisition of therapeutic RNAi specialist company Sirna Therapeutics. This announcement was covered in a July 29, 2011 article in Xconomy, and in a news brief in the 4 August issue of Nature and a linked Nature news blog article.

According to the Xconomy article, the shutdown will include the loss of around 50 jobs. Around ten people are being offered transfers to other Merck facilities in nearby Palo Alto CA and on the East Coast.

The Merck facility shutdown continues the exit or retrenchment from therapeutic RNAi research at other Big Pharma companies. The Biopharmconsortium Blog has covered these moves at Roche and Pfizer.

As we discussed in the Roche article, Novartis had also decided to end its 5-year partnership with therapeutic RNAi specialty company Alnylam In September 2010. However, Novartis acquired technology and exclusive development rights for RNAi therapeutics against 31 targets for in-house use as the result of its partnership with Alnylam.  Alnylam is entitled to receive milestone payments for any RNAi therapeutic products that Novartis develops based on these targets. Thus Novartis is still involved in RNAi therapeutics, despite the termination of the Alnylam partnership.

Moreover, according to the Nature news blog, Ian McConnell of Merck’s Scientific Affairs, R&D and Licensing and Partnerships said that Merck will continue to have over 100 scientists working on RNA-based therapeutics, and that it continues to invest significantly in the field. Closing the San Francisco lab represents an effort to trim the budget by eliminating the cost of maintaining a separate RNAi facility.

In our previous blog articles on Big Pharma RNAi therapeutics retrenchment, and in our October 2010 book -length report, RNAi Therapeutics: Second-Generation Candidates Build Momentum, we discussed the strategic issues that are involved in undertaking (or in retrenching from) R&D programs in RNAi therapeutics, and in investing in that area. The therapeutic RNAi (and microRNA) field represents an early-stage area of science and technology. The field may be technologically premature, as was the monoclonal antibody (MAb) drug field in the 1980s.

Big Pharma originally got into RNAi therapeutics in order to help fill weak pipelines, and with the hope of staking out a commanding position in the RNAi field once it became successful. However, with the short-term pressure at Big Pharma companies to cut expenses and programs, Big Pharmas have been losing the needed patience to continue with a technologically premature field like RNAi therapeutics.

In the June 2011 issue of Molecular Therapy, there is an editorial by Arthur Krieg, M.D. (former Chief Scientific Officer of the now-closed Pfizer Oligonucleotide Therapeutics Unit, and now Entrepreneur in Residence at Atlas Venture, Cambridge, MA), entitled “Is RNAi dead?” As discussed in the editorial, the move of Big Pharma away from RNAi, according to some observers, signals the death of the therapeutic RNAi platform. Dr. Krieg outlines an alternative view.

According to Dr. Krieg, Big Pharmas got into RNAi therapeutics with the hope of enabling the rapid development of targeted drugs without the long time lags and uncertainties of small molecule drugs and biologics. In theory, if a research team has a good target, it could rationally design a lead RNAi drug specific for the target and ready for human clinical trials within 15 months. And researchers would not have to worry about “undruggability” of targets. However, there have been several unforeseen hurdles to the development of RNAi drugs, the most formidable of which is the issue of drug delivery. Although certain high-profile publications suggested that the challenge of RNAi drug delivery could be easily overcome, this proved not to be the case in practice.

However, Dr. Krieg believes that the progress in RNAi delivery in recent years has been “nothing short of spectacular”. In 2008, the best RNAi delivery systems for a liver target might have an IC50 (i.e., the RNAi dose required for 50% inhibition of target expression) of 1–3 mg/kg, but in 2010/2011, the IC50 has been reduced to about 1% of this value, which is an improvement of two logs. Dr. Krieg also says that there have also been significant advances in reducing off-target and other undesired systemic effects of RNAi therapeutics in animal models in recent years.

Nevertheless, the advances in RNAi delivery and safety are moving too slowly for Big Pharma’s current short-term mindset. According to Dr. Krieg, if companies are not able to take an RNAi drug into clinical development this year, then the next time there is an R&D portfolio review, investments in “high-risk” technology platforms such as RNAi are likely to be cut. As we have discussed in this blog, and as is well-known to most of you, every Big Pharma company has been cutting R&D and shedding poorly productive and high-risk programs. The focus at many Big Pharmas is on fast, sure returns. High-risk or premature technologies that have not yet yielded any marketed drugs, such as RNAi (and for example, stem cells/regenerative medicine) is not likely to offer such returns.

Dr. Krieg also notes that in the case of another once-premature technology, monoclonal antibody (MAb) drugs, it took several waves of technology development to advance from repeated clinical failure to one of the most successful classes of drugs today. In our view, MAb technology is the classic case (in the life sciences, anyway) of how researchers and companies can take such a premature technology up the technology curve by developing enabling technologies. We discussed this case in our September 28, 2009 blog article, and its applicability to RNAi and stem cells in our July 13, 2009 blog article. As discussed in these articles, and as noted by Dr. Krieg, it was not Big Pharmas, but biotech companies “on the cutting edge” (together with academic labs) that advanced the therapeutic MAb field. Big Pharmas later bought into the MAb field, typically by large acquisitions. This is especially exemplified by the acquisition of MAb drug leader Genentech by Roche.

With respect to RNAi, as mentioned above, at least Merck and Novartis among the Big Pharmas are continuing with in-house RNAi therapeutics programs. And such biotechs as Alnylam, Silence Therapeutics, Quark Phamaceuticals, Dicerna, and Santaris have RNAi and/or microRNA-based drug candidates in clinical trials, often partnered with Big Pharma companies (such as Pfizer) that have cut or reduced their own RNAi drug programs. Therefore, there are companies that are working on advancing RNAi therapeutics up the technology curve. As Dr. Krieg says in his editorial, success in such programs will be expected to lead to Big Pharma reinvestment in RNAi/microRNA therapeutics, just as in the case of MAb drugs.

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Development of personalized therapies for deadly women’s cancers

Published by on August 2, 2011 | Leave a response

 

Two recent research reports may point the way to developing more effective, personalized therapies for two deadly women’s cancers for which their are currently few treatment options–triple-negative breast cancer and ovarian cancer. The approach followed in both reports is to use gene expression analysis to stratify each of the two diseases into subtypes. Researchers can then use gene expression and order aspects of the biology of each subtype to design subtype-specific targeted therapies, whether single drugs or drug combinations. If the drugs (whether approved or experimental) already exist, they can be tested in clinical trials, stratified by subtype. If no appropriate drugs exist, researchers can discover the drugs based on subtype-appropriate drug targets.

Triple-negative (TN) breast cancer refers to breast cancers that are negative for expression of estrogen receptor (ER), progesterone receptor (PR), and HER2. [HER2 is the target of trastuzumab (Roche/Genentech's Herceptin) and lapatinib (GlaxoSmithKline's Tykerb/Tyverb)]. Lacking all three receptors, it cannot be treated with standard receptor-targeting breast cancer therapeutics (e.g., tamoxifen, aromatase inhibitors, trastuzumab) but must be treated with cytotoxic chemotherapy. TN breast cancer is generally more aggressive than other types of breast cancer, and even treatment with aggressive chemotherapy regimens typically results in early relapse and metastasis.

TN breast cancers constitute approximately 25 percent of breast cancers. They are diagnosed most often in younger women, those who have recently given birth, women with BRCA1 mutations, and African-American and Hispanic women.

There is a Triple Negative Breast Cancer Foundation, which was founded in 2006 in honor of a mother in her mid-thirties who died of the disease.

Ovarian cancer, the ninth most common cancer in women, caused nearly 14,000 deaths in the U.S. in 2010. In its earliest stages, its symptoms are usually very subtle and mimic other, less serious diseases. As a result, it is usually detected at later stages in which treatment is more difficult and gives poorer outcomes. The 2001 five-year survival rate was 47%, up from 38% in the mid-1970s. This compared to an overall survival rate for cancer of 68% in 2001, up from 50% in the mid-1970s.

Treatment usually involves surgery and chemotherapy, and sometimes radiotherapy. Surgery (preferably by a gynecological oncologist) may be sufficient for earlier-stage tumors that are well-differentiated and confined to the ovary. In this early-stage disease (which represents about 19% of women presenting with ovarian cancer), the five-year survival rate is 92.7%. However, about 75% of women presenting with ovarian cancer already have stage III or stage IV disease, in which the cancer has spread beyond the ovaries. Then the prognosis is much poorer, and the vast majority of patients will have a recurrence.

The triple-negative breast cancer study

The TN breast cancer study was carried out by researchers at the Vanderbilt-Ingram Cancer Center (Vanderbilt University, Nashville, TN), and published in the 1 July 2011 issue of the Journal of Clinical Investigation. In this study, the researchers analyzed gene expression profiles from 21 publicly available breast cancer data sets, and identified  587 cases of TN breast cancer (by non-expression of mRNAs that encode ER, PR, and HER2). Using cluster analysis, they identified six TN breast cancer subtypes:

  • two basal-like subtypes (BL1 and BL2),
  • an immunomodulatory (IM) subtype (i.e., expressing genes involved in immune cell processes)
  • a mesenchymal (M) subtype
  • a mesenchymal stem–like (MSL) subtype
  • a luminal androgen receptor (LAR) subtype.

Using gene expression analysis, the researchers identified TN breast cancer model cell lines that were representative of each of these subtypes. On the basis of their analysis, the researchers predicted “driver” signaling pathways, and targeted them pharmacologically as a proof-of-principle that analysis of gene expression signatures of cancer subtypes can inform selection of therapies.

BL1 and BL2 subtypes had higher expression of genes involved in the cell cycle and response to DNA damage, and model cell lines preferentially responded to cisplatin. M and MSL subtypes were enriched for expression of genes involved in the epithelial-mesenchymal transition (EMT), and growth factor-related pathways in model cell lines responded to the PI3K/mTOR inhibitor BEZ235 (Novartis, now in Phase 1 and 2 for solid tumors) and to the ABL/SRC inhibitor dasatinib [Bristol-Myers Squibb's Sprycel, currently approved for treatment of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL), and under investigation for treatment of solid tumors). The LAR subtype was characterized by androgen receptor (AR) signaling, and included patients with decreased progression-free survival. LAR model cell lines were uniquely sensitive to the AR antagonist bicalutamide (AstraZeneca's Casodex/Cosudex, currently approved for the treatment of prostate cancer and hirsutism, and under investigation for treatment of androgen receptor-positive, ER negative, PR negative breast cancer).

The researchers plan to use the TN breast cancer subtype-specific model cell lines for further molecular characterization, to identify new components of the “driver” signaling pathways for each subtype. These pathways can be targeted in further drug discovery efforts. The subtype-specific cell lines can also be used in preclinical studies with targeted agents, and in identification of subtype-specific biomarkers that can potentially be used in stratifying TN breast cancer patients so that they might be treated with the best agents for their disease.

The ovarian cancer study

The ovarian cancer study was carried out by the Cancer Genome Atlas Research Network [a consortium of academic researchers jointly funded and managed by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI)], and published in the 30 June 2011 issue of Nature. In this study, the researchers analyzed mRNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas, as well as the DNA sequences of exons from coding genes in 316 of these tumors. Serous adenocarcinoma is the most prevalent form of ovarian cancer, accounting for about 85 percent of all ovarian cancer deaths.

The researchers found that nearly all of the high-grade serous ovarian cancers (HGS-OvCa) studied had mutations in the TP53 gene, which encodes the p53 tumor suppressor protein. On the basis of their gene expression (mRNA) signatures, the researchers divided the population of HGS-OvCa into four subtypes:

  • an immunoreactive subtype (i.e., expressing genes involved in immune cell processes)
  • a differentiated subtype (high expression of markers of differentiated female reproductive tract epithelia)
  • a proliferative subtype (high expression of markers of cell proliferation)
  • a mesenchymal subtype (high expression of HOX genes and of markers of mesenchymal-derived cells)

The researchers also determined subtypes on the basis of microRNA expression and promoter methylation. microRNA subtype 1 overlapped the mRNA proliferative subtype and miRNA subtype 2 overlapped the mRNA mesenchymal subtype. Patients with miRNA subtype 1 tumors survived significantly longer that those with tumors of other microRNA subtypes.

Although the researchers found no significant difference in survival between the four transcriptional subtypes, they did identify a 193-gene expression signature that was predictive of overall survival. 108 genes were correlated with poor survival and 85 were correlated with good survival.

The researchers identified cancer-associated pathways in the HGS-OvCA population; this is equivalent to the prediction of “driver” signaling pathways in the TN breast cancer study. They found that 20% of the HGS-OvCA samples had germline or somatic mutations in BRCA1 or BRCA2, and that 11% lost BRCA1 expression through DNA hypermethylation. As we discussed in an earlier article on this blog, BRCA1- or BRCA2-negative tumor cells cannot repair their DNA via homologous recombination. They are dependent on an alternative pathway of DNA repair, which involves the enzyme poly(ADP) ribose polymerase (PARP). These tumors are thus sensitive to a class of drugs known as PARP inhibitors, such as KuDOS/AstraZenaca’s olaparib. There are now six PARP inhibitors, including olaparib, in clinical development.

The researchers found genetic alterations in several other genes involved in homologous recombination. Altogether, defects in homologous recombination may be present in approximately half of HGS-OvCa cases, and these tumors may be sensitive to PARP inhibitors. This provides a rationale for clinical trials of PARP inhibitors in women with ovarian cancers with defects in homologous recombination-related genes.

Olaparib and other PARP inhibitors are in clinical trials in women with advanced with BRCA-1 or -2 mutations and with other defects in homologous recombination. As discussed in the 2011 ASCO meeting, early Phase 2 results indicate that olaparib gives dramatic improvements in progression-free survival in these women. (See this article and this video.) In these studies, in addition to tumors with genetic defects in homologous recombination, olaparib or another PARP inhibitor, Abbott’s ABT-888, appears to give improved progression-free survival in women who have previously been treated with chemotherapy drugs that result in DNA damage. This suggests that oncologists may be able to use a “one-two punch”, consisting of a DNA-damaging drug [such as the alkylating agent temozolomide [Merck's Temodar]) followed by a PARP inhibitor, to treat advanced ovarian cancer.

In addition to BRCA-1 and BRCA-2 mutations and other genetic alterations that result in defects in homologous recombination, the HGS-OvCa population exhibited genetic changes that would result in deregulation of several other cancer related pathways. These pathways included the RB1 (67% of cases), RAS/PI3K (45% of cases), and NOTCH (22% of cases) pathways, as well as the FOXM1 transcription factor network (87% of cases). All of these pathways represent opportunities for target identification and drug discovery. FOXM1 (Forkhead box protein M1) was named the Molecule of the Year for 2010 by the International Society for Molecular and Cell Biology and Biotechnology Protocols and Research (ISMCBBPR) because of “its growing potential as a target for cancer therapies.” FOXM1 overexpression results in destabilization of the cell cycle, which can lead to a malignant phenotype.

The researchers also identified 22 genes that were frequently amplified or overexpressed in HGS-OvCA tumors (other than genes that are involved in homologous recombination). Inhibitors (including approved and experimental compounds) already exist for the products of these genes, and researchers might assess these compounds in HGS-OvCa cases in which target genes are amplified.

Can Verastem develop new therapeutics for triple negative breast cancer?

The private biotechnology company Verastem (Cambridge, MA) focuses on discovery and development of drugs to target cancer stem cells. The company was founded in 2010, and is based on a strategy for screening for compounds that specifically target cancer stem cells. This strategy, published in the journal Cell in 2009, was developed by Drs. Robert Weinberg (MIT Whtehead Institute), Eric Lander (Broad Institute of MIT and Harvard University), and Piyush Gupta (MIT and Broad Institute) and their colleagues. Drs. Weinberg, Lander, and Gupta are on the Scientific Advisory Board of Verastem.

On July 14, 2011, Verstem announced that it had raised $32 million in a Series B financing. Verastem had previously raised $16 million from a group led by former Christoph Westphal’s Longwood Founders Fund. Dr. Westphal (formerly of Sirtris) is now Chairman of Verastem.

Cancer stem cells are best known in acute myeloid leukemia (AML), but their existence in other cancers (especially solid tumors) is controversial. The cancer stem cell hypothesis asserts that a small subpopulations of cells in a leukemia or solid tumor have characteristics that resemble normal adult stem cells, such as self renewal, the ability to give rise to all the cell types found in the leukemia or cancer, and stem cell markers. The hypothesis further asserts that most cancer treatments fail to knock out cancer stem cells, which can repopulate a tumor cell population, resulting in treatment relapses. Cancer stem cell researchers therefore propose developing cancer stem-cell specific therapeutics that can be used to eliminate these cells, which can block these relapses.

Whether cancer stem cells are involved in the pathobiology of solid tumors or not, the biology of the putative cancer stem cell phenotype can be important in certain subtypes of cancer. Cancer stem cells are characterized by the epithelial-mesenchymal transition (EMT), and in the Cell paper the researchers screened for compounds that specifically targeted breast cancer cells that had been experimentally induced into an EMT, and which as a result exhibited an increased resistance to standard chemotherapy drugs.   They identified the compound salinomycin as a drug that specifically targeted these cells, as well as putative cancer stem cells from patients.

As discussed earlier in this article, TN breast cancer includes two subtypes that have gene expression signatures related to the EMT: the mesenchymal (M) subtype and the mesenchymal stem–like (MSL) subtype. One or both of these subtypes might be sensitive to compounds that specifically target putative breast cancer stem cells. This may be true whether the cancer stem cell hypothesis applies to TN breast cancer or not. Verastem recognizes this, and is thus focusing on TN breast cancer as its first therapeutic target. The Vanderbilt TN breast cancer study suggests that trials of any “cancer stem cell-specific” therapeutics for TN breast cancer should be guided by subtype-specific biomarkers.

Hope for treatment of TN breast cancer and advanced ovarian cancer

Researchers and oncologists have made great strides in increasing the percentage of breast cancers that are treatable or even curable in recent years. For example, prior to the FDA approval of trastuzumab in 1998, HER2 positive breast cancer carried a grim prognosis. But the advent of trastuzumab (and later, lapatinib) has had a major impact on treatment of this once uniformly deadly type of breast cancer.

We hope that the new, personalized medicine-based approach to TN breast cancer and advanced serous ovarian adenocarcinoma will also result in successful new therapeutic strategies for these deadly women’s cancers.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

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Pfizer makes massive R&D cuts, and exits RNAi and regenerative medicine therapeutics

Published by on February 15, 2011 | Leave a response

Piwi-siRNA base pairing. Source: Narayanese http://bit.ly/eEtQQR

In our November 23, 2010 blog post, we discussed Roche’s November 2010 R&D cuts, especially its decision to discontinue R&D in RNAi therapeutics. This had followed closely on the October 2010 publication of our report RNAi Therapeutics: Second-Generation Candidates Build Momentum (Insight Pharma Reports, Cambridge Healthtech Institute). Our report included a discussion of Big Pharma efforts in therapeutic RNAi R&D, specifically including Roche.

Now a second Big Pharma with a significant internal therapeutic RNAI R&D project area covered in our report, Pfizer, announced on February 1, 2011, that it was exiting therapeutic RNAi R&D. This was a small part of a global R&D restructuring plan aimed at saving the company $1.5 billion. The new R&D cuts at Pfizer will eliminate an estimated 3500 jobs worldwide, and will close Pfizer’s large R&D facility in Sandwich, U.K. (eliminating 2400 jobs) and eliminate 1100 jobs at its large R&D facility in Groton, Connecticut.

In addition to exiting RNAi therapeutics research, Pfizer is also discontinuing most of its regenerative medicine research. Both research groups are located at the company’s Memorial Drive laboratory in Cambridge, MA, which will be closed, resulting in approximately 100 layoffs.

Other areas to be discontinued include allergy and respiratory medicine and internal medicine (located in Sandwich), and antibacterials (located in Groton). Pfizer will focus its R&D efforts in neuroscience, cardiovascular, metabolic and endocrine diseases, inflammation and immunology, oncology, and vaccines. The company will create new units in pain and sensory disorders, biosimilars, and Asia R&D. Pfizer’s regenerative medicine group in Cambridge, UK (which had been focusing on development of preclinical embryonic stem (ES) cell-based ophthalmology therapies, in collaboration with the University of London) will be folded into the new pain and sensory disorder research unit.

Although Pfizer will be closing the Memorial Drive laboratory in Cambridge, MA, it intends to expand its R&D efforts in Cambridge/Boston, creating an estimated 450 new jobs. Cardiovascular and neuroscience units will be moved from Groton to a new facility (yet to be acquired or built) in Cambridge/Boston. Pfizer will also maintain its manufacturing and research facility in Andover, MA, which specializes in biologics. Pfizer plans for its R&D units in Cambridge/Boston to interact more intensively with the local biomedical research and entrepreneurial community.

Pfizer’s Sandwich laboratories have long served as the company’s center for small-molecule drug discovery. Researchers at Sandwich discovered such drugs as the erectile dysfunction treatment Viagra, the blood pressure medicine Norvasc, and the antifungal Diflucan.

According to company spokespeople, it is possible that Pfizer might partner, out-license, or spin off some of its discontinued research programs. And some venture capitalists also expect to see new biotech companies emerge, at least from the Sandwich site.

This latest Pfizer R&D restructuring is on top of the 15% of its 128,000 employees Pfizer laid off over the past two years after its acquisition of Wyeth. In late 2009, the company said it was closing six of its 20 research sites as it reduced its R&D operations by 35%. A major factor in the latest round of layoffs and facility closings is the impending loss of patent protection (in Novemer 2011) for Pfizer’s largest-selling drug, the cholesterol-lowering agent Lipitor (atorvastatin). This is coupled with Pfizer’s R&D productivity deficit, and resulting inability to bring enough large-selling drugs to market to maintain its growth.

According to Pfizer’s new CEO, Ian C. Read, “The most fundamental question that Pfizer has to fix is our innovative core. This [restructuring] is the start of fixing that in a way that will give us consistent productivity in our innovation.” Read further says that the company’s goal is to stop putting resources into high-risk areas that provide a low return on investment or where Pfizer lacks the expertise to compete.

Pfizer’s exit from RNAi and regenerative medicine: the issue of technological prematurity

The RNAi therapeutics research and biotech company community, is as expected focused on Pfizer’s discontinuation of its efforts in this area. Even the New York Times has echoed this emphasis, with an article that is marred by several erroneous statements. [For example, in humans the RNAi pathway, although one of its functions is defense against viruses (as stated in the article), is mainly involved in a fundamental process of cellular regulation, principally via microRNAs.] Pfizer’s exit from the RNAi therapy field comes on the heels of the discontinuation of therapeutic RNAi research at Roche, and of Novartis’ termination of its 5-year partnership with Alnylam. According to  Dirk Haussecker’s RNAi Therapeutics blog, Big Pharmas have decided to exit internal development of RNAi technologies and drugs, and to wait to partner with or acquire RNAi specialty companies as their RNAi therapeutics programs yield meaningful clinical results. (Even Pfizer already has two external RNAi collaborations, with Quark and Tacere.) Dr. Haussecker himself plans to blog less, and only resume blogging as clinical results come in.

Despite this focus on Pfizer’s RNAi discontinuation by RNAi researchers and some journalists, Pfizer’s exit from RNAi therapeutics R&D is a small part of the company’s restructuring. It should therefore be put into the context of the strategic intent of the company’s restructuring as a whole. From our point of view, it is significant that Pfizer is discontinuing not only RNAi therapeutics R&D, but also regenerative medicine R&D.

The very first article on this blog, dated July 13, 2009, is entitled “RNAi, embryonic stem cells, and technological prematurity”. Both RNAi therapeutics and ES cell research (the latter of which includes induced pluripotent stem cells as well as ES cells per se, and which is the basis for Pfizer’s regenerative medicine R&D) are technologically premature, or at the very least very early-stage technologies. (Regenerative medicine based on adult stem cells is also technologically premature.) As the New York Times article–among others–points out, monoclonal antibody (MAb) therapeutics took 20 years from the time of the discovery of MAbs to achieve market success, and RNAi therapeutics might have a similar timeline. So might regenerative medicine based on stem cell technology.

However, a premature technology is not simply a technology that takes a long time to be translated into successful products. It is a technology that requires development of enabling technologies to overcome hurdles to development, and to move the technology up the development curve. MAb therapeutics represented a classic case of a premature technology. We discussed the history of the MAb therapeutics field in our September 28, 2009 blog article. Successful enabling technologies for MAb therapeutics began to be developed in the early 1980s, by biotechnology companies and by academic laboratories. Some of these companies eventually became leaders in the MAb field.

Arguably the most successful MAb development company, Genentech, developed enabling technologies in collaboration with academic researchers beginning in the early 1980s. But Genentech’s first MAb products, the highly successful antitumor agents Rituxan (codeveloped with Idec) and Herceptin, did not reach the market until 1997 and 1998, respectively. Roche purchased a majority stake in Genentech in 1990, when Genentech needed an infusion of capital to complete clinical development of its MAb products. In 2009, Roche moved to fully acquire Genentech, which now operates as a wholly-owned subsidiary. Most of the other leaders in the MAb therapeutics field were acquired by Big Pharmas or Big Biotechs in the late 1990s, after the MAb field became successful.

The take-home lessons for RNAi therapeutics and stem cell-based regenerative medicine R&D are that enabling technologies are necessary to move these fields up the technology development curve as well. In the case of RNAi therapeutics, specialty biotech companies in that area have been busy working on such enabling technologies, in two principal areas–design of the oligonucleotide molecules themselves, and delivery technologies. With respect to oligonucleotide design, certain types of chemical modifications enabled researchers to develop siRNAs (small interfering RNAs) that do not trigger an innate immune response. The immunogenicity of early siRNA drug candidates was a significant hurdle to the development of siRNA therapeutics. The New York Times article sounds as if the problem of immunogenicity of siRNAs has not been overcome, which is not true.

Ironically, the article quotes Arthur Krieg, the head of the RNAi group at Pfizer, in support of this contention. But although Dr. Krieg did the studies quoted in the article that showed the extent of the problem of immunogenicity in early siRNA candidates, he himself is one of the researchers who developed means to overcome this problem. Dr. Kreig came to Pfizer via the company’s 2008 acquisition of Coley Pharmaceuticals, where he was the head of R&D. Coley was focused on developing RNA-based immunotherapeutics, so Dr. Kreig is a leader in the field of RNA-mediated immunogenicity. As a result of the Coley acquisition, Pfizer has been developing oligonucleotide vaccine adjuvants, which are now in Phase III trials and have been licensed to GlaxoSmithKline.

Even when enabling technologies that ultimately prove to be successful have been developed, it typically takes many years before this produces promising clinical results, let alone approved drugs. The example of Genentech, which developed its patented MAb enabling technology platform in the early 1980s, but produced no marketed drugs based on that technology platform until the late 1990s, is illustrative of this point. (Of course, the long timeline to produce any marketed drug, from initial drug discovery to approval, is a large part of the reason for this time gap.) Therefore, any company that undertakes to develop products based on an exciting, but premature, technology must be both highly creative and very patient–and have patient capital behind it. An infusion of capital as such a company moves into the clinical phase–as with Roche’s 1990 equity investment in Genentech, helps as well.

The reward for companies that develop products based on a premature technology is that such a company may become a leader in an important new area of technology, with a large market. However, the risk of undertaking such a course of action is high.

As we discussed in our 2010 RNAi therapeutics report, Big Pharma was interested in getting into RNAi therapeutics, despite the field’s risks, in part because of its past experience with MAbs and other biologics. Because Big Pharma companies had failed to get into the now highly successful biologics field early, acquiring a major stake in that field had been expensive. Seeing the promise of RNAi therapeutics, Big Pharmas were therefore eager to get into RNAi therapeutics early, in the hope of capturing a commanding position in the field once drugs reached the market.

However, with any RNAi drugs still far in the future, and with their increasing short-term pressures, Big Pharmas have been losing the needed patience to continue with a technologically premature field like RNAi therapeutics. Therefore. their interest has been cooling. As (according to the New York Times article) Klaus Stein, head of therapeutic modalities for Roche, said, “I have no doubt that at a certain point in time RNAi will make it to the market….[but] when we looked into this, we came to the conclusion that we have opportunities that have higher priorities.”

Meanwhile, R&D and dealmaking continues in the small RNAi and microRNA specialty companies. For example, on February 3, 2010, it was announced that RNAi specialty firm Marina Biotech (Bothell, WA) entered into an agreement with Swiss biotech development group Debiopharm to develop and commercialize Marina’s preclinical RNAi-based therapy for bladder cancer. The deal is worth up to $25 million to Marina, based on predefined R&D milestones and royalties on the sales of products resulting from the agreement. Also in February 2010, Marina raised $5.1 million in a new public offering, and plans to use the proceeds to fund development of a drug candidate for familial adenomatous polyposis (FAP).

Preclinical and clinical studies are also continuing at such leading RNAi or microRNA therapeutics companies as Alnylam, Tekmira, Quark, RXi, Silence, Calando, Dicerna, Regulus, Santaris, and miRagen. If and when the products of these companies reach late-stage trials or commercialization, Big Pharmas may have to partner for or acquire these products or companies on a similar basis as for biologics in the last decade. A  key question is whether the RNAi/microRNA therapeutic sector can raise enough capital to fund its R&D, now that several Big Pharmas’ exit from the field appears to have dampened investors’ interest.

Pfizer’s restructuring strategy as a whole

As for Pfizer’s restructuring as a whole, we discussed the Big Pharma strategy of attempting to deal with loss of revenues from aging blockbusters and the lack of R&D productivity via megamergers, restructuring, and outsourcing in our February 19, 2010 blog post. Earlier megamergers, such as Pfizer’s acquisitions of Warner-Lambert in 2000 and of Pharmacia in 2002, followed by restructurings, enabled Pfizer to acquire blockbuster products (including Lipitor) and to realize significant cost savings from staff reductions. However, the continuing lack of productivity in R&D and the looming patent expiration of Lipitor and other large-selling drugs, motivated Pfizer management to enter into yet another megamerger, with Wyeth in 2009.

However, the Wyeth acquisition has not altered Pfizer’s fundamental issues. R&D productivity remains low, and Pfizer is the Big Pharma company that is most affected by upcoming patient expirations. Patent expirations are expected to expose approximately two-thirds of Pfizer’s total sales to generic competition over the next three years. This is mainly due to Pfizer’s dependence on revenues from Lipitor.

Meanwhile, Pfizer is maintaining its stock price not only by R&D retrenchment, but by spending $5 billion to buy back its own stock. The combination of cutting R&D and stock buy-backs is popular with investors. As of February 4, Pfizer’s stock was up 5.2% since the February 1 announcement of the R&D cuts and stock buy-back. In contrast, Merck’s new CEO Ken Frazier said on February 3 that that company would not make the cuts necessary to meet its long-term earnings forecasts. Instead, it would focus on investing in pharmaceutical R&D to drive future growth. Merck’s stock dropped 2.7% that day. However, Pfizer’s stock buy-back and R&D cuts only provide temporary relief, since they do not alter the fundamentals.

Meanwhile, the “other Merck”, Merck KGaA (Darmstadt, Germany), is expanding its R&D. This includes expansion of the company’s facility in Billerica, MA, where it will hire about 100 new researchers, doubling its staff. The Billerica R&D team will focus on discovery and development of new agents for cancer, neurodegenerative diseases and infertility.

As for Pfizer’s exiting the therapeutic areas of allergy, respiratory medicine, and internal medicine, it makes sense for a company to terminate programs that have not been productive. However, which areas to cut will vary by company. For example, in our February 19, 2010 blog post, we mentioned that GlaxoSmithKline (GSK) had eliminated its R&D in depression, anxiety, and pain. In contrast, Pfizer is building a new unit in pain and sensory disorders.

The main issue, however, as Pfizer’s CEO Ian Read said, is for Pfizer to fix its “innovative core”. The restructuring may help by freeing resources that had been devoted to low productivity therapeutic areas, and to high-risk/low-return areas. However, the cutbacks will not fix Pfizer’s low R&D productivity in any fundamental way.

As with other Big Pharma companies, Pfizer needs to fundamentally rethink its R&D strategy, and move towards the types of “smarter R&D” and partnering discussed in our December 3, 2010 blog article, and in the one-page article by GSK CEO Andrew Witty referenced in that article. This does not mean copying other companies’ “smart R&D” strategies, even Novartis’ or Roche/Genentech’s strategies that have been the most successful. It means developing a new R&D and partnering strategy specific for Pfizer, based on the fundamentals of what has worked in R&D in the past ten years or so, and building on Pfizer’s R&D assets. (Given the fast-changing nature of biomedical science and technology, as well as of the pharmaceutical and health care business landscape, even companies like Novartis and Roche/Genentech need to keep honing their R&D and partnering strategies.)

As we stated in our December 3 2010 article, this revamping of R&D strategy may well enable Pfizer to achieve additional cost savings. However, such selective R&D budget cuts would not impair the ability of the company to successfully discover and develop new, medically-significant drugs as across-the-board cuts tend to do.

Pfizer’s decision to concentrate its R&D facilities in research hubs such as Greater Boston, and to mandate that its researchers interact more intensively with academic and biotechnology researchers and entrepreneurs located in these hubs, can facilitate moving towards a “smarter R&D” and partnering strategy. We in the Boston area welcome Pfizer researchers and executives who will be moving here, and hope that we can work with Pfizer to help facilitate its R&D success.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

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A frog jumps into the animal model lineup

Published by on May 13, 2010 | Leave a response

The cover of the 30 April 2010 issue of Science bears a photo of a tadpole of the western clawed frog Xenopus tropicalis. In that issue is a report on the draft sequence of the genome of this organism, and a short companion news feature. The report on the genome emphasizes X. tropicalis’ role as an emerging animal model in developmental and evolutionary biology and in comparative genomics.

X. tropicalis is also an emerging animal model in biomedical research, potentially including development of disease models for drug discovery. We emphasize that potential role in Chapter 5 (“Xenopus tropicalis: an emerging model system”) of our book-length report, Animal Models for Therapeutic Strategies, published by Cambridge Healthtech Institute in March 2010.

The Nature news feature, authored by Elizabeth Pennisi, also cites the potential role of this frog in biomedical research. X. tropicalis has about 1700 genes that are related to human genes that have been linked to disease. Some of these diseases are type 2 diabetes, acute myeloid leukemia, congenital muscular dystrophy, alcoholism, and sudden infant death syndrome. In our book chapter, we discuss efforts to develop an X. tropicalis model of congenital spinal muscular atrophy (SMA). We also discuss studies aimed at using the frog as an animal model of human congenital heart disease, and for developing novel therapies for these conditions.


The related frog Xenopus laevis (known as the African clawed frog) is an old animal model that has long been used in developmental and cell biology research. However, X. laevis (pictured above) is genetically intractable, since its genome is allotetraploid, having been formed by fusion of diploid genomes from two different species. This makes genetic and genomic studies with this frog difficult. In contrast, X. tropicalis is diploid. X tropicalis also has a much shorter generation time than X. laevis, and is much smaller, thus requiring less space and making breeding and experimentation much more feasible than with X. laevis.

Some of the same researchers that have been participating in the X. tropicalis genome sequencing project have been developing genetic tools such as transgenics, genetic screening, and gene knockdown using antisense morpholinos. With the determination of the genome sequence, X. tropicalis may join the zebrafish as a lower vertebrate animal model in developing novel therapeutic strategies for human diseases.

Elsewhere on the animal model genome front, researchers recently published a draft sequence of the genome of Hydra magnipapillata. Hydra, a freshwater cnidarian or polyp, has long been a staple of high school and university biology lab courses, so is a favorite of many biologists. The University of California at Irvine, whose researchers participated in the Hydra genome project along with many others (e.g., leading genomics researcher J. Craig Venter), has long been a center of Hydra research, beginning in the late 1960s.

Hydra is used as an animal model in the study of regeneration, body patterning, and stem cell biology. The determination of the genome sequence of Hydra will facilitate these studies, as well as studies of comparative genomics and evolutionary biology.

Hydra may also be of interest for biomedical research. As discussed in the genome report, Hydra possesses four homologues of the Myc oncogene, which is involved in human cancers and also regulates pluripotency and self-renewal of mammalian stem cells. Myc is also central to the pluripotentency of Hydra stem cells. The researchers also found genes in the Hydra genome that are linked with Huntington’s disease and with the beta-amyloid pathway of Alzheimer’s disease.

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