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The founding members of Chimera Research Group have over 50 years of combined experience in the biotech and pharmaceutical sector. Their experience includes work at Investment Banks, Hedge Funds, Pharmaceutical Companies, top-tier Universities, and the U.S. Food and Drug Administration (FDA).... More
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  • Taiwan Liposome Company- Ahead of the Pack
    Biotechnology is an emerging industry in Taiwan. After the country’s immense success in high tech, the government is searching for another engine of economic growth. There are now at least five science research parks and as of 2004, at least 238 biotechnology companies. Perhaps due, in part to Taiwan’s roots in computer sciences and manufacturing, a large number of these biotechs focus on genomics, bioinformatics, and pharmaceutical manufacturing. The industry is beginning to mature and companies are increasingly focused on working toward drug development. A couple, like AndroScience and TaiGen Biotechnology have some early stage pre-clinical compounds. A DPP-IV inhibitor for diabetes was recently hailed in the Asian press as the first novel drug to enter clinical trials on the island nation and is being developed by a consortium of six biotechnology companies. With a combination of homegrown scientists and repatriated talent, Taiwan is hoping to become a global biotechnology hub.

    All About Liposomes
    As the name suggests, Taiwan Liposome Company (TLC) is focused on liposomal technology; its goal is to use the technology as the core of their drug development. Its main operations are in Taipei, Taiwan, with a small unit in South San Francisco. TLC is a small privately held company founded in 1997 by Dr. Keelung Hong, an expert on liposomes, with 20 years research background at UCSF. An initial funding round of NT$27 million allowed the company to test and bring their version of liposomal doxorubicin (Lipo-Dox) to market in 2002 in Taiwan and other Asian countries, proving the viability of their technology. Lipo-Dox was soon licensed to TTY Biopharm for distribution and now has sales of over NT$220 million.

    In a 2006 interview, TLC’s General
    Manager, George Yeh, described his company’s strategy as one based on a platform technology rather than product based. He believes their technology allows for the cost-effective development of drugs that can efficiently fulfill the needs of both TLC and other pharmaceutical companies.

    Product lifecycle management is a mainstay of drug development today, but has become increasingly important as blockbuster drugs lose patent protection, with nothing fill in behind them. TLC’s technology has the potential to play an important role in lifecycle management. It can extend a product’s patent life through the enhancement of its performance- by reducing a drug’s toxicity, improving its stability, targeting its delivery. These improvements can be made possible by converting existing drugs into TLC’s proprietary liposomal formulation.

    Cutting Edge Information “Defending brand revenue - Pharmaceutical life cycle management planning” June 2005, the authors compared the value creation of product reformulation to other lifecycle management strategies and found product reformulation to be more cost effective than all other strategies other than patent litigation. 

    An alternate use for TLC’s technology follows in the path of their first product, Lipo-Dox, where their liposomal technology was used to reformulate an off-patent drug and bring it to market with minimal testing while enjoying additional patent protection. With this blueprint, the company has developed a pipeline of reformulated generics. Along with these generics, they have also ventured into the development of novel drugs.

    Developmental Products
    Lead product ProFlo is a new Prostaglandin E1 emulsion formulation for the treatment of Peripheral Arterial Disease (PAD), Diabetic neuropathy, and Ulcers. It has the biological activity of Liple, but with a longer shelf life, sustained release, and targeted delivery. It is now going through regulatory approval.

    Other reformulations include AmBiL, a generic form of AmBisome, and Doxisome, a generic of Doxil. Branded sales of the latter two drugs are about $800 million. Both AmBiL and Doxisome are in bioequivalence testing.

    The company is developing a novel compound, Lipotecan, a modified version of topotecan in a liposomal formulation. It is the first new drug from Taiwan to be developed in the US and is currently in a dose-escalating Phase I study. Data presented this past ASCO showed prolonged stable disease in 5 of 32 patients with advanced solid malignancies. The best response appeared in a patient with
    sorafenib-refractory hepatocellular carcinoma. The authors indicated they intend to pursue further study of the drug in this indication as a result.

    Finances and Future Plans
    TLC set its sights on building an international presence early on, partnering with South San Francisco based Hermes Biosciences in 2003 (since acquired by Merrimack Pharmaceuticals) to develop liposomal vinorelbine (NanoVNB) for cancer. NanoVNB is being tested in Taiwan in Phase II. Of note, Hermes Biosciences was also a liposome technology company with roots at UCSF.

    In 2006, TLC had been considering an initial public offering in the US as a way to raise cash and their international profile, but changing markets have made biotech IPOs here incredibly difficult. They are now setting their sights on a Taiwan listing sometime next year. Being acquired by another pharmaceutical company was also considered as a way for investors to obtain a return on their investments.

    TLC completed its fifth financing round in July 2009 with participation from
    Burrill & Company, YFY Biotech Management Company, TaiAn Technologies Eminent VC, and Boston Life Science Venture Corp. This strong list of backers is a showcase to TLC’s leading position in a highly competitive industry. So even without a US IPO, this influx of cash now allows the organization to continue with its plans for expansion. A representative from Burrill & Company now sits on the company’s board.
    Exchange rates as of 8/6/2010 (1 US dollar = 31.765 Taiwan dollars)

    Disclosure: No Position
    Aug 07 9:32 PM | Link | Comment!
  • Why Arena’s Lorcaserin Will Not Be Used In Combination With Phentermine
    It is tempting to believe that once Lorcaserin has been approved, it will be used off-label in combination with phentermine to create a safe and efficacious version of Fen-Phen, the once popular diet drug. This is not to be the case.
    Some history:
    Fenfluramine, the “Fen” in Fen-Phen, a potent agonist of 5-HT2B receptors, a type of serotonin receptor found in the brain as well as in high quantities on heart valves. It was approved in 1973, its enantiomer, dexfenfluramine was approved by the FDA in 1996 to Wyeth. Neither fenfluramine nor dexfenfluramine were popular diet drugs due to their mediocre efficacy. It wasn’t until 1992 when an article was published showing fenfluramine combined with Phentermine led to 15% weight loss when the Fen-Phen diet craze began. While Fenfluramine and Phentermine each on their own led to similar weight losses of around 8%, the synergistic effect of the combination allowed for use of lower doses of both drugs, but resulted in a significantly better effect.
    In 1997, the Mayo Clinic documented 24 cases of women with valvular heart defects who were taking Fen-Phen, playing large role in the recall of fenfluramine and dexfenfluramine from the market. Further testing by the Mayo Clinic found about 30% of patients on Fen-Phen who were asymtomatic for heart disease were found to had abnormal echocardiographic results.
    To this day, scientists are still debating how exactly fenfluramine (fenfluramine will refer to both it and dexfenfluramine) causes the heart defects, but revolves around stimulation of the 5-HT2B receptors, leading to excess cell proliferation and vascular remodeling. 
    Lorcaserin is designed as a potent agonist of 5-HT2C, with greater than 100 fold selectivity over 5-HT2B, the apparent culprit in Fen-Phen. It has been tested in thousands of patients and shows no signs of causing heart defects. Lorcaserin has been shown to have mild side-effects, however, its efficacy is similar to that of fenfluramine- modest. Would it not make perfect sense to boost its effects with a dose of phentermine? After all, phentermine was not taken off the market, in fact, it is currently the number one prescribed stimulant obesity drug in the US.
    Not so simple. As previously mentioned, the exact mechanism of Fen-Phen induced heart valve defects has not been deduced. It is known that Fenfluramine by itself is a culprit; it is also known that Phentermine on its own is not. But the combination of the two may increase the risk of heart problems through multiple mechanisms. Though this is far from proven, Phentermine faces guilt by association- cases of heart defects were not noticed until the two drugs were used together. A large part of this is because relatively few people used fenfluramine before the study documenting the superior effects of its combined use with phentermine. Also, in a retrospective JAMA, 2000 study, researchers showed 4.1% of untreated patients had Aortic Regurgitation, compared to 8.9% of patients who took fenfluramine only, and 13.7% of patients on the Fen-Phen combo. (Note: this was a Wyeth sponsored paper.)
    Arena, being smart, has not tested Lorcaserin in combination with phentermine. If it did, even preclinical, it would have to report the data to the FDA. There is just no way to predict exactly what will happen when you put two compounds together. Arena will not be able to promote Lorcaserin as a combination pill without the studies, it will depend entirely on doctors prescribing the combo off-label. Aggressive doctors may be tempted to do just that, but I believe the FDA, with its emphasis on safety, already has that in mind. Until there is evidence to the contrary, there is likely to be a warning against the use of Lorcaserin in combination with phentermine. This warning would deter most doctors from prescribing a Lorcaserin-Phentermine combo.

    Disclosure: No Positions
    Jul 07 7:55 PM | Link | 6 Comments
  • Calistoga Pharmaceuticals and Plexxikon- Two Biotechs to Keep an Eye On
    Calistoga and Plexxikon are on the leading edge of two of the hottest targets in drug development today. Both are privately held.
    Seattle based Calistoga Pharmaceuticals was founded when Icos was acquired by Eli Lilly for its Erectile Dysfunction drug, Cialis. Former scientists acquired IP from the company in 2007 that formed the basis of their startup, Calistoga. They focused their research on developing isoform selective PI3K inhibitors, seeded with an initial $21 million in venture funding from Frazier Healthcare Ventures, Alta Partners, Three Arch Partners and Amgen Ventures.
    Lead compound CAL-101, a PI3K delta specific inhibitor, is set to begin pivotal trials the second half of this year. CAL-101 has shown promising data in Phase I for leukemia and lymphoma. It is difficult to compare between trials, but CAL-101 appears to perform better than other PI3K inhibitors as a single agent. In all likelihood, however, these compounds will be used in combination with either other targeted therapies or chemotherapy. The compound will also be tested in solid tumors- a much larger market- as well as leukemia and lymphoma.
    CAL-263, a second PI3K delta inhibitor is in Phase I for inflammation; it will enter Phase II later this year. A third compound is also expected to enter the clinic this year. PI3K delta is a very attractive target due to its clear role in mediating the inflammatory response. Aside from cancer, it has implications in the treatment of Rheumatoid Arthritis, asthma, and chronic obstructive pulmonary disease (COPD). This has piqued the interest of many small biotechs as well as large Pharmaceutical companies.
    Calistoga has yet to partner any of their compounds. Indications are they are getting ready to do so, having recently hired a former dealmaker from Icos. Any partnership would be substantial. Looking at recent deals in this space: Exelixis partnered with Sanofi Aventis in 2009, with $140 million upfront and $1 billion in potential milestones for two Phase 1 compounds, and in 2008, Genentech paid $175 to purchase Piramed for its pre-clinical PI3K inhibitors, particularly interested in its PI3K delta selective compounds.
    Calistoga has not had any problems raising money and will not be in a rush to partner with Pharma. Just last year it completed a $30 million Round B financing. Good data, an attractive target, and time are all on its side. In previous years, with a closed IPO market, Calistoga would have been ripe for a takeover. It has more options today as the economy mends and the biotech IPO window continues to stay open.
    Plexxikon is an entirely different animal altogether. A Berkeley, CA company born in 2001, it is a drug discovery engine that seeks to partner its compounds at an early stage. Using its scaffold-based technology, it has developed compounds for a multitude of indications, including oncology, neurology, cardiology, inflammation, and metabolic disorders. The company has three compounds in various stages of clinical trials, including one in registration trials.
    With only three rounds of financing netting $67 million in its nine years of existence, Plexxikon’s venture backers have faced minimal dilution. This is made possible by the significant sums the company commands for its early stage compounds. In 2004, Wyeth paid $22 million upfront for co-development rights to PLX-204, plus $350 million in milestones (recently discontinued). In 2006, Roche licensed PLX-4032 for $40 million and $660 million in milestones. Then in 2009, Roche took a second dip with PLX-5568 for $60 million and $275 million down the road. To date, Plexxikon has raised $170 million from licensing of its compounds.
    Plexxikon’s most advanced compound is PLX-4032, a selective of the mutant B-RAF V600E. This mutation is a major driver of disease in more than 40% of melanomas, 80-90% of papillary thyroid carcinomas, and 8-30% of colorectal cancers. PLX-4032 has shown outstanding activity in B-RAF mutant melanoma patients in early stage trials. It has now initiated a Phase III trial in that indication with partner Roche.
    RAF inhibitors took the scientific world by storm when Bayer received faster than expected approval for Sorafenib in renal cell carcinoma in 2005. Since then, a multitude of companies have also begun developing RAF inhibitors. Five years later, Sorafenib is still the only approved RAF inhibitor I know of, likely because much of its activity is attributed to inhibition of kinases other than RAF, particularly VEGFR2. PLX-4032, if approved, would be the only specific RAF inhibitor, and selective for B-RAF V600E as well. This will distinguish it from many compounds in development, as they are often non-selective, inhibiting multiple RAF isoforms. A regulatory filing for PLX-4032 in melanoma could come as early as 2011.
    The specific RAF target in the PLX-5568 partnership with Roche has not been mentioned. My guess is it is likely to be B-RAF due to the enzyme’s involvement in Polycystic Kidney Disease, the indication to be pursued under the Roche partnership. Plexxikon is also developing PLX-5568 for pain management, but has yet to partner that program. Its chemistry expertise, particularly in designing highly specific kinase inhibitors, has served it well.
    Both Calistoga and Plexxikon look to be on the verge of success. They have managed to make significant progress on their programs in a very short time, with relatively little spend. My hope is they go the public route and continue their growth rather than end up in the belly of a Pharmaceutical company; either one would make a nice addition to a biotech portfolio.

    Disclosure: Long RHHBY.PK
    Tags: RHHBY, LLY, EXEL, SNY, Kinase, IPO, PI3K, RAF
    Jun 29 5:45 PM | Link | 2 Comments
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