Happy New Year from Haberman Associates!

In our November 20, 2012 article on this blog, entitled “Novel hypercholesterolemia drugs move toward FDA decisions”, we discussed two drugs–Aegerion Pharmaceuticals’ lomitapide, and Isis/Sanofi/Genzyme’s mipomersen. In October 2012, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee recommended that both drugs be approved for treatment of homozygous familial hypercholesterolemia (HoFH).

In that article, we discussed issues involved in the development and commercialization of lomitapide–a small-molecule drug, and mipomersen–an antisense oligonucleotide, for treatment of HoFH, a rare genetic disease which is mechanistically related to more common types of hypercholesterolemia. We also stated that were were awaiting FDA action–expected in the next several weeks after publication of our article–on the approval of the two drugs.

On Christmas Eve–December 24, 2012–a day on which few people in the United States and in many other countries were thinking about work–Aegerion (Cambridge, MA) announced that the FDA had approved lomitapide for treatment of HoFH. Lomitapide has been given the brand name Juxtapid.

The FDA based its approval of lomitapide on the results of a pivotal Phase 3 study, which evaluated the safety and effectiveness of the drug in 29 adult patients with HoFH. As we discussed in our November 20, 2012 article, the results of this study were published in the online version of The Lancet on November 2, 2012.

As we also discussed in our earlier article, lomitapide has serious adverse effects, including hepatic fat accumulation and elevated liver aminotransferase levels. According to the December 24, 2012 Aegerion press release, the most common adverse reactions seen in the Phase 3 study were gastrointestinal, including diarrhea, nausea, vomiting, dyspepsia and abdominal pain. Ten of the 29 patients in the study had at least one elevation in liver enzymes greater than or equal to three times the upper limit of normal. Liver enzyme elevations were managed through dose reduction or temporary discontinuation of dose. Hepatic fat accumulation was also observed in the Phase 3 trial.

As we also discussed in our earlier article, a finding of elevated liver aminotransferase levels is enough to stop development of most drugs. As of October 2012, the FDA and its Advisory Panel believed that a risk evaluation and mitigation strategy (REMS) would support appropriate use of these drugs in patients with homozygous FH, because of their life threatening disease, and because they have limited therapeutic options.

According to the December 24, 2012 Aegerion press release, the label for lomitapide contains a Boxed Warning citing the risk of hepatic toxicity. A Boxed Warning is the strongest warning that the FDA requires.

Lomitapide is avaiable only through the Juxtapid Risk Evaluation and Mitigation Strategy (REMS) Program. Aegerion will certify all health care providers who prescribe Juxtapid and the pharmacies that will dispense the medicine.

The goals of the REMS are:

• To educate prescribers about the risk of hepatotoxicity associated with the use of lomitapide, and the need to monitor patients during treatment with the drug.
• To restrict access to therapy with lomitapide to patients with a clinical or laboratory diagnosis consistent with HoFH.

The safety and efficacy of lomitapide have not been established in patients with hypercholesterolemia who do not have HoFH. The effects of the drug on cardiovascular morbidity and mortality has not been determined. The safety and effectiveness of lomitapide have not been established in pediatric patients.

In addition to establishing the REMS, Aegerion has made a commitment to the FDA to conduct a post-approval, observational cohort study.  The company has also developed a comprehensive support services program for patients and their healthcare providers.

As we discussed in our November 20, 2012 article, Aegerion will be marketing lomitapide on its own, without a larger partner, and has been ramping up its marketing and sales organization in anticipation of approval. The company has set up a website for the product, www.juxtapid.com.

We await the FDA’s decision on the approval of mipomersen, to see how this chapter in the hypercholesterolemia drug development story will unfold.

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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.

Agios Germanos, Greece. Source: http://bit.ly/YRDIBJ

I was quoted in an article in the November 19, 2012 issue of Chemical & Engineering News (C&EN) by senior editor Lisa M Jarvis. The article is entitled “Agios Takes A Long View In Cell Metabolism.”

The article focuses on Agios Pharmaceuticals’ (Cambridge, MA) strategy for building a company that can endure as an independent firm over a long period of time, and that can also demonstrate sustained performance.

This contrasts with the recent trend toward “virtual biotech companies”–lean companies with only a very few employees that outsource most of their functions, and that are designed for early acquisition by a Big Pharma or large biotech company. The virtual company strategy is designed to deal with the inability of most young biotech companies to go public in the current financial environment. Without the ability to go public, young companies cannot provide early-stage venture capital investors with a profitable exit within a few years after launching the company. Virtual companies typically have a few assets, such as molecules that are ready for preclinical studies or early clinical trials. The goal is to obtain enough evidence that their compounds can become drugs to interest a Big Pharma.

In contrast, there are a few young  “platform companies” that are built on a broad technology platform, which aim to address important areas of biology and potentially to develop numerous products with the potential to address important areas of unmet medical need. One of these is Agios.

“Built to Last” in the current biotech ecosystem

In the C&EN article, I was quoted as saying that only a few platform companies have been launched in recent years. In the Boston area, in addition to Agios, such companies include Forma Therapeutics and Aileron Therapeutics. I was further quoted as saying “These companies are built to last.”

That brings up the old business paradigm from the 1990s and early 2000s–“Built to Last” versus “Built to Flip”. Those involved in building virtual biotech companies–especially venture capitalists and angel investors–do not like the use of “Built to Flip” to characterize their companies. And there are some fine virtual biotechs–some, such as Energesis and Zafgen–which we have covered in our blog.

(Plexxikon, the developer of targeted melanoma drug vemurafenib, also operated as a virtual company. However, it had a technology platform, and had the potential to become an independent biotech with marketed products. Thus Plexxikon did not fit the usual “virtual biotech model”. Nevertheless, it was acquired by Daiichi Sankyo in 2011.)

However, some industry commentators believe that “Built to Flip” is an appropriate designation for virtual biotech companies, and that the virtual model is likely to be detrimental to drug discovery and to the biotech/pharma industry as a whole.

Meanwhile, the 2012 BIO International Convention in Boston had a session entitled “Moving the Goal Posts: How to Build a Free-Standing Biotech from Scratch in Today’s Environment.” This session focused on how to build the “next Vertex or even the next Genentech” (i.e., a “Built to Last” biotech company) in today’s environment. John Evans, the Vice President of Business Development & Operations of Agios was a speaker at that session. The session was moderated by Bruce Booth of Atlas Ventures. Thus, despite the preference for lean virtual biotech companies in the current funding environment, there is an interest in the entrepreneurial and venture capital communities for how free-standing biotechs might emerge under current conditions.

How to build a young platform biotech company

The Biopharmconsortium Blog has included three articles about Agios:

• Cancer metabolism as a target for drug discovery: Agios Pharmaceuticals (December 31, 2009)
• Agios Pharmaceuticals partners with Celgene (April 23, 2010)
• Cancer metabolism specialist Agios Pharmaceuticals continues its spectacular fundraising success (November 30, 2011)

These articles, as well as the November 19 2012 C&EN article, outline how Agios has been building a free-standing biotech in today’s unfavorable environment. Agios’ strategy is based on three elements:

• A stellar group of scientific founders–Drs. Craig B. Thompson, Tak W. Mak, and Lewis C. Cantley.
• A strong proprietary technology platform based on cancer metabolism
• A financing strategy that includes both venture capital and partnerships with established companies. In the case of Agios, their partner is Celgene. The Agios/Celgene partnership provides Agios with $150 million, and allows Agios to maintain control over the direction of its early stage research.

As stated in the C&EN article, the financial security gained via Agios’ funding by its venture investors and by Celgene enables Agios to work on multiple potential targets, with the goal of dominating the field of cancer metabolism. Agios focuses on two types of targets: metabolic enzyme species that are found only in cancer cells, and enzyme species on which a cancer cell has become dependent. Agios researchers intend to develop drugs against targets for which their are predictive biomarkers that identify the right patients for clinical studies.

New developments outlined in the November 19, 2012 C&EN article

Both the November 19, 2012 C&EN article and our Bipharmconsortium Blog articles outline Agios’ program to target a mutated form of isocitrate dehydrogenase 1 (IDH1), which together with mutated IDH2 has been implicated in 70% of human brain cancers. As stated in the C&EN article, Agios researchers have recently reported a series of compounds that selectively inhibit the mutant form of IDH1. This research had been carried out in collaboration with researchers from Ember Therapeutics (Watertown, MA). As we stated in another Biopharmconsortium Blog article, Ember specializes in targeting beige adipocytes for treatment of metabolic diseases.

As we noted in our November 30, 2011 Biopharmconsortium Blog article, Agios had slated a portion of the $78 million that it raised in its Series C financing to expand its R&D efforts into inborn errors of metabolism (IEMs). IEMs comprise a large class of inherited disorders of metabolism, most of which are defects in single genes that code for metabolic enzymes. These rare metabolic diseases have a high level of unmet medical need.

As outlined in the C&EN article, Agios’ work with mutant IDH1 and IDH2 is serving as a bridge to the company’s programs in IEMs. IDH2 mutations have been found in a class of children with 2-hydroxyglutaric aciduria, a rare inherited neurometabolic disorder that can cause developmental delay, epilepsy, and a set of other pathologies.

According to the C&EN article, IEMs are of special strategic interest to Agios. Agios CEO David Schenkein stated that expanding the company’s R&D efforts into IEMs helps the company to manage the risk profile of its portfolio. In the case of cancer, Agios researchers must identify and validate targets involved in the pathobiology of these diseases, and then to find drugs that modulate these targets. In the case of IEMs, disease biology is already validated by genetics.

Moreover, IEMs have small patient populations. Thus only small clinical trials are needed to bring a drug to market. Agios therefore believes that it can bring drugs for these diseases to market on its own, without the need for a larger partner such as Celgene or a Big Pharma.

As we discussed in a Biopharmconsortium Blog article on improving the clinical trial system, although rare diseases only require small clinical trials, finding and recruiting patients for the trials is made more difficult because of the very small number of patients with a particular disease. One solution is to work with patient advocates and “disease organizations”, some of which have patient registries. In the case of 2-hydroxyglutaric aciduria and other organic acidemias, a “disease organization” exists–the Organic Acidemia Association (OAA). Perhaps Agios will find it fruitful to work with the OAA in its patient recruitment efforts.

Currently, Agios is focused on getting compounds into the clinic–both for IEMs and for cancer. Looking down the road, the company’s $180 million war chest should enable Agios to put several compounds through proof-of-concept studies, according to Dr. Schenkein. (This is besides any cancer drug candidates that are licensed by Celgene.) Despite Agios’ strategy of conducting small trials for IEM drug candidates, Dr. Schenkein said that the company will eventually need to go public to achieve its strategic goal of dominating the cancer metabolism 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 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

Lomitapide

Mid-October 2012 was a busy time for the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee. On October 17, 2012, the panel voted 13-2 to recommend approval of Aegerion’s lomitapide for treatment of homozygous familial hypercholesterolemia. The next day, October 18, 2012, the same panel voted 9-6 to recommend approval of Isis/Sanofi/Genzyme’s mipomersen for the same condition.

Familial hypercholesterolemia (FH) is a rare genetic condition characterized by very high levels of low-density lipoprotein (LDL, or “bad cholesterol”), in the blood and early cardiovascular disease. Most patients with FH have mutations in either the LDL receptor (which functions to remove LDL from the circulation), or in apolipoprotein B (ApoB) (the protein moiety of LDL, which binds to the LDL receptor).

Patients who are heterozygous for an FH mutation (but have one normal copy of the affected gene) may have premature cardiovascular disease in their thirties. Patients who are homozygous for an FH mutation may have severe cardiovascular disease in childhood. Heterozygous FH is a common genetic disease, which is inherited in an autosomal dominant pattern, and occurs in one out of 500 people. Homozygous FH, however, occurs in about 1 in a million births. Homozygous FH thus qualifies as a “rare disease”.

Physicians generally treat heterozygous FH with statins, bile acid sequestrants or other lipid-lowering agents that lower cholesterol levels. Homozygous FH often does not respond to these drugs. It may require chronic treatment via LDL apheresis (removal of LDL in a method similar to dialysis) and in some cases liver transplantation.

Aegerion (Cambridge, MA), the developer of lomitapide, is a publicly-traded biotech company that seeks to “change the way that rare, genetic lipid disorders are treated”. It is currently focused on the development of lomitapide, a small-molecule compound (pictured above).

Lomitapide inhibits the microsomal triglyceride transfer protein (MTTP) which is necessary for very low-density lipoprotein (VLDL) assembly and secretion in the liver. A 2007 article in the New England Journal of Medicine (NEJM) concluded that inhibition of MTTP by lomitapide (then known as BMS-201038) resulted in the reduction of LDL cholesterol levels in patients with homozygous FH. BMS-201038/lomitapide was originally developed by Bristol-Myers Squibb (BMS), donated to the University of Pennsylvania in 2003 and licensed to Aegerion in 2006. BMS had abandoned development of the compound after early Phase 1 and Phase 2 trials had found increases in heptatic fat content and gastrointestinal disturbances. The NEJM study (conducted by Penn researchers in collaboration with other academic researchers and with BMS) also found that therapy with the compound was associated with elevated liver aminotransferase levels and hepatic fat accumulation.

78-week data from Aegerion’s pivotal Phase 3 study of lomitapide in adults patients with homozygous FH were published in the online version of The Lancet on November 2, 2012.

Mipomersen (which will be called Kynamro if and when it is commercialized) is an antisense oligonucleotide that targets the messenger RNA for apolipoprotein B. We discussed mipomersen in our August 21, 2009 blog article on oligonucleotide therapeutics. Mipomersen represents the most advanced oligonucleotide drug in development that is capable of systemic delivery. (The only two marketed oligonucleotide drugs both treat ophthalmologic diseases and are delivered locally.) Mipomersen targets the liver, without the need for a delivery vehicle. Thus mipomersen–potentially the first systemically-delivered oligonucleotide drug to reach the market–represents the “great hope” for proof-of-concept for oligonucleotide drugs, including antisense and  RNAi-based drugs.

Patients treated with mipomersen, as with lomitapide, exhibit liver-related adverse effects, especially hepatic fat accumulation and elevated liver aminotransferase levels. Moreover, unlike lomitapide, which is an orally-delivered compound, mipomersen, which is delivered via subcutaneous injection, can cause injection site reactions and flu-like symptoms. Moreoever, mipomersen has a much longer half-life than lomitapide (30 days versus 20 hours).

Industry commentators, and well as the FDA Advisory Committee, generally favor lomitapide over mipomersen, because lomitapide appears to be the more efficacious drug in lowering LDL-cholesterol, and also because lomitapide is an oral drug. However, most of the FDA panelists, as well as other industry commentators believe that not all patients with homozygous FH would be likely to benefit from only one drug. Thus having two alternative drugs may well be better in treating this disease.

Both lomitapide and mipomersen have potentially serious adverse effects. A finding of elevated liver aminotransferase levels is enough to stop development of most drugs. However, the FDA and its Advisory Panel believe that a risk evaluation and mitigation strategy (REMS) would support appropriate use of these drugs in patients with homozygous FH, because of their life threatening disease, and because they have limited therapeutic options. Both Aegerion and Genzyme are proposing that their compounds be approved with REMS programs, including an education program for physicians and active monitoring of patients. The REMS program would also include monitoring to ensure that only adult homozygous FH patients would be treated with the drugs. However, Aegerion plans to conduct clinical trials of the use of lomitapide in pediatric homozygous FH patients, as well as patients with another rare disease, familial chylomicronemia. Genzyme has already tested mipomersen in a small number of pediatric patients.

Companies developing therapeutics for rare diseases whose mechanisms are related to those of more common diseases often attempt to first get their drugs approved for the rare disease, and then perform additional clinical trials to expand the drug’s indications to larger populations. We discussed this strategy in an earlier article on this blog. Homozygous FH is mechanistically related to not only heterozygous FH, but also to cases of severe hypercholesterolemia that are poorly controlled by statins. Both companies have shown interest in treating patients with homozygous FH and severe hypercholesterolemia, since they have preformed clinical trials that included patients with these conditions. However, the adverse effects of these drugs may limit their use to homozygous FH, at least in the near future.

Aegerion intends to market lomitapide on its own, and is ramping up its marketing and sales organization in anticipation of approval. Mipomersen, if approved, would have the benefit of the Sanofi marketing organization behind it. However, industry commentators expect lomitapide to have a large advantage over mipomersen, if both are approved. That is because of the greater efficacy of lomitapide, its oral dosing, and other factors related to injection site reactions for mipomersen and the half-lives of the compounds.

We await FDA action in the next several weeks on the approval of lomitapide and mipomersen.

Meanwhile, researchers and companies are working on potential drugs for severe hypercholesterolemia that act via an entirely different mechanism–PCSK9 (proprotein convertase subtilisin/kexin 9) inhibition. These drugs are in an earlier stage of development than lomitapide and mipomersen. However, they might eventually provide strong competition to these drugs, or replace them altogether.

For oligonucleotide drug developers and enthusiasts, the case of mipomersen–considered the “great hope” for proof-of-concept for oligonucleotide drugs by many in the field–provides several lessons. 1. At the end of the day, oligonucleotide drugs must meet the same standards of safety and efficacy as other drugs. 2. Oligonucleotide drugs may encounter competition from drugs in other classes, such as small molecules or monoclonal antibodies.

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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.

Source: Madprime http://bit.ly/RLmMqL

On October 11, 2012 we published an article entitled “Is gene therapy emerging from technological prematurity?” on the Biopharmconsortium Blog. The centerpiece of that article was the July 20, 2012 ruling by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) that recommended marketing uniQure’s Glybera. Glybera (alipogene tiparvovec) is a gene therapy for the ultra-rare genetic disease lipoprotein lipase deficiency (LPLD).

On November 2, 2012, the European Commission approved Glybera, which now becomes the first gene therapy approved in a regulated market. This was announced by uniQure, and covered by BioWorld Today and Reuters, among others.

Now that Glybera is approved in Europe, uniQure is exploring registration of Glybera in North America, and is developing its strategy for interaction with relevant regulators, especially the FDA. uniQure is aiming for a U.S. launch of Glybera in 2014.

According to uniQure, the commercial roll-out of Glybera will begin in the second half of 2013. uniQure estimates that there are 400 to 500 patients in Europe eligible to receive the therapy.

uniQure also says that the approval of Glybera validates the company’s  adeno-associated virus (AAV) vector-based gene therapy platform. In that connection, uniQure is planning to develop four other gene therapies that utilize its platform–treatments for hemophilia B, for acute intermittent porphyria, for Parkinson’s disease, and for Sanfilippo B, a rare liposomal storage disorder. These four gene therapy products have approval to enter clinical trials within the next nine months.

uniQure faces a short-term funding gap until revenues from Glybera start coming in. It is seeking to raise €20 million (US$26.7 million) in investment over the next five months.

uniQure’s ability to successfully commercialize Glybera depends on the pricing for the therapy allowed by payers. The company is now negotiating with payers to set prices. uniQure is basing its pricing for Glybera for the prices of enzyme replacement products for treating lysosomal storage disorders, such as those developed by Genzyme. For example, Genzyme’s Cerezyme (imiglucerase), a treatment for Gaucher’s disease, cost $200,000 per year in the United States in 2009. However, unlike Genzyme’s enzyme replacement therapies, Glybera, being a gene therapy, is a one-time treatment designed to restore a natural body function rather than providing short-term amelioration of a genetic disease.

According to the Reuters article, Glybera is expected to cost approximately €1.2 million ($1.6 million) per patient. This would be a new record for expensive modern therapeutics. Jörn Aldag, uniQure’s CEO, believes that the high price is justified by the long-term benefit provided by a gene therapy, as opposed to the classic protein replacement strategy in which the drug must be administered repeatedly for life.

Different European countries prefer different payment schemes for Glybera. Some favor charging an annual price for the therapy, while others prefer a single up-front charge, based on multiplying the annual cost of treating a similar disease (e.g., Gaucher’s disease) by the number of years Glybera is known to have an effect. Currently, that is five years.

For an in-depth discussion of the prospects for the gene therapy field, and the implications of the approval of Glybera for the future of gene therapy, see our October 11, 2012 article on this blog.

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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.

[For updated information on gene therapy, please see our articles on this blog dated November 16, 2015 and November 23, 2015.]

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 a 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 of 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.

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