Atherosclerosis. Source: Nephron http://bit.ly/jL6Zos

In our November 20, 2012 Biopharmconsortium Blog article, entitled “Novel hypercholesterolemia drugs move toward FDA decisions”, we discussed two drugs–Aegerion Pharmaceuticals’ lomitapide, and Isis/Sanofi/Genzyme’s mipomersen. These drugs were nearing approval decisions by the FDA, following the recommendations of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee that both drugs be approved for treatment of homozygous familial hypercholesterolemia (HoFH).

In our December 31, 2012 blog article, we reported that the FDA had approved Aegerion’s small-molecule drug lomitapide (Juxtapid). That left us waiting for “the other shoe to drop”–the decision on the approval of mipomersen.

On January 29, 2013, Genzyme (a Sanofi company) and Isis Pharmaceuticals (Carlsbad, CA) reported that the FDA had approved mipomersen (Kynamro) for the treatment of HoFH. Mipomersen, given as a 200 mg weekly subcutaneous injection, has been approved as an adjunct to lipid-lowering medications and diet for the treatment of dyslipidemia in patients with HoFH. In contrast to mipomersen, Aegerion’s lomitapide is an oral drug.

The approval of mipomersen triggered a $25 million milestone payment to Isis from Genzyme.

MIpomersen is an antisense oligonucleotide that targets the messenger RNA for apolipoprotein B. This agent represents the first oligonucleotide drug capable of systemic delivery to be approved in a regulated market. (The two previously marketed oligonucleotide drugs both treat ophthalmologic diseases and are delivered locally.) Mipomersen targets the liver, without the need for a delivery vehicle. Thus mipomersen represents the “great hope” for proof-of-concept for oligonucleotide drugs, including antisense and  RNAi-based drugs.

In the January 29, 2013 press release, Stanley T. Crooke, M.D., Ph.D., Chairman of the Board and CEO of Isis, said:

“Kynamro is the first systemic antisense drug to reach the market and is the culmination of two decades of work to create a new, more efficient drug technology platform. As evidenced by our robust pipeline, our antisense drug discovery technology is applicable to many different diseases.” This indicates that Isis considers the approval of mipomersen as a proof-of-concept for its approach to antisense oligonucleotide drug discovery and development, and in particular for its pipeline.

Clinical trials of mipomersen

The FDA approval of mipomersen is based on the results of a randomized, double-blind, placebo-controlled, multi-center trial that enrolled 51 HoFH patients age 12 to 53 years, including 7 patients age 12 to 16 years, who were on lipid lowering medications. The trial found that mipomersen treatment further reduced LDL-cholesterol levels by an average of 113 mg/dL, or 25%, from a treated baseline of 439 mg/dL, and further reduced all measured endpoints for atherogenic particles. In March 2010, these data were published in The Lancet.

Safely data for mipomersen are based on pooled results from four Phase 3 trials. Eighteen percent of patients on the drug and 2% of patients on placebo discontinued treatment due to adverse effects. The most common adverse effects of mipomersen treatment were injection site reactions, increases in the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) , flu-like symptoms, and an abnormal liver function test.

As a result of these safety findings, the label for Kynamro contains a Boxed Warning citing the risk of hepatic toxicity. The label for Aegerion’s Juxtapid (lomitapide) also contains such a Boxed Warning. A Boxed Warning is the strongest warning that the FDA requires.

The FDA is also requiring four postmarketing studies of mipomersen, and wants the developers to carefully track the long-term safety of the drug.

As an antisense drug, mipomersen is metabolized without affecting the CYP450 pathways used in commonly prescribed drugs. It thus is potentially free of drug-drug interactions. No clinically relevant pharmacokinetic interactions were reported between mipomersen and warfarin, or between mipomersen and simvastatin or ezetimibe.

The safety and effectiveness of mipomersen have not been established in patients with hypercholesterolemia who do not have HoFH. Nor has the effect of mipomersen on cardiovascular morbidity and mortality been determined.

Because of the risk of hepatotoxicity, mipomersen is available only through a Risk Evaluation and Mitigation Strategy (REMS) called the Kynamro REMS. The goals of the REMS are:

• To educate prescribers about the risk of hepatotoxicity associated with the use of mipomersen, and the need to monitor patients during treatment with mipomersen as per product labeling.
• To restrict access to therapy with mipomersen to patients with a clinical or laboratory diagnosis consistent with homozygous familial hypercholesterolemia (HoFH).

Genzyme has also developed an HoFH and Kynamro support program for healthcare providers, patients, and their families.

Wider implications of the FDA approval of mipomersen

Mipomersen achieved FDA approval despite an unenthusiastic 9-6 recommendation for approval by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee. This compares to a 13-2 vote to recommend approval of lomitapide. Meanwhile, mipomersen received a negative opinion from a European Medicines Agency panel. And it faces strong competition in the market from lomitapide. Therefore, mipomersen is unlikely to become a large-selling drug.

Nevertheless, Sanofi has been positioning itself around Genzyme (and its rare disease platform) in its drug discovery and development strategy. Therefore, any and all Genzyme/Sanofi drug approvals represent important victories.

Although the FDA Advisory Committee and industry commentators favor lomitapide over mipomersen, they also believe that not all patients with HoFH would be likely to benefit from only one drug. Thus having two alternative drugs may well be better in treating this disease.

Does the approval of mipomersen herald a new age of oligonucleotide drugs? The first antisense agent to reach the market, fomivirsen (Isis/ Novartis Ophthalmics’ Vitravene), which is indicated for treatment of cytomegalovirus retinitis in AIDS patients was approved in 1998. However, it is delivered locally to the eye, and has not been profitable.

Even though mipomersen is unlikely to become a large-selling drug, it could become the first commercially successful antisense agent. As stated by Arthur Krieg, M.D., chief executive of RaNA Therapeutics, “What many people have been waiting for is validation where someone actually makes a profit and where patients actually benefit.”

As we have discussed in earlier blog posts, oligonucleotide drugs (especially antisense and RNAi) represent a premature technology. It is therefore not unusual that it would take over 20 years for the first profitable drug in this class to reach the market. This was also recently stated by Dr. Crooke.

Finally, as we stated in our November 20, 2012 blog article:

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.

________________________________

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.

Niacin

We have published two articles on high-density lipoprotein (HDL, or “good cholesterol”) raising drugs on this blog:

• Can HDL-raising drugs be a big field after all?  (May 19, 2011)
• HDL-raising drugs revisited  (June 1, 2011)

The more recent of these article has received quite a few hits lately. This is probably because of recent news of a clinical trial failure in the HDL drug field. It therefore seems appropriate to publish an update on HDL-raising drug clinical trials, in order to bring our blog up to date.

Update on the trials and tribulations of niacin-based HDL-raising drugs

As of the time of our June 1, 2011 article, high-dose niacin was the only drug that was approved by the FDA for raising HDL. However, generic high-dose niacin can cause adverse effects such as skin flushing and itching. Therefore, two companies, Abbott and Merck, were developing high-dose niacin-based products designed to reduce these adverse effects.

In May 2011, as discussed in our June 1, 2011 article, the National Heart Lung and Blood Institute (NHLBI) of the National Institutes of Health (NIH) stopped a large clinical trial (known as AIM-HIGH) of Abbott’s Niaspan, an extended-release formulation of high-dose niacin, because the drug failed to prevent heart attacks and strokes. There was also a small increased rate of strokes in patients taking Niaspan, which researchers cautioned may have been due to chance. Niaspan remains an FDA-approved drug, and it is now owned by Abbot spin-off AbbVie. However, Niaspan is scheduled to go off-patent later in 2013.

Merck’s high-dose non-flushing niacin product is known as Tredaptive or Cordaptive in different markets. It is a combination product consisting of extended-release high dose niacin plus laropiprant. Laropiprant is designed to block the ability of prostaglandin D2 to cause skin flushing; niacin-induced skin flushing works via the action of prostaglandin D2 in the skin.

In 2008, the FDA rejected Merck’s New Drug Application for Tredaptive/Cordaptive, so the drug remained investigational in the US. However, in 2009 Merck launched Tredaptive in international markets including Mexico, the UK and Germany. The drug has been approved in over 45 countries. Merck had also been conducting a 25,000-person trial of Tredaptive for reducing the rate of cardiovascular events in patients who are at risk for cardiovascular disease (CVD). Merck intended to file for approval of the drug in the US in 2012, based on the results of this trial if it had been positive.

However, on December 20, 2012, Merck announced that its clinic trial of Tredaptive, known as the HPS2-THRIVE Study (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events), did not achieve its primary endpoint.

As a result of this finding, Merck does not plan to seek regulatory approval for this medicine in the United States. It also–as of January 11, 2013–began a recall of Tredaptive in the 40 countries in which it had been approved. The  HPS2-THRIVE Study not only showed that Tredaptive was of no benefit in reducing cardiovascular events in high-risk patients on statins, but it also significantly raised the incidence of such adverse effects as blood, lymph and gastrointestinal problems, as well as respiratory and skin issues.

The results of a new study published online on February 26 2013 showed that around a quarter of all patients taking the niacin/laropiprant combination Tredaptive had dropped out of the trial–compared to fewer than 17% in the placebo arm.  This was mostly due to itching, rashes, indigestion and muscle problems. There were also dozens of serious reactions, including 29 cases of myopathy.

Skin-related adverse effects seen in some patients with Tredaptive resemble those seen with high-dose niacin. The addition of laropiprant was supposed to ameliorate these adverse effects, but may not have done so in all patients. As for the serious adverse effects such as myopathy, several medical researchers assert that it is not known whether niacin, laropiprant or drug-drug interactions between these two agents and/or the statin (simvastatin) used in the study was responsible. Simvastatin is known to have adverse interactions with certain other drugs. Moreover, one-third of subjects enrolled in HPS2-THRIVE were Chinese, a patient population that is known to be more sensitive to the effects of statins, especially the 40-milligram dose of simvastatin used in the trial. It was the Chinese patients enrolled in the trial who showed the highest risk of myopathy.

In addition, some of the researchers question whether laropiprant is a “clean drug” that has no effects on atherosclerosis and thrombosis. A recent study has shown aneurysm formation and accelerated atherogenesis in mice with deleted prostaglandin D2 receptors; these receptors are the target of laropiprant. Thus the use of laropiprant may have been a factor in the failure of the trial, as well as in the adverse effects seen in patients treated with the niacin/laropiprant combination.

Full results of the HPS2-THRIVE study will be presented by lead investigator Dr Jane Armitage (Oxford University, UK) on March 9, 2013 at the American College of Cardiology 2013 Scientific Sessions (San Francisco, CA.)

Thus–although generic niacin and Niaspan remain FDA-approved HDL-raising drugs–the results of the AIM-HIGH and the HPS2-THRIVE studies have put niacin-based HDL-raising drugs–and the whole HDL-raising drug field–under a cloud.

Update on development of CETP inhibitors

As discussed in our earlier articles, the development of cholesteryl ester transfer protein (CETP) inhibitors has been a particular focus of several pharmaceutical companies.  CETP catalyzes the transfer of cholesteryl esters and triglycerides between LDL/VLDL and HDL, and vice versa. In vivo (in animals and in humans), CETP inhibitor drugs raise HDL and lower LDL.

The clinical failure of Pfizer’s CETP inhibitor torcetrapib in 2006 put a severe damper on development of drugs in this class. However, the toxicity of torcetrapib was found to be due to an off-target effect, and other CETP inhibitors do not display this toxicity. Thus companies have been developing three CETP inhibitors: Roche’s dalcetrapib, Merck’s anacetrapib, and Lilly’s evacetrapib.

However, on May 7, 2012 Roche announced that it had–following the recommendation of an independent group of experts (the Data and Safety Monitoring Board)–halted its Phase 3 trial of dalcetrapib “due to a lack of clinically meaningful efficacy.”

Dalcetrapib’s lack of efficacy might possibly be due to its relatively low potency in raising HDL. Dalcetrapib boosted HDL by 30%, as compared to 138% for anacetrapib and 130% for evacetrapib, depending on the dose. Moreover, anacetrapib and evacetrapib, unlike dalcetrapib, also lower LDL (“bad cholesterol”).

Currently, anacetrapib and evacetrapib are being evaluated in large Phase 3 clinical trials–REVEAL (Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification) and ACCELERATE (A Study of Evacetrapib in High-Risk Vascular Disease), respectively.

Is HDL-raising drug development high-stakes gambling or rational clinical research?

Given the lack of success–so far–in developing a safe HDL-raising drug that lowers the frequency of cardiovascular events in high-risk patients, some commentators speculate that attempting to develop HDL-raising drugs such as CETP inhibitors might be a form of high-stakes gambling. Chemist and leading pharmaceutical industry blogger Derek Lowe in particular takes this point of view. As we discussed in our June 1, 2011 article, the biology of HDL is complex. For example, HDL particles in blood serum are heterogeneous, with some HDL particles having a greater degree of positive effects on atherosclerotic plaque biology than others. As a result, treatments (e.g., drugs, diet) that raise HDL, as determined by standard clinical assays for serum HDL, may not necessarily result in clinical benefit, because of qualitative changes in populations of HDL particles.

The unknowns of HDL biology, combined with the need to conduct huge expensive clinical trials and the big payoffs for success in the large dyslipidemia market, convinced Derek Lowe that CETP inhibitor development more resembles gambling (in which only Big Pharmas can play) than rational clinical research. The same, according to Lowe, applies to Alzheimer’s disease drug development. According to Lowe, Big Pharmas may be undertaking these “go-for-the-biggest-markets-and-hope-for-the-best” research undertakings because they think that success in large markets are the only things that can rescue them.

Nevertheless, Steven Nissen, M.D. (chief of cardiovascular medicine at Cleveland Clinic), a veteran HDL researcher who has often been critical of the pharmaceutical industry, persists in running clinical studies of novel HDL-raising drugs. Although he considered dalcetrapib a “long-shot”, he continues to believe that anacetrapib and evacetrapib have a reasonable chance of success. And he has expressed particular enthusiasm for anacetrapib.

Dr. Nissen is involved in clinical trials of Resverlogix’s epigenetic agent RVX-208, a first-in-class small-molecule drug related to resveratrol that induces endogenous production of the protein component of HDL, apolipoprotein A1. On August 28, 2012, Resverlogix reported that RXV-208 significantly increased HDL-C, the primary endpoint of a Phase 2b clinical trial known as SUSTAIN. SUSTAIN also successfully met secondary endpoints–showed increases in levels of Apo-AI and large HDL particles. Both of these are believed to be important factors in enhancing reverse cholesterol transport activity. Safety data from SUSTAIN indicate that increases in the liver enzyme alanine aminotransferase (ALT) reported in previous trials were infrequent and transient, with no new increases observed beyond week 12 of the 24-week trial. Thus the drug appears to be suitable for chronic use.

Thus, despite the features of CETP-inhibitor clinical trials that resemble high-stakes gambling, we must wait for the results of the clinical trials to draw any meaningful conclusions about the prospects for development of these agents. Moreover, other approaches to developing HDL-raising drugs, such as Resverlogix’ epigenetic strategy, may turn out to be superior to older approaches. And as with Alzheimer’s disease, continuing studies on the basic biology of HDL may eventually yield breakthrough strategies to discovery and development of novel antiatherosclerotic drugs.

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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 contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

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.

________________________________

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.

________________________________

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.

Eltrombopag

On April 13, 2012, Informa’s Scrip Insights the publication of a new book-length report, Advances in the Discovery of Protein-Protein Interaction Modulators, by Allan B. Haberman, Ph.D.

Protein-protein interactions (PPIs) are of central importance in biochemical pathways, including pathways involved in disease processes. However, PPIs have been considered the prototypical “undruggable” or “challenging” targets. The discovery of small-molecule drugs that can serve as antagonists or agonists of PPIs, and which are capable of being successfully taken into human clinical trials, has been extremely difficult. Among the theoretical reasons for this is that contact surfaces involved in PPIs are usually large and flat, and lack the types of cavities present in the surfaces of proteins that bind to small-molecule ligands.

Nevertheless, over the last twenty years, researchers have developed a set of technologies and strategies that have enabled them, in a several cases, to discover developable small-molecule PPI modulators. One direct PPI agonist, the thrombopoietin mimetic eltrombopag (Ligand/GlaxoSmithKline’s Promacta/Revolade), has reached the market. The chemical structure of this compound is illustrated in the figure above. Several other small-molecule PPI modulators are in clinical trials. Despite this progress, the discovery and development of small-molecule PPI modulators has been one-at-a-time, slow and laborious.

The new strategic importance of protein-protein interactions as drug targets

Meanwhile, PPIs as potential drug targets have acquired a key strategic importance for the success of the pharmaceutical industry. Over at least the last decade, pharmaceutical R&D has failed to develop enough high-valued new drugs to make up for or exceed revenues from blockbusters that are losing patent protection. As we have discussed in previous publications and in , this low productivity is mainly due to pipeline attrition. There are several factors (ranging from target selection through drug design, preclinical studies, identification and use of biomarkers, and design of clinical trials) that can influence pipeline attrition.

However, increasing numbers of industry leaders and analysts identify target selection as the key factor that is limiting the productivity of pharmaceutical R&D. For example, I served as a workshop leader at Hanson Wade’s   last summer, which took that point of view. There are at least several such conferences throughout the year, which are organized at the request of industry leaders.

Industry experts who identify poor target selection as a major cause of pharma R&D’s productivity woes conclude that the main issue is that companies are running out of “druggable” targets that have not already been addressed by marketed drugs. As of 2011, only 2% of human proteins have been targeted with drugs. Most of the remaining disease-relevant proteins, including transcription factors and many other types of signaling proteins, work via interacting with other proteins in PPIs. Therefore, in order to reverse its R&D slump, the pharmaceutical industry needs to develop technologies and strategies to address PPIs and other hitherto “undruggable” targets.

Contents of the report

Our report discusses technologies and strategies that enable the discovery of drugs targeting PPIs, including both small-molecule and synthetic peptidic modulators. It includes case studies on the discovery of compounds that address specific target classes, with emphasis on agents that have reached human clinical studies. This includes addressing the issue of the need to produce PPI modulatory agents that have pharmacological properties that will enable them to be good clinical candidates.

The report also includes discussions of second-generation technologies for the discovery of small-molecule and peptidic PPI modulators, which have been developed by such companies as Forma, Ensemble, and Aileron, and by academic laboratories. The field of PPI modulator discovery has represented a “premature technology”, i.e., a field of biomedical science in which consistent practicable therapeutic applications are in the indefinite future, due to difficult technological hurdles. We have discussed premature technologies on earlier on this blog. The second-generation technologies are designed to overcome the hurdles and to thus enable a more accelerated and systematic approach to PPI drug discovery and development.

In part as the result of the development of these technologies, and of the increasing strategic importance of PPI modulator development, companies have been moving into the field. Examples include Bristol-Myers Squibb, Pfizer, Novartis, and Roche. A key issue is to what extent the new technologies for PPI modulator R&D will enable this area to be commercially successful, and to meet the strategic needs of the industry for expanding the universe of targets for which drugs can be developed.

To see the report Advances in the Discovery of Protein-Protein Interaction Modulators, please click here.

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