Biopharmconsortium Blog

Expert commentary from Haberman Associates biotechnology and pharmaceutical consulting.

Monthly Archives: June 2011

Haberman Associates Multitargeted Therapies report published by CHI Insight Pharma Reports

 


On June 1, 2011, Cambridge Healthtech Institute’s (CHI’s) Insight Pharma Reports announced the publication of our new book-length report, Multitargeted Therapies: Promiscuous Drugs and Combination Therapies.

In the past 20 years or so, pharmaceutical and biotechnology industry R&D has been increasingly aimed at developing drugs to treat complex diseases such as cancer, cardiovascular disease, type 2 diabetes, and Alzheimer’s disease. However, the one drug-one target-one disease paradigm that has become dominant in the post-genomic era has proven to be inadequate to address complex diseases, which have multiple “causes”, and each of which may be more than one disease. This has been a major cause of clinical failure and the low productivity of the pharmaceutical industry.

Moreover, researchers have found that most of the successful, FDA-approved small-molecule drugs that were developed prior to the year 2000 are promiscuous, i.e., they are single drugs that address multiple targets. In addition, the great majority of kinase inhibitors, one of the most successful drug classes of the early 21st century, are also promiscuous.

The study of small-molecule drug promiscuity has spawned the emerging field of network pharmacology, which can be applied both to study drug promiscuity and to rationally design small-molecule multitargeted drugs. (Researchers can discover or design multitargeted kinase inhibitors without the use of network pharmacology, however.)

Meanwhile, the development of targeted drugs such as kinase inhibitors and monoclonal antibodies has resulted in the need to develop multitargeted combination therapies. This has been especially true in cancer, where disease causation may involve multiple signaling pathways. In particular, the development of resistance to targeted antitumor drugs has spawned the need to develop second-generation treatments, many of which are multitargeted combination therapies.

Our report covers both discovery and design of small-molecule promiscuous/multitargeted drugs, and of multitargeted combination therapies.

The design of multitargeted combination therapies is one of the hottest areas of cancer R&D today, especially with respect to developing means to overcome resistance to targeted therapies. This area was the focus of many key presentations at the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting, which was held in Chicago on June 3-7. For example, treatment with vemurafenib (PLX4032) of metastatic melanoma patients whose tumors carry the B-Raf(V600E) mutation has produced spectacular overall response rates and increased survival. However, in nearly all cases, the tumors relapse. The latest results with vemurafenib were discussed at ASCO 2011, as well as strategies to overcome resistance to therapy. Our new report also discusses strategies for overcoming vemurafenib resistance, all of which involve design of multitargeted combination therapies.

Another topic discussed at ASCO 2011 was antitumor strategies based on synthetic lethality. We discussed this strategy in an earlier article on this blog, especially with respect to poly(ADP) ribose polymerase (PARP) inhibitors such as KuDOS/AstraZenaca’s olaparib. At a session at the ASCO meeting entitled “PARP Inhibitors, DNA Repair, and Beyond: Theory Meets Reality in the Clinic”, speakers reviewed current progress in developing PARP inhibitors, of which six are now in clinical development.

This session also included a presentation by Michael B. Kastan, MD, PhD (St. Jude Children’s Research Hospital, Memphis TN) on other ways of using the synthetic lethally strategy, for example by targeting kinases involved in DNA repair pathways such as ATM (Ataxia-Telangiectasia Mutated) or Chk1 checkpoint kinase, or even utilizing features of the tumor microenviroment such as hypoxia. Such strategies might be used to design multitargeted combination therapies that specifically target cancer cells with defects in DNA repair and/or in hypoxic solid tumors, and/or to sensitize cancer cells to radiation.

Our new report includes a chapter on using the synthetic lethality strategy to design combination therapies of a cytotoxic drug with a chemosensitizing agent, and to develop therapies for p53-negative cancers. (The key tumor suppressor p53 is deleted, mutated, or inactivated in the majority of human cancers).

Although design of multitargeted combination therapies, as well as discovery and design of kinase inhibitors, are of key importance for current oncology R&D and are also being applied to other diseases, design of single small-molecule multitargeted drugs via network pharmacology is an early-stage, and perhaps a premature, technology. Nevertheless, given the current pharmaceutical company R&D business model that emphasizes outsourcing early-stage R&D, academic research groups and biotechnology companies that are active in this area may be able to forge partnerships with pharmaceutical companies.

For more information on Multitargeted Therapies: Promiscuous Drugs and Combination Therapies, or to order it, see the Insight Pharma Reports website.

HDL-raising drugs revisited

 

Niacin (nicotinic acid)

 

In our blog post of May 19, 2011, we discussed the late-stage development of two cholesterol ester transfer protein (CETP) inhibitors, designed to raise serum high-density lipoprotein (HDL), or “good cholesterol”. These agents are Merck’s anacetrapib and Roche’s dalcetrapib. The clinical results with these agents have  have reignited enthusiasm for CETP inhibitors in the medical and drug discovery and development community.

Now comes the news that The National Heart Lung and Blood Institute (NHLBI) of the National Institutes of Health (NIH) stopped a large clinical trial of Abbott’s Niaspan, an extended-release formulation of high-dose niacin, because the drug failed to prevent heart attacks and strokes. High-dose niacin is the only drug that is approved for raising HDL. Generic high-dose niacin is usually taken 2-3 times per day, and can cause adverse effects such as skin flushing and itching. Niaspan, as an extended-release formulation of the drug, is taken once a day, and was developed to reduce the extent of these adverse effects. Niaspan is an FDA-approved drug.

Merck has meanwhile been developing its high-dose non-flushing niacin product, Tredaptive/Cordaptive (extended-release niacin/laropiprant). This 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 remains investigational in the US. However, in 2009 Merck launched Tredaptive in international markets including Mexico, the UK and Germany. The drug is approved in over 45 countries. Merck is also 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 intends to file for approval of the drug in the US in 2012, based on the results of this trial if it is positive.

According to an NIH press release, the NHLBI trial, known as AIM-HIGH, involved combination therapy with Niaspan and a statin (simvastatin). Participants selected for the trial had been taking a statin and had well-controlled LDL, but were still at risk for cardiovascular events since they had a history of CVD, as well as low serum HDL and high serum triglycerides. In the treatment arm of the study, participants received a combination of a stain and Niaspan, while those in the control arm received a statin plus placebo.

During the 32 months of the study, subjects in the treatment arm exhibited increased HDL and lower triglyceride levels, as compared to participants in the control arm.  However, combination Niaspan/statin treatment did not reduce cardiovascular events or strokes as compared to statin treatment plus placebo. The NIH therefore stopped the trial 18 months earlier than planned.

In the AIM-HIGH study, subjects had a lower rate of cardiovascular events and strokes than the trial researchers expected. Of the 1,718 people in the treatment arm, 5.8 people per year had cardiovascular events, as opposed to 5.6 cardiovascular events per year among the 1,696 people in the control arm. There was a small increased rate of strokes in patients taking Niaspan, but researchers cautioned that this may have been due to chance. However, the increased rate of strokes, along with the failure to demonstrate efficacy, contributed to the NHLBI’s decision to end the trial early.

As noted by the AIM-HIGH researchers (and mentioned in the NIH press release), the lack of efficacy of high-dose niacin was unexpected, and in striking contrast to the results of previous trials and of observational studies. For example, a 2010 meta-analysis of clinical trials evaluating niacin, alone or in combination with other lipid-lowering drugs (published between 1966 and mid-2008) found significantly positive effects of niacin in preventing cardiovascular events and in reversing or slowing the progression of atherosclerosis. However, the bulk of the studies analyzed had been performed before statin therapy had become the standard of care. As pointed out in a recent article by clinical outcomes researcher Harlan Krumholz, MD (Yale University School of Medicine), it was important to compare Niasapn with a good treatment–in this case, the standard treatment with a statin–rather than comparing it to a poor treatment or to placebo alone.

The results of the AIM-HIGH study may not apply to other patient populations, including higher-risk groups such as patients with acute heart attack or acute coronary syndromes, or in patients who have poorly-controlled LDL despite statin treatment. As a press release from Abbott pointed out, the relevance of the results of AIM-HIGH to patient populations other than the one studied–patients with stable, non-acute, pre-existing cardiovascular disease and very well controlled LDL on simvastatin–is unknown. However, it is not known whether there are any patient populations that might benefit from treatment with Niaspan plus a statin as compared to a statin alone.

The results of AIM-HIGH also do not apply to other drugs that are designed to raise levels of serum HDL. Each drug must be tested in the clinic before drawing conclusions about its efficacy and safety. Various drugs may have different effects on human disease biology. Thus, for example, one should not use the results of the AIM-HIGH trial of Niaspan to conclude that the CETP inhibitors anacetrapib and dalcetrapib, discussed in our previous blog post, are not likely to be efficacious.

The 19 May issue of Nature contains a special Insight section on cardiovascular biology. An article in this section, by leading cardiovascular researcher Peter Libby (Brigham and Women’s Hospital, Boston MA, where he is the Chief of the Division of Cardiovascular Medicine) and his colleagues, is entitled “Progress and challenges in translating the biology of atherosclerosis”. That article refers to HDL as a “frustrating next frontier” (beyond lowering LDL with statins) in cardiovascular drug treatment. HDL biology is complex, with HDL promoting efflux of cholesterol from macrophages in atherosclerotic plaques and exerting anti-inflammatory and other beneficial effects, as also discussed in our previous blog post. 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.

In this connection, the 2010 study by Alan Tall and his colleagues, which we discussed in our May 19, 2011 blog article, provides hope for the efficacy of anacetrapib. These researchers showed that although niacin treatment in humans resulted in a moderate increase in the ability of HDL to promote net cholesterol efflux (measured in in vitro assays), anacetrapib treatment caused a more dramatic increase. This was due not only to a higher level of HDL in anacetrapib-treated subjects, but also to enhanced ability of anacetrapib-induced HDL particles to promote cholesterol efflux, especially at high HDL concentrations. Although this study suggests that anacetrapib treatment induces increases in HDL particles that promote beneficial effects on atherosclerotic plaque biology, we must wait for the results of the REVEAL trial (expected in 2014-2016) to determine the efficacy of this drug. Meanwhile, the clinical trial of Roche’s CETP inhibitor dalcetrapib, known as dal-OUTCOMES, is ongoing, with efficacy results expected in 2012-2013.

Steven Nissen, M.D. (chief of cardiovascular medicine at Cleveland Clinic), a veteran HDL researcher who has often been critical of the pharmaceutical industry, was recently interviewed on public television about the AIM-HIGH trial. He said that ever since the introduction of statins in 1987, we have not had a successful new drug class that provides significant clinical benefits by modulating serum lipids. Even when new types of lipid-modulating drugs have given apparently better biochemical results (e.g., LDL lowering or HDL raising), they have not provided clinical benefit in terms of preventing cardiovascular events.

Nevertheless, despite past disappointments with HDL-raising therapies, and despite the results of AIM-HIGH, Dr. Nissen persists in running clinical studies of novel HDL-raising drugs. He is now working on testing Resverlogix’ (Calgary Alberta, Canada) RVX-208, a small-molecule drug related to resveratrol that induces endogenous production of the protein component of HDL, apolipoprotein A1. And, as discussed in our last blog post, Dr. Nissen is enthusiastic about the prospects of Merck’s anacetrapib, although he states that the FDA will require hard clinical evidence of this drug’s efficacy before approving it.

Statins, despite their leading role in cardiovascular therapy, only reduce the risk of heart attack and stroke by 25% to 35%. Thus there is the need for new classes of drugs, and HDL is–frustrating though it be–the next frontier. Thus researchers persist in discovery and development of HDL-raising drugs, and there are promising new candidates on the horizon.

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