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30 January 2013

HDL drug update

By |2018-09-19T20:07:43+00:00January 30, 2013|Cardiovascular Disease, Drug Development, Epigenetics|

Niacin

Niacin

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

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.

24 January 2013

Determining the molecular cause of a disease does not necessarily enable researchers to develop disease-modifying drugs

By |2013-01-24T00:00:00+00:00January 24, 2013|Drug Development, Drug Discovery, Gene Therapy, Rare Diseases, Strategy and Consulting|

NBD1 of human CFTR. Source: PDBbot http://bit.ly/11UmpkS

NBD1 of human CFTR. Source: PDBbot http://bit.ly/11UmpkS

A major objective of research in genomics is to identify mutations that cause genetic diseases. However, doing so does not necessarily directly enable researchers to discover and develop drugs to treat these diseases.

Two examples of genetic diseases whose causes were identified decades ago, without directly enabling the development of any disease-modifying drug, are sickle cell disease (SCD) (also known as sickle cell anemia) and cystic fibrosis (CF).

Sickle cell disease

The causative mutation of SCD was identified by protein researchers, decades before the era of genomics. Vernon M. Ingram, Ph.D. showed in 1957 that a glutamic acid to valine mutation at position 6 of the β-chain of hemoglobin was the sole abnormality in SCD. For this discovery, Dr. Ingram has been called The Father of Molecular Medicine. Dr. Ingram’s work was made possible by a 1949 study by Linus Pauling and his colleagues, which showed that SCD hemoglobin had a different electrophoretic mobility than normal hemoglobin. Thus the sickle cell trait was likely to be due to a mutation in the β-hemoglobin gene that changed its amino acid composition, as confirmed by Dr. Ingram.

Yet to this day, although SCD (which occurs in individuals who are homozygous for the sickle-cell mutation) can be managed by various treatments (such as hydroxyurea and blood transfusions and bone marrow transplants) that can result in survival into one’s fifties, there is no mechanism-based therapy for this disease. Thus the identification of the causative mutation of SCD has not led to any treatments.

The reason why discovery and development of drugs for SCD has been so very difficult is that the mutation that causes this disease affects an intracellular protein, hemoglobin, which is neither a receptor nor an enzyme. Unlike secreted proteins such as insulin, it is not possible to develop protein drugs to replace missing or defective hemoglobin. It is also not possible to replace the missing function of normal hemoglobin by treatment with a small molecule drug.

Diseases such as SCD–in which the function of an essential intracellular protein is defective or missing–have often been cited as candidates for gene therapy.

However, as we discussed in our October 11, 2012 and our November 8, 2012 Biopharmconsortium Blog articles, it is only this past fall that the first gene therapy was approved for marketing in a regulated market. As we discussed in the first of these articles, gene therapy has a history going back to at least the early 1970s. However, gene therapy has displayed the characteristics of a premature technology. Several notable failures, including some that caused the deaths of patients, put a severe damper on the gene therapy field. Only recently–between around 2003 and 2012–have researchers been 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.

As also we discussed in our October 11, 2012 article, among the many companies that are developing gene therapies, bluebird bio (Cambridge, MA) has been singled our for special attention lately. Among the diseases being targeted by bluebird bio are SCD, and beta-thalassemias, which are also genetic diseases that affect hemoglobin. bluebird bio is in Phase 1/2 trials for its beta-thalassemia therapy, and in Phase 1 for its SCD program.

Cystic fibrosis

CF causes a number of symptoms, which affect the skin, the lungs and sinuses, and the digestive, endocrine, and reproductive systems. Notably, people with CF accumulate thick, sticky mucus in the lungs, resulting in clogging of the airways due to mucus build-up. This leads to inflammation and bacterial infections. Ultimately, lung transplantation is often necessary as the disease worsens. With proper management, patients can live into their late 30s or 40s.

The affected gene in CF and the most common mutation that causes the disease (called ΔF508 or F508del) were identified by Francis S Collins, M.D., Ph.D. (then at the Howard Hughes Medical Institute and Departments of Internal Medicine and Human Genetics, University of Michigan, Ann Arbor, MI) and his colleagues in 1989. Dr. Collins was subsequently the leader of the publicly-funded Human Genome Project and is now the Director of the U.S. National Institutes of Health, Bethesda, MD.

The gene that is affected in cystic fibrosis encodes a protein known as the cystic fibrosis transmembrane conductance regulator (CFTR).  CFTR regulates the movement of chloride and sodium ions across epithelial membranes, including the epithelia of lung alveoli. CF is an autosomal recessive disease, which is most common in Caucasians; one in 2000–3000 newborns in the European Union is found to be affected by CF. ΔF508 is a deletion of three nucleotides that causes the loss of the amino acid phenylalanine at position 508 of the CFTR protein. The ΔF508 mutation accounts for approximately two-thirds of CF cases worldwide and 90% of cases in the United States. However, there are over 1500 other mutations that can cause CF.

In the case of CF, the affected protein, CFTR, is an ion channel–specifically a chloride channel.

Ion channels constitute an important class of drug targets, which are targeted by numerous currently marketed drugs, e.g., calcium channel blockers such as amlodipine (Pfizer’s Norvasc; generics) and diltiazem (Valeant’s Cardizem; generics). These compounds were mainly developed empirically by traditional pharmacology before knowing anything about the molecular nature of their targets. However, discovery of novel ion channel modulators via modern molecular methods has proven to be challenging, mainly because of the difficulty in developing assays suitable for drug screening. In addition, development of suitable assays for assaying chloride channel function has lagged behind the development of assays for the function of cation channels (e.g., sodium and calcium channels).

Moreover the most common CFTR mutation that causes CF, ΔF508, results in defective cellular processing, and the mutant CTFR protein is retained in the endoplasmic reticulum. In the case of some other mutant forms of CTFR (accounting for perhaps 5% of CF patients), the mutant proteins reach the cell membrane, but are ineffective in chloride-channel function.

Given these difficulties, researchers first attempted to develop gene therapies for CF. Genzyme (a Sanofi company since 2011) has been a leader in developing gene therapy for CF, and has been conducting research in this area since the 1990s. However, as with most gene therapies, development of treatments capable of reaching the market has been elusive.

Genzyme is still researching gene therapies for CF, as are others. An academic group in the U.K., known as the U.K. Cystic Fibrosis Gene Therapy Consortium is working to develop CF gene therapies, using Genzyme’s nonviral cationic lipid vector GL67 (Genzyme lipid 67) as the delivery vehicle. GL67 is the current “gold-standard” for in vivo lung gene transfer. Recently, the Consortium received funding from the U.K. Medical Research Council and National Institute of Health Research to continue its Phase 2B trial of its CF gene therapy product,GL67A/pGM169. This is a combination of GL67 and plasmid DNA expressing CFTR (pGM169).

Very recently, R&D on disease-modifying small-molecule drugs for CF has begun to bear fruit. In January 2012, the FDA approved the first such drug, ivacaftor (Vertex’ Kalydeco.) In July 2012, Vertex received European approval for this drug. Ivacaftor only works in patients with the G551D  (Gly551Asp) mutation in CFTR, which only accounts for around 4% of CF patients. Vertex and other companies–including Genzyme–are working on development of other small-molecule disease-modifying drugs with the potential to treat greater numbers of CF patients.

We shall discuss the new wave of disease-modifying CF drugs, including ivacaftor, in a later post on this blog.

Conclusions

SCD and CF are two examples of cases in which the identification of the genetic or molecular cause of a disease did not directly lead to new treatments. In the case of SCD, even though over 55 years have elapsed since the identification of the genetic cause of the disease, no therapy had yet emerged from this discovery. In the case of CF, it took over two decades from the identification of the molecular cause of the disease to the approval of the first disease-modifying drug.

Many other cases in which molecular targets involved in disease have been identified also lack disease-modifying treatments because the targets are “undruggable”. This especially applies to protein-protein interactions (PPIs). However, PPIs have assumed increasing strategic importance in drug discovery and development in recent years, and researchers and companies have been developing new technologies and strategies to discover  developable drugs that address PPIs.

Back in the early 2000s, researchers and commentators hailed the sequencing of the human genome as heralding a new era in drug discovery and development. However, the “industrialized biology” approach that grew out of the genomics of that era gave very few successes in terms of drug development. Now–a decade later–we have next-generation sequencing and  are approaching the “$1000 genome.” Once again, at least some commentators are expecting immediate breakthroughs in therapeutic development to come out of these breakthroughs in sequencing technology. Others, such as CFTR gene discoverer Francis Collins, believe that we can “speed the development of genetic advances into treatments” by more rapidly weeding out “what turn out to be..nonviable compounds.”

However, in the case of CF there were barriers to drug discovery, such as limited understanding of disease biology and difficulties in assay development, that were the true causes of lack of progress in developing disease-modifying genes. Moreover, once they had good assays, researchers needed to come up with effective strategies to develop small-molecule drugs for CF. In the case of SCD, because of the nature of the target, only gene therapy–with its manifold difficulties–had any hope of addressing the disease. In the case of PPIs, there was the need to discover new breakthrough strategies to address these “undruggable” targets.

Thus, despite breakthroughs in sequencing technologies, determining of disease-related sequences is likely to only be the first step in effective discovery of disease-modifying drugs. And there may continue to be a considerable time lag between sequence determination and drug development.

________________________________

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.

9 January 2013

Identification of a novel Alzheimer’s disease pathway provides potential new avenues for drug discovery

By |2013-01-09T00:00:00+00:00January 9, 2013|Animal Models, Anti-Aging, Drug Discovery, Neurodegenerative Diseases|

Neurofibrillary tangle.

Neurofibrillary tangle.

In August and September of 2012, we published three articles on Alzheimer’s disease on the Biopharmconsortium Blog:

Subsequent to the publication of our articles–on 21 November, 2012–the Wellcome Trust announced the identification of a novel pathway involved in the pathogenesis of Alzheimer’s disease (AD). This research was led by Professor Simon Lovestone and Dr Richard Killick (Kings College, London U.K.), and was published in the online edition of Molecular Psychiatry on 20 November 2012. The Wellcome Trust helped to fund the research.

As we have discussed in earlier articles on this blog, the dominant paradigm among AD researchers and drug developers is that the disease is caused by aberrant metabolism of amyloid-β (Aβ) peptide, resulting in accumulation of neurotoxic Aβ plaques. This paradigm is known as the “amyloid hypothesis”. AD is also associated with neurofibrillary tangles (NFTs) which are intracellular aggregates of hyperphosphorylated tau protein. In contrast to the amyloid hypothesis, some AD researchers have postulated that NFT formation is the true cause of AD. The new research links amyloid toxicity to the formation of NFTs, and identifies potential new drug targets.

The new study is based on the discovery of the role of clusterin–an extracellular chaperone protein–in sporadic (i.e., late-onset, non-familial) AD. The gene for clusterin, CLU, has been identified as a genetic risk factor for sporadic AD via a genome-wide association study published in 2009. Clusterin protein levels are also increased in the brains of transgenic mouse models of AD that express mutant forms of amyloid precursor protein (APP), as well as in the serum of humans with early stage AD.

The researchers first studied the relationship between Aβ and clusterin in mouse neuronal cells in culture. Aβ rapidly increases intracellular concentrations of clusterin in these cells. Aβ-induced increases in clusterin drives transcription of a set of genes that are involved in the induction of tau phosphorylation and of Aβ-mediated neurotoxicity. This pathway is dependent on the action of a protein known as Dickkopf-1 (Dkk1), which is an antagonist of the cell-surface signaling protein wnt. The transcriptional effects of Aβ, clusterin, and Dkk1 are mediated by activation of the wnt-planar cell polarity (PCP) pathway. Among the target genes in the clusterin-induced DKK1-WNT pathway that were identified by the researchers are EGR1 (early growth response-1), KLF10 (Krüppel-like factor-10) and NAB2 (Ngfi-A-binding protein-2)–all of these are transcriptional regulators. These genes are necessary mediators of Aβ-driven neurotoxicity and tau phosphorylation.

The researchers went on to show that transgenic mice that express mutant amyloid display the transcriptional signature of the DKK1-WNT pathway, in an age-dependent manner, as do postmortem human AD and Down syndrome hippocampus. (Most people with Down syndrome who survive into their 40s or 50s suffer from AD.) However, animal models of non-AD tauopathies (non-AD neurodegenerative diseases associated with pathological aggregation of tau, and formation of NFTs, but no amyloid plaques) do not display upregulation of transcription of genes involved in the DKK1-WNT pathway, nor does postmortem brain tissue of humans with these diseases.

The Kings College London researchers concluded that the clusterin-induced DKK1-WNT pathway may be involved in the pathogenesis of AD in humans. They also hypothesize that such strategies as blocking the effect of Aβ on clusterin or blocking the ability of Dkk1 to drive Wnt–PCP signaling might be fruitful avenues for AD drug discovery. According to the Wellcome Trust’s 21 November 2012 press release, Professor Lovestone and his colleagues have shown that they can block the toxic effects of amyloid by inhibiting DKK1-WNT signaling in cultured neuronal cells. Based on these studies, the researchers have begun a drug discovery program, and are at a stage where potential compounds are coming back to them for further testing.

________________________________

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

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