In recent months, there have been quite a few articles on the need to fix the clinical trial system. Among the most recent articles is the one by Boston-based Nature writer Heidi Ledford, Ph.D. published as a News Feature in the 29 September issue of Nature. In my humble opinion, this is the best article on the subject among those that have been published recently.

The pharmaceutical/biotechnology industry is frustrated with the increasing expense and the low output of the clinical trial system. This low productivity is economically unsustainable. The current clinical trial paradigm is over 50 years old. Back in the 1960s, the norm was to conduct single trials at single sites, each designed to answer a single question.

Nowadays, the norm is the large, multicenter clinical trial, especially for Phase 3 trials. “Multicenter” means that a trial is conducted at multiple sites, often in different countries, and could involve thousands of investigators and staff members. As pointed out in Dr.Ledford’s article, the large trials are mandated by the need in our more risk-adverse world to detect safety issues that occur in only a small percentage of patients, and to obtain good statistics for drugs that confer only a small benefit over the standard of care. However, certain major diseases require large trials of long duration even for drugs that may confer large benefits. For example, because the percentage of patients per year in cardiovascular disease (CVD) trials who experience cardiovascular events is small, these trials must be large and multiyear, in order to see any benefit even for a breakthrough drug.

The advent of personalized medicine–developing drugs and combinations of drugs that are specific for the molecular mechanism behind a patient’s disease–has put additional burdens on the clinical trial system. A disease may be found to be a collection of rare diseases in terms of mechanistic subtypes, each of which affects only a small number of people. This makes patient recruitment difficult.

As stated by Dr.Ledford, “Solving the problem may require fundamental changes to the clinical-trial system to make it faster, cheaper, more adaptable and more in tune with modern molecular medicine.”

Don’t use an “e-commerce” approach to determining drug efficacy!

Other commentators have recently noted the need to make clinical trials “faster, cheaper, and more adaptable.” Several of them have suggested bringing in strategies from other industries, especially e-commerce and social media.

For example, in an editorial published in the 23 September issue of Science, Andrew Grove, the former Chief Executive Officer of Intel, proposes moving towards an “e-trial” system, based on such large-scale e-commerce platforms as that of Amazon.com. Under the proposed e-trial system, the FDA would ensure safety only, not efficacy, and would continue to regulate Phase 1 trials. Once Phase 1 trials have been successfully completed, patients would be able to obtain a new drug through qualified physicians.

Patients’ responses to a drug would be stored in a database, along with their medical histories. There would be measures to protect a patient’s identity, and the database would be accessible to qualified medical researchers as a “commons.” The response of any patient or group of patients to a drug or treatment could then be tracked and compared to those of others in the database who were treated in a different manner or were untreated. These comparisons would provide insights into a drug’s efficacy, and how individuals or subgroups (perhaps defined in part via biomarkers) respond to the drug. This would liberate clinical trials from the “tyranny of the average” that characterize most trials today. As the database grows over time, analysis of the data would also provide information needed for postmarketing studies and comparative effectiveness studies.

Dr. Grove’s proposal is one of several in which the mandate of the FDA (and regulatory agencies in Europe, Japan, etc.) is to regulate safety only (via Phase 1 clinical trials) not efficacy. Efficacy is then determined via some sort of open system, with information gathered and provided to patients and physicians electronically, via systems reminiscent of e-commerce or social media.

We are opposed to removing efficacy from the oversight of the FDA and other regulatory agencies. There are two reasons for this, both of which are illustrated graphically in Box 1 of Dr. Ledford’s article, entitled “the clinical trial cliff”. Approximately half of Phase 2 clinical trials between 2008 and 2010 failed due to inability to demonstrate efficacy. (Around one-third of Phase 2 failures were due to safety, and the remaining failures were mainly due to strategic decisions to terminate a drug.) Among Phase 3 failures between 2007 and 2010, around two-thirds were due to efficacy, and around one-quarter were due to safety. These results indicate that the majority of drugs entered into clinical trials lack efficacy.

The second reason is that many safety problems–especially the rarer safety issues that occur in only a small percentage of patients–are typically not detected in Phase 1, but in Phase 3 and even the postmarking period.

Reduce clinical attrition with new trial designs and improved animal models

Dr. Ledford’s proposals for fixing clinical trials leave regulatory agencies in charge of overseeing both safety and efficacy. They mainly focus on improving clinical trials by reducing “attrition”–i.e., failure of drugs in the clinic, especially in Phase 2 and Phase 3, and on improving patient recruitment. Haberman Associates has produced publications–as well as articles on this blog–during the 2009-2011 period that provide a more in-depth discussion of strategies for reducing attrition than is possible in a 3-page article such as Dr. Ledford’s.

Two of Dr. Ledford’s strategies involve modifications of clinical trial design. Both of these are discussed in Chapter 6 of our book-length Cambridge Healthtech Institute (CHI) Insight Pharma Report, Approaches to Reducing Phase II Attrition. The first is the “Phase 0” trial. This is a type of pre-Phase 1 clinical trial, which uses microdoses of a drug to assess such parameters as pharmacokinetics and target occupancy. As Dr. Ledford suggests, in some cases Phase 0 trials can reduce or eliminate pharmacological testing in animals, and allow researchers to get human data more quickly.

The other trial design strategy mentioned in Dr, Ledford’s article is the use of adaptive clinical trials. This type of trial allows researchers to change the course of a trial in response to trial results. For example, this may mean assigning new patients to specific doses, changing the numbers of patients assigned to each arm of a trial, and changes in hypotheses or endpoints. Monitoring and changing the trial is typically done by an independent data monitoring committee [DMC] so that ideally, double-blind conditions are maintained.

As Dr. Ledford states, adaptive clinical trials may result in shortening the time and cost of the clinical trial process. But, as with Phase 0 microdosing trials, there are many controversies surrounding adaptive clinical trials. Both of these strategies are works in progress.

The other strategy for reducing attrition discussed in Dr. Ledford’s article is to use improved animal models (i.e., animal models designed to more faithfully model human disease) in preclinical studies. We discussed this strategy in Approaches to Reducing Phase II Attrition, and in greater detail in another book-length report, Animal Models for Therapeutic Strategies. I also recently led the workshop “Developing Improved Animal Models in Oncology and CNS Diseases to Increase Drug Discovery and Development Capabilities” at Hanson Wade’s 2011 World Drug Targets Summit.

Several articles on our Biopharmconsortium Blog also focus on improved animal models for predicting efficacy of drug candidates in discovery research and in preclinical studies. Our April 15, 2010 blog post, based on an article in The Scientist, focused on “co-clinical mouse/human trials”. This type of clinical trial was developed by Pier Paolo Pandolfi, MD, PhD (Director, Cancer and Genetics Program, Beth Israel-Deaconess Medical Center Cancer Center and the Dana-Farber/Harvard Cancer Center) and his colleagues.

These trials utilize genetically engineered transgenic mouse strains that have genetic changes that mimic those found in specific human cancers. These mouse models spontaneous develop cancers that resemble the corresponding human cancers. In the co-clinical mouse/human trials, researchers simultaneous treat a genetically engineered mouse model and patients with tumors that exhibit the same set of genetic changes with the same experimental targeted drugs. The goal is to determine to what extent the mouse models are predictive of patient response to therapeutic agents, and of tumor progression and survival. The studies may thus result in validated mouse models that are more predictive of drug efficacy than the currently standard xenograft models.

The new Ledford Nature article discusses co-clinical trials as a means to develop more predictive animal model studies–not only using improved, potentially more predictive animal models, but also treating these animals in similar way (in terms of doses, formulations, schedules of medication, etc.) to the humans in the parallel human clinical trial.

The Ledford article mentions the animal-model portion of a co-clinical trial, which was published in January 2011. This trial utilized two genetically-engineered PDGF (platelet-derived growth factor)-driven mouse models of the brain tumor glioblastoma multiforme (GBM), one of which has an intact PTEN gene and the other of which is PTEN deficient.

Unlike the “standard” mouse xenograft models, these models more closely mimicked the human disease, including growth of tumors within the brain, not subcutaneously. Thus any drug administered to these mice systemically (e.g., intraperitoneally, as was done in this study) had to cross the blood-brain barrier (BBB), as in the case of human clinical trials. This would not be the case with a standard xenograft model, which is one deficiency of these models for brain tumors such as GBM.

GBM is both the most common and the most malignant primary brain tumor in adults. It has a poor prognosis. PDGF-driven GBMs, which results from deregulation of the PDGF receptor (PDGFR) or overexpression of PDGF, account for about 25-30% of human GBMs. These mutations result in the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. These tumors may also exhibit mutation or loss of heterozygosity of the tumor suppressor PTEN, which also upregulates the PI3K/Akt/mTOR pathway.

The researchers tested the Akt inhibitor perifosine (Keryx Biopharmaceuticals, an alkylphospholipid) and the mTOR inhibitor CCI-779 (temsirolimus; Pfizer’s Torisel; originally developed by Wyeth prior to the Pfizer merger and approved for treatment of renal cell carcinoma), both alone and in combination, in vitro and in vivo. Specifically, the drugs and drug combinations were tested in cultured primary glioma cell cultures derived from the PTEN-null and PTEN-intact mouse PDGF-driven GBM models, and in the animal models themselves.

The studies showed that both in vitro and in vivo, the most effective inhibition of Akt and mTOR activity in both PTEN-intact and PTEN-null cells or animals was achieved by using both inhibitors in combination.  In vivo, the decreased Akt and mTOR signaling seen in mice treated with the combination therapy correlated with decreased tumor cell proliferation and increased cell death; these changes were independent of PTEN status. The co-clinical animal study also suggested new ways of screening GBM patients for inclusion in clinical trials of treatment with perifosine and/or CCI-779.

According to Dr. Ledford’s Nature article, the National Cancer Institute (NCI) invested $4.2 million in Dr. Pandolfi’s co-clinical trials in prostate and lung cancer in 2009. In addition to the co-clinical trials with genetically-engineered mouse models run by Dr. Pandolfi and others, researchers at the Jackson Laboratory are conducting co-clinical trials with mouse xenograft models that receive tumor cells from patients to be treated in human clinical trials.

Use patient registries in recruitment of patients for clinical trials

In Dr, Ledford’s article, she discusses a crucial factor other than clinical attrition that hinders progress in conducting clinical trials–patient recruitment. According to the article, at least 90% of trials are extended by at least six weeks because of failure to enroll patients on schedule. Only about one-third of the sites involved in a typical multicenter trial manage to enroll the expected number of patients. As a result, clinical trials are longer and more expensive, and some of them are never completed.

Personalized medicine, in which researchers use biomarkers or other criteria to determine what fraction of patients with a particular disease are eligible for a trial (e.g., cancer patients with an activating mutation in a kinase that is the target of the drug to be tested), makes recruitment harder. That is because researchers must screen large numbers of patients to identify the fraction of patients that would be eligible for the trial. So they need to recruit (and screen) a much larger number of patients than in conventional clinical trials with no patient stratification.

Therefore, researchers, “disease organizations”, and patient advocates are devising new strategies to facilitate recruitment of eligible volunteers. Dr. Ledford cites the example of the Alpha-1 Foundation (Miami, Florida), a “disease organization” that focuses on the familial disease alpha-1 antitrypsin deficiency. (This disease renders patients susceptible to lung and liver diseases.) This foundation has  created a registry of patients with alpha-1 antitrypsin deficiency who are willing to be contacted about and to participate in clinical trials.

There are also cancer registries. Dr. Ledford mentions the Total Cancer Care program run by the Moffitt Cancer Center (Tampa, Florida). This program, which involves 18 hospitals, compiles medical history, tissue samples (stored for future analysis) and genetic information about each patient’s tumor. Patients can consent to doctors contacting them about trials. There are other similar programs being developed in the Netherlands and elsewhere. Dr.Ledford mentions the difficulty in negotiating agreements between institutions, and the need for adequate, ultra-secure networks to support registries that connect multiple hospitals and research centers.

Patient registries that are designed to proactively support recruitment for clinical trials have some resemblance to a “social media” approach to recruitment. However, there is a big difference–the need to secure the privacy of patient records. The current trend in social media (and in some e-commerce platforms) is anti-privacy. This is yet another important reason why a social media or e-commerce approach to clinical trials or other aspects of biotech/pharma R&D is not a suitable model. (To his credit, Dr. Grove mentions the need to maintain patient privacy and confidentiality. But this is not the norm with e-commerce and social media.)

Cutting red tape for faster and cheaper clinical trials

Dr Ledford also mentions ways to deal with more bureaucratic issues that can slow down or block the progress of clinical trials. The NCI is now initiating a data-management system that will standardize data entry across all 2,000 sites that conduct NCI-sponsored trials. This should help reduce costs and cut down on record-keeping errors and omissions.The FDA is also looking into ways to reduce reporting requirements and paperwork. so that investigators can submit summaries of case reports rather than each individual document.

To adapt to the multicenter nature of clinical trials, the US Office for Human Research Protections (Rockville, Maryland), which oversees NIH-funded human studies, has proposed changes to its guidelines that would require designation of a single review board for each project. This may greatly improve the current situation, in which multicenter trials must get approval from each center’s institutional review board. This can take months or even years. Despite the definite advantages of more centralized review, individual research centers may be reluctant to give up their direct oversight of clinical trials.

Something important was not in Dr. Ledford’s article

The space limitations for Dr. Ledford’s “News Feature” article, plus its strict focus on clinical trials per se, did not permit her to include something of crucial importance to reduce clinical attrition. That is utilizing such strategies as biology-driven drug discovery in the research phase of drug development. These strategies are designed to select the best targets and to discover drugs that are more likely to be efficacious in treating a particular group of patients. These research strategies are then coupled with early development strategies that emphasize designing clinical trials aimed at obtaining rapid proof of concept in humans. Such trials typically involve the use (and often the discovery) of biomarkers.

We discussed these issues extensively in our report, Approaches to Reducing Phase II Attrition, as well as in an article published in Genetic Engineering and Biotechnology News (and available on our website) “Overcoming Phase II Attrition Problem“. We also discussed a specific case of the use of this strategy in our October 25, 2010 article on this blog.

Conclusions

Given the low productivity of pharmaceutical R&D, it is tempting to take an envious look at the success of e-commerce and social media, and to attempt to devise strategies that apply methodologies from these industry sectors to the biotech/pharmaceutical industry. We should remember, however, that not so long ago some pharmaceutical executives attempted to apply methodologies from such industries as aerospace, computer hardware, and the auto industry to pharma R&D. Not only did that not work too well for the pharmaceutical industry, but as we all know, the industries that served as a model for these approaches haven’t done very well in recent years either.

In contrast, pharmaceutical and biotechnology companies that have formulated strategies that embrace the uniqueness of biology, such as Novartis and Genentech (the latter now merged with Roche), have done a lot better.

There are other strategies for making clinical trials faster, cheaper, and better that are now under discussion in the biotech/pharma industry and the FDA.  These strategies are based on clinical experience, not e-commerce. We shall discuss them in further blog posts.

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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 click here. We also welcome your comments on this or any other article on this blog.

 

This article is an update of a three-part series on insulin sensitizers for treatment of type 2 diabetes that was published on this blog in August and September of 2010.

Summary of our August/September 2010 blog articles on insulin sensitizers

In part 1 of the series (posted August 23, 2010), we focused on safety issues with the two marketed thiazolidinedione (TZD) peroxisome proliferator-activated receptor gamma (PPARγ) agonists–rosiglitazone (GlaxoSmithKline’s Avandia) and pioglitazone (Takeda’s Actos). Both of these insulin sensitizing, antidiabetic agents induce weight gain, and carry an increased risk of edema and heart failure. In addition, rosiglitazone carries an increased risk of myocardial infarction. On September 23, 2010, the FDA restricted access to Avandia, and the European Medicines Agency (EMA) recommended that the drug be pulled from the market.

In part 2 of the series (posted on August 29, 2010), we discussed a breakthrough discovery by Bruce Spiegelman (Dana-Farber Cancer Institute and Harvard Medical School, Boston MA) and his colleagues, published in the 22 July 2010 issue of Nature. It was the Spiegelman group that originally identified PPARγ as the master regulator of adipocyte biology and differentiation, which eventual led to the development of the TZD drugs.

In that research, the Spiegelman group found evidence that the insulin sensitizing and antidiabetic effects of PPARγ agonists may not be due to the agonistic effects of these compounds on PPARγ, but to their ability to inhibit phosphorylation (at Ser 273) of PPARγ by the enzyme cyclin-dependent kinase 5 (CDK5). A weak PPARγ agonist, the benzoyl 2-methyl indole (non-TZD) MRL24, inhibits CDK5 phosphorylation of PPARγ as well as rosiglitazone, and also has very good antidiabetic activity.

CDK5 phosphorylation of PPARγ does not change the ability of PPARγ to upregulate transcription of genes involved in adipocyte differentiation. However, it inhibits the ability of PPARγ to upregulate transcription of a set of genes, including the gene for the adipokine adiponectin, that induce insulin sensitivity and resistance to obesity. Although both rosiglitazone and MRL24 inhibit CDK5 phosphorylation of PPARγ, treatment with the strong agonist rosiglitazone results in upregulation of both the adipogenic and the pro-insulin resistance sets of genes, while treatment with MRL24 results only in upregulation of the pro-insulin resistance set.

Researchers hypothesize that it is the upregulation of the adipogenic gene set that is responsible for the adverse effects of strong agonists of PPARγ–weight gain, edema, and the risk of heart failure. In contrast, the upregulation of adiponectin and the other members of the pro-insulin resistance gene set is thought to be responsible for the desirable, antidiabetic effect of PPARγ agonists.

In part 3 of the series (published on September 16, 2010), we discussed two essays, also published in the 22 July 2010 issue of Nature, that discuss using the new breakthrough results of the Spiegelman group to discover and develop improved insulin sensitizers. These essays recommended that researchers screen for compounds that inhibit CDK5 phosporylation of PPARγ rather than those that are strong PPARγ agonists. We also discussed the prospects for early-stage non-TZD partial or selective agonists of PPARγ, which might constitute second-generation insulin sensitizers.

New research from the Spiegelman group based on their 2010 breakthrough result

On September 4, 2011, Nature published, as an “advance online publication”, a new paper [subsequently published in Nature’s 22 September 2011 print edition] by Bruce Spiegelman, Patrick R. Griffin and Theodore Kamenecka (Scripps Research Institute, Jupiter, Florida) and their colleagues on discovery of novel compounds that bind to PPARγ and block its phosphorylation by CDK5, and which completely lack PPARγ agonist activity. (These compounds are thus neither full nor partial/selective agonists of PPARγ.)

One of these compounds, SR1664, exhibited potent antidiabetic and insulin sensitizing activity in two mouse models of obesity-associated type 2 diabetes. However, unlike full agonists such as rosiglitazone, it did not cause fluid retention and weight gain in these animal models. Fluid retention and weight gain are major adverse effects of TZDs in their own right, and are also thought to be related to the even more serious cardiovascular adverse effects of TZDs. Moreover, SR1664 did not interfere with bone mineralization in cultured osteoblasts; this assay is a model for the loss of bone mineral density and increase risk of fracture seen with TZDs.

The researchers developed SR1664 by starting with a partial agonist of PPARγ developed by GlaxoSmithKline, known as compound 7b. Using compound 7b as a scaffold for chemical modification, the researchers optimized for (1) high binding affinity for PPARγ, (2) blocking of CDK5-mediated PPARγ phosphorylation and (3) lacking classical agonism. The structure of two resulting compounds, SR1664 and SR1824, are given in the new Spiegelman/Griffin paper.

Although the new study suggests that SR1664 may be as efficacious an insulin sensitizer as TZDs without inducing their major adverse effects, the safety of these compounds in humans (as opposed to the mouse models) remains unproven. Moreover, SR1664 has unfavorable pharmacokinetic properties and is thus not a good candidate for development as a drug. According to a press release, Dr. Griffin’s molecular therapeutics group and Dr. Kamenecka’s medicinal chemistry group at Scripps have been using S1664 as a molecular scaffold for the discovery of derivatives with improved pharmacokinetic properties. They are advancing such newer compounds into additional studies.

Why develop new insulin sensitizers rather than depending on current antidiabetic drugs?

In Heidi Ledford’s commentary published in the 22 July 2010 issue of Nature, the author points out that some observers believe that pharmaceutical companies will be reluctant to attempt to develop new insulin sensitizers that target PPARγ, given the checkered history of that class of drugs. And other medical authorities believe that the older, inexpensive, and well proven type 2 diabetes drugs–insulin, metformin, and sulfonylureas–are adequate for the treatment of type 2 diabetes.

However, there remain important unmet needs in the treatment of type 2 diabetes. These especially include dealing with the relentlessly progressive nature of type 2 diabetes–for example, even patients who initially succeed in reaching glycemic goals with only diet/exercise and metformin will eventually need multidrug treatment, including insulin. Progression of type 2 diabetes is mainly due to the loss of pancreatic beta-cell function, which results in increased impairment of a patient’s ability to produce insulin in response to increased blood glucose.

Despite the major safety issues with TZDs, there is both animal model and human evidence that these agents may work to preserve and/or enhance beta-cell function. It will be important to determine if nonagonist second-generation insulin sensitizer candidates, such as those being developed by the Spiegelman and Griffin groups, also have the beta-cell preserving or enhancing effects of TZDs.

The Harvard/Scripps efforts to discover safer insulin sensitizers illustrate the potential role of academia (based on breakthrough science) in areas of drug discovery and development that industry is reluctant to undertake. However, although these academic groups might potentially take the nonagonist insulin sensitizers through lead optimization and preclinical studies, eventually industry (whether a biotech company or a pharmaceutical company) will need to take the compounds through clinical trials in order for any drugs to reach the market.
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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 click here. We also welcome your comments on this or any other article on this blog.

 

On July 29, 2011, Merck announced that It was shutting down the San Francisco research laboratory that it had acquired as part of its $1.1 billion acquisition of therapeutic RNAi specialist company Sirna Therapeutics. This announcement was covered in a July 29, 2011 article in Xconomy, and in a news brief in the 4 August issue of Nature and a linked Nature news blog article.

According to the Xconomy article, the shutdown will include the loss of around 50 jobs. Around ten people are being offered transfers to other Merck facilities in nearby Palo Alto CA and on the East Coast.

The Merck facility shutdown continues the exit or retrenchment from therapeutic RNAi research at other Big Pharma companies. The Biopharmconsortium Blog has covered these moves at Roche and Pfizer.

As we discussed in the Roche article, Novartis had also decided to end its 5-year partnership with therapeutic RNAi specialty company Alnylam In September 2010. However, Novartis acquired technology and exclusive development rights for RNAi therapeutics against 31 targets for in-house use as the result of its partnership with Alnylam.  Alnylam is entitled to receive milestone payments for any RNAi therapeutic products that Novartis develops based on these targets. Thus Novartis is still involved in RNAi therapeutics, despite the termination of the Alnylam partnership.

Moreover, according to the Nature news blog, Ian McConnell of Merck’s Scientific Affairs, R&D and Licensing and Partnerships said that Merck will continue to have over 100 scientists working on RNA-based therapeutics, and that it continues to invest significantly in the field. Closing the San Francisco lab represents an effort to trim the budget by eliminating the cost of maintaining a separate RNAi facility.

In our previous blog articles on Big Pharma RNAi therapeutics retrenchment, and in our October 2010 book -length report, RNAi Therapeutics: Second-Generation Candidates Build Momentum, we discussed the strategic issues that are involved in undertaking (or in retrenching from) R&D programs in RNAi therapeutics, and in investing in that area. The therapeutic RNAi (and microRNA) field represents an early-stage area of science and technology. The field may be technologically premature, as was the monoclonal antibody (MAb) drug field in the 1980s.

Big Pharma originally got into RNAi therapeutics in order to help fill weak pipelines, and with the hope of staking out a commanding position in the RNAi field once it became successful. However, with the short-term pressure at Big Pharma companies to cut expenses and programs, Big Pharmas have been losing the needed patience to continue with a technologically premature field like RNAi therapeutics.

In the June 2011 issue of Molecular Therapy, there is an editorial by Arthur Krieg, M.D. (former Chief Scientific Officer of the now-closed Pfizer Oligonucleotide Therapeutics Unit, and now Entrepreneur in Residence at Atlas Venture, Cambridge, MA), entitled “Is RNAi dead?” As discussed in the editorial, the move of Big Pharma away from RNAi, according to some observers, signals the death of the therapeutic RNAi platform. Dr. Krieg outlines an alternative view.

According to Dr. Krieg, Big Pharmas got into RNAi therapeutics with the hope of enabling the rapid development of targeted drugs without the long time lags and uncertainties of small molecule drugs and biologics. In theory, if a research team has a good target, it could rationally design a lead RNAi drug specific for the target and ready for human clinical trials within 15 months. And researchers would not have to worry about “undruggability” of targets. However, there have been several unforeseen hurdles to the development of RNAi drugs, the most formidable of which is the issue of drug delivery. Although certain high-profile publications suggested that the challenge of RNAi drug delivery could be easily overcome, this proved not to be the case in practice.

However, Dr. Krieg believes that the progress in RNAi delivery in recent years has been “nothing short of spectacular”. In 2008, the best RNAi delivery systems for a liver target might have an IC50 (i.e., the RNAi dose required for 50% inhibition of target expression) of 1–3 mg/kg, but in 2010/2011, the IC50 has been reduced to about 1% of this value, which is an improvement of two logs. Dr. Krieg also says that there have also been significant advances in reducing off-target and other undesired systemic effects of RNAi therapeutics in animal models in recent years.

Nevertheless, the advances in RNAi delivery and safety are moving too slowly for Big Pharma’s current short-term mindset. According to Dr. Krieg, if companies are not able to take an RNAi drug into clinical development this year, then the next time there is an R&D portfolio review, investments in “high-risk” technology platforms such as RNAi are likely to be cut. As we have discussed in this blog, and as is well-known to most of you, every Big Pharma company has been cutting R&D and shedding poorly productive and high-risk programs. The focus at many Big Pharmas is on fast, sure returns. High-risk or premature technologies that have not yet yielded any marketed drugs, such as RNAi (and for example, stem cells/regenerative medicine) is not likely to offer such returns.

Dr. Krieg also notes that in the case of another once-premature technology, monoclonal antibody (MAb) drugs, it took several waves of technology development to advance from repeated clinical failure to one of the most successful classes of drugs today. In our view, MAb technology is the classic case (in the life sciences, anyway) of how researchers and companies can take such a premature technology up the technology curve by developing enabling technologies. We discussed this case in our September 28, 2009 blog article, and its applicability to RNAi and stem cells in our July 13, 2009 blog article. As discussed in these articles, and as noted by Dr. Krieg, it was not Big Pharmas, but biotech companies “on the cutting edge” (together with academic labs) that advanced the therapeutic MAb field. Big Pharmas later bought into the MAb field, typically by large acquisitions. This is especially exemplified by the acquisition of MAb drug leader Genentech by Roche.

With respect to RNAi, as mentioned above, at least Merck and Novartis among the Big Pharmas are continuing with in-house RNAi therapeutics programs. And such biotechs as Alnylam, Silence Therapeutics, Quark Phamaceuticals, Dicerna, and Santaris have RNAi and/or microRNA-based drug candidates in clinical trials, often partnered with Big Pharma companies (such as Pfizer) that have cut or reduced their own RNAi drug programs. Therefore, there are companies that are working on advancing RNAi therapeutics up the technology curve. As Dr. Krieg says in his editorial, success in such programs will be expected to lead to Big Pharma reinvestment in RNAi/microRNA therapeutics, just as in the case of MAb drugs.

 

The time for the July 2011 World Drug Targets Summit in Cambridge MA is looming closer and closer! Registration for the conference is still open, however.

I will lead a workshop entitled “Developing Improved Animal Models in Oncology and CNS Diseases to Increase Drug Discovery and Development Capabilities” at the Summit on July 19.  A workshop on addressing kinase signaling in drug discovery and development will take place later that day. The main conference follows on July 20-21. I am planning to attend the entire conference.

Our workshop will be a discussion of four case studies involving development of novel animal models in oncology and CNS diseases, aimed at more closely modeling human disease than current models. Drug discovery and development in these therapeutic areas has been severely hampered by animal models that are  poorly predictive of efficacy. This is a major cause of clinical attrition in these areas.

There will be one case study on a zebrafish cancer model, two on mouse cancer models, and one on a mouse CNS disease model. The case studies will include applications of these animal models to understanding disease biology, developing new therapeutic strategies, overcoming resistance to breakthrough targeted cancer therapeutics, and identifying drug candidates and advancing them into the clinic.

The main conference will focus on developing improved target discovery and validation strategies that are capable of meeting the challenges of drug discovery and development in the early 21st century–minimizing drug attrition in the clinic, and delivering commercially differentiated products that address unmet medical needs to the market. Speakers will include target discovery and validation leaders from leading pharmaceutical companies, biotechnology companies, and academic institutions.

 

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.