Stem cells. Source:

Stem cells. Source:

As reported in Nature News on 27 February 2013 ophthalmologist Masayo Takahashi M.D., Ph.D. and her colleagues at the RIKEN Center for Developmental Biology (Kobe, Japan), plan to submit an application to the Japanese health ministry for a clinical study of induced pluripotent stem cell (iPS)-derived cells. The researchers planned to submit their application in March 2013; if approved, they could begin recruiting patients as early as September.

The author of the Nature News article is Nature‘s Asian-Pacific Correspondent, David Cyranoski, who is based in Tokyo.

The researchers plan to treat approximately six people with severe age-related macular degeneration (AMD). Specifically, the researchers are targeting “wet” AMD, in which angiogenic blood vessels invade the retina, destroying the retinal pigment epithelium (RPE) that supports the light-sensitive photoreceptors.

AMD is a common cause of blindness that affects at least 1% of adults over 50. Wet AMD can be treated with anti-vascular endothelial growth factor (anti-VEGF) agents such as ranibizumab (Genentech/Novartis’ Lucentis), pegaptanib (Gilead/OSI/Pfizer’s Macugen), aflibercept (Sanofi/Regeneron’s Eylea), and–off-label–small doses of the anticancer agent bevacizumab (Genentech/Roche’s Avastin). However, the use of these agents requires that they be injected repeatedly into the eye.

According to the Nature News article, Dr. Takahashi and her colleagues will take an upper arm skin sample the size of a peppercorn, and transform the cells from this sample into iPS cells by using specific proteins. They will then add other factors that will induce differentiation of the iPS cells into retinal cells. Then a small sheet of these retinal cells will be placed under the damaged area of the retina, where they are expected to grow and repair the damaged RPE.

Although the researchers would like to demonstrate efficacy of this treatment in ameliorating the disease, the main focus of these studies will be on safety. Safety concerns include immunogenicity of the transplanted cells, and formation of tumors if the transplanted cells multiply uncontrollably. Another concern is that the transplanted cells might fail to engraft, and to integrate with the host tissue. It is also possible that the RPE identity of the transplanted and differentiated cells might not be stable over time.

With respect to these concerns, studies published by Japanese researchers in 2013 (Araki et al.) and reviewed in a recent Nature News article contradicted the original mouse studies that suggested that syngeneic or autologous iPS cells might be immunogenic.

With respect to tumor formation, Dr. Takahashi’s proposed studies will involve using only a few iPS cells, thus reducing the probability of forming tumors. Moreover, since the eye is relatively accessible, any tumors would be relatively easy to remove.

In addition, Dr, Takahashi has presented preclinical studies at conferences, which indicate that her iPS cells do not form tumors in mice and are safe in non-human primates. (Dr. Takahashi’s preclinical studies have also been submitted for publication.) The studies have provided reassurance of the cells’ safety to at least some leading researchers, such as Martin Pera (University of Melbourne, Australia) and George Daley (Harvard Medical School, Boston MA).

However, other researchers believe that to take iPS cell-derived tissue into the clinic at this time is premature. Robert Lanza, M.D., the chief scientific officer at Advanced Cell Technology (ACT) (Santa Monica CA) says that he cannot imagine regulatory agencies permitting studies such as Dr. Takahashi’s without years of preclinical testing.

As mentioned in the Nature News article, ACT has a program involving human embryonic stem cell (hES cell) and iPS-derived platelets for transfusion. This program is in the preclinical stage. Since platelets lack a nucleus and cannot form tumors, it is inherently less risky that clinical programs of stem-cell (and especially iPS cell) derived differentiated cells that have nuclei.

Dr. Takahashi’s proposed study of her therapy in humans is considered a “clinical study”, not a clinical trial. In Japan’s regulatory system, clinical studies are less tightly regulated than clinical trials. However, a clinical study cannot by itself lead to approval of a potential therapeutic for clinical use as a treatment. If Dr. Takahashi’s clinical study data is positive, that might attract investors or help her to get approval for a formal clinical trial. As in the U.S. or Europe, successful clinical trials will be required if Dr. Takahashi’s cellular therapy is ever to be used to treat patients.

Dr. Takahashi’s clinical study was approved by institutional review boards at both the natural sciences institute RIKEN in Wako and the Institute of Biomedical Research and Innovation in Kobe, where the surgical procedures will be carried out. Final approval will depend on the action of a committee of the Japanese Ministry of Health, Labour and Welfare. If Dr. Takahashi wins approval by September 2013 as expected, it will take another eight months to produce the tissue implants needed for her clinical study.

Other retinal repair programs involving human embryonic stem cell-derived RPE cells

Dr. Takahashi’s research does not represent the only RPE cell-based retinal repair program now being developed. There are at least two others, both of which are based on hES cells, not iPS cells.

As was not mentioned in the Nature News article, ACT has Phase 1 trials underway in its own RPE retinal repair program. ACT’s RPE cells are derived from human embryonic stem cells (hES cells). The company’s Phase 1 safety studies are in Stargardt’s Macular Dystrophy (SMD) and in dry AMD (which results from atrophy of the RPE layer, and causes vision loss through loss of photoreceptors in the central part of the eye. Dry AMD does not involve angiogenesis.). SMG is a rare inherited juvenile macular degeneration.

In February 2012, Dr. Lanza and his academic collaborators at the University of California at Los Angeles published a preliminary report of their clinical studies in dry AMD and SMG. In this study, one patient with each of the two conditions was treated with hES cell-derived RPE cells. The hES cell-derived RPE cells showed no signs of hyperproliferation, tumorigenicity, ectopic tissue formation, or apparent rejection after 4 months. Neither patient showed loss of vision, and there were signs of improvement of vision. As a result of this very preliminary study, the researchers decided in the design of future clinical studies to treat patients earlier in the disease processes, potentially increasing the likelihood of improvement of vision.

The other RPE-based retinal repair program is a collaborative effort between Neusentis (A Cambridge U.K. and Durham NC-based Pfizer research unit) and “The London Project” which was formed by Professor Pete Coffey [Institute of Ophthalmology, University College London (UCL)] and his collaborator Lyndon da Cruz (Moorfields Eye Hospital) to develop cellular therapies for all types of AMD. The London Project began collaborating with Pfizer in 2008; this collaboration was brought under the aegis of Neusentis when it was formed in 2011. Research is based on RPE cells derived from hES cells.

The Neusentis/London Project group claims to have developed a deep understanding of the biology of hEC cell-derived RPE cells, and to have worked out methods of producing enough RPE cells under GMP conditions to support clinical studies. They also claim to have developed a clear approach to establishing the safety of the therapy via preclinical studies. The collaborative group is now moving towards clinical studies of their therapies, which they “hope to achieve in the not too distant future”.

As we discussed in our February 15, 2011 article on this blog, Pfizer–as of February 1, 2011–closed its Memorial Drive laboratory in Cambridge, MA. This laboratory housed most of Pfizer’s regenerative medicine research, as well as the company’s RNAi therapeutics research group. However, as we said in this article, Pfizer was folding its Cambridge, UK regenerative medicine group–“which had been focusing on development of preclinical embryonic stem (ES) cell-based ophthalmology therapies, in collaboration with the University of London”–into a “new pain and sensory disorder research unit”. According to its website, Neusentis, which was formed in 2011, has “a particular focus on pain and sensory disorders”.

Japanese government backing for iPS cell research and commercialization

Japan has been a hotbed of iPS cell research, since these cells were first produced by Shinya Yamanaka, M.D. Ph.D. (Kyoto University) in 2006. He received The Nobel Prize in Physiology or Medicine in 2012 for his work on iPS cells. The co-recipient of the Prize, Sir John B. Gurdon, successfully cloned a frog using intact nuclei from the somatic cells of a Xenopus tadpole back in 1958. The two scientists received the 2012 Prize “for the discovery that mature cells can be reprogrammed to become pluripotent”. Since their discovery, iPS cells have been employed in such areas as basic research, disease modeling, and drug screening. (Follow this link for a recently-published example of the potential use of iPS cells in designing personalized treatments for Alzheimer’s disease.)

In 2013, as part of its stimulus package, the Japanese government has been providing generous funding for iPS research. This funding includes ¥700 million for a cell-processing centre at the Foundation for Biomedical Research and Innovation in Kobe, mainly to support Dr. Takahashi’s regenerative medicine research. In general, the iPS funding under the stimulus is aimed at moving university research on iPS cells into commercial and medical applications.

Moreover, according to Mr. Cyranoski’s 27 February 2013 Nature News article, the Japanese parliament is expected to rule by late June 2013 on a provision of a revised drug law, which would fast-track iPS-based therapies that appear to be effective in phase 2 or phase 3 trials. However, the success of the Japanese government’s efforts to accelerate commercialization of iPS-based therapies may depend in part on the success of Dr. Takahashi’s clinical research.


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.

Lumacaftor (Vertex’ VX-809)

Lumacaftor (Vertex’ VX-809)

I was quoted in an article in the March 11, 2013 issue of Elsevier Business Intelligence’s The Pink Sheet by senior writer Joseph Haas. The article is entitled “Cystic Fibrosis Market Snapshot: Disease-Modifying Drugs Elusive 24 Years After Discovery Of Root Cause”. A subscription is required to view the full text of this article.

The article focused on the newly-approved disease modifying drug ivacaftor (Vertex’ Kalydeco), as well as programs in drug discovery and development of disease-modifying drugs for cystic fibrosis (CF) at Vertex, PTC Therapeutics, Proteostasis Therapeutics, Pfizer, and Genzyme. It also discussed pipeline products aimed at treating or preventing life-threatening infections in CF patients at such companies as KaloBios, Insmed, and Savara.

Mr. Haas interviewed me for this article. Most of the content of our interview is available in our February 15, 2013 article on the Biopharmconsortium Blog. One company whose R&D program we did not cover in that article is Proteostasis. Proteostasis’ CF program, which is being carried out in collaboration with the Scripps Research Institute, is aimed at discovery and development of compounds that promote CFTR ΔF508 folding and trafficking. This program is in the research and lead optimization stage. We discussed R&D programs at other companies (Vertex, Pfizer) that are also aimed at correction of improper CFTR ΔF508 folding and trafficking in our February 15, 2013 article.

KaloBios’ KB001-A, a bacterial virulence factor-targeting agent

Among the agents aimed at ameliorating life-threatening infections in CF patients that were discussed in the Pink Sheet article is KB001-A, a monoclonal antibody (MAb) agent being developed by KaloBios (South San Francisco, CA). KB001-A is now in Phase 2 development for prevention of Pseudomonas aerguinosa infections in the lungs of CF patients. KB001-A targets an extracellular component of the bacterium’s type III secretion system. This system enables the bacteria to kill immune cells by injection of protein toxins into these cells.

The type III secretion system is an example of a virulence factor. Virulence factors are not expressed by a strain of pathogenic bacteria in vitro, but are expressed only when the bacteria infect a host. Once expressed, they enable the bacteria to colonize the host and cause disease.

In our June 11, 2012 article on this blog, we discussed an antibacterial drug discovery strategy aimed at targeting two related physiological systems that are important in the ability of pathogenic bacteria to cause disease, but are not essential for bacterial proliferation or survival. These systems are virulence factors and quorum sensing. At least by hypothesis, agents that disrupt these systems will prevent pathogenic bacteria from causing disease without selecting for resistant strains of the bacteria. This will give such agents an advantage over conventional antibiotics, which notoriously generate resistant strains when used to treat infections. According to the Pink Sheet article, KaloBios believes that P. aerguinosa bacteria will not develop resistance to KB001-A, which is in accord with this hypothesis.

Another issue with anti-infectives used to treat CF that is discussed in the Pink Sheet article is the definition of a “disease-modifying” agent for CF. We define disease-modifying agents as drugs that ameliorate or cure a disease by targeting the root cause of that disease. However, KaloBios considers KB001-A to be a disease-modifying agent. That is because the company believes that most CF patients die of the effects of P. aerguinosa infection, which causes deterioration of the patients’s lungs. Thus an effective anti-P. aerguinosa agent may produce dramatic increases in patients’ lifespans.

Perhaps the real issue is that one should not classify CF drugs as “disease-modifying” agent and agents that merely treat “symptoms” (as is done in the Pink Sheet article) but should define infections of CF patients as “complications” of the disease. Thus anti-infectives such as KB001-A may effectively treat a major life-threatening complication of CF, without modifying the underlying disease. Such an agent would result in increased lifespans (and improved quality of life) for CF patients, without affecting their underlying disease. As KaloBios asserts, anti-infective agents like KB001-A would be complementary to such disease-modifying agents as ivacaftor.


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.


Normal and Alzheimer's brains compared.

Normal and Alzheimer’s brains compared.

Once again, approaches to improving clinical trials for candidate disease-modifying drugs for Alzheimer’s disease (AD) are in the news. On February 7, 2013, the FDA issued a Draft Guidance for Industry entitled “Alzheimer’s Disease: Developing Drugs for the Treatment of Early Stage Disease”.

This document has been distributed for comment purposes only, and the FDA is seeking public comment on the draft guidance for 60 days.

The wording of the Draft Guidance illustrates the extreme difficulty of defining populations with pre-AD or very early-stage AD, and of demonstrating the efficacy of a drug in ameliorating early-stage disease, and/or in preventing its progression to later-stage disease. The document states that the FDA is “open to considering the argument that a positive biomarker result (generally included as a secondary outcome measure in a trial) in combination with a positive finding on a primary clinical outcome measure may support a claim of disease modification in AD.”

However,  there is currently no evidence-based consensus as to which biomarkers might be appropriate to support clinical findings in trials in early AD. Moreover, in “pre-AD” or very early-stage AD (i.e., before the onset of overt dementia) mild disease-related impairments are extremely challenging to assess accurately. Thus both measuring clinical outcomes and assessment via biomarkers in very early-stage AD are fraught with difficulty, making determination of drug efficacy extremely difficult. The FDA thus appears to be seeking guidance from industry and from the academic community on how these knotty problems might be solved.

The move toward conducting clinical trials in early-stage AD patients

By issuing the Draft Guidance, the FDA adds its voice to that of an ever-increasing segment of the scientific community that calls for a new focus on conducting clinical trials in early-stage AD. We discussed this trend in our August 19, 2012 and August 28, 2012 articles on the Biopharmconsortium Blog.

As we discussed, this trend is driven in part by the Phase 3 failures of Pfizer/Janssen’s bapineuzumab and Lilly’s solanezumab in 2012. Now–in February 2013–Russell Katz, M.D. (director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research) says, “The scientific community and the FDA believe that it is critical to identify and study patients with very early Alzheimer’s disease before there is too much irreversible injury to the brain. It is in this population that most researchers believe that new drugs have the best chance of providing meaningful benefit to patients.”  In line with this statement, the FDA refused to entertain Lilly’s  secondary analysis of early stage patients in the solanezumab study that we discussed in our August 28, 2012 blog article. Instead, the FDA mandated that Lilly conduct a new Phase 3 trial that will exclude the moderate-stage patients who hadn’t responded, and focus only on early-stage patients.

Recent news on clinical trials in early-stage AD

Despite the difficulties highlighted in the Draft Guidance in conducting clinical trials in early-stage AD patients, three research groups are actually conducting such trials. We outlined these studies in our August 28, 2012 blog article, and discussed one of these studies, the one begin carried out by Genentech, in greater detail in our August 19 2012 article.

The three studies are:

  • Roche/Genentech’s Phase 2a trial of its its anti-amyloid MAb crenezumab, in presymptomatic members of a large Colombian kindred who harbor a mutation in presenilin 1 (PS1) that causes dominant early−onset familial AD.
  • Studies conducted in conjunction with the Dominantly Inherited Alzheimer Network (DIAN), a consortium led by researchers at Washington University School of Medicine (St. Louis, MO). This study will include people with mutations in any of the three genes linked to early-stage, dominantly-inherited AD–PS1, PS2, and amyloid precursor protein (APP). Initial studies focused on changes in biomarkers and in cognitive ability as a function of expected age of AD onset in people with these mutations. These included changes in concentrations of amyloid-β1–42 (Aβ42) in cerebrospinal fluid (CSF), and amyloid accumulation in the brain. In the first stage of the actual trial, three drugs (which have not yet been selected) will be tested in this population, and changes in biomarkers and cognitive performance will be followed.
  • The Anti-Amyloid Treatment of Asymptomatic Alzheimer’s (A4) trial, will involve treating adults without mutations in any of the above three genes, whose brain scans show signs of amyloid accumulation. A4 is thus designed to study prevention of sporadic AD (by far the most common form of the disease). It will enroll 500 people age 70 or older who test positive on a scan of amyloid accumulation in the brain. (This is in contrast to the two trials in subjects with gene mutations, who are typically in their 30s or 40s.) A4 will also have a control arm of 500 amyloid-negative subjects. Amyloid-positive and control subjects will be entered into a three-year double-blind clinical trial that will look at changes in cognition with drug treatment. The A4 researchers [led by Reisa Sperling, Brigham and Women’s Hospital/Harvard University (Boston, MA), and Paul Aisen, University of California, San Diego] planned to select a drug for testing by December 2012.

Now there is more recent news on two of these trials.

1. On December 13, 2012, the Los Angeles Times reported that Genentech and its collaborators [affiliated with the University of Antioquia medical school (Medellin, Colombia), the University of California at Los Angeles (UCLA), and the Banner Alzheimer’s Institute (Phoenix, AZ)] will begin their $100 million clinical trial of crenezumab with 100 Colombians who carry the PS1 mutation in the spring of 2013. Genentech is contributing $65 million of the study’s $100-million cost. The NIH and the Banner Alzheimer’s Institute (Phoenix, AZ) are financing the remainder.

This story was also reported on December 14, 2012 by Fierce Biotech.

The design of the trial calls for 100 additional patients in Colombia with the same Alzheimer’s-related gene to receive a placebo, and an equal number of other at-risk patients without the gene to take crenezumab.  A branch of the trial will include U.S. patients as well. A “branch study” will also be conducted at UCLA, where researchers have discovered a similar genetic disposition among members of an extended family from Jalisco, Mexico. Some 30 individuals from this family who have immigrated to Southern California could participate. Around 150 other U.S. patients with similar mutations will also participate in the trial.

The trial is designed to provide evidence that targeting amyloid with crenezumab at an early stage or even before patients show signs of dementia can have a positive effect on the course of disease.

2. On January 18, 2013, Fierce Biotech reported that the researchers conducting the A4 study have chosen Lilly’s solanezumab as as the first therapeutic drug candidate to be evaluated in the trial. The A4 trial’s principal investigator, Reisa Sperling said that the researchers chose solanezumab (after considering a number of anti-amyloid drugs) because the compound has a good safety profile, and appeared to show a modest clinical benefit in the mild AD patients in Lilly’s Phase 3 trial. The A4 researchers’ confidence in solanezumab grew when this was confirmed via an independent academic analysis by the Alzheimer’s Disease Cooperative Study (ADCS), a consortium of academic Alzheimer’s disease clinical trial centers. The ADCS, which was established by NIH, will help facilitate the A4 trial.

The A4 researchers hope that starting treatment with solanezumab before symptoms are present, as well as treating for a longer period of time, will slow cognitive decline and ultimately prevent AD dementia.

After the failure of solanezumab in Lilly’s own Phase 3 studies, and the FDA’s rebuff of the company’s secondary analysis of early stage patients, the A4 study’s choice of solanezumab gives the drug a new lease on life. Meanwhile, Lilly will be continuing its own clinical trial program for solanezumab.


The three clinical trials discussed in this article should allow the scientific and medical community to answer the question as to whether treating patients with pre-AD or very early-stage AD with anti-amyloid MAb drugs can have a positive effect on the course of the disease, and slow or prevent cognitive decline. The studies may also help the scientific and medical community, and the FDA, with issues of evaluation of biomarkers and clinical outcome measures in determining disease prognosis and the efficacy of drug treatments. Given the large size and rapid growth of the at-risk population, finding safe and efficacious disease-modifying preventives and treatments for AD is of increasing urgency.


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.