Secret History: Return of the Black Death Channel 4, 7-8pm In 1348 the Black Death swept through London, killing people within days of the appearance of their first symptoms. Exactly how many died, and why, has long been a mystery. This Secret History documentary follows experts as they pick through the evidence and reveal why the plague killed on such a scale. And they ask, what might be coming next?

Medscape

Given the high attrition rates, substantial costs and slow pace of new drug discovery and development, repurposing of 'old' drugs to treat both common and rare diseases is increasingly becoming an attractive proposition because it involves the use of de-risked compounds, with potentially lower overall development costs and shorter development timelines. Various data-driven and experimental approaches have been suggested for the identification of repurposable drug candidates; however, there are also major technological and regulatory challenges that need to be addressed. In this Review, we present approaches used for drug repurposing (also known as drug repositioning), discuss the challenges faced by the repurposing community and recommend innovative ways by which these challenges could be addressed to help realize the full potential of drug repurposing.

Drug repurposing: progress, challenges and recommendations

Many drugs that target transforming growth factor-β (TGFβ) signalling have been developed, some of which have reached Phase III clinical trials for a number of disease applications. Preclinical and clinical studies indicate the utility of these agents in fibrosis and oncology, particularly in augmentation of existing cancer therapies, such as radiation and chemotherapy, as well as in tumour vaccines. There are also reports of specialized applications, such as the reduction of vascular symptoms of Marfan syndrome. Here, we consider why the TGFβ signalling pathway is a drug target, the potential clinical applications of TGFβ inhibition, the issues arising with anti-TGFβ therapy and how these might be tackled using personalized approaches to dosing, monitoring of biomarkers as well as brief and/or localized drug-dosing regimens.

/pdf/targeting-the-tgfb-signalling-pathway-in-disease-1wlregb4sc.pdf

Targeting the TGFβ signalling pathway in disease.

Small-molecule drug discovery has traditionally focused on occupancy of a binding site that directly affects protein function, and this approach typically precludes targeting proteins that lack such amenable sites. Furthermore, high systemic drug exposures may be needed to maintain sufficient target inhibition in vivo, increasing the risk of undesirable off-target effects. Induced protein degradation is an alternative approach that is event-driven: upon drug binding, the target protein is tagged for elimination. Emerging technologies based on proteolysis-targeting chimaeras (PROTACs) that exploit cellular quality control machinery to selectively degrade target proteins are attracting considerable attention in the pharmaceutical industry owing to the advantages they could offer over traditional small-molecule strategies. These advantages include the potential to reduce systemic drug exposure, the ability to counteract increased target protein expression that often accompanies inhibition of protein function and the potential ability to target proteins that are not currently therapeutically tractable, such as transcription factors, scaffolding and regulatory proteins.

/pdf/induced-protein-degradation-an-emerging-drug-discovery-4jbmzgyyxh.pdf

Induced protein degradation: an emerging drug discovery paradigm

Population-based study からみた神経予後不良因子の検討

Problems in interpreting diagnostic tests for HER2 may be compromising patient access to effective treatments. As new versions of therapies targeting HER2 work their way through clinical trials, will the situation get even murkier? Malorye Allison investigates.

The HER2 testing conundrum

pany with which it codeveloped Tysabri. Al Sandrock, senior vice president of neurology R&D at Biogen Idec says they will also be working with Roche-Genentech, which copromotes Rituxan in the US market and in Europe. “All three companies have signed a letter of intent. We have ideas on what to work on but we will nail that down early in the new year,” Sandrock says. A Genentech spokesperson confirmed by e-mail that “there have been discussions between several companies, including Biogen, Genentech and Roche, in forming a consortium dedicated to PML” but added that “to date no contracts have been finalized.” Biogen and Elan have the advantage of access to thousands of banked blood and urine samples from patients who have taken Tysabri, according to Ted Yednock, the Elan researcher who invented the antibody and from the psoriasis market; and at the end of last year, more cases were associated with its anti-CD20 blockbuster Rituxan, which is marketed for rheumatoid arthritis and nonHodgkin’s lymphoma. Initially, the association of PML with Tysabri had suggested only drugs with mechanisms of action related to VLA-4 would be affected. But the finding of PML in patients on Raptiva and Rituxan, which bind two unrelated targets, has added urgency to the quest to better understand the reactivation process of John Cunningham (JC) virus, the human polyomavirus that causes the disease. Now, researchers are trying to determine exactly why these particular drugs make people more susceptible to this otherwise extremely rare condition, and how this effect can be avoided. Biogen Idec has been collaborating on the PML problem with Elan of Dublin, the comLast October, Roche-Genentech and the US Food and Drug Administration (FDA) issued a “Dear Doctor” letter notifying rheumatologists about a case of progressive multifocal leukoencephalopathy (PML) in an arthritis patient treated with Rituxan (rituximab). This, the third PML case to emerge, is prompting concerns because the affected patient is the first to contract the condition on Rituxan without any prior treatment with another immune suppressant. Elsewhere, news that once again, cases of PML continue to be a concern for multiple sclerosis (MS) patients receiving Biogen Idec’s Tysabri (natalizumab) is again prompting regulators to scrutinize current monitoring and control of this brain malady. As reports of PML cases mount, drug developers are understandably anxious that the potentially fatal brain infection could seriously compromise their most valuable antibody franchises. When Cambridge, Massachusetts–based Biogen Idec launched Tysabri in late 2004, the monoclonal antibody (mAb) was one of biotech’s brightest lights. It was the first IgG4 mAb directed against the α4 subunit of the integrin VLA-4 (very late antigen 4) adhesion complex expressed on activated lymphocytes, monocytes and other leukocytes. In addition, its safety profile appeared favorable and it was about twice as efficacious as existing treatments, such as interferon β and Copaxone (glatiramer acetate). In 2005, Biogen voluntarily withdrew the drug after PML, a rare, life-threatening brain disease, was diagnosed in two patients on Tysabri (Nat. Biotechnol. 23, 397–398, 2005). But the company was able to get the drug back on the market in 2006 after implementing a stringent PML patient monitoring program (Fig. 1; Nat. Biotechnol. 27, 986, 2009). The latest 23 additional documented cases of PML in Tysabri patients prove these safety problems have not gone away. What’s more, cases of the disease have also turned up in patients on two other immune modulating products, both from S. San Francisco, California–based Genentech. Last June, PML cases prompted the company to withdraw its anti-CD11a mAb Raptiva (efalizumab) PML problems loom for Rituxan

PML problems loom for Rituxan.

volume 30 number 4 APrIl 2012 nature biotechnology The first license for a cord blood product has been granted to the New York Blood Center (NYBC) for Hemacord, hematopoietic stem/ progenitor cells (HSCs) isolated from human cord blood for use in allogeneic transplantation in certain blood disorders or malignancies. The approval has reignited a long-simmering debate over whether such products need additional regulation. “This has been a very long story, and it’s not clear that this [license] will have the intended effect,” says Joanne Kurtzberg, director of Carolinas Cord Bank, and the Pediatric Blood and Marrow Transplant Program at Duke University Medical Center, Durham, North Carolina. There is also concern that the US Food and Drug Administration (FDA) will now move to further regulate HSC therapies derived from peripheral blood. Hemacord is prepared by drawing blood from the umbilical cord or placenta of a newly born infant. The HSCs in the cord blood are then purified, concentrated and frozen for future use. Once transplanted into an allogeneic recipient, Hemacord progenitor cells migrate to the bone marrow, which has been depleted of endogenous cells by radiotherapy. Donor HSC cells then seed themselves and mature, finally moving to the bloodstream where they can partially or fully reconstitute the complement of adult blood cells and restore immune function. The Hemacord registration signals that the FDA will now require licenses for all cord blood products from public banks if they are being stored for potential use by a patient unrelated to the donor. Cord blood stored for future use must “meet the definitions of drug under the Food, Drug & Cosmetic (FDA&C) Act and biological product under Section 351 of the Public Health Service Act,” writes Paul Richards, public affairs specialist at the FDA’s Center for Biologics Evaluation and Research, in an e-mail. But some institutions with established cord banking programs disagree. Legislation issued in 2000 set up a National Cord Blood Coordinating Center to support unrelated-donor-blood stem cell transplants and establish a single point of access for patients and providers to search for the best available cells, among other things. The latest layer of licensure for these products “was meant to create a higher quality product,” Kurtzberg says, “But all it has done is put obstacles in the way of the banks.” Colleen Delaney, director of the Program in Cord Blood Transplantation at the Fred Hutchinson Cancer Research Center in Seattle, agrees. Although centers can still offer the products under an investigative new drug application (INDs), that is a cumbersome and complex process for smaller centers to maneuver, she says. “Big centers like ours have more resources to deal with INDs and more expertise in regulatory affairs.” Cord blood is selected based upon finding the optimal match, so burdening blood centers with new regulations could restrict access. “I don’t think that was taken into consideration,” Delaney says. Concerns have also been raised that insurers will start to treat nonlicensed cord blood products as inferior, and therefore will not cover them. “If you are a patient who can’t travel, getting to a center that is licensed could be a problem,” Delaney says. There is no sign yet that insurers are planning to take that tact. Over 30,000 unrelated-cord-blood transplants have occurred around the world, according to Kurtzberg, and both she and Delaney consider the current accreditation process sufficiently stringent. It’s also unclear how much licensure is going to cost. “It was a very expensive process and required a lot of resources and man hours, and we had to change a lot of processes,” says Eva Quinley, senior vice president of quality at the NYBC. “I’ve heard people estimate the cost at anywhere between $2 and $3 million.” But the NYBC went through the process because “licensed products will be the product of choice when a match is available.” The initial regulations also did not cover the use of cord blood transplantation for certain indications, such as sickle cell anemia, in which the blood centers felt there is a sufficient body of data to support use. “Transplantation can cure these patients, but FDA originally said there wasn’t enough data,” Kurtzberg says. Complaints from the banks led the agency to revise its guidance and include more conditions. Kurtzberg also objects to the agency’s insistence on an expiration date. If collected properly, she says, “no one knows the expiration date yet.” Others argue that licenses granted only cover cells processed after licensure, and existing banks have many units already on hand. The biggest question, however, will be whether the agency extends licensure to peripheral stem cells as well. NYBC’s Quinley argues that cord blood cells are more drug-like because they are manipulated more than peripheral stem cells. “There is huge fear and dissent against FDA licensing peripheral stem cells,” Kurtzberg says. Malorye Allison Acton, Massachusetts Cells isolated from human cord blood now require a license. Hemacord approval may foreshadow regulatory creep for HSC therapies

Hemacord approval may foreshadow regulatory creep for HSC therapies.

volume 30 number 10 oCTober 2012 nature biotechnology The news that Thousand Oaks, California– based Amgen halted the phase 3 trials of ganitumab (AMG-479) in metastatic pancreatic cancer appears to have pounded a nail in approaches attempting to target the insulin-like growth factor 1 receptor (IGF-1R) in cancer. No safety concerns popped up, but the interim data provided no evidence the fully human monoclonal antibody (mAb) would benefit patients, echoing other studies with IGF-1R inhibitors. The only sliver of hope for the field may now lie in drugs acting against IGF-1 itself or against downstream signaling pathways. Christine Regan, Amgen’s director of Corporate Communications, refused to comment on the company’s future plans for IGF-1 programs, although data from the study will be made public at an upcoming conference, she says. AMG-479 is the latest in a string of mAbs targeting the IGF-1R to fail in cancer-treatment trials. “If this was the first failure, it might suggest there were other issues,” says Michael Yee, managing director at RBC Capital Markets in San Francisco. “Given that there have been failures in multiple different tumor types, this suggests the target isn’t what we had hoped.” The disappointment is particularly pointed because at one time anti–IGF-1 drugs were thought to hold much promise as anti-neoplastic agents, with a rationale built around a substantial scientific literature. IGF-1 is a target that came to the party rather late, eventually attracted a lot of attention and then broke a bunch of hearts. The target first got attention in the mid-1980s, when Genentech’s Axel Ullrich cloned the receptor. Because IGF-1 is a growth stimulant, it was initially regarded as a potential target for wound healing. In 1987, Clinical setbacks reduce IGF-1 inhibitors to cocktail mixers

Clinical setbacks reduce IGF-1 inhibitors to cocktail mixers.

Ventures focusing on gene therapy, adoptive T-cell therapy, protein homeostasis and the microbiome are among those selected by the editors in 2013's crop of startups.

Nature Biotechnology 's academic spinouts of 2013

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