Roche seems to think there is promise in the technology. Under its agreement, Roche will guarantee at least $25 million in funding for technology access fees and research and development to Aileron, which is eligible to receive up to $1.1 billion in payments based on discovery, development, regulatory, and commercialization milestones, if drug candidates are developed for five undisclosed drug targets in the following areas: oncology, virology, inflammation, metabolism, and central nervous system.

Aileron’s “stapled peptides” are designed to address pharmacological limitations of small molecules and existing biologics in intracellular protein–protein interactions. Although small molecules are able to penetrate cells, the large binding surfaces for intracellular protein–protein interactions often make small-molecule modulators ineffective. Although peptides and proteins have the size and functionality to effectively modulate intracellular protein–protein interactions, they often do not permeate cells and therefore are used to modulate extracellular targets such as receptors (1). These limitations of small molecules and existing biologics make a vast array of potential drug targets “undruggable.” Approximately 80% of potential drug targets are considered “undruggable” by either modality (1, 2).

So how can these limitations be addressed? The concept of using peptides to modulate intracellular processes is not new, but these strategies have historically failed because peptides lack the ability to enter cells, are inherently unstable within the body, are rapidly broken down into inactive fragments by circulating enzymes such as proteases, and are quickly filtered from the bloodstream by the kidneys. Stapled peptides seek to resolve those problems. Because many “undruggable” therapeutic targets include those protein–protein interactions in which α-helices are required in lock-and-key-type mechanisms, an approach is to design α-helical peptides that have structural and functional properties that enable them to penetrate into the cell, bind to the therapeutic target, and modulate the biological pathway (1). Aileron stabilizes peptides by “stapling” them with hydrocarbon bonds into an α-helix. Once constrained in the α-helix structure, the peptides are protected from degradation by proteases. The stabilized α-helical peptides can penetrate cells by energy-dependent active transport and typically have a higher affinity to large protein surfaces (1, 2).

In advancing stapled peptides, Aileron has brought together scientific and financial weight. Aileron was cofounded in 2005 by Gregory L. Verdine, current chair of Aileron’s scientific advisory board and a chemical biologist at Harvard University, with initial funding from a private investment group. In 2006, the company acquired exclusive rights from Harvard University and the Dana-Farber Cancer Institute to develop and commercialize a drug-discovery pipeline of stapled peptides. In 2006/2007, Aileron licensed rights from the fine-chemicals and technology firm Materia (Pasadena, CA) for catalysts used in olefin metathesis. Materia holds the rights to the olefin metathesis technology developed by Robert H. Grubbs, professor at the California Institute of Technology, who was awarded the Nobel Prize in Chemistry in 2005 with Richard R. Schrock and Yves Chauvin for their work in olefin metathesis using ruthenium-based catalysts. Part of the reaction scope of olefin metathesis is ring-closing metathesis (RCM), which transforms a diene into a cyclic alkene and is used to create macrocycles, including bioactive cyclic peptidomimetics. Grubbs was one of the first to offer research describing RCM to tether residues of helical peptides (3, 4). In 2008, Aileron acquired exclusive rights from New York University for additional methods to stabilize peptides and peptidomimetics. In 2009, Aileron received $40 million in venture capital funding, which included funding from four pharmaceutical venture capital funds: SR One (GlaxoSmithKline’s venture capital fund), the Novartis Venture Fund, Lilly Ventures (Eli Lilly’s venture capital fund), and Roche Venture Fund.

So with a sound scientific basis and financial support from the pharmaceutical majors, it will be interesting to see how stapled-peptides fare. Like their “cousins,” aptamers and peptidomimetics, it has yet to be seen if “the offspring” of the marriage of small-molecules and biologics-based approaches can find a place at the drug-development table.

References
1. T. Sawyer, Chem. Biol. Drug. Des. 73 (1), 3–6 (2009).
2. W. Wolfson, Chem. & Biol. 16 (9), 910–911 (2009).
3. J.B. Binder and R. Raines, Curr. Opin. Chem. Biol. 12 (6), 767–773 (2008).
4. R. Grubbs, Angew. Chem. Int. Ed. 37, 3281–3284 (1998).

Termeer’s response came this morning. It can be summed up in two words: nothing doing.

In his letter, Termeer said that sanofi’s offer was identical with one it had made last month, which was not public. Termeer called both offers “opportunistic” and said that they did not “begin to recognize the significant progress underway to rectify our manufacturing challenges or the potential for our new-product pipeline.”

Indeed, days before sanofi’s public bid, Genzyme said it would end rationing of its Gaucher disease drug Cerezyme for US patients in September. If things go according to plan, Genzyme will have begun to convince the industry that its manufacturing crisis is nearly over. Genzyme’s board of directors seems to want to use this good news as a bargaining chip to get a higher offer from sanofi.

Trouble is, sanofi might be loath to sweeten the deal. Cosmetics company L’Oréal and oil company Total own roughly 15% of sanofi between them. They probably will not support an offer above $70 per share, bankers close to those companies told Reuters. Yet insiders say that Genzyme won’t come to the table without an opening offer of $75 per share—and will hold out for a final price of $80—according to Reuters.

What will sanofi’s next move be? According to Bloomberg, sanofi might consider buying Celgene (Summit, NJ) or Allergan (Irvine, CA) if Genzyme refuses to negotiate. But OrbiMed Advisors said that Celgene and Allergan would be more expensive targets for sanofi, and that the report was a ploy to push Genzyme’s price down. On the other hand, sanofi could consider buying Shire (Dublin), which would cost them less than Genzyme.

sanofi’s share price has fallen roughly 19% this year, partly because several of its patents will expire soon. Acquiring a biopharmaceutical company could improve sanofi’s sales and profits. Yet L’Oréal and Total seem to think that acquisitions are not a good strategy for the drugmaker, according to Reuters.

So even though sanofi’s offer is now public, its future, and that of Genzyme, is as clear as mud.

J&J issued a recall of millions of its daily disposable contact lenses, 1 Day Acuvue, sold in Japan and more than two dozen other Asian and European countries, according to a report from the Associated Press. Consumers complained that they experienced a stinging sensation when inserting the lenses. The company estimates that the recall includes roughly 100,000 boxes of contact lenses. The recalled lenses were not sold in the US or Canada, and J&J did not announce the recall in the US.

According to a company spokesperson interviewed by AP, the problem arose because a piece of equipment failed during manufacture and the lenses were not properly rinsed, and the recalled lenses contain a substance that was used in the manufacturing process. The company has identified and corrected the problem, which affected only one manufacturing line in the Ireland-based manufacturing facility, according to the AP report.

In related J&J news, this week the US Food and Drug Administration posted on its website an Aug. 19 Warning Letter to DePuy Orthopaedics, a business unit of J&J that makes joint replacements, issued for marketing violations for two of its products. FDA says it never approved the sale of DePuy’s TruMatch Personalized Solution System, a device that features proprietary software and a CT scanner that produces a three-dimensional model of a patient’s knee prior to knee replacement surgery. FDA’s letter also states that DePuy marketed its Corail Hip System for two uses that were not approved by the agency. The agency asked DePuy to stop marketing the products and correct the violations detailed in the letter.

This quality assurance story seems to relate to the plethora of food and drug recalls occurring in the United States recently. Since April alone, we’ve seen brand-name, over-the-counter cold and allergy medications for children and adults taken off the shelves, as well as certain brands of cereal, frozen fruit products, hand sanitizers, alfalfa sprouts, romaine lettuce, and medical devices. And this past week, consumers, grocers, and restaurateurs have faced a massive shell-egg recall. (The egg recall in particular is quite ironic given that FDA issued a guidance on April 13 of this year for small egg producers to help them comply with a 2009 federal egg-safety regulation designed to prevent Salmonella Enteritidis in shell eggs during production, transportation, and storage.)

However, the seemingly constant flow of recalls begs the question—what in the world is going on? Why are so many recalls occurring? Clearly, it’s never been this bad. Or has it?

It turns out that FDA publishes on its website an archive of recalls, market withdrawals, and safety alerts going back to 2004. A quick review of all the recalls, withdrawals, and alerts issued in December of each year shows the following: in 2009, FDA issued 28 recalls, withdrawals, and alerts; in 2008, there were 16; in 2007, there were 22; in 2006, there were 10; in 2005, there were 13; and in 2004, there were 21. Based on this quick (nonstatistical) review, it would appear that the number of recalls over a five-year period isn’t changing too significantly. Although 2009 had the highest of the archived recalls, withdrawals, and alerts (28), there were 21 such instances in the year 2004.

It’s possible that FDA (and industry) is becoming more vigilant in identifying contaminated and faulty products. It’s also possible that because of one recall, another company may be looking more closely at its own goods and finding problems. Or, it may be that just as cold and flu seasons are sometimes worse one year compared with another year, and just as the financial market ebbs and flows, so too do manufacturing and quality deviations. And unfortunately, no one can accurately predict any of these changes, even when they negatively affect consumers, patients, and bank accounts.

Psychedelics such as lysergic acid diethylamide (LSD), psilocybin (aka “magic mushrooms”), and ketamine (aka “special K”) are known primarily as recreational drugs. These chemicals cause hallucinations that some enthusiasts in the 1960s saw as a means to expand consciousness, and others as a means of escape. US Food and Drug Administration scrutiny and tragic stories of acid casualties soon focused public attention on the dangers of psychedelics. For years, negative associations and legal restrictions have discouraged researchers from studying these drugs.

Franz Vollenweider of Zurich’s University Hospital of Psychiatry believes that psychedelics could offer bona fide clinical benefits. Studies suggest that the drugs act on the brain circuits and neurotransmitter systems that are altered in patients suffering from depression and anxiety. Coupled with therapy, psychedelics might help alleviate these mental-health problems, according to Vollenweider’s article in Nature Reviews Neuroscience.

The idea of using psychedelics as psychiatric drugs is not new. A recent article in Vanity Fair detailed the practice that therapist Mortimer Hartman and psychiatrist Arthur Chandler set up in the 1950s to treat people they described as “neurotics.” Among their patients was Cary Grant, who reportedly claimed that LSD had deepened his understanding of himself and helped cure his shyness and anxiety.

Psychedelics’ potential for treating mental disorders is intriguing, but it should not be surprising in light of the fact that whether a drug is helpful or harmful often depends on the way a patient uses it. Pharmaceutical companies should take notice of Vollenweider’s paper. The National Institute of Mental Health estimates that depression and anxiety afflict a combined 54.8 million American adults in a given year. With more research, the industry eventually could provide a sizeable patient population with beneficial medicines, which would be a win for all involved.

According to WSJ’s report, J&J appointed company veteran Ajit Shetty to head the quality group, which will oversee the company’s three major business segments: pharmaceuticals, medical device, and consumer. Chief quality officers for each of these business units will report to Shetty’s group. Weldon also told WSJ that the managers of J&J’s 120 global manufacturing facilities will report to the new quality group.

Weldon told WSJ that he understands that the recalls “have sapped trust and confidence in J&J,” saying that the company has “a lot to do to earn that back,” echoing his sentiments in his May 7 open letter posted on J&J’s blog. A company-wide emphasis on manufacturing quality is a step in the right direction.

See related posts:

J&J and Guilt by Association

A Timeline of J&J/McNeil’s Recent Recall Troubles

J&J CEO Invited to Second Congressional Hearing

Five More Lots Added to January 2010 Tylenol and Benadryl Recall

More Trouble for J&J: Blacksmith Brands’ PediaCare Recall and J&J’s “Phantom Recall”

Tylenol Hearing to Take Place Today

Some Recalled Infants’ Tylenol Had Too Much Acetaminophen

This controversial comment comes from a press statement issued by the American Sociological Association about a study — Pharmaceuticals: A Two-Tier Market for Producing ‘Lemons’ and Serious Harm —that was presented at the associations annual meeting, which was held earlier this week. The study, authored by Donald Light, a professor of comparative health policy at the University of Medicine and Dentistry in New Jersey (USA), claims that about 85% of new drugs offer “few if any” new benefits and claims that drug companies sometimes hide or downplay information about side effects and overstate the drug’s efficacy.

It’s a harsh statement against pharma, as is Light’s claim that pharma companies spend “two to three times more on marketing than on research”. After a quick look at some third-party takes on the story though it seems that not everyone is shocked by the claims being made.

“I’d like to tell you this comes as a shock. But like every other doctor, I remember sitting in pharmacology lectures at medical school, being taught how drug companies would try to trick us into prescribing their latest wonder drug, and poring over the statistics to try to work out how they had manipulated the research to produce a positive result,” wrote Max Pemberton, a doctor who writes for the UK’s The Telegraph.

According to Light, there are three reasons why the pharma industry is producing “lemons”:

• having companies in charge of testing new drugs
• providing barriers of legal protection to hide information about the harm or effectiveness of drugs
• the low bar set for drug efficacy in order for a new drug to be approved.

He also claims that some pharma companies “swamp the regulator” with large numbers of “incomplete, partial substandard clinical trials”. In the press statement he said: “In one study of 111 final applications for approval, 42% lacked adequately randomized trials, 40% had flawed testing of dosages, 39% lacked evidence of clinical efficacy and 49% raised concerns about serious adverse side effects.”

According to the UK’s The Independent, the study has initiated a response from the Association of the British Pharmaceutical Industry (ABPI). The ABPI is claimed to have released a statement saying:

“Professor Light is long on accusation and woefully short on hard evidence. There is now much greater transparency in clinical trial results. The UK pharmaceutical industry also adheres to a strict code of practice on the sales and marketing of its products.

“The patient information leaflet provided in every pack with a medicine details the side effects which have been reported in clinical trials and reviewed by the regulator.”

The team tested several waste streams that had been generated at a Pfizer API synthesis plant in Kalamazoo, Michigan. The researchers examined whether those streams could be easily recovered with traditional separation and purification processes, using a small-scale distillation, solvent-recovery system, according to the release. The results were compared with Pfizer’s current waste-disposal practice. The team also evaluated the economic feasibility of an improved carbon footprint.

Overall, the Rowan team determined that Pfizer could reduce its life-cycle emissions for the three drugs studied [Revolution (selamectin), Viracept (nelfinavir), and toluene, used in hydrocortisone manufacture]. They projected that the CO2 reductions that could be gained would be equivalent to the “amount of emissions saved by not driving cars 1.4 million miles in a year,” according to the release. Pfizer plans to use the data when evaluating its solvent use and disposal practices, according to the release.

In 2008, Rowan students worked with Pfizer to improve the environmental profile of the manufacturing process for Celebrex’s active ingredient, celecoxib. This earlier project was sponsored by Pfizer’s Green Chemistry initiative and the US Environmental Protection Agency.

When the academic community collaborates with the corporate world, it’s clear that many insights can be gained. The National Institutes of Health website includes a list of additional educational initiatives in green chemistry across the United States, although it’s not clear how up to date the list may be.

In May, the company and the US Food and Drug Administration signed a consent decree that requires Genzyme to correct the well-publicized manufacturing-quality violations at its Allston, Massachusetts, manufacturing plant. The company originally predicted that its remediation would take two to three years to complete. But in a new regulatory filing, Genzyme estimated that the fixes could require as long as four years.

The news seems like yet another embarrassment for the beleaguered biopharmaceutical company. Patients who rely on the company’s specialized enzyme therapies might be understandably dismayed. But maybe we have reason for optimism.

By May of this year, Genzyme was able to produce only enough Cerezyme, its treatment for Gaucher disease, to meet about 50% of patient demand. In a sign that its remediations are proceeding, the company said that patients would be able to receive normal dosing in the fourth quarter of this year. The company also will be able to increase shipments of Fabry-disease therapy Fabrazyme in the fourth quarter.

sanofi-aventis’s (Paris) reported offer to buy Genzyme could benefit that company and its customers alike. Bloomberg reported that sanofi had offered roughly $70 per share, but Genzyme’s shareholders want more than $80 per share. The prospect of winning a better offer from sanofi could induce Genzyme to pursue its facility improvements with extra diligence. Also, market analysts expect sanofi to be sending experts to make sure that manufacturing problems are being resolved, thus supplementing current oversight by FDA and Quantic, a third-party consultant.

Even if Genzyme’s new and longer timetable seems like another black eye for the company, the consent decree and possibility of a merger could mark the beginning of the end of the company’s troubles. With the carrot of a desirable share price and the stick of abundant oversight, Genzyme will likely improve its production operations. Such changes could mean a better future for the company and the availability of high-quality treatments for its patients.

The trial will study a combination of two vaccine candidates, Ad26.ENVA.01 (manufactured by Crucell) and Ad35-ENV (developed by IAVI), in healthy adults who do not have HIV. The trial will focus on the vaccines’ safety and effectiveness as a prime-boost regimen. The goal of a prime-boost combination is that one vaccine is administered to prime the immune system and elicit a certain immune response before a second, or booster, dose is given to enhance the overall immune response.

A previous clinical trial based on a prime-boost combination took place in Thailand and represents the first time an AIDS vaccine showed promise in reducing the risk of infection. Results released in September 2009 showed that the combination of vaccines lowered the risk of acquiring HIV by roughly 30%. Additional data were presented at the AIDS Vaccine 2009 Conference and published in the New England Journal of Medicine. The research team wrote that, “Although the results show only a modest benefit, they offer insight for future research.”

Also announced this week was that the International AIDS Vaccine Initiative (IAVI) appointed Michael Caulfield executive director of the IAVI AIDS Vaccine Design and Development Laboratory (DDL). Caulfield previously held research positions at Merck (Whitehouse Station, NJ) and the Cleveland Clinic. As leader of the DDL, he will be responsible for IAVI’s translational research and vaccine discovery, as well as for expanding its R&D team.

“Mike’s joining at a critical time for the field,” said Wayne Koff, IAVI’s chief scientific officer, in a press release. “We’re in the middle of a renaissance in AIDS vaccine design and development.”

In related news, scientists at the National Institutes of Health (NIH) announced the discovery of two human antibodies that can stop more than 90% of HIV strains from infecting human cells in the laboratory. The team, part of the Vaccine Research Center, a division of the National Institute of Allergy and Infectious Diseases at NIH, also demonstrated how one of the antibodies does this. The scientists said the antibodies could be used to design improved HIV vaccines, or could be further developed to prevent or treat HIV infection, according to the group’s press release. The work was published in Science in two articles, found here and here.

The NIH team’s discovery plus the results of the Thailand vaccine trial are examples of exciting progress in the field of AIDS vaccine research. Many are hopeful that the Crucell clinical trial will add to the upswing of encouraging results.

See previous posts on this topic:

The AIDS Vaccine Challenge

Roche Ends HIV Research Program

Vaccine Makers Prepare for Challenges Old and New