February 11, 2014

Drug Discovery — Even When You Win, You Still Can Lose

By Josh Bloom | February 11th 2014 03:21 PM

It would be almost impossible to find a better example of the difficulties that face the pharmaceutical industry than the campaign against hepatitis C.

Unfortunately, this example is now at the expense of Vertex Pharmaceuticals, a small, but top-notch drug discovery organization that began as a biotech startup in 1989.

Vertex had the “good” fortune of becoming the first drug company to launch a successful antiviral drug, which had a real impact on hepatitis C—a disease with enormous worldwide public health implications. But, within a year, their fortunes turned sour.

Called “The Silent Killer,” the viral blood-borne disease infects the liver, progressively doing irreversible damage over a two- to three-decade period. Most people who are infected are unaware of this until symptoms of liver disease show up, at which time the resulting cirrhosis or liver cancer are life threatening.  The majority of liver transplants in the U.S. are due to liver failure caused by long-term hepatitis C infection.

Although hepatitis C is much less newsworthy than HIV, the worldwide infection rate is estimated to be four percent—about four-times greater than for HIV. With an estimated 150 million infected people worldwide, the disease became the focus of most infectious disease research beginning in the mid-1990s—surpassing even HIV in research effort.

Virtually every major drug company launched massive research campaigns designed to discover specific antiviral therapies to eradicate the infection. It was far more difficult than anyone could have imagined.

Although researchers used a very similar strategy that was supremely successful for HIV, hepatitis C proved to be a much tougher nut to crack.

Indeed, after a decade of research, and dozens of drug candidates that failed because of toxicity or lack of efficacy, in 2004, scientists at BoehringerIngelheim in Quebec hit the jackpot—or so it seemed. Ciluprevir—the product of arguably one of the most impressive campaigns in the history of medicinal chemistry—was shown to reduce the amount of the virus in the blood to nearly zero after a few doses.

However, unexpected cardiac toxicity forced the discontinuation of the development of the drug. Even though Ciluprevir provided the first proof of principle that a specific antiviral drug could essentially wipe out the virus, this must have been little comfort for Boehringer.

It would be another seven years until the first HCV drugs would be approved. Within two weeks, Vertex Pharmaceuticals and Schering-Plough (now Merck) both launched improved versions of Ciluprevir.

Vertex’s drug, Incivek was superior to Merck’s Victrelis, and it captured essentially the entire anti-HCV market, with sales of an astonishing $457 million in its first full quarter.

But then things went downhill. Given the enormous (and scientifically brilliant) effort that Vertex put forward to discover Incivek, it is perfectly fair to expect them to be financially rewarded. But life is not always fair—especially in the pharmaceutical world.

What went wrong?  The efforts of other companies working in this area (especially AbbVie,Gilead, Johnson and Johnson, and Bristol-Myers Squibb)—although a bit behind Vertex—were beginning to pay off. Clinical results have been astounding, with cure rates approaching 100 percent with certain drug combinations. And aside from the exquisite efficacy of these newer drugs, one enormous advantage is that interferon—an injectable immune stimulant that is still part of the standard of care—can be avoided. This is critical because the side effects of interferon are so brutal that many patients discontinue treatment, essentially committing pharmaceutical suicide.

Now, doctors are advising their patients to wait until some of these second-generation drugs are approved, and this has had a profound impact on Vertex. Sales have plummeted to $86 million this past quarter, and the company just announced a staff reduction of 370 employees—15 percent of its workforce.

This perfectly illustrates two points: 1) Even when a drug goes through a 10-year approval process and makes it out the other end, it still may lose money. In fact 70-80 percent of marketed drugs do just that; 2) Perennial critics of the pharmaceutical industry, such as Marcia Angell of the Harvard Medical School, who maintain that second- and third-generation drugs (often derisively ‘called me-too drugs’) are unnecessary and serve only the companies that make them, must be living on another planet. Because on this planet the first drug for any given disease is rarely the best.

Had research and development ceased after the introduction of Incivek, therapy for hepatitis C would have remained difficult to endure, and less than optimally effective.

There is no tougher business than drug discovery. You can win the race and often still come out the loser.

Update 2/11/14: Gilead is now seeking approval for their drug combo consisting of  Sovaldi and ledipasvir—two potent anti-HCV drugs that work by different mechanisms (like the AIDS cocktail approach). This will be the first non-interferon therapy for the infection. 


New nanoparticles offer best-ever gene silencing, could help treat liver diseases

Posted: Feb 11, 2014

(Nanowerk News) Inspired by tiny particles that carry cholesterol through the body, MIT chemical engineers have designed nanoparticles that can deliver snippets of genetic material that turn off disease-causing genes.

This approach, known as RNA interference (RNAi), holds great promise for treating cancer and other diseases. However, delivering enough RNA to treat the diseased tissue, while avoiding side effects in the rest of the body, has proven difficult.

The new MIT particles, which encase short strands of RNA within a sphere of fatty molecules and proteins, silence target genes in the liver more efficiently than any previous delivery system, the researchers found in a study of mice.

“What we’re excited about is how it only takes a very small amount of RNA to cause gene knockdown in the whole liver. The effect is specific to the liver — we get no effect in other tissues where you don’t want it,” says Daniel Anderson, the Samuel A. Goldblith Associate Professor of Chemical Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research.

Anderson is senior author of a paper describing the particles in the Proceedings of the National Academy of Sciences ("Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates") the week of Feb. 10. Robert Langer, the David H. Koch Institute Professor at MIT, is also an author.


MIT engineers designed nanoparticles that can deliver short strands of RNA (green) into cells (nuclei are stained blue). (Image: Gaurav Sahay, Yizhou Dong, and Omid Veiseh)

The research team, which included scientists from Alnylam Pharmaceuticals, also found that the nanoparticles could powerfully silence genes in nonhuman primates. The technology has been licensed to a company for commercial development.

Natural inspiration

RNA interference is a naturally occurring phenomenon that scientists have been trying to exploit since its discovery in 1998. Snippets of RNA known as short interfering RNA (siRNA) turn off specific genes inside living cells by destroying the messenger RNA molecules that carry DNA’s instructions to the rest of the cell.

Scientists hope this approach could offer new treatments for diseases caused by single mutations, such as Huntington’s disease, or cancer, by blocking mutated genes that promote cancerous behavior. However, developing RNAi therapies has proven challenging because it is difficult to deliver large quantities of siRNA to the right location without causing side effects in other tissues or organs.

In previous studies, Anderson and Langer showed they could block multiple genes with small doses of siRNA by wrapping the RNA in fatlike molecules called lipidoids. In their latest work, the researchers set out to improve upon these particles, making them more efficient, more selective, and safer, says Yizhou Dong, a postdoc at the Koch Institute and lead author of the paper.

“We really wanted to develop materials for clinical use in the future,” he says. “That’s our ultimate goal for the material to achieve.”

The design inspiration for the new particles came from the natural world — specifically, small particles known as lipoproteins, which transport cholesterol and other fatty molecules throughout the body.

Like lipoprotein nanoparticles, the MIT team’s new lipopeptide particles are spheres whose outer membranes are composed of long chains with a fatty lipid tail that faces into the particle. In the new particles, the head of the chain, which faces outward, is an amino acid (the building blocks of proteins). Strands of siRNA are carried inside the sphere, surrounded by more lipopeptide molecules. Molecules of cholesterol embedded in the membrane and an outer coating of the polymer PEG help to stabilize the structure.

The researchers tuned the particles’ chemical properties, which determine their behavior, by varying the amino acids included in the particles. There are 21 amino acids found in multicellular organisms; the researchers created about 60 lipopeptide particles, each containing a different amino acid linked with one of three chemical groups — an acrylate, an aldehyde, or an epoxide. These groups also contribute to the particles’ behavior.

David Putnam, an associate professor of biomedical engineering at Cornell University, says he is impressed with the team’s approach to mimicking how the body transports fatty molecules with lipoprotein particles.

“They hijacked that machinery and made something that looks like the lipoprotein structures and will carry siRNA straight to the liver. They’re building on Mother Nature and making it as efficient as possible,” says Putnam, who was not part of the research team.

Targeted strike

The researchers then tested the particles’ ability to shut off the gene for a blood clotting protein called Factor VII, which is produced in the liver by cells called hepatocytes. Measuring Factor VII levels in the bloodstream reveals how effective the siRNA silencing is.

In that initial screen, the most efficient particle contained the amino acid lysine linked to an epoxide, so the researchers created an additional 43 nanoparticles similar to that one, for further testing. The best of these compounds, known as cKK-E12, achieved gene silencing five times more efficiently than that achieved with any previous siRNA delivery vehicle.

In a separate experiment, the researchers delivered siRNA to block a tumor suppressor gene that is expressed in all body tissues. They found that siRNA delivery was very specific to the liver, which should minimize the risk of off-target side effects.

“That’s important because we don’t want the material to silence all the targets in the human body,” Dong says. “If we want to treat patients with liver disease, we only want to silence targets in the liver, not other cell types.”

In tests in nonhuman primates, the researchers found that the particles could effectively silence a gene called TTR (transthyretin), which has been implicated in diseases including senile systemic amyloidosis, familial amyloid polyneuropathy, and familial amyloid cardiomyopathy.

The MIT team is now trying to learn more about how the particles behave and what happens to them once they are injected, in hopes of further improving the particles’ performance. They are also working on nanoparticles that target organs other than the liver, which is more challenging because the liver is a natural destination for foreign material filtered out of the blood.

Source: By Anne Trafton, MIT


All-Oral Combination of Ledipasvir, Vedroprevir, Tegobuvir, and Ribavirin in Treatment-Naive Patients with Genotype 1 HCV Infection

Hepatology. 2014 Feb 5. doi: 10.1002/hep.27053. [Epub ahead of print]

Wyles DL, Rodriguez-Torres M, Lawitz E, Shiffman ML, Pol S, Herring RW, Massetto B, Kanwar B, Trenkle JD, Pang PS, Zhu Y, Mo H, Brainard DM,Subramanian GM, McHutchison JG, Habersetzer F, Sulkowski MS.


This phase 2 trial assessed the efficacy and safety of a combination regimen of the NS5A inhibitor ledipasvir (LDV), NS3 protease inhibitor vedroprevir (VDV), nonnucleoside NS5B inhibitor tegobuvir (TGV), and ribavirin (RBV) in treatment-naive patients with chronic hepatitis C virus (HCV) genotype 1 without cirrhosis. Patients were randomized 1:2 to LDV 30 mg once daily (QD) (Arm 1; n = 46) or LDV 90 mg QD (Arm 2; n = 94); patients in both arms also received VDV 200 mg QD, TGV 30 mg twice daily, and RBV 1000-1200 mg/day. Patients in Arm 2 with vRVR, defined as HCV RNA <LLOQ from treatment weeks 2-10, were randomized 1:1 to stop treatment at 12 weeks or continue for 24 weeks. Sustained virologic response 12 weeks after treatment (SVR12) was higher in patients receiving 90 mg LDV for 24 weeks (63%) compared to LDV 90 mg for 12 weeks (54%) and LDV 30 mg for 24 weeks (48%). In patients with vRVR in Arm 2, SVR12 was achieved by 68% and 81% of patients treated for 12 and 24 weeks, respectively. Virologic breakthrough was more common in patients with HCV genotype 1a and was associated with resistance-associated variants for all three direct-acting antiviral agents (DAAs); however, in all but 1 patient who relapsed, RAVs directed against only one or two of the DAAs were detected. The most common adverse events were fatigue, headache, nausea, rash, and diarrhea. Conclusion: In patients with HCV genotype 1, an interferon-free regimen containing LDV/VDV/TGV/RBV was well tolerated and led to SVR12 in up to 63% of patients. LDV 90 mg is currently being investigated in combination with the nucleotide polymerase inhibitor sofosbuvir. (Hepatology 2014;).

Copyright © 2014 American Association for the Study of Liver Diseases.

KEYWORDS: NS3 protease inhibitor, NS5A inhibitor, antiviral therapy, hepatitis C, nonnucleoside NS5B polymerase inhibitor

PMID: 24501005 [PubMed - as supplied by publisher]


inPractice® and American Association for the Study of Liver Diseases Announce Collaboration in Hepatology Education and Reference


Leading liver disease society endorses point-of-care decision support tool

RESTON, Va., Feb. 11, 2014 /PRNewswire-USNewswire/-- inPractice® Resources, LLC, today announced that the American Association for the Study of Liver Diseases (AASLD) has endorsed inPractice Hepatology, an education and reference tool for its members, hepatologists, and other clinicians who treat patients with liver disease. AASLD will also support additional content development, and inPractice will also proudly showcase the AASLD logomark on its hepatology program. inPractice outreach efforts will be supported and officially endorsed by AASLD.

inPractice is designed to meet the reference and educational needs of specialists, with deep, specialty-specific information and recommendations for patient care. inPractice is currently available in specialties including hepatology, HIV, oncology, oncology nursing, and rheumatology, with plans to expand into additional specialties.

Clinicians can browse specific original expert-authored content developed by the inPractice world-renowned authors, led byinPractice Hepatology Editors-in-Chief Nezam H. Afdhal, MD, FRCPI, and Stefan Zeuzem, MD, or quickly search for information from multiple clinical databases simultaneously, including the latest drug information, PubMed abstracts, practice guidelines, clinical trials, and CME-certified activities. The system, the first of its kind for specialists, offers a seamless blend of reference and education, with Point of Care CME credits earned for topics searched.

AASLD is the leading organization of scientists and healthcare professionals committed to treating and curing liver disease. Under the agreement, AASLD will contribute clinical content for adaptation into inPractice Hepatology to broaden the range of topics from its currently available viral hepatitis content to additional areas of liver disease. AASLD will also partner withinPractice to publicize the value of inPractice and encourage its use by AASLD members and other liver disease specialists.

Adrian M. Di Bisceglie, MD, FACP, President of the AASLD Governing Board said, "Our two organizations share a common goal: enhancing the quality of care for patients with liver disease by ensuring their clinicians have access to state-of-the-art information, educational content, and practice guidelines. AASLD believes that the inPractice resource provides an excellent blend of education and reference, and we are delighted to support its adoption among our members."

"We are proud to partner with AASLD," added Edward King, MA, Chief Innovation Officer of inPractice. "The inPractice technology platform allows clinicians to quickly and easily access clinical information and recommendations at the point of care. Our partnership with AASLD will help us to expand both the content and the utilization of inPractice Hepatology, making it an even more valuable resource."

About inPractice
inPractice, a subsidiary of Clinical Care Options, is a point-of-care clinical reference tool designed for specialists. Available in specialties including hepatology, HIV, oncology, oncology nursing and rheumatology, inPractice offers focused specialty-based content written specifically for patient care and a seamless blend of reference and education, with earned CME for topics searched. inPractice Africa is the latest resource to be produced by inPractice, authored by expert African clinicians for healthcare professionals working in resource-constrained settings. For more information, visit inPractice.com

About Clinical Care Options
Clinical Care Options is the leader in the development of innovative educational technology platforms that integrate all levels of medical education and information with personalization and moderated social media. CCO has been a pioneer in the creation of continuing education and decision support resources for healthcare professionals for more than a decade. For more information, visit clinicaloptions.com.

About the AASLD
AASLD is a medical subspecialty society representing clinicians and researchers in liver disease. The work of our members has laid the foundation for the development of drugs used to treat patients with viral hepatitis. Access to care and support of liver disease research are at the center of AASLD's advocacy efforts.

AASLD is the leading organization of scientists and healthcare professionals committed to preventing and curing liver disease. AASLD was founded in 1950 by a small group of leading liver specialists and has grown to an international society responsible for all aspects of hepatology.

Additional information about AASLD may be found online at aasld.org.

SOURCE inPractice



NIH-Funded Researchers Use Antibody Treatment to Protect Humanized Mice from HIV

National Institute of Allergy and
Infectious Diseases (NIAID)

Tuesday, Feb. 11, 2014


NIH-funded scientists have shown that boosting the production of certain broadly neutralizing antibodies can protect humanized mice from both intravenous and vaginal infection with HIV. Humanized mice have immune systems genetically modified to resemble those of humans, making it possible for them to become HIV-infected.

Led by David Baltimore, Ph.D., of the California Institute of Technology, the investigators inserted the genes encoding the NIH-discovered broadly HIV neutralizing antibody VRC01 into a vector, a virus that infects mice but does not cause disease. In a unique technique known as vectored immunoprophylaxis (VIP), the researchers infected laboratory mice with this altered virus, enabling certain of their cells to produce the antibodies for extended periods. To test the applicability of this approach to human infections, the researchers used a novel method of repeatedly exposing these mice to low doses of HIV in a manner that mimics human sexual intercourse. In two separate experiments, the investigators assessed protection from infection with two strains of HIV: a standard laboratory strain as well as one that is commonly transmitted among humans.

Two of the 10 mice expressing VRC01 antibodies became infected with the laboratory strain of HIV after 13 to 15 exposures to the virus. In contrast, all nine mice without the antibodies were infected with HIV within six exposures. In the second experiment, researchers used a modified form of the VRC01 antibody, known as VRC07, and challenged the mice with an HIV strain known to be heterosexually transmitted among people. The mice expressing the VRC07 antibody were completely resistant to infection during repeated intravaginal challenge. Taken together, these results indicate that VIP can protect mice from infection with strains of HIV that cause human disease and suggest that a similar strategy could be developed to reduce transmission in people, the authors write.

Balazs AB et al. Vectored immunoprophylaxis protects humanized mice from mucosal HIV transmission. Nature Medicine DOI: 10.1038/nm.3471 (2014).

NIAID director Anthony S. Fauci, M.D., is available to discuss the findings.

To schedule interviews, please contact Nalini Padmanabhan, (301) 402-1663, niaidnews@niaid.nih.gov.

NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at www.niaid.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

NIH...Turning Discovery Into Health ®


Does Gilead Sciences Inc (NASDAQ:GILD) Prioritize Money Over Human Health?

Provided by Wall Street PR

Posted on Feb 10 2014 - 10:12am by Nicholas Maithya

Boston, MA 02/10/2014 (wallstreetpr) – Gilead Sciences Inc (NASDAQ:GILD) has made a name in the area of providing treatment solutions for people living with Hepatitis C. However, in the eyes of some people, GILD is benefiting a great deal by selling treatment for people suffering from Hepatitis C, at huge rates that shows the company is only interested in nothing more than profits. This debate has been ignited by the belief that the latest Hepatitis C drugs to leave GILD’s laboratories are priced too high and beyond the ability of many people who need it but cannot afford the new rates.

This debate has roped in Express Scripts, which is the largest pharmacy benefits manager in the US. Express Scripts now says that it will advise patients suffering from Hepatitis C on cheaper drugs that they can take instead of the more expensive options, especially where no demonstrable difference can be seen. The cheaper drugs may not offer the same level of convenience as the ones that are highly priced, but if they offer the same results once taken as per the recommendations, Express Scripts believes that the more affordable option would be better.

The reason behind he perception that GILD has an insatiable need for money, which it prioritizes more than anything else has come about due to the realization that the company has put a $84,000 price tag on its latest Hepatitis C drug. The Hepatitis C drug is known as Sovaldi, and is supposed to be taken within a 12-week period. In essence, what GILD has said here is that this drug will be taken in a three-month period, which amounts to around $28,000 per month. No matter how you look at it, the amount is too much to pay for a single drug.

Pricing is never an easy thing to consider. Many factors go into deciding which price is best for a particular drug. Each drug manufacturer looks at factors that it considers favorable to its business. The manufacturers may also have target market in mind when coming up with such prices. However, drug manufacturers need to be cautious on matters to do with perception. If the end user, who in this case is the Hepatitis C patient, feels that the drug is too expensive, and that the manufacturer is more concerned with money, they may be unwilling to buy the drug.

Gilead is not the only Hepatitis C drug manufacturer that has placed such a huge price on is product. Its competitor, Vertex Pharmaceuticals, sells its Incivek for $66,000, which is much higher than the $49,000 it started with when the drug first entered the market. One of the reasons that have convinced GILD to set a higher price for its Hepatitis C drug is the fact that it is used to treat genotypes 1 all the way to 4, while the other drugs only treat a single genotype. The most common genotype of Hepatitis C is 1a, and Sovaldi enjoys a 92 percent cure rate.

If you consider all factors and the fact that Solvadi, which is Gilead’s Hepatitis C drug, performs much better than the other drugs that are commonly used to treat this health condition, then it is safe to say that the company does not have an insatiable appetite for money.