Welcome to BioMarketing Insight's monthly newsletter.  

Over the last year or two, the infectious disease market has been heating up with recent drug approvals, promising additional drug trials and acquisitions. Yet drug development in one category of the market has almost disappeared. Do you know which one? 

Feel free to share this newsletter with your colleagues using the social media icons at the top left or by simply forwarding the newsletter by email.

Please email me if you have any questions, comments, or suggestions.

Sincerely,

Regina Au

Principal, Strategic Marketing Consultant

BioMarketing Insight 

One of the major problems in infectious disease is resistance to drugs due to bacterial or viral mutations. The infectious disease market can be divided into five (5) major therapeutic areas: 1) viral (i.e. HIV, Hepatitis B, and C), 2) bacterial, (i.e. MRSA, and other hospital acquired infection such as E. coli, pseudomonas, klebsiella), 3) malaria, 4) tuberculosis, and 5) some cancers (complications of HPV can lead to cervical cancer, Hepatitis B & C can lead to liver cancer and H. pylori can lead to stomach cancer).

This newsletter covers the trends in the anti-viral (i.e. HIV, Hepatitis C), and the anti-bacterial, (i.e. MRSA, and other hospital acquired infection such as E. coli, pseudomonas, klebsiella) markets.

Top 

HIV/AIDS

Today, many patients with HIV are alive as a result of drug companies, NIH and non-profit institutions spending years investing in research. These companies and institutions have developed a highly active antiretroviral therapy, or HAART. HAART is a potent combination of at least three active antiretroviral medications (ARVs) that target three enzymes, reverse transcriptase, protease, and integrase. All three are needed for the virus to replicate itself.   This regiment, known as the AIDS cocktail includes three new classes of drugs: 1) Nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), 2) Protease inhibitors (PIs) and 3) Integrase inhibitors. A number of drugs have been approved in each of these three classes of drugs. For the 2009 Department of Health and Human Services (DHHS) published preferred initial treatment regiments click here. 

In addition, other HIV medications -- such as fusion or entry inhibitors, which block HIV's entry into a cell can also be part of treatment. Because the HIV virus will eventually mutate and become resistant to these medications, there will always be a demand for new drugs. Gilead Science has an experimental HIV therapy booster that is a four-in-one, once-a-day quad pill called "Cobicistat" that has "met the goal of a phase III trial," the company said.

Researchers are now searching for "broadly neutralizing antibodies" or bNAbs. These antibodies can protect cells from many different strains of HIV, one of the most variable viruses and therefore one of the most difficult targets for vaccine development.  The International AIDS Vaccine Initiative (IAVA) has sponsored a global search for bNAbs. "Most antiviral vaccines depend on stimulating the antibody response to work effectively," says Dennis Burton, director of the IAVI Neutralizing Antibody Center at the Scripps Institute. "Because of HIV's remarkable variability, an effective HIV vaccine will probably have to elicit broadly neutralizing antibodies."

Hepatitis C

The Hepatitis C market has learned from the HIV development regiment. Hepatitis C is treated with the combination cocktail of peg interferon; Pegasys (pegylated interferon alfa-2a) or PegIntron (pegylated interferon alfa-2b) and ribavirin (Rebetol, Copegus). Hepatitis C (HCV) is now a triple therapy with a protease inhibitor, a new class of direct-acting antiviral agent that specifically targets and inhibits the replication of the hepatitis C virus plus peg interferon and ribavirin. The introduction of the protease inhibitor improved the standard of care treatment for HCV.

This year, two protease inhibitors were approved a mere 10 days apart by the FDA. On May 13th, VICTRELIS ™ (boceprevir) by Merck Inc. and on May 23rd INCIVEK™ (telaprevir) by Vertex was approved.  

The data seems to indicate that telaprevir has better efficacy than boceprevir for three points: 1) percentage of patients cured, 2) the rapid response rate in treatment-naïve patients vs. standard treatment (75% vs. 46%) and 3) in nonresponders based on three studies (Advance, Illuminate and Realize) using telaprevir. The indication for telaprevir is broader (treatment-naïve, those previously been treated with interferon-based treatment including prior null responders (did not respond at all to treatment)--partial responders, and relapsers.  In contrast, boceprevir is indicated in those who were previously untreated (68%) or who have failed previous interferon and ribavirin therapy but not studied in previous null responders. Only a side by side comparison will give us a definitive answer as to which product is better.  

Interferon plus ribavirin has a high side effect profile: headache, fever, chills, muscle aches, insomnia, depression and other mood changes, nausea, vomiting, skin rashes, extreme tiredness, loss of appetite and weight. Adding a protease inhibitor to this already harsh regiment may add more side effects.

However, in clinical trials, telaprevir seemed to have higher side effect profile than boceprevir. For patients taking telaprevir, 56% reported getting a rash; around 20% experienced discomfort (such as itchiness or inflammation) in the anus or rectum; however, these symptoms were mild or moderate and did not lead to discontinuation of the drug. A small number of participants taking telaprevir experienced life-threatening rashes. Three patients were suspected cases of Stevens Johnson Syndrome, a rare and potentially fatal condition in which the top layer of skin begins to die due to a severe immune system reaction. The most common side effects with boceprevir and telaprevir were anemia and rash.  Ribavirin patients experienced  these side effects, and also anemia.

The rapid response rate is an important benefit for telaprevir: treatment-naïve patients had a significantly improved response rate and were able to finish the treatment (duration of treatment is based on the patients response) in 24 weeks--half the time for interferon and ribavirin alone.  Shortening the drug regiment duration reduces compliance issues associated with a difficult dosing regiment and side effect profile. The broadness of the indication for non-responders also gives telaprevir an advantage over boceprevir.

If your product is going to be second in the market, or your product is going to be competing with another drug in the same class, the product needs to demonstrate superiority to be the market leader. The jury is out as to which drug physicians consider to be more superior. According to the  New York Times, Incivek beat out Merck, $420 million for Incivek and $31 million for Victrelis in third quarter sales.   

Other promising clinical trial results are also creating a lot of buzz:

Pharmasset - In early November, Pharmasset reported results on their 40 patient HCV trial where all 40 patients who took their oral experimental drug PSI-7977 were essentially cured in the course of the small 12-week study, changing the treatment game yet again. The goal of this study was to see if interferon could be eliminated from the treatment regiment.

Pharmasset "impressed a packed house of (American Association for the Study of Liver Disease) AASLD attendees by showing a 100% SVR rate in genotype 2/3 patients receiving PSI-7977 and ribavirin but no interferon," stated analysts at Brean Murray Carret. "We believe this validates the company's decision to move into Phase III program with this combination and supports a new front line standard of care in these patients. Given the substantially better safety profile, we believe it will be unethical to use interferon in untreated Gt. 2/3 patients once PSI-7977 is approved."    

Inhibitex - At the same meeting, Inhibitex reported on their mid-stage trial of its oral nucleotide polymerase inhibitor INX-189, which offers another promising treatment for HCV that doesn't require injections of interferon.  Inhibitex's Phase II trial on INX-189 was used as a standalone drug and in combination with the antiviral ribavirin. In the first group that took INX-189 over 7 days, there was "potent and dose-dependent antiviral activity with a median HCV RNA reduction from baseline of -4.25 log10 IU/mL. Further, 200 mg INX-189 was generally well tolerated, and there were no serious adverse events (SAE) or dose dependent adverse events (AE) observed," the company said.

Tibotec Pharmaceuticals (TMC) - also presented their HCV trial at the AASLD meeting. Their investigational, second-generation, once-a-day protease inhibitor given with interferon and ribavirin for HCV was found to be safe and effective in a phase IIB randomized trial, a researcher there reported.   

"Between 75% and 86% of patients treated with TMC435 had undetectable hepatitis C RNA after 24 weeks of treatment, depending on dose, reported Michael Fried, MD, of the University of North Carolina in Chapel Hill."

Boehringer Ingelheim Pharmaceuticals Inc. - reported on their Phase 2b study of two oral hepatitis C (HCV) compounds - a protease inhibitor and a polymerase inhibitor that showed positive signs of lowering levels of the virus.

According to a news release from the company, the two compounds do not contain interferon. The combination of the protease inhibitor BI 201335, along with the polymerase inhibitor BI 207127, and ribavirin was able to bring HCV to an undetected level in patients. 

Fueling for future competition, San Diego-based iTherX Pharmaceuticals raised almost $3.2 million to advance its development of a prophylactic treatment for Hepatitis C, according to a regulatory filing. The startup stated in their press release in March that its drug candidate "TX-5061 represents a first-in-class compound that inhibits entry of the hepatitis C virus into liver cells" and has shown "potent preclinical antiviral activity against all HCV genotypes."  The company raised $2.8M in 2010.

Acquisitions and collaborations:

In late November, Gilead Science Inc. agreed to buy Pharmasset for $11B.  The deal is expected to speed development of treatments for hepatitis C, an area where Pharmasset recently expanded a trial of an oral treatment it is developing. Gilead already has seven unique molecules in development for the treatment of this disease.

Then J&J and Bristol-Myers Squibb (BMS) announced plans to combine oral drugs (no interferon) and test them in patients with HCV.  BMS and Tibotec Pharmaceuticals will also combine their respective compounds, daclatasvir and TMC435, in a Phase II study in patients with genotype 1 hepatitis C. This study is anticipated to start in the beginning of 2012.  It will test the pair of experimental drugs alone, in combination with the antiviral drug ribavirin and with interferon, enabling the companies to compare the sustained viral response of the three regimens at 12 weeks and 24 weeks.  

For more information on HIV or HCV, feel free to contact us. 

The Hepatitis C market is teaming with new competitive treatments. The standard of treatment has changed with telaprevir and boceprevir. Will the standard of treatment change again to a no interferon regiment?  It sounds promising for Pharmasset, Inhibitex, and Boehringer but only time will tell.  Any future competitor will have to have a drug regiment that does not include interferon, has less side effects and a shorter duration of treatment than the current products on the market or in trials.  It's an interesting and very exciting time for the HCV world.

In the mid 80s and 90s, antibiotics were a major focus for majority of the large pharmaceutical companies.  Everyone had a second and third generation cephalosporin or macrolide (i.e. erythromycin).  Then a new class of beta-lactam antibiotics or carbapenems emerged called imipenin and meropenon.  It was nicknamed "Gorillacillin" for its broad spectrum (aerobic and anaerobic organisms) killing everything.  Imipenin and meropenon were used for unusual and highly antibiotic-resistant organisms.  Like other beta-lactam antibiotics, they exert an antibacterial effect by binding penicillin-binding proteins, thereby disrupting bacterial cell wall synthesis.

With little difference between the antibiotics in each class, the market became crowded and competitive.  If you weren't the first or second in the market, it was hard to become a market leader or obtain a significant market share since there was no advantage of your product over the current products in the market. The market soon became a commodities market where price was the main focus and margins were low.

Over time, bacteria develop resistance. And as antibiotics are used more frequently, the bacteria develop resistance faster. The bacterial antibiotic resistance can also exhibit what is called a class effect: bacteria resistant to one antibiotic in a class of drugs, are resistant to the whole class of drugs. In some cases these "smart bugs" were developing resistance before the antibiotic went off patent.

Just as we all know the enormous commitment it takes in time and money to develop and market a drug, it became apparent that this was not a lucrative market for antibiotics. So many companies decided to get out of the antibiotic market.

Then monoclonal antibiotics were developed to stay ahead of the resistance problem by using ones own body's defenses. Unfortunately, monoclonal antibodies proved more difficult to develop than existing antibiotics.  At that time, the biotech industry was just venturing into developing therapeutic proteins and understanding their desired biological responses as well as unexpected cross reactions with unrelated antigens.

Today, as methicillin resistant staphylococcus aureus (MRSA) and other hospital acquired infections grow out of control, we lack the armamentarium of antibiotics we need to fight these infections effectively.

In November, the European Commission (EC), hoping to incentivize drug developers to develop more antibiotics have adapted a €2 billion Innovative Medicines Initiative--a public/private venture--to spur developers.  The EC strategy includes swifter approvals along with a commitment to gain governments' support for adequate pricing.

This proposal quickly drew support from Europe's pharma trade association, the EFPIA, and GlaxoSmithKline, one of the few companies still focusing on this field. "We need to take swift and determined action if we do not want to lose antimicrobial medicines as essential treatment against bacterial infections in both humans and animals," EU health commissioner John Dalli told reporters, according to Reuters.  

"Unfortunately, the current commercial model doesn't stimulate the innovation needed in this area," GSK chief Andrew Witty told Reuters' Ben Hirschler. "We need a fundamentally different approach and public-private collaboration, with the sharing of information and funding, providing us with a significant opportunity to reduce the hurdles in our way."

But is this enough? Margaret (Peg) Riley, professor in the Dept. of Biology, UMass Amherst, and co-founder of the Institute for Drug Resistance spoke at a meeting by Science Shaping Our World (SHOW) on drug resistance. She went back to the fundamentals of biology in asking "How would Microbes Solve this Challenge?" Our natural skin flora has a lot of microbes, yet we do not have an issue with infection. It's when our ecosystem is unbalanced do we encounter problems. Her theory is that we need more narrow spectrum antibiotics because when we use a broad spectrum antibiotic, we also kill all the good microbes and destroy the ecosystem. To achieve this, she recommended developing bacteriocins that will only kill specific bacteria and are nontoxic, highly stable and has little resistance selection.

For more information on anti-bacterial drugs, feel free to contact us.

I agree with Peg Riley that using broad spectrum antibiotics frequently is wrecking havoc on our ecosystem. Broad spectrum antibiotics were used when we didn't have the tools to identify the bacteria in a timely manner to choose a narrow spectrum antibiotic. Culturing bacteria took days, and the patient needed to be treated immediately with an antibiotic. Once the cultures came back, the patient was switched over to a narrow spectrum antibiotic. Now with new diagnostic tools being available, one can identify critical bacteria in hours or minutes and give the appropriate antibiotic.

This change in practice along with government incentives as proposed by the EC, may encourage more drug developers to develop antibiotics in this field. Whether we should develop bacteriocins or other types of antibiotics, we should investigate them all, since resistance is a natural occurring phenomenon. Until we know more about the biology of resistance, we should continue to develop newer antibiotics to deal with these smart bugs.

I also think we need to change our philosophy on when, where and how often we use antibiotics. From a very young age, we give kids antibiotics for every ear infection a child has. We give our cattle, chickens, and swine antibiotics that remain in the food we eat. We also have become a "germ-free" society with antimicrobial soaps and cleaners. These actions are destroying the fine balance inherent in our ecosystem.

Please feel free to send any comments or feedback to us.

Top 

Researcher at Children's Hospital in Boston believe they have may have discovered a way to genetically engineer blood vessels to secrete recombinant, protein-based drugs directly into the bloodstream on demand. The researchers were successful in reversing anemia in mice by deploying engineered vessels that secreted erythropoietin.

This discovery could allow for fewer injections of expensive recombinant drugs that require a multiple dosing regiment. The proof-of-concept study is highlighted in the Nov. 17 issue of Blood.

"The paradigm shift here is why don't we instruct your own cells to be the factory?" said lead investigator Juan Melero-Martin in a statement. Melero-Martin teaches at Harvard Medical School and is a member of the hospital's Department of Cardiac Surgery.

For the full story in FierceDrugDelivery, click here.

Top 

Twenty-Two Medical Device and Sixteen Pharma/Biotech Funding Deals

The fund raising environment is getting worse. Morgenthaler Ventures in Menlo Park, CA and Advanced Technology Ventures in Boston, MA are shedding their life science investing teams and merging them into a new independent biotech fund. ScaleVP is getting out of the healthcare sector. The number one reason cited is the regulatory path. They said "unpredictable rigors of FDA review are making it harder to get new treatments to patients-is not compatible with the firm's focus on mid-stage investing."

A bit of good news, the U.S. House overwhelmingly passed two bills in helping startups and early-stage businesses raise capital.

1) On Nov. 3, the House passed 407-17 the Entrepreneur Access to Capital Act, which makes it easier for businesses to raise capital through "crowd funding."  The legislation allows businesses to use crowd funding via the internet to solicit small equity investments from large numbers of people in selling unregistered securities as long as the total amount raised is $2 million or less. The bill also limits individual investments in crowd-funded securities to $10,000 or 10 percent of the investor's annual income, whichever is lower.

2) On Nov. 2, the House voted 421-1 to reform the Securities and Exchange Commission's Regulation A. This rule currently allows small companies to offer up to $5 million in stock to the public without registering it with the SEC. The Small Company Capital Formation Act raises that threshold to $50 million, which would allow more companies to raise capital without going through the lengthy SEC registration process. 

$0 = No financial terms disclosed. For more information, read more....

$0 = No financial terms disclosed. For more information, read more...     

$0 = No financial terms disclosed. Acquisitions are both US and International. For more information, read more....

Top  

About BioMarketing Insight

We help companies de-risk their product development process by conducting the business due diligence to ensure that it is the right product for the right market and the market potential for the product meets the business goals of the company. We can then develop marketing strategies to drive adoption for the product.

Top