Category: Drug Development

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ARE BOTANICAL DRUGS THE “NEXT BIG THING” IN PHARMACEUTICALS?

By Daniel Dupuis

BOTANICAL DRUGS OFFER THE BEST OF BOTH WORLDS

Almost all new drug development is on a quest to deliver maximum efficacy, while being not only safe, but well tolerated due to exhibiting few side effects. Anyone that has brought a prescription home from the pharmacy or listened to the warnings listed at the conclusion of any drug advertisement on television realizes that all conventional drugs have a long list of warnings about the dangers and side effects that are inherent to all medications.

Botanical drugs, however, offer the promise of comparable efficacy, but with little or no side effects, while exhibiting negligible safety risks. It is a sector that is no longer in its infancy and has become part of the research and development activity for most large pharmaceutical companies, as well as a number of smaller entities with a long history in this arena.

GROWTH WITHIN THE BOTANICAL DRUG MARKET

The botanical market in the United States has been stalled for a number of reasons in the United States, but recent regulatory changes and the growth of the immuno-therapy sector are attracting immense interest from all elements of the pharmaceutical and biotech industry.

The already exploding global market for botanicals and plant-derived drugs will grow from $29.4 billion in 2017 to around $39.6 billion by 2022 for an anticipated compound annual growth of just under 7%, however, the botanical sector alone has a projected growth rate of 49.5%. Much of this growth will be driven by the United States market, as botanicals have only recently gained a foothold in the United States over the last several years, while being a long-accepted component of health care in both Asia and Europe.

While the scientific world can sometimes ignore business projections, innovation is driven by capital investment and a confluence of factors has dictated that botanicals will be an area of concentration within the drug industry over the next decade.

WHAT IS A BOTANICAL DRUG?

Per the FDA, a botanical drug goes through many of the same rigors as a conventional drug.

Unlike a dietary supplement that can make no disease-based claims, a botanical drug product is intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease in humans.

  • A botanical drug product consists of vegetable materials, which may include plant materials, algae, macroscopic fungi, or combinations thereof.
  • A botanical drug product may be available as (but not limited to) a solution (e.g., tea), powder, tablet, capsule, elixir, topical, or injection.
  • Botanical drug products often have unique features, for example, complex mixtures, lack of a distinct active ingredient, and substantial prior human use. Fermentation products and highly purified or chemically modified botanical substances are not considered botanical drug products.

There is nothing new about medications that are derived from plant-based sources. While Bayer introduced aspirin in 1899, it was synthesized from willow bark and its use was found in the writings of Hippocrates in 400 BC. A major component of Alexander Fleming accidentally inventing penicillin was the mold that grew on a plate of cheese that was on the top of a stack of dirty dishes that were left in the sink.

WHY NOW?

 The main drivers of growth include increasing population, rising awareness towards botanical and plant-derived drugs and the increasing prevalence of chronic diseases.  Most botanical drugs have a favorable side effect profile and present few safety risks, but many in the United States have questioned the efficacy claims of botanicals.

As botanical research has evolved, they have now been the subject of numerous clinical trials and have demonstrated efficacy that is comparable to traditional drugs.

The United States has lagged behind the rest of the world in the development of botanical therapies, mainly because of a lack of regulatory guidelines. The problems are largely due to the semantics employed by the FDA. For example, Germany has over 70 commonly prescribed therapies that are not recognized in the U.S. for no other reason than they fell into what was, until recently, a “gray” area within the FDA. While the majority of countries do not see a distinction between botanicals, plant derived or synthesized drugs, the United States did not even create a botanical category until 2004. The FDA, however, amended the botanical guidelines in 2016 in a manner that is much more favorable to their development.

ONCOLOGY IS THE MAIN AREA OF CONCENTRATION

While “Big Pharma” was slow to enter the botanical market, they are now actively involved (Sanofi alone has 12 different botanicals under development). While doing some in-house research, many large pharmaceutical companies augmented their development strategy by licensing formulations from smaller companies, or simply acquiring them, in addition to partnering with foreign-based entities that have documented success in this sector.

This confluence of foreign entities, academic research, large pharmaceutical companies and research and development from smaller companies that have pioneered this field has led to an explosion of submissions to the FDA.

As of 2016, more than 600 botanical applications were in various phases of development with the FDA.

There are a number of disease states that are currently targeted for treatment by botanicals, but oncology is a clear area of concentration, with cancer research being the sector that has the highest number of active FDA filings.

In fact, over one third of all applications are for cancer treatment, while no other disease state exceeds 10% (see table). This is not surprising as the immuno-oncology sector has been the most robust among all drug development initiatives over the last several years from both an active research and investment perspective. Consider that Keytruda, which can only be administered to populations that have a unique genetic expression, has been projected to be the third-best-selling prescription in the world within the next five years with global sales of over $12 billion.

The promise of immuno-oncology is comparable, or enhanced, efficacy, with significantly reduced side effects. Botanicals, however, have an inherent advantage to deliver on that promise due to their lack of toxicity.

The leap from “traditional” drugs to botanicals in the oncology sector is not as considerable as some might imagine. Two of the first, and most commonly prescribed medications for a variety of cancers, are paclitaxel and docetaxel. Paclitaxel (Taxol) was derived from an extract from the bark of the rare Pacific yew tree. Due to the scarcity and difficulty of formulating paclitaxel, scientists developed docetaxel (Taxotere), which is synthesized from the renewable and more readily available leaves of the European yew tree.

ONCOLOGY IS THE DISEASE STATE WITH THE HIGHEST NUMBER OF PENDING BOTANICAL APPLICATIONS

The following is a small sample of some of the companies in various stages of botanical drug development:                                               

 Omnitura Has Developed a Botanical Immuno-Oncology Drug 

Omnitura is a company that was an early entrant into the botanical drug sector and is further along than many of the relatively new entrants into the field. They utilized a PDX model (implanting human tumors into mice with no immune system) to develop Aneustat, their lead drug candidate, which is a multifunctional, multitarget, systems biology platform that is their first submission to the FDA for prostate cancer.. It has been shown in studies to both kill, and inhibit the growth, of cancer cells as either a stand-along medication or as a companion to many current standard of care cancer medications. In addition to prostate cancer, Aneustat is currently in phase II development for a wide array of cancers, including, lung, breast, pancreatic, liver and colon.

The fact that Aneustat has been shown to be effective as a stand-alone therapy is a rare trait, even when compared to the many new medications being developed within the “traditional” drug sector. Many of the new immuno-therapy drugs are meant to enhance the efficacy or limit the side effects as a component of a combination therapy, but few have demonstrated effectiveness in killing cancer cells as a stand-alone medication.

Yiviva Publishes Clinical Trial for Cancer Drug

Yale biotech startup Yiviva was recently awarded an Innovation Award at the U.S. China Health Summit. Yiviva is developing therapeutics, inspired by botanical medicines, to treat chronic diseases and cancer.

Yiviva’s lead candidate cancer drug, PHY906, is based on an 1800-year old traditional

Chinese medicine formula.

In clinical studies targeting liver, colorectal and pancreatic cancer, PHY906 has been shown to increase the safety and efficacy for a broad spectrum of cancer treatments. In a Phase I/II hepatocellular carcinoma study at Yale, Stanford and City of Hope, data suggests that PHY906 may significantly reduce gastrointestinal side-effects and increase the survival rate for patients with Hepatitis B-associated liver cancer.

Axcella Targets Amino Acids For Multiple Disease States

Axcella is pioneering revolutionary new medicines with a focus on amino acid homeostasis. The company has discovered more than 2,000 diseases with amino acid imbalances and developed a systems pharmacology approach to restore health at the cellular level.

Axcella’s proprietary platform is clinically validated across several indication areas, with clinical-stage candidates in muscle, neurodegenerative and liver conditions.

Izun Pharmaceuticals Completes Phase II Trial

Izun Pharmaceuticals Corporation is a clinical-stage company focused on developing high efficacy products based on pharmaceutically active compounds derived from botanical sources. They have  announced that the results from a recently completed double-blind, Phase II clinical study for oral mucositis, indicated promising positive outcomes for the investigational product IZN-6N4.

The study was conducted at 12 centers in the United States and Israel. The trial enrolled a total of 110 patients with head and neck cancer who were scheduled to receive standard regimens of concomitant chemoradiation. Not only did patients treated with IZN-6N4 have less mouth and throat pain and soreness than controls, but more importantly, they were also more able to maintain their weights throughout the course of radiotherapy. The data supports that the best efficacy of IZN-6N4 was related to its initiation of use at the start of chemoradiation.

Dantonic is Shown to Prevent Chronic Stable Angina

T89, a 3-herb composition drug that improves microcirculation in and increases energy supply to the heart, and reduces blood viscosity in patients with chronic stable angina (A) and has been shown to improve clinical outcomes in comparison to current anti-anginal drug (CAAD), such as β-blockers, Ca++ channel blockers or nitrates that only targets on coronary arteries.

CONCLUSION

As some of the 600 applications become approved the medical community may learn to embrace medications that are not only effective, but safe and easy to take without troubling side effects. While botanicals have a long history, their use, especially in the United States, is truly the most forward looking direction that new drug development can undertake and offers patients the promise of new therapies that can help cure disease and dramatically improve their quality of life.

 

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VITAMIN D AND FISH OIL SUPPLEMENTS MOSTLY DISAPPOINT IN LONG AWAITED RESEARCH RESULTS

 

 

 

By Patti Neighmond

Taking fish oil supplements to prevent cardiovascular disease and cancer may not be effective, a new study suggests.

Cathy Scola/Getty Images

Many people routinely take nutritional supplements such as vitamin D and fish oil in the hopes of staving off major killers like cancer and heart disease.

But the evidence about the possible benefits of the supplements has been mixed.

Now, long-awaited government-funded research has produced some of the clearest evidence yet about the usefulness of taking the supplements. And the results — published in two papers — are mostly disappointing.

“Both trials were negative,” says Dr. Lawrence Fine, chief of the clinical application and prevention branch of the National Heart, Lung, and Blood Institute, a part of the National Institutes of Health, which funded the studies.

“Overall, they showed that neither fish oil nor vitamin D actually lowered the incidence of heart disease or cancer,” Fine says.

The results were presented at the American Heart Association Scientific Sessions in Chicago and released online Saturday by The New England Journal of Medicine. One paper focused on vitamin D supplementation, and the other focused on fish oil.

The trials involved nearly 26,000 healthy adults age 50 and older with no history of cancer or heart disease who took part in the VITAL research project. Twenty percent of the participants were African-American.

Some of the participants took either 1 gram of fish oil — which contains omega-3 fatty acids — plus 2,000 international units of vitamin D daily. Others consumed the same dose of vitamin D plus a placebo, while others ingested the same dose of fish oil plus a placebo. The last group took two placebos. After more than five years, researchers were unable to find any overall benefit.

While the overall results were disappointing, there appeared to be a beneficial effect when it came to one aspect of heart disease and fish oil: heart attacks.

A secondary analysis showed taking fish oil lowered the risk of heart attack by about 28 percent, which is a “statistically significant” finding, says Dr. JoAnn Manson, who is chief of the division of preventive medicine at the Brigham and Women’s Hospital in Boston. She led the research.

Those who appeared to benefit the most were people who didn’t ordinarily eat much fish in their day-to-day diet, as well as African-Americans, Manson says.

African-Americans in the study experienced a 77 percent lower risk of heart attack compared with taking a placebo, which is a “dramatic reduction,” Manson says. Further research is needed to confirm these findings, she adds, but, “in the meantime, it would be reasonable for African-Americans to talk with their health care providers about whether they may be candidates for taking fish oil supplements.”

In an editorial also published in the New England Journal of Medicine, authors Dr. John F. Keaney and Dr. Clifford J. Rosen take issue with some of the analysis in the study and write that the positive findings about heart attacks and African-Americans and individuals who don’t eat much fish need to be interpreted with caution.

There were no serious side effects, such as bleeding, high blood calcium levels or gastrointestinal symptoms found with either supplement.

Manson and her colleagues plan to further analyze their data and look for possible links between vitamin D and fish oil and cognitive function, autoimmune disease, respiratory infections and depression. Earlier research suggests the supplements may have some benefit for these conditions.

In the meantime, NIH official Lawrence Fine says, don’t throw out your fish oil and vitamin D.

“At this point, if one is thinking about supplementation, either omega-3s or vitamin D, talking to your physician or health care provider is the next step,” Fine says.

Fine and Manson stressed that vitamin D and the omega-3 fatty acids found in fish oil are important nutrients, but that the best way to get them is as part of a well-balanced diet. That includes eating fatty fish like sardines, tuna and salmon, and vitamin D-fortified cereals, milk and orange juice.

Another study presented at the same meeting examined whether a substance derived from a component of fish oil, known as icosapent ethyl, might reduce adverse events among people who already have cardiovascular risk factors, such as hardening of the arteries, diabetes or high blood fats known as triglycerides.

Overall, that study found there was a 25 percent risk reduction for patients taking the extract. These patients were less likely to die from heart disease, have a heart attack or stroke, be hospitalized for chest pain or need procedures such as angioplasty, stenting or bypass surgery, researchers reported.

“We are reporting a remarkable degree of risk reduction,” says Dr. Deepak Bhatt, who headed the study and is a cardiologist at Brigham and Women’s Hospital.

The study, which was also a randomized clinical trial, tracked participants for an average of five years. The volunteers took icosapent ethyl, which is sold under the brand name Vascepa and was developed by the Amarin Corporation, which funded Bhatt’s research.

The product is available by prescription only for patients with high triglycerides. But the company is expected to apply for FDA approval within the next year to expand treatment to include all high-risk cardiovascular patients.

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4 DRUG AND BIOTECH STOCKS AWAITING FDA APPROVAL IN JULY 2017

FDA Decisions in July

by Kinjel Shah

http://bit.ly/2KqNeLd

We are into the second half of the year. It’s time to analyze how the first half turned out to be for pharma and biotech stocks in terms of FDA decisions. The regulatory body approved 17 novel drugs in the first half of 2018, which is less than the year-ago period figure of 23. However, with several FDA decision lined up for the second half, a higher number of drugs could be approved in the rest of the year.

Key FDA approvals in the first half included Amgen/Novartis’s first CGRP antibody Aimovig/erenumab for prevention of migraine, Johnson & Johnson’s next-generation oral androgen receptor (“AR”) inhibitor Erleada (apalutamide) for pre-metastatic prostate cancer (CRPC), Vertex Pharmaceuticals’ third medicine to treat the underlying cause of CF, Symdeko, which is a combination of tezacaftor and ivacaftor and BioMarin Pharmaceuticals’ Palynziq to treat phenylketonuria (PKU).

With the drug development process being lengthy and time-consuming, plus requiring the utilization of a lot of funds and resources, key pipeline events including data readouts and regulatory updates are of paramount importance and could act as major catalysts.

Let’s take a look at a few important regulatory events scheduled for the month of July.

Drug and Biotech Stocks Awaiting FDA Decisions in July: Indivior (INVVY)

FDA Decision on Indivior’s Schizophrenia Injection RBP-7000: On Jul 28, the FDA is expected to give its decision on Indivior‘s RBP-7000, which has been developed for the treatment of schizophrenia.

RBP-7000 is a once-monthly injectable risperidone given using the Atrigel delivery system. Indivior is a Zacks Rank #3 (Hold) stock.

Drug and Biotech Stocks Awaiting FDA Decisions in July: Progenics (PGNX)

Progenics Pharmaceuticals’ Azedra Review: Progenics new drug application (NDA), looking to get its pipeline candidate, Azedra approved for the treatment of patients suffering from malignant rare neuroendocrine tumors — pheochromocytoma and paraganglioma — is under review.

The FDA is expected to give its decision on Jul 30, after a three-month delay from the previous FDA action date in March. Azedra was added to Progenics’ portfolio with the acquisition of Molecular Insight Pharmaceuticals in 2013.

Drug and Biotech Stocks Awaiting FDA Decisions in July: Insys Therapeutics (INSY)

Decision on Insys Therapeutics’ Pain Candidate: On Jul 28, the FDA is also expected to give its decision on Insys Therapeutics’ buprenorphine sublingual spray for moderate-to-severe acute pain. It is important to remember that in May an FDA advisory committee voted against its approval.

The company had filed a new drug application (“NDA”) in September last year based on positive data from a pivotal study on the candidate. The FDA accepted the NDA for review in December assigning a PDUFA date of Jul 28, 2018.

It is quite possible that the unfavorable vote by the committee may influence the FDA’s decision and delay the approval of the drug.

Drug and Biotech Stocks Awaiting FDA Decisions in July: GlaxoSmithKline (GSK)

Will an FDA Panel Back New Indication for Glaxo’s Nucala?: Toward the end of the  month, an FDA panel is expected to give its opinion on GlaxoSmithKline‘s  label expansion filing for eosinophilic asthma drug, Nucala (mepolizumab) for a  new indication –  chronic obstructive pulmonary disease (COPD). With the latest filing, Glaxo is looking to get Nucala approved as an add-on maintenance treatment of COPD with an eosinophilic phenotype.

Nucala is presently approved for treating severe eosinophilic asthma and eosinophilic granulomatosis with polyangiitis (“EGPA”). Glaxo hadfiled a supplemental Biologics License Application (sBLA) to the FDAfor label expansion of Nucala to include use in COPD in November last year.

Although the FDA takes the recommendations of its panels/advisory committee into account while reviewing applications, it is not bound to follow the same.

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EXISTING DRUG MAY HELP TO TREAT AGGRESSIVE BRAIN CANCER

by Maria Cohut

https://www.medicalnewstoday.com/articles/322427.php

https://www.medicalnewstoday.com/authors/maria-cohut

View all articles written by Maria Cohut

Glioblastoma is an aggressive brain cancer that progresses very rapidly and often becomes treatment resistant. The commonest chemotherapy drug used to treat glioblastoma, temozolomide, tends not to be as effective as one might hope. But could a common altitude sickness drug enhance its success?

https://www.medicalnewstoday.com/articles/322427.php

To enhance the effectiveness of chemotherapy against glioblastoma, scientists turn to an unlikely aid: an altitude sickness drug.

 https://www.ncbi.nlm.nih.gov/pubmed/22122467

Temozolomide (TMZ) works by modifying DNA, so that certain proteins that allow the tumors to grow and expand do not express.

But, some tumor cells are able to “resist” TMZ’s action.

This means that the drug’s effectiveness is often limited, which affects patient survival rates.

But a new study conducted by researchers from the University of Chicago in Illinois has made an intriguing discovery.

https://pubchem.ncbi.nlm.nih.gov/compound/acetazolamide

Acetazolamide (brand name Diamox) — a drug commonly used to treat altitude sickness and other health problems, such as glaucoma and even seizures — may counteract the resistance put up by glioblastoma cells, thus enhancing TMZ’s effect.

Study director Dr. Bahktiar Yamini explains that, if the new findings hold strong, acetazolamide would be a very convenient therapeutic aid, since it is “cheap to make, easy to take, and has limited side effects.”

The researchers’ results have now been published in the journal Science Translational Medicine.

Hope for a combination treatment

The research team found that patients with this aggressive form of brain cancer tended to be TMZ treatment resistant if they had high levels of B cell CLL/lymphoma 3 (BCL-3), a protein able to counteract the action of the chemotherapy drug.

BCL-3 blocks TMZ by activating carbonic anhydrase II, an enzyme that shields the tumor cells, and allows them to continue their cycle. HYPERLINK https://www.medicalnewstoday.com/articles/322410.php?iacp

“‘Backpacked drugs’ can boost immunotherapy for solid tumors”

Working with a mouse model of glioblastoma, the team experimented with acetazolamide, testing to see whether it, in turn, would block the activity of carbonic anhydrase, thereby allowing TMZ to do its work.

“We tested this combination treatment strategy in several animal models,” explains Dr. Yamini.

This strategy, the researchers found, cured some of the mice, while other animals saw a 30–40 percent increase in survival time following the combination treatment.

That is because acetazolamide is, in fact, a carbonic anhydrase inhibitor, and the team was able to gauge this by looking, initially, at existing studies looking at human patients with glioblastoma.

In their preliminary research, Dr. Yamini and team found that individuals with lower BCL-3 levels also had longer survival rates after treatment with TMZ, compared with other patients with high levels of this protein.

“An important feature of predictors like BCL-3 is that they are informative,” explain the researchers. “They can identify pathways to improve treatment response.”

So, by looking at BCL-3 mechanisms, the scientists were eventually able to pinpoint acetazolamide as a carbonic anhydrase inhibitor that could support the effect of TMZ.

“Our data,” add the authors, show that it is the “induction of [carbonic anhydrase II] by TMZ that is important in modulating response to therapy.”

Dr. Yamini and colleagues suggest that, in the future, a prospective randomized clinical trial should be conducted in order to confirm that testing for BCL-3 can indicate which patients will respond best to TMZ, and which are likely to be treatment resistant.

The researchers hope that a combination of TMZ and acetazolamide could eventually be used to enhance treatment efficacy for patients with high levels of BCL-3. The team is already planning clinical trials and looking to recruit participants.

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RESEARCH TEAM DISCOVERS DRUG COMPOUND THAT STOPS CANCER CELLS FROM SPREADING

June 22, 2018, Oregon Health & Science University

https://medicalxpress.com/news/2018-06-team-drug-compound-cancer-cells.html

Fighting cancer means killing cancer cells. However, oncologists know that it’s also important to halt the movement of cancer cells before they spread throughout the body. New research, published today in the journal Nature Communications, shows that it may be possible to freeze cancer cells and kill them where they stand.

Raymond Bergan, M.D., Division Chief of Hematology and Medical Oncology and professor of medicine at OHSU, says that the majority of cancer treatment therapies today are directed toward killing cancer. To date, he says, no one has developed a therapy that can stop cancer cells from moving around the body.

“For the vast majority of cancer—breast, prostate, lung, colon, and others—if it is detected early when it is a little lump in that organ and it has not spread, you will live. And generally, if you find it late, after it has spread throughout your body, you will die,” says Bergan, also the associate director of medical oncology in the OHSU Knight Cancer Institute and director of the OHSU Bergan Basic Research Laboratory. “Movement is key: the difference is black and white, night and day. If cancer cells spread throughout your body, they will take your life. We can treat it, but it will take your life.”

For that reason, the study of cancer cell movement, or motility, has been the focus of his group’s research for several decades.

Stopping cancer cell movement

In 2011, Bergan and team took a novel approach to their research by working with chemists to jointly discover a drug that will inhibit the movement of cancer cells. The Nature Communications paper outlines the multidisciplinary team’s work with KBU2046, a compound that was found to inhibit cell motility in four different human cell models of solid cancer types: breast, prostate, colon and lung cancers.

“We used chemistry to probe biology to give us a perfect drug that would only inhibit the movement of cancer cells and wouldn’t do anything else,” Bergan says. “That basic change in logic lead us to do everything we did.”

A multidisciplinary team

The team of investigators includes Bergan’s team at OHSU, a chemist from Northwestern University as well as researchers from Xiamen University in China, the University of Chicago, and the University of Washington. Ryan Gordon, Ph.D., research assistant professor in the OHSU School of Medicine and co-director of the Bergan lab, says drawing upon the strengths of this cross-functional group was key to the research’s success. “As we identified areas we were lacking, we looked at new cutting-edge technologies, and if there was something that didn’t meet our needs, we developed new assays to address our needs,” he says.

The lab of Karl Scheidt, Ph.D., professor of chemistry and professor of pharmacology; director of the Center for Molecular Innovation and Drug Discovery; and executive director of the NewCures accelerator at Northwestern University, was responsible for the design and creation of new molecules which were then evaluated by Bergan’s team for their ability to inhibit cell motility. Using chemical synthesis approaches, Scheidt and team accessed new compounds that minimized motility in tumor cells, with few side effects and very low toxicity.

“We’ve taken a clue provided by nature and through the power of chemistry created an entirely new way to potentially control the spread of cancer,” Scheidt says. “It’s been a truly rewarding experience working together as a team toward ultimately helping cancer patients.”

Refining the drug

Bergan notes the process for narrowing down the specific drug compound was a process of refinement. “We started off with a chemical that stopped cells from moving, then we increasingly refined that chemical until it did a perfect job of stopping the cells with no side effects,” he says. “All drugs have side effects, so you look for the drug that is the most specific as possible. This drug does that.”

Bergan says the key to this drug was engaging the heat shock proteins—the “cleaners” of a cell. “The way the drug works is that it binds to these cleaner proteins to stop cell movement, but it has no other effect on those proteins.” He says it is a very unusual, unique mechanism that “took us years to figure out.”

“Initially, nobody would fund us,” Bergan says. “We were looking into a completely different way of treating cancer.”

Next step: testing the drug in humans

Ultimately, Gordon says the goal of this research is to look for a new therapeutic to benefit humans.

“The eventual promise of this research is that we’re working toward developing a therapeutic that can help manage early stage disease, preventing patients from getting the more incurable later-stage disease,” he says. He’s quick to note this work has not been tested in humans, and doing so will require both time and money. The team’s best estimate is that will take about two years and five million dollars of funding. They are currently raising money to do IND (investigational new drug) enabling studies, a requirement to conduct a clinical trial of an unapproved drug or an approved product for a new indication or in a new patient population.

In addition, Drs. Bergan and Scheidt have founded a company, Third Coast Therapeutics, aimed to bring this type of therapy to patients.

“Our eventual goal is to be able to say to a woman with breast cancer: here, take this pill and your cancer won’t spread throughout your body. The same thing for patients with prostate, lung, and colon cancer,” Bergan says. “This drug is highly effective against four cancer types (breast, colon, lung, prostate) in the in vitro model so far. Our goal is to move this forward as a therapy to test in humans.”

Bergan says his team feels lucky to have the opportunity to conduct this challenging research at the OHSU Knight Cancer Institute, an institute dedicated to novel approaches to detecting and treating cancer.

“What early detection is trying to do is detect an early, lethal lesion. Cancers are lethal because they move,” he says. “This drug is designed to stop that movement.”

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A NEW STUDY FOCUSES ON A BREAKTHROUGH IMMUNO-ONCOLOGY DRUG COMBINATION

by Daniel Dupuis

A number of immuno-therapies formulations for the treatment of cancer have been developed in a quest to extend patient survival rates, while also mitigating life-altering side effects and safety concerns. While no current or proposed drug can make this claim, a recently published study that was featured in the British Journal of Cancer provides data that indicates that the initial promise of immunotherapies has been realized.

Previous studies have demonstrated that Aneustat™ is not only effective as a stand-alone oncology therapy, but can also best be described as a “foundational” drug for combination cancer therapy. Aneustat™ has been paired in studies with a wide array of oncology medications that have been recognized as standard-of-care therapies and the results have consistently demonstrated that the addition of Aneustat™ offers dramatically improved outcomes and reduced drug resistance, thereby, expanding the therapeutic window.

A recently published study, Treatment with docetaxel in combination with Aneustat leads to potent inhibition of metastasis in a patient-derived xenograft model of advanced prostate cancer, Qu, et al.,1 11/doi:10,1038/bjc.2017,474, appears in the British Journal of Oncology and assesses the therapeutic advantages of combining Aneustat™ with docetaxel for advanced stage prostate cancer.

The study utilizes the patient-derived cancer tissue xenograft mode, which is the preferred methodology of the National Cancer Institute.

Docetaxel + Aneustat™ markedly inhibited C4-2 cell migration and LTL-313H lung micro-metastasis/kidney invasion. The drug combination downregulated expression of cancer driver genes such as FOzM1 (and FOXM1-target genes).

Aneustat™ has been clinically proven to boost the immune system to kill cancer cells thru aptosis and regulate the metabolic system (tumor microenvironment) to stop proliferation while therapeutically affecting 1750 cancer related genes.

These results confirm earlier results by the same researcher that demonstrated that Aneustat™ alone was more effective than docetaxel for tumor shrinkage and inhibition of cancer cell growth. The combination of docetaxel and Aneustat™, however, was superior to either drug as a single agent.

The significance of this study is considerable in that it not only demonstrates improved efficacy, but offers a combination therapy that is also safer, while reducing the debilitating side effects common to oncology medications.

This study is a part of a series of studies that demonstrate that Anuestat™ has improved the overall efficacy of a wide array of medications known to be accepted as first-line therapies for prostate cancer, including enzalutamide, bicalutamide, abiraterone and apalutamide. Of even greater significance, however, is that Aneustat™ has been proven to be effective against tumors that have already been deemed to be resistant to these medications. This indicates that the various combination therapies will be viable for a longer period of time than any single agent.

  

More than 1 in 10 men will be diagnosed with prostate cancer at some point in their lives, and 1 in 41 will die of the disease, making it the second leading cause of cancer death in American men, according to the American Cancer Society. Additionally, a recent report states that while the incidence of most cancers is in decline, late stage prostate cancer has risen since 2015.

Aneustat™/docetaxel is entering phase III trials and it is anticipated that it will be a fast track candidate for approval in 2020. This conclusion is based on the fact that the major obstacles that confront phase III candidates have been addressed in previous studies. Aneustat™ is non-toxic, with a negligible side effect profile (minor nausea) and no apparent safety risks. As a multi-target immuno-therapy, it can prevent, rather than be a contributing factor to the onset of co morbidities.

This recent study confirms that Aneustat™ is a foundational drug that can be combined with numerous standard of care medications that can improve overall efficacy, while reducing side effects and safety concerns and mitigate the inherent drug resistance associated with current oncology medications.

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CAN A NEW DEVEOPMENT MODEL PREVENT COSTLY PHASE III DRUG DEVELOPMENT FAILURES?

by Daniel Dupuis

Attaining FDA approval for a new drug is certainly the ultimate goal of any drug research initiative. Accelerating that process can not only prove to be beneficial to patients, but is also a key component of increasing the return on investment for any entity that has a vested interest in a new medication.

Due to decreased productivity, the internal return on investment for research and development within the pharmaceutical industry has been sliding for years, and reports have indicated that it is already below break-even when the cost of capital is included and it will continue to fall in the ensuing years.

Pharmaceutical companies share the characteristics of many large, multi-national corporations that have enjoyed substantial profits for decades in that they suffer from corporate paralysis. The ramifications of this malady have resulted in them being slow to adopt new development models.

One methodology that can offer great benefits to pharm aceutical companies is the patient-derived xenograft (PDX) model. Oncology has been the recipient of the largest share of venture capital over the last few years, with immuno-therapy being an area of considerable focus and the PDX model is especially applicable to this sector.

In a PDX model, a live human tumor is grafted onto an immuno-deficient mouse and the results have demonstrated that it very closely replicates the therapeutic responses that take place in human trials. This allows companies to predict outcomes in the early stages of development and make the decision to abandon, or alter the molecular structure of a drug, long before the start pf pivotal Phase III trials.

What is the value of such a model? Companies often spend $700 to $800 million in development before they reach the pivotal Phase III trials. One only has to scan recent biotech news stories to quickly realize that adoption of PDX models, when applicable, will soon be viewed as the preferred methodology.

On April 6th of this year, shares of Incyte plummeted 23% in one day, while Merck shares fell 2.5%, on the news that the results of the Phase III trial of the combination of Merck’s Keytruda and Incyte’s epacadostat failed to show a significant improvement in efficacy over Keytruda as a stand-alone therapy. This unexpected outcome also cast doubt on other similar drugs in development and NewLInk Genetics saw its stock plummet by 42.6%.

A similar scenario befell Jounce Therapeutics on June 4th of 2018 as its stock fell 38% in one day when their drug candidate, JTX-2011, failed to deliver robust patient responses, either as a stand-alone treatment, or in combination with Opdivo (Bristol-Myers Squibb), against a range of solid tumor cancers.

The aim of immuno-therapy is to deliver efficacy, while either minimizing, or eliminating, the debilitating side effects of current cancer medications. In light of the precipitous drop in stock price of the aforementioned companies, recent criticism has now focused on the fact that none of the new formulations had any demonstrated efficacy as stand-alone therapies prior to being combined with current standard of care drugs.

There are current medications that are already in the marketplace, or in development, that have implemented the PDX model with unparalleled success. Of note, is that these single medications have been shown to be effective against several forms of cancer, which is a direct result of PDX models identifying biomarkers of therapeutic responses and allowing for numerous tests to be conducted at a cost effective rate.

Abraxane™, a cancer drug developed by Celgene, effectively utilized PDX models. It is a protein-bound paclitaxel in an injectable form that is used to treat breast cancer, lung cancer and pancreatic cancer. In June 2010, positive results were published for a Phase III trial for NSCLC (non-small cell lung cancer) when compared to solvent-based paclitaxel and Abraxene™ was approved in 2012 for the treatment of NSCLC. In September of 2013 it received approval for use in treating advanced pancreatic cancer as a less toxic alternative to FOLFIRINOX.

An immuno-oncology drug candidate that is now poised to enter a Phase II/III trial is perhaps the best example of how a PDX model was used to identify therapeutic responses for prostate cancer and also for its pipeline development. Aneustat™, a multivalent foundational drug developed by Omnitura Therapeutics, used a PDX model to derive their pre-clinical data proving Aneustat’s efficacy, both as a monotherapy and as a combination therapy with docetaxel, while exhibiting reduced toxicity, side effects, and drug resistance.   

The high rate of predictability of the PDX cancer model makes their upcoming pivotal trial much more of a foregone conclusion than a high level risk.

HOW A SHIFT IN DEVELOPMENT STRATEGY MAY AFFECT INVESTMENT

Venture capital over the last few years has focused almost exclusively on early-stage companies, while limiting investment in mid or late stage biotech companies. This is understandable in that the chances of successfully completing Phase III trials to the satisfaction of the FDA are 1 in 5. The emergence of the PDX model, however, may dramatically change this assessment as it directly mirrors what may transpire in Phase III trials, but in the early stages, when it’s cost effective. Would a a venture capitalist be far more willing to invest in a drug prior to a Phase III trial if their predictive model indicated their successful outcome was probable rather doubtful?

Some companies may be hesitant to utilize the PDX cancer model, as the results may not be favorable and companies have attracted substantial investment and/or shareholder capital long before proof of concept. Now that PDX models are known to accurately mirror therapeutic responses in human trials, however, investors may ultimately demand their inclusion.

Considering the enormous cost of the aforementioned Phase III failures, special attention should be focused on the utilization of PDX models and the drugs that are developed utilizing this strategy. It is ultimately cost effective and will be of great benefit to patients that are in need of safe and effective new therapies.

*The number of PDXs evaluated

The Predictive Value of PDXs for Clinical Outcome

A recent pooled study has been published that provides a clear relationship between PDXs and human clinical trials. In fact, it not only indicates how efficacious a medication may be, but also allows for targeting specific characteristics. For example, the study of non-small cell lung cancer indicated that Gefitinib was effective, but only with the EGFR Exon19 Del mutation, while EGFR wild-types were rendered ineffective. This directly correlates with the results accrued from the human studies. These results are indicative of the value of the PDX model, as it allows for the development of new drugs within a narrow parameter and provides valuable information in the early stages of development.

CONCLUSION:

It is clear that the utilization of PDX models in the development of cancer drugs is an increasingly valuable tool that is not only cost effective, but will help companies to more quickly develop medications that have considerably better odds of being ultimately approved.

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NEW DRUGS ON THE HORIZON 2018

by Daniel Dupuis

There are a number of new drugs in late stage trials that may soon become available to patients suffering from a wide array of either life threatening diseases or conditions that significantly affect a person’s quality of life.

There is, however, both good and bad news for people that are in need of these new medications. The pharmaceutical business is just that, a business, and they are going to dedicate their resources to drug candidates that offer the most revenue potential. This is good news if you suffer from a disease that is share d by a significant portion of the population, but perhaps not for those that are afflicted with a a rare illness.

Luckily, they still do conduct research for diseases that only affect a relatively small percentage of the population, but the price for these new medications can be staggering. For example, a company called Spark can now cure a rare form of blindness, but the price tag is $850,000, while a new drug for hemophilia has now earned the dubious distinction of now being the world’s most expensive medication at a cost of $1.5 million. While this certainly seems outrageous, insurance companies will embrace this new drug as it cures, rather than treats the illness, and they currently spend $800,000 a year, every year to manage this specific form of hemophilia.

Fortunately, there are a number of drugs in late-stage develop ment that may help the millions that suffer from the not-so-rare illnesses.

PAIN

In an admittedly crowded news environment, perhaps no other story has received more recent attention than the opioid crisis. The ravaging effects of opioid addiction have wreaked havoc on not only families, but entire communities. Due to increased scrutiny, physicians are rightfully afraid to even consider writing any pain medication. The other side of the story, however, is rarely told. A recent  HYPERLINK “https://nccih.nih.gov/news/press/08112015” \t “_blank” analysis from the National Institute of Health estimates that more than 25 million people in the United States (or over 11 percent of the country’s adult population) live with chronic pain. This means that they have experienced pain every day for the past 3 months. The majority of people taking medication for acute and/or chronic pain have a legitimate need for a solution.

The opioid problem is a relatively recent phenomenon and there has not been a new pain reliever to enter the market in over 50 years (ibuprofen), so most drug companies are only in the early stages of development and people suffering from pain are not really interested in something that may not be available for ten years or more.

Scientists at Eli Lilly partnered with Pfizer in 2013 to work on a new type of non-opioid pain medication called Tanezumab. It works by blocking what are called nerve growth factor inhibitors and has now been fast-tracked for approval by the FDA.

Early indications are that it provides substantial pain relief, but without any of the accompanying euphoria that can lead to addiction. This will be a welcome option that can help patients suffering with chronic, or even acute pain and allow physicians to again prescribe a medication without limitations.

MACULAR DEGENERATION

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss among people over 50 years of age. The condition isn’t curable, but there are current injectable treatments available that can slow down the progression of the disease.

Holding back macular degeneration requires constant dosing, and patients are obviously not so thrilled about regular eyeball jabs. But Novartis has had encouraging results from their recently completed phase 3 testing of brolucizumab. It can e xtend the time between injections to 12 weeks from the current 8-week schedule required by Elyea.

While the idea of getting a needle inserted in the eye is certainly horrific, for those that suffer from the dry version of macular degeneration, it would, most likely, be a welcome option. There are a number of drugs under development, but the variety of underlying causes may dictate that it will be a combination of medications that ultimately offers some progress. The implantation of camera-like devices does offer some hope, but may be years away. Unfortunately, the promise of stem cell therapies has proven to be ineffective and the FDA has cracked down on clinics that have promoted a variety of stem cell therapies. The only currently available option is to start, and continue, to take one of the various AREDs 2 formulas that are available as it has proven to slow down the progression of the disease. It can be costly as it is best to take it as soon as macular degeneration is detected and it must be taken in perpetuity, but there are now less expensive options available, just but be sure to carefully examine the ingredients.

HEART DISEASE

There have been promising new studies that link inflammation and heart disease, so it is no surprise that a pharmaceutical agent that can reduce inflammation could have substantial cardiac benefits.

Canakinumab has been used for juvenile arthritis, but has shown to h elp lower the risk of heart attack, stroke and cardiovascular death in people who have already had a cardiac event. Of special interest is that 50% of people at risk of a heart attack do not have high cholesterol, but do exhibit inflammation. This will allow physicians to target specific patients that do not present the obvious risk factors.

Canakinumab has reached it primary endpoints in a phase 3 trial (CANTOS trial), which should lead to a new indication for the drug to be used to treat heart disease.

CANCER

There are over 2000 new immuno-therapy drugs in development for the treatment of cancer, with a few already in the market. They aim to help the patient’s immune system combat cancer so that the debilitating side effects and/or safety concerns of current therapies can be mitigated. So far the results have been somewhat disappointing, but one new drug in that has completed phase 2 trials and is preparing to enter phase 3 may deliver on the initial promise of immuno-therapy.

Aneustat™ regulates 1750 cancer related genes, while significantly boosting a patient’s immune system. While most almost all cancer therapies, either new, or in development, are single target, Aneustat™ is multi-target and multi-functional. It is the first non-toxic formulation that has been proven to inhibit and/or kill active cancer cells. In trials, it has been paired with numerous drugs that are already in use, but can limit the life threatening side effects of standard cancer therapy, thereby, offering a new breakthrough therapy.

Additionally, Aneustat™ is an oral medication that will be offered for far less than the last three approved oral cancer therapies that cost approximately $170,000 per patient.

The unprecedented combination of efficacy, lack of side effects and ease of use have led many health organizations and insurance companies to champion Aneustat™, which is generally unheard of before the start of phase 3 trials.

BALDNESS

Sure, it may seem to be of little importance considering the aforementioned disease states and it is certainly not life threatening, but it can have a substantial effect on the perceived quality of life for both men and women. A common trait that is shared among people that say it is meaningless is that they generally have a full head of hair.

The researchers at Columbia University Medical Center found 75 percent of patients with moderate to severe alopecia showed “significant” hair regrowth after taking the drug ruxolitinib. Additionally, most drugs in development for alopecia only target men, but ruxolitinib does not affect hormone levels so it may be a viable option for both men and women.

By the end of the treatment 92% of patients had hair regrowth

Ruxolitinib is currently being used to treat a specific form of leukemia, but like many drugs, studies have demonstrated unintended outcomes that can benefit a large number of people. Remember, Viagra was being studied for high blood pressure and at the end of the trial most of the men, with perhaps a nudge from their wives, asked if they could stay in the study past its completion date.

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HOW NEW DEVELOPMENT MODELS CAN LEAD TO CANCER BREAKTHROUGHS

by Daniel Dupuis

The pharmaceutical industry’s long and successful strategy of placing big bets on a few molecules, promoting them heavily and turning them into blockbusters, worked well for many years, but its R&D productivity has now plummeted and the environment is changing.

Various analysts (notably, Deloitte and BCG) have tried to measure Big Pharma’s R&D productivity in terms of the internal rate of return (IRR) and have concluded that it has been in steady decline and have predicted that it will be unsustainable by 2020. In short, when the estimated cost of capital is included, the return on investment for new drug development is no longer a break even investment.

WHAT IS DRIVING THESE CHANGES?

The standard formula for decades has been to assume 13 years of development and 7 years in the market as a branded drug at commensurate prices for a substantial return on investment, but this is no longer an applicable formula.

Why?

Healthcare payers are increasingly measuring the “pharmacoeconomic” performance of medicines. Medical innovation must be paired with a reduced cost of care.

Currently, a new branded drug may prove to be demonstrably superior to current standard-of-care medications, but will struggle to land on any formulary (prescribing protocol), even as a fourth-tier option with a substantial co-pay, unless it can be offered at a cost effective price or mitigate costly side effects.

Most common disease states are assumed to be effectively managed with existing generics, so there is no real demand for a new formulation. Is there any real need for a new hypertension drug?

Research expenditures have steadily increased and the odds of phase 3 approval are still no better than 1 in 5, and this is after spending an average of $700 to $800 million prior to entering phase III.

New drugs need to have flexibility which allows for numerous revenue streams. Prevention, maintenance, and disease management are now the components of a blockbuster drug.

There is little incentive to develop medications for rare diseases as the price point necessary to recoup costs would have to be at a level that would be met with not only resistance, but negative publicity (a new treatment for a rare form of hemophilia will cost $1.5 million). Areas of need with a large patient population are a mandatory requirement for new drug development.

“Corporate paralysis” has become the norm. The prevailing management culture, mental models and strategies on which the industry relies have remained unchanged for decades, even though other industries have adopted far more efficient methodologies.

HOW CAN BIG PHARMA ADDRESS THESE ISSUES?

Big Pharma has increasingly adopted a more efficient model of outsourcing research and development by forming licensing agreements with smaller, more specialized companies, to secure the rights to new therapies that are already in development.

Investing in “combination drugs,” that combine a new medication with an already accepted generic medication, where the combination of two drugs can improve the overall efficacy or side effect/safety profile at a cost effective price point.

Adopting newer, more effective methodologies. For example, using a PDX (patient-derived xenograft) model in the early stages of development. This model of implanting a live tumor into a series of mice can accurately predict the outcome of phase III trials in the early stages of drug development for immunotherapy drugs for oncology.1 See recent phase III failures of Incyte, Jounce and Vascular Biogenics.

Embracing broad changes by utilizing new technologies to treat diseases, such as gene therapy, tissue engineering, botanical formulations and regenerative medicine.

Focusing on medications that can not only treat an existing disease, but serve as a preventative and/or a post-disease maintenance therapy. This can exponentially increase the overall return on investment for any new medication.

Developing or licensing new drugs that can potentially treat a wide array of disease states.

Concentrate on chronic diseases, as they generate the most revenue, both now and in the future.

SOME CHANGE IS ALREADY TAKING PLACE

The past two years has resulted in unprecedented investment in drug development by innovative biotech companies for disease states with large and growing markets.

Oncology attracted much of this investment and is a great example of the implementation of new technologies.  In fact, there are currently 2000 immuno-therapies in clinical or pre-clinical testing,

Much of the development in cancer immunotherapy was driven by smaller companies that are not immersed in traditional methods of drug development.

For example, Arvinas™ is developing a new class of drugs that engage the body’s own natural protein disposal system to treat cancers and other difficult to treat diseases. As a potential improvement over traditional small molecule inhibitors, their PROTACs (Proteolysis-Targeting Chimeras) platform is able to degrade disease-causing proteins rather than merely blocking them, which can potentially treat cancer, but elicit fewer side effects. This unique technology has resulted in an investment/licensing agreement with Pfizer for $830 million, in addition to an already existing deal with Genentech for $650 million.

Another company, Omnitura™, is a great example of applying many of the modern principles of drug development. It is a marriage of technology and medicine that has led to the development of Aneustat™, an unprecedented multivalent immuno-oncology drug candidate that was developed using the aforementioned patient-derived xenograft model.

Aneustat™ is unique in that it’s a multifunctional and multi-targeted immuno-therapy that regulates thousands of genes in molecular pathways associated with survival of cancer. The pre-clinical and clinical data indicates that it is effective as both a stand-alone drug and as a foundation for combination therapy with any current standard-of-care drugs for prostate and numerous other cancers. When compared to the existing therapies for prostate cancer (e.g., docataxel), the addition of Aneustat™ reduced toxicity, side effects and drug resistance, while providing better overall outcomes.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most adaptable to change.”

                                                                Charles Darwin

1Pompili et al., Patient derived tumor xenografts: transforming clinical samples into mouse models. Journal of Experimental & Clinical Cancer Research (2016) 35:189 DOI       10.1186/s13046-016-0462-4