Author: NutrientPharm

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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