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Espaço de publicação e discussão sobre oncologia. GBM IMMUNOTHERAPY ONCO-VIRUS ONCOLOGY CANCER CHEMOTHERAPY RADIOTHERAPY



Segunda-feira, 24.11.14

IMMUNOTHERAPY NW BIO VACCINE possible COSTS

 

 

Ryan Pawell,

Northwest Biotherapeutics' DCVax-L:

A Reimbursement Perspective

Nov. 22, 2014 4:41 AM ET  

Summary

  • NWBO is currently in talks with regulators regarding reimbursement.
  • DCVax-L reimbursement numbers vary significantly amongst sources.
  • This article examines DCVax-L reimbursement from a value perspective putting a reasonable price at approximately $96,600 per patient.

Northwest Biotherapuetics (NASDAQ:NWBO) received $64 million in financing since mid-August. Much of this money is allocated to manufacturing and ongoing clinical trials.

Additionally, NWBO is currently in talks with the German Sickness funds regarding reimbursement for DCVax-L under the Hospital Exemption program.

Current estimates for DCVax-L reimbursement vary.

For example, Steve Giardino places the value at $110,000 per batch in Germany with an estimated global price range of $50,000 to $100,000 in one article. He also estimates a 'conservative' price of $70,000 per patient for up to 5 years of treatment via the German Sickness Funds in another article.

As another example, astrocytomaoptions.com discusses two business reports: (1) one assuming a price of $14,000 per dose or $154,000 for 11 doses over the course of 3 years and (2) another assuming a price of $120,000 per patient.

A third example, provided by Grant Zeng, puts the price at $37,000 per year for up to three years or $111,000 total per patient.

In summary, readily-available price estimates range from $50,000 to more than $150,000 for DCVax-L.

For comparison purposes, this article examines Dendreon (NASDAQ:DNDN) as it also manufactures an autologous dendritic cell cancer therapeutic, and serves as benchmark for analysing both the cost and effectiveness of DCVax-L.

As seen with DNDN, the reimbursement price can make or break the business. The current reimbursement price, set at $93,000 in early 2010, was not sufficient to generate profits and resulted in the recent Chapter 11 bankruptcy.

From 2011 to 2013, DNDN operations resulting in a net negative income equal to about 1.1 times revenue. Indicating a price point of $194,000 may have resulted in long-term commercial viability --barely. However, it is unlikely that the market would support that price as $93,000 is equal to 20 months supply of a competing therapeutic, Zytiga (Abiraterone), which increased overall survival from 10.9 months to 14.8 months in Phase III trials.

Pricing can be estimated using the incremental cost effectiveness ratio with therapeutics costing more than $50,000 per quality adjusted life year rarely receiving reimbursement. Pricing depends on a variety of factors including the safety and efficacy of the therapeutic along with the jurisdiction and relevant politics, however, a fair-value price point may be estimated using the incremental cost effectiveness ratio and the $50,000 per quality adjusted life year threshold.

For newly-diagnosed glioblastoma multiforme patients the benchmark is the Stupp Protocol, which provides 6.9 months of median progression free survival and 12.1 months of median overall survival at an estimated cost of $34,200 USD ($27,365 EUR). The Stupp Protocol refers to the current standard of care for treating newly diagnosed glioblastoma multiforme patients. Phase I/II DCVax-L clinical data suggests median progression free survival will be 24.0 months and median overall survival will be 36.0 months.

Assuming an average quality of life of 0.75 where a patient cares for themselves, but cannot perform active work during the progression free survival period -- the inclusion criteria for the DCVax-L Phase III trial requires a KPS rating of at least 70/100. An average quality rating of 0.5 assumes quality of life decays logarithmically from 0.75 for the remaining period. We can approximate the amount of quality adjusted life years added by the Stupp Protocol and DCVax-L for newly-diagnosed glioblastoma multiforme patients.

These numbers can be used to estimate the total amount of quality adjusted life years added by calculting the sum of progression free period multiplied by 0.75 and the remaining period by 0.5.

The above values mean the Stupp Protocol adds 0.8 quality adjusted life years, whilst DCVax-L adds 2.0 quality adjusted life years. Using the incremental cost effectiveness ratio, the $50,000 per quality adjusted life year threshold and the $34,200 cost of the Stupp Protocol, we can estimate the value of DCVax-L to be $96,600 per newly diagnosed glioblastoma multiforme patient.

This is slightly above the $93,000 reimbursement for DNDN's Provenge, which extend median survival by 4.1 months during the Phase III trial for a different type of cancer. This indicates $96,600 for DCVax-L is a bargain and the reimbursement price might be higher.

Manufacturing costs for DCVax-L should be much lower than for Provenge. For example, Provenge requires 3 leukaphereses where rare cell types are mobilised, blood is drawn and the desired cells are selected - this costs $6,500 each time suggesting a savings of $13,000 for DCVax-L cell collection alone when compared to Provenge. Additionally, DCVax-L is cryopreserved or frozen allowing it to be stored and shipped in a manner that is more cost-effective than live cell culture. Furthermore, DCVax-L can be administered intradermally, like a flushot, instead of requiring multiple infusions, like Provenge. These savings significantly improve the long-term commercial viability of DCVax-L.

A major consideration for the bull thesis is long-term commercial viability. NWBO will need to generate a profit based on the initial reimbursement price to avoid going the way of DNDN. This could be the case if the improved manufacturing, distribution and reimbursement price allow for the appropriate margins.

In summary, Phase I/II clinical data indicates DCVax-L adds substantial value in terms of quality adjusted life years with minimal side affects when compared to the standard of care and when compared to another dendritic cell cancer therapy, Provenge. Value analysis puts the price point slightly above DNDN's Provenge, and improvements in manufacturing substantially reduce cost of goods sold.

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por cyto às 11:26

Domingo, 23.11.14

IMMUNO-ONCOLOGY

 

Sharon di Stefano

Cel-Sci Is A Leader In The I-O Class Of Cancer Therapies

Aug. 12, 2014 10:43 AM ET  |  11 comments  |  About: Cel-Sci Corporation (CVM), Includes: ABLYF, AZN, BMY, CLDX, CLSN, DNDN, FPRX, INCY, INO, MRK, NLNK, NWBO, PPHM, RHHBY by: Sharon di Stefano

Summary

  • Tumor cells that refuse to die have led researchers to develop immuno-oncology drugs, a brand new class, with Big Pharma participation.
  • Cel-Sci Corporation has been ahead of the game for years with Multikine, now in advanced clinical trials for head and neck cancer.
  • Smaller biotechs are entering the race, with varied results.
  • Cel-Sci may face deep-pocketed competition, and must surmount clinical and regulatory hurdles.
  • If successful, a huge global market awaits Cel-Sci's solution to disfiguring surgery.

Tumor cells, tending to persist after treatment, lead to remission and have been a bane to cancer researchers and doctors for decades. Only recently, immuno-oncology, labeled "I-O" first by Bristol-Myers Squibb Co. (NYSE:BMY), has emerged to become a new class of cancer medicines that may someday take a meaningful place alongside chemotherapy, surgery, and radiation. Investors associate cancer immunotherapy with forerunner Dendreon Corporation (NASDAQ:DNDN), whose PROVENGE vaccine shocked health plans with its exorbitant price that only extended life a few months. I-O, in its new form, has sparked a pharmaceutical rivalry reminiscent of the antihypertensive race of the 1990s. Central roles in I-O are occupied by Merck & Co. (NYSE:MRK), Bristol-Myers, AstraZeneca PLC (NYSE:AZN) and Roche Holding AG (OTCQX:RHHBY) in various stages of clinical trials, but with a common scientific theme - the inhibition of programmed cell death proteins, or PD-1 and PD-L1, that block immune responses to allow tumor proliferation.

Cel-Sci Corporation (NYSEMKT:CVM), with its flagship drug Multikine, has been ahead of the pack, investigating the I-O space for many years and currently enrolling a global Phase III trial in head and neck cancer. Multikine is a leukocyte interleukin injection, a cocktail of proteins and cells designed to augment the human immune system in fighting tumor cell infiltration into tissue. In studies as early as 2003, treatment with Multikine in patients with primary tumors of the head and neck proved beneficial by stimulating T-cell migration into cancer "nests", enabling the immune system to elicit an anti-tumor response before tumor recurrence.

Decision Resources, data provider to the biopharmaceutical industry, predicts the I-O market will grow to almost $9 billion worldwide by 2022, from $1.1 billion in 2012, dominated by only a handful of firms. Small wonder four of the top Big Pharma companies are in what has been described by analysts and journalists as a race to reach FDA approval first.

Merck, AstraZeneca, Bristol-Myers and Roche have all developed drugs in the PD-1 or PD-L1 class to treat lung cancer, with potential indications in melanoma and kidney. The method of action sounds like science fiction - PD proteins allegedly let tumors disguise themselves from the immune system. Inhibiting these proteins from their receptor targets allows biochemical components to recognize the tumor cells as invaders, and kill them as they would any virus or bacteria. Whether the immune response is sustainable against constantly mutating tumor cancer cells has not yet been proven.

Boosting its position in the I-O contest, this past spring, AstraZeneca began a Phase III trial for MEDI4736, acquired with its purchase of MedImmune in 2007, for non-small cell lung carcinoma (NSCLC), the first of its kind. Around the same time, MedImmune joined forces with Incyte Corporation (NASDAQ:INCY) to combine their biochemical potions to erect immune responses to different tumor types.

Bristol-Myers has succeeded in being first to approval: its nivolumab will be available for sale in Japan, and it recently formed a pact with Ono Pharmaceutical Co. (OTC:OPHLF) to market I-O therapies in select Pacific Rim countries upon commercialization of nivolumab and Yervoy, Bristol-Myers' monoclonal antibody for melanoma, gained in the acquisition of Medarex. Working feverishly against big competitors, Bristol-Myers also cut a $350 million deal with Five Prime Therapeutics (NASDAQ:FPRX) for I-O drug discovery.

Merck's I-O pembrolizumab was recently submitted as a rolling biologic license application (BLA) for melanoma, viewed as a coup among its rivals. The drug is fast-tracked at the FDA, and has been given the desired "breakthrough" designation because clinical trials show the possibility of extending life for one year. Merck's intent is to gain approval for pembrolizumab for melanoma patients who have failed Bristol-Myers' Yervoy, a pharmaceutical nose-thumbing to a fellow drug firm developing I-O therapies. Marking its place in the race, Merck began collaborating with foreign-based Ablynx NV (OTC:ABLYF) for joint development of I-O drugs in a deal worth up to $2.3 billion. Pembrolizumab is currently enrolled in 10 clinical trials, a total of 4,000 patients, for cancers of the bladder, stomach, kidney, colon and breast, including some hematological disorders.

Roche, known more for its diagnostic tests and services, bought its way into the I-O field with its 2009 acquisition of Genentech's deep knowledge of making monoclonal antibodies. Toiling behind the curve of its drug company counterparts, Roche's MPDL3280A only recently publicized results of a Phase I study that shrank tumors in 43% of people with refractory metastatic bladder cancer.

The drug is also tested in melanoma and kidney. Roche, like Merck, has been granted the FDA's breakthrough therapy designation.

Cel-Sci has a handful of smaller competitors; some promising, others not. Celldex Therapeutics (NASDAQ:CLDX) has a potential I-O in a late-stage study for brain cancer that is designed to help T-cells better recognize tumors. It caught the attention of Bristol-Myers, who wants to mix Celldex's varlilumab with its nivolumab in a Phase I/II trial on various solid tumor cancers. The technology of NewLink Genetics (NASDAQ:NLNK) looks like voodoo science to me - an immunotherapy platform called HyperAcute is intended to stimulate the immune system via cancer cell lines modified to express a carbohydrate, basically a starch, to attack tumors. Yet, the company is in two Phase III trials for pancreatic cancer. Inovio Pharmaceuticals (NASDAQ:INO) recently announced positive Phase II results with its I-O for cervical neoplasia related to human papillomavirus (HPV), an area Cel-Sci investigates, but treatment is for precancerous lesions, and the company has met with some controversy whether cancer itself can be addressed.

Two additional firms are particularly troubled. Peregrine Pharmaceuticals' (NASDAQ:PPHM) lead drug bavituximab, a monoclonal antibody turned I-O, is in Phase III for NSCLC, but critics question improvements following lackluster and unreliable Phase II data and wonder why more robust statistical information is not provided. The worst in the I-O hopeful category is Northwest Biotherapeutics (NASDAQ:NWBO), in Phase III with DCVax for brain, ovarian and prostate cancer. Widespread controversy not only exists about its choice of clinical endpoints and their acceptance by regulators, but also the dissemination of information, for which it was chastised by renowned cancer center MD Anderson for making unjustified claims related to DCVax.

Yet, these companies carry much higher valuations than Cel-Sci, despite being neck-in-neck along in clinical trial progress, as the table below illustrates. Their separate issues apparently do not figure into investor opinion. However, disparity in value makes for opportunity, especially in this new class of drugs that has captured medical attention.

Company

Ticker

Market Cap

Disease Indication and Trial Phase

Celldex Therapeutics

CLDX

$1.35 billion

Glioblastoma - Phase 3

NewLink Genetics

NLNK

$691.3 million

Pancreatic Cancer - Phase 3

Inovio Pharmaceuticals

INO

$539.6 million

Cervical Dysplasia HPV - Phase 2

Peregrine Pharmaceuticals

PPHM

$301.1 million

Non-small Cell Lung Cancer - Phase 3

Northwest Biotherapeutics

NWBO

$385.5 million

Brain Cancer - Phase 3

Cel-Sci Corp.

CVM

$72.57 million

Head and Neck Cancer - Phase 3

Smaller biotechs that have traditionally adopted other medical modalities to treat cancer have been drawn by I-O's promise. Recently, Celsion Corporation (NASDAQ:CLSN) acquired privately held EGEN, Inc., developer of an immunotherapeutic using a small circle of DNA called a plasmid that, combined with interleukin (IL)-12 and a chemotherapeutic agent wrapped inside a nano-sized material, can be directed to tumors to induce remission.

Big Pharma's approach wants to combine I-Os with other cancer remedies or treat patients that have failed prior therapy, but Cel-Sci seeks to use Multikine first, before any compromise of the immune system takes hold, to create a greater anti-tumor response. The company has undertaken the huge task of enrolling the largest Phase III for an I-O, in head and neck cancer (a disease with very poor prognosis), with the goal of petitioning the FDA and other agencies to approve Multikine as a first-line treatment. Besides its potential benefit as the first medicine given before surgery, radiation or chemotherapy, Multikine has been developed to be an "off-the-shelf" drug, much easier to manufacture large-scale. Making monoclonal antibodies (the basis for I-Os) is tedious business, and batch-to-batch consistency is an ever-present challenge.

There are side effects to consider. Drugs that stimulate the immune system run the risk of damaging healthy tissue or triggering autoimmunity. Bristol-Myers' Yervoy may well extend a melanoma patient's life by four months, but colitis can result. Merck's leading I-O caused fatigue in 30% of subjects, rash and itching in another 21%. Patients developed inflammation of the lungs. Roche's drug fared better, although 12.6% of patients had more serious Grade 3 or 4 side effects, including fatigue, shortness of breath and vomiting. By contrast, Multikine's trials have shown no severe adverse effects, with events limited to pain and swelling at the injection site, headache and nausea.

Cel-Sci's change in contract research organizations (CRO) is resulting in faster enrollment: the company announced last month's total patient enrollment of 232 people, more than one-quarter towards its goal of 880 by the end of next year. Critics complain that Cel-Sci cannot meet its target, but do not take into consideration acceleration of enrollment made possible by the number of countries and organizations for which trials have been and continue to be approved, with multiple sites available in each. In the past three months alone, Turkey, Austria, Sri Lanka, France and the UK have come on board, totaling 17 countries in all. This is truly a global trial - sites also include those in Canada, India, Israel, Poland, Hungary, Russia, Taiwan, Ukraine, Serbia, Croatia and Bosnia and Herzegovina.

In the US, Cel-Sci gained approval from Detroit's Henry Ford Health System, one of the nation's largest group practices, with over 1,200 doctors in 40 specialties. This followed 21st Century Oncology of Greenville, North Carolina, with 166 treatment centers in 16 states and six Latin American countries. My question is why would management, by keeping a running count of enrollees, hold itself up to public embarrassment and investor scorn if it did not fully expect to reach its desired enrollee numbers?

No doubt, Cel-Sci has a long road ahead, and a pivotal trial of this magnitude may quickly burn through its remaining cash, forcing it to seek dilutive financing. Its own clinical and regulatory risks notwithstanding, Cel-Sci faces upcoming competition from AstraZeneca, Merck and Bristol-Myers, who plan studies in head and neck cancer, big firms with deep pockets. The I-O arena is also drawing critics: oncologists have gone on-record urging caution concerning the results being churned out by Big Pharma, citing small sample sizes, lack of control groups, efficacy in only a minority of cancer patients and bad side effects. Particularly when using two I-Os in combination for best results, a trend seen recently.

Regardless of risks, Cel-Sci is well-positioned to enter the I-O race. Head and neck cancer, including disease of the larynx, thyroid, salivary glands and nasal passages, account for up to 5% of all cancers in the US and cause 12,000 deaths per year, for a total market of slightly over $3 billion. Because of its prominent, visible position on the body, better agents are needed to reduce the size of tumors and limit the amount of disfiguring surgery. Cel-Sci is ahead of Big Pharma in filling this medical need, and given its undervalued status compared to competitors large and small, presents a golden opportunity to take advantage of the budding I-O industry.

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por cyto às 03:46

Domingo, 23.11.14

Long Or Short: Cancer Cures

 

Ryan Pawell,

Long Or Short: Cancer Cures

Jun. 26, 2014 10:12 AM ET  

Summary

  • Autologous immune cells for curative cancer therapies.
  • Dendritic cells initially proven to be safe and effective.
  • Dominant market player will need autologous immune cells that are safe, effective and affordable.

Recently, Forbes ran an article titled "Is This How We'll Cure Cancer?" and discussed the potential benefits of chimeric antigen receptor T lymphocytes (CARTs) or white blood cells that are engineered to hunt down and attack cancer.

These engineered white blood cells are exciting - clinical trials demonstrate these cells "[make] blood cancers seem to disappear and then stay vanished".

Companies large and small are placing bets on this potential cancer cure and the value of these deals range from millions to billions of dollars. Juno Therapeutics recently raised an unprecedented nine-figure Series A and claims "CARTS… eradicate treatment-resistant cancers in patients with a large tumor burden"

CARTS are enjoying a healthy amount of attention and funding, however, the use of engineered immune cells for cancer therapeutics is far from the bleeding edge. Dendreon (NASDAQ:DNDN), a company spun out of Stanford Medical School in 1992, demonstrated engineered dendritic cells (DC) are both safe and effective for treating metastatic prostate cancer, receiving FDA approval in 2010. Some believe DNDN is a flop as their current model is struggling to turn a profit.

Most of these exciting therapies use autologous cells or cells from your own body and require a centralized manufacturing plant with an eight-figure price tag. For autologous cell therapies, the centralized manufacturing requires one's own cells to be extracted at a local hospital or blood bank then shipped to the manufacturing plant for engineering, and shipped back for infusion. Logistics is a major bottleneck for this centralized manufacturing model.

Ask any biologist, working with live cells is not easy and live cells require constant feeding in a controlled environment if you cannot freeze them. Live cells require a precisely controlled sterile environment with respect to temperature, pH, osmotic pressure, O2, CO2 - it ain't easy to keep cells alive in a lab, let alone during transportation. Additionally, live cells must be surrounded by the appropriate hormones and nutrients, which are consumed quite quickly.

For DNDN, logistics looks to be their most daunting challenge. DNDN maintains a logistics command center for coordinating each personalized therapeutic across the United States and the complexity of this system significantly adds to the cost of goods sold.

The key technical advantage for CARTs is cryopreservation or freezing, CARTs can be frozen down and shipped in vials immersed in liquid nitrogen increasing the shelf-life of the cells. DNDN's DCs could not be frozen and may require complex environmental controls described above if short shipping times are not available - transporting biologics in a timely manner is quite expensive. For this reason, CARTs look to be a safe, effective and economically viable choice.

Another dendritic cell initiative is Northwest Biotherapuetics (NASDAQ:NWBO). NWBO maintains a healthy clinical pipeline with therapeutics for brain cancer, metastatic ovarian cancer, colon cancer metastases and prostate cancer. An NWBO patient received their therapy nearly a decade ago and is still kicking, whereas the average patient in a DNDN clinical trial lived 4.1 months longer when compared a placebo patient.

NWBO looks to be taking a more holistic approach with their therapeutic. The NWBO cells are engineered to identify a range of biomarkers, if the cancer adapts it can still be recognized by the DCs. For some reason, NWBO does not disclose this on their "DCVax ® Technology" webpage nor is this key technical advantage disclosed on their Wikipedia page, but NWBO can freeze their dendritic cells.

From a biological perspective, dendritic cells are the ideal choice. These cells could be likened to a parent cell that can teach its kids to attack cancer in the body where the kids are T-cells.

On balance, these promising cancer cures come in two platforms (1) engineered T-cells and (2) engineered dendritic cells. Both look to be fairly effective in eradicating previously untreatable cancers. However, NWBO's use of the ideal biological platform and their ability to freeze these cells positions them to dominate the market in the long term.

I believe the winner of this race will be autologous engineered dendritic cell therapies manufactured in a safe, effective and affordable manner.

DNDN demonstrated Provenge, a DC-based therapy, is safe and effective for the treatment of metastatic or advanced prostate cancer. According to Yahoo! Finance, DNDN's operations resulted in negative net income of about $300 - $400 million for 2011 - 2013. This is about 22 years after launch and some attribute these losses to live cell logistics.

NWBO has been around for quite some time too, with the IPO occurring in late 2001. And, according to Yahoo! Finance, NWBO enjoyed negative net income of $30 - $70 million for 2011 - 2013. NWBO's therapeutic looks to be safe and effective just like DNDN's and Steven Giardion did a great job addressing recent negative publicity. NWBO worked out a way to freeze DCVax - a key competitive advantage over DNDN. A physician just needs to warm up a few drops of DCVax and inject the patient intradermally.

Going long on DNDN might mean you think it can turn itself around, going short on NWBO might mean you do not think its therapeutic will be safe and effective. Going long on NWBO after regulatory approval means you might think NWBO's therapeutics are going to be safe, effective and economically viable.

A final note, both DNDN and NWBO employ complex laboratory processes in their manufacturing facilities. If economic viability is simply not in the cards with current processes, both DNDN and NWBO will need to look to alternative technologies to reduce the cost of goods sold. That technology exists. It is just a matter of implementation.

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por cyto às 03:42

Domingo, 23.11.14

Gliobastoma Valorizaçao farmaceuticas NASDAQ

 

Rajiv Puri 

Why Immunotherapies Have Made DelMar's Lead Drug A Necessity In Brain Cancer

Jul. 15, 2014 2:40 PM ET  

Summary

  • A large void in the Glioblastoma Multiforme treatment paradigm leaves patients with poor prognosis.
  • DelMar is tremendously undervalued on a NPV/DCF basis and relative to peers Northwest Biotherapeutics, Agenus, Celldex, and ImmunoCellular.
  • My estimates put fair value at $3.5/share, or 3X upside; analysts have assigned price targets as high as $8/share.
  • DelMar's VAL-083 addresses a large GBM population (>50%) unresponsive to standard of care, Temodar, and could be the answer to failures rampant in cancer vaccines (aka immunotherapies).
  • VAL-083 has approval in China for the treatment of Lung Cancer and CML. This serves as positive precedence for regulatory approval by the FDA and EMA.

In Glioblastoma Multiforme (GBM), the deadliest form of brain cancer, companies like Northwest Biotherapeutics (NASDAQ:NWBO), ImmunoCellular Therapeutics (NYSEMKT:IMUC) and Celldex Therapeutics (NASDAQ:CLDX) have stolen the spotlight, prematurely. As I explain later, these companies present a less than compelling case for producing strong risk-adjusted returns. They have also necessitated DelMar Pharmaceuticals' (OTCQB:DMPI) lead product, VAL-083, which is initially vying for a low-hanging $250M+ opportunity in 3rd line therapy that its peers have ignored. With ~45M shares outstanding on a fully diluted basis, DelMar is valued at just $40M. By any conservative measure, shares are worth at least $3.5, or 3X recent prices (valuation discussed below). If DelMar were valued in line with its peers, shares would trade at $5+. Maxim analyst Jason Kolbert assigned DMPI a 12-month target price of $8/share. But to understand the opportunity, we first need to understand GBM and where the current standard of care lies.

The Trending Combinational Therapy Model in GBM

With poor prognosis for patients and minimal improvement in the standard of care, Glioblastoma Multiforme is a highly focused area of cancer research. Like other areas of cancer research, novel targeted immunotherapies have been headlining developments. Similarly, these immunotherapies are primarily being implemented as the targeting agent in combinational therapies for reasons I have previously written about, here and here.

The driving force behind this paradigm shift is the presence of an enzyme which renders the chemotherapeutic agent Temodar, currently the first-line standard, useless in roughly 50% of patients. With the second-line treatment (Avastin, discussed later) having no evidence of improving chances of overall survival, patients are left without options. For analysis of the current state of GBM refer to the next section.

As an investor looking at the evolving treatment model, it is easy to forget that the chemotherapeutic agent, or more generally non targeting agent, plays a vital role in the overall success of the treatment. Some might argue even more importance, being that the one can exist as a stand-alone therapy. That being said, developments on that front (part B in figure 1) may prove useful in improving the current stand-alone model and further amplify the success of next-generation combinational treatments. For an investor, these developments may be a better bet given the uncertainty and volatile track record associated with immunotherapies.

With all the hype surrounding immunotherapies, DelMar Pharmaceuticals, which is involved in introducing a known (approved and selling in China) chemotherapeutic agent in GBM, has fallen under the radar. DelMar is undervalued and presents an asymmetrical risk/reward investment considering it is entering at least a $250M market (10x current market cap) of patients who have failed the standard of care and are left without options. The total addressable market remains upwards of $1B.

Background Information On The State Of GBM

According to the Cancer Research Institute, Glioblastoma Multiforme is one of the most aggressive types of brain cancer, with most patients failing to reach the one year survival mark and few living to see three years following diagnosis. For newly diagnosed GBM patients treated under the current standard of care, median progression free survival is 6.9 months and median overall survival is 14.6 months. Only 25% of newly diagnosed patients survive for 24 months and less than 10% survive more than 5 years. With approximately 16,000 newly diagnosed patients and 10,000 deaths from the disease in the US alone, there is a dire need to improve the standard of care.

The current standard of care consists of Temodar as the chemotherapeutic agent in chemoradiative therapy as a first line treatment. Temodar received approval in 2005 for the treatment of newly diagnosed GBM on the basis that it improved overall survival by 2.5 months. In 2009, the FDA approved Avastin as a second line treatment for patients with disease progression following treatment with temodar. Avastin's approval was based off an improvement in progression free survival.

The inability of the standard of care to effectively treat the GBM patient population can be attributed to the effect of the presence of an enzyme called MGMT. Also known as the DNA repair enzyme, MGMT corrects any damage done to the genetic information of the cancer cells by the chemotherapeutic agent. This effectively renders the treatment useless. Roughly 50% of GBM tumors highly express this enzyme, leaving a large void in the standard of care for this large subgroup of patients. As a result, many novel immunotherapeutic developments have received large visibility from investors.

Drawbacks Of Investing In the Current Targeting Therapies in GBM

As it pertains to GBM, immunotherapeutic vaccines are thought to be the answer to the Temodar's MGMT resistance issue. In theory, when combined, the drugs should have a synergistic effect; however, it seems unlikely that the net effect will sustain if the chemotherapy is ineffective. A clear example of this is ImmunoCellular Therapeutics' comparison between the unmethylated and methylated MGMT subgroup of patients expressing the HLA-A2 antigen from their Phase II trial studying their dendritic vaccine, ICT-107. For those wondering, unmethylated refers to a higher expression of the MGMT enzyme and methylated the lower expression.

HLA-A2 Patients

PFS in Control Group

PFS in Active Group

Unmethylated MGMT

6 months

15.8 months

Methylated MGMT

8.5 months

24.1 months

The chart above highlights the difference between the two groups. There was a 2.5 month difference between the control groups and a 8.3 month difference between the treated groups. This huge discrepancy suggests that the vaccine is marginally helping deal with Temodar's resistance to MGMT. The underlying issue is still there. As a disclaimer, the subgroups mentioned were not powered to show statistical significance. For IMUC investors, this last statement is taken directly from their latest press release and should raise some red flags considering the company has rationalized moving forward with a Phase III trial. Especially since the Phase II trial mentioned above did not meet its primary endpoint of overall survival (OS).

Northwest Biotherapeutics should be approaching the conclusion of their Phase III study of GBM vaccine DC-Vax-L, with the primary endpoint being extended PFS in newly diagnosed patients. This seems strange since approval as a first-line treatment would usually demand improvement in OS which was the primary endpoint of IMUC's trial. At face value, it would seem the company is leading the pack in GBM, with its Phase III trial scheduled to conclude in September 2014, as per the clinical trial page; however, the controversy surrounding the company provokes uncertainty. NWBO has its fair share of skeptics challenging the drug's efficacy following the failure of IMUC's similar dendritic cell immunotherapy, ICT-107. Granted, there are differences between the two vaccines; however, they are both dependent on the presence of an effective chemotherapeutic agent. In my opinion, the necessary coupling with effective Temodar treatment will prevent the two vaccines from becoming a benchmark under the evolving standard. The company has also been scrutinized for its "inappropriate" reporting of data, which has proven disconcerting to investors to say the least.

Anecdotal evidence of the associated risk of investing in vaccine type cancer immunotherapies can be derived from the story of Dendreon's (NASDAQ:DNDN) Provenge. Behind the approval of Provenge, the first and only cancer vaccine (but not immunotherapy), the company's stock rose to an all-time high of $54. This was short-lived due to the competitive landscape that formed in the field of prostate cancer subsequent to Provenge's approval. Both Johnson & Johnson's (NYSE:JNJ) Zytiga and Medivation's (NASDAQ:MDVN) Xtandi offered better results at a cheaper cost making both more favorable to Provenge. Currently, Dendreon has a market cap of $350M and trades at $2.30/share. As it relates to GBM, the anecdote is meant to remind investors of companies such as NWBO that even if the drug is approved (in my opinion, not likely), a position in the marketplace is not guaranteed.

On an optimistic note, Agenus Inc. (NASDAQ:AGEN) announced encouraging final results from a Phase II study on its autologous cancer vaccine Prophage. The drug is being developed for patients with newly diagnosed Glioblastoma Multiforme. Like the other two GBM vaccines, the treatment is designed to be in combination with the current standard of care. Since the drug is being developed for newly diagnosed GBM patients, it will be implemented as a first-line treatment. This means that the company will have to register for a lengthy Phase III trial prior to FDA approval.

Next in line, after NWBO's DCVax-L, to gain regulatory approval is Celldex Therapeutics' Rindopepimut. The company is expecting to conclude its Phase III ACT IV trial of its GBM drug candidate Rindopepimut in November of 2016 as outlined in its clinical trial page. ACT IV is modelled after a successful ACT III Phase II trial that produced an OS of 21.8 months and 26% 3-year survival vs. the 15.1 months OS and 18% 3-year survival obtained from an independent control dataset. The drug is also involved in a Phase II trial assessing Rindopepimut as a second line treatment in combination with Avastin. The trial is set to conclude in June of 2015. Using the Avastin approval in 2004 as a baseline, the drug could get approval from a Phase II study and potentially be on the market as early as late 2015. Like DCVax-L, the drug is designed to be in combination with the standard of care. However, unlike DCVax-L, Rindopepimut is specifically targeted at patients expressing EGFRvIII, representing at most a 30% subgroup of all GBM tumors. With that being said, the targeted drug market for GBM will not see any change from Celldex's Rindopepimut until early 2016 following the conclusion of ACT IV. This means that when (or, more appropriately IF) immunotherapies finally penetrate the standard of care, they won't apply to the majority 70% of patients.

From an investor's perspective, prospects on the immunotherapeutic front, in particular cancer vaccines, seem volatile given their uncertainty and the possibility of inadequacy. This is not to write off all immunotherapies, treatments under this umbrella have shown promise. In particular, checkpoint inhibitors have and continue to impress.

On the contrary, enhancing the current treatment paradigm or future combinational treatments through exploring the benefit of other known chemotherapeutic agents presents a more compelling investment opportunity with an asymmetrical risk/reward. Companies such as the one I am about to discuss have been overshadowed due to the hype surrounding immunotherapies.

VAL-083: The Answer To Temodar's Resistance?

As an investment opportunity, DelMar's chemotherapeutic drug VAL-083 has flown under the radar due to the hype of higher profile immunotherapies.

VAL-083 is an alkylating agent similar to its present market counterpart Temodar. The drug works by binding to DNA and interfering with the normal processes within the cancer cell. The cell is rendered dysfunctional and dies from improper protein production. Unlike Temodar, VAL-083 has demonstrated functionality in the presence of the enzyme MGMT. This is ultimately because Temodar damages with DNA at the O-6 guanine position and VAL-083 targets at the N-7 guanine position. This inherent attribute could threaten Temodar's reign in GBM. This short video better elaborates on the science.

What makes the company a particularly attractive investment is the approach it is taking to gain approval. The drug is being tested as a possible treatment for patients who have failed both first and second line therapy. The company would like to establish the drug as a "third line" treatment which, according to their 10-K, roughly represents 50% of all patients under the current standard of care, amounting to a $250M market in GBM alone (Refer to Valuation Section). Using Avastin's FDA approval as a comparative metric, the drug would likely have to show a good safety profile and demonstrate progression free survival.

To Reiterate: The company is seeking to treat a patient population with no current treatments available or likely to be available in the foreseeable future. This population is roughly half of all GBM patients.

Also streamlining its approval process and de-risking shareholder value is the data the company brings from over 40 clinical trials sponsored by the National Cancer Institute, NCI. The company is looking to approve a drug that has been tested on over 1000 patients and presents a safety profile that is well tolerated. To further solidify its case, the company can leverage the drug's international approval in China for CML and NSCLC.

An important fact about VAL-083 is that it is a drug that has been studied since the 70s under the name DAG (Dianhydrogalactitol). So why were developments dropped then and renewed now? According to the company's 10-K, this was ironically due to the attention targeted therapies were receiving which is consistent with the history of immunotherapies. The resurgence of the drug is fueled by a better understanding of cancer mechanisms and, as CEO Jeffrey Bacha explains, the increased availability for screening patients that are more prone to response from the drug.

VAL-083 is currently being studied in a Phase I/II, open label, single-arm study to determine the safety and maximal tolerated dose (NYSE:MTD) of VAL-083. Highlights of their clinical trial interim data from their presentation at ASCO include:

1) One of two patients in cohort 6 exhibited stable disease after one cycle of treatment. Outcome of analysis of cohorts 6 and 7 are ongoing.

2) No drug related serious adverse events have been detected, and maximum tolerated dose has not been reached at doses up to 30mg/m^2. Enrolment and evaluation of cohort 7 (40mg/m^2) is ongoing.

3) Pharmacokinetics are linear and consistent with previous published data, suggesting that concentrations of VAL-083 being obtained are effective against glioma cell lines in vitro.

If the MTD is not determined following treatment of the 7th cohort, DelMar will likely request regulatory approval for studying the drug in doses larger than 40mg/m^2. This will likely delay, with good reason, the readout of final data. Following the conclusion of the trial, DelMar will likely obtain guidance from the FDA before proceeding with a final Phase II/III trial. Assuming the trial can produce positive data, the drug would be in a position to penetrate the US GBM market in 2017.

DelMar's Valuation Reveals An Upside of 300% to $3.45/Share

Below is a table of assumptions that I used in my valuation. Most important among these is that sales are solely contingent on VAL-083 use in refractory GBM. This analysis neglected the future cashflows from possible label expansion into first and second line therapy, as this may be looking too far ahead for the cautious investor. Inclusion of this would cause the company's valuation to further increase. With 16,000 newly diagnosed patients in GBM every year, this represents $800M market opportunity under the same assumptions mentioned below.

Table 1. Valuation Assumptions

The company obtains FDA approval and begins marketing the drug as a "third line" treatment in 2017.

The 10,000 patients that die annually from GBM are the targeted patient population. For conservatism, I assumed that only 50% of this population can afford the treatment either through insurance coverage or otherwise.

The cost of one round of treatment is $50,000. The total addressable market is therefore $250M. Sales experience a 30% growth rate in the 7 years (2017-2024) of market exclusivity following approval.

Sales are discounted backwards at a rate of 15% and additionally a 60% margin of safety is applied to net present value.

All Outstanding warrants are exercised.

 

Options

3,240,000

Estimated Out Shares following exercise of warrants

41,360,245

Fully Diluted Shares

44,600,245

Source: Prospectus as of April 29, 2014

Below is a Sensitivity Table, illustrating the change in market valuation as a function of the market penetration.

Mkt Penetration(%)

5

10

15

20

25

Mkt Cap ($)

51.4

102.8

154.1

205

257

**Market Cap is in millions.

Assuming a 15% market penetration, the company should be valued at $154.1M. This reveals an approximate 300% upside from the current price of a share to $3.45.

In my opinion, this valuation represents a significant upside given its conservatism.

Understanding The Risks Associated With DelMar

The main risk associated with the company's success is its ability finance its operations for the foreseeable future. The company most recently raised $2.4 million in net proceed upon the closing of a lead order, which management believes will fund operations till December 2015. The company has also filed a tender offer on June 9, 2014 to outstanding warrant holders, decreasing the exercise price from $0.80 to $0.65. Potential exercise of these warrants could bring in a total of $6M and fund the registration trial of VAL-083. This financing is not truly dilutive, as all current warrants were introduced from previous rounds of financing. There still remains the risk that the company may need to raise funds via purely dilutive financing.

The second major risk is that company's success is solely contingent on the approval and commercialization of VAL-083. Although the company has approval in China for CML and Lung Cancer, it requires the approval of the FDA, which may be more stringent than other regulatory bodies. There are no other drugs in the company's pipeline, although the company has presented pre-clinical data of VAL-083 in treatment of non-small-cell-lung-cancer (NSCLC). This means that the drug's failure in GBM does not imply the end of VAL-083 in all cancer indications.

The third major risk is competition. The immunotherapy companies mentioned above can all be considered competition. With that being said, DelMar does have one major advantage that would allow them to gain approval on a much shorter time scale. DelMar is trying to treat patients who have failed the current standard of care making them a "third line" treatment. This is in contrast to the companies mentioned above who are either going for first or second line treatment, and likely to be scrutinized more heavily prior to regulatory approval. On the chemotherapeutic front, the company also has a competitor in CyTRX Corporation. Just like its counterparts in immunotherapy, the company will likely face a relatively long road to approval as it begins its Phase II trial determining efficacy and safety in patients who have failed first line treatment with Temodar.

Near Term De-Risking Catalysts and Concluding Remarks

The company performance should see upside from approaching catalysts, most notably from the conclusion of its current clinical trial, meetings with regulatory authorities and registration of its Phase II/III trial, among others. For a more extensive list of catalysts, refer to this. Each of these milestones will likely serve as de-risking events in the company's maturation and drug's approval process.

As a concluding remark, I would like to remind investors of the benefits that prospective combinational treatments bring. The use of multiple drugs not only improves results for patients, but also creates multiple investment opportunities within the same indication. This creates an interesting dichotomy between therapies, such as chemotherapy and immunotherapy, where the two are symbiotic competitors. This decouples the risk for agents that are more integral to the overall efficacy, such as Temodar, under the current treatments and hopefully VAL-083 in future treatments.

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por cyto às 03:36

Sábado, 22.11.14

Clinical and Pharmacokinetic Study of Humanized Anti-CD47 Antibody as Single Agent

A service of the U.S. National Institutes of Health

Phase I, Multicenter, Open-label, Dose-escalating, Clinical and Pharmacokinetic Study of Humanized Anti-CD47 Antibody as Single Agent in Patients With Advanced or Metastatic Solid Tumors

This study has been withdrawn prior to enrollment.

(Lack of funding)

Sponsor:

Ukrainian Antitumor Center

Collaborator:

Anticancer Research Foundation

Information provided by (Responsible Party):

Ukrainian Antitumor Center

ClinicalTrials.gov Identifier:

NCT02096770

First received: March 22, 2014

Last updated: May 30, 2014

Last verified: May 2014

 

  Purpose

Phase I, Multicenter, Open-label, Dose-escalating, Clinical and Pharmacokinetic Study of Treatment with Chimeric Humanized anti-CD47 antibody as Single Agent in Patients With Advanced or Metastatic Solid Tumors

Condition

Intervention

Advanced or Metastatic Solid Tumors

Biological: Experimental Humanized Anti-CD47 Monoclonal Antibody

 

   

Study Type:

Interventional

Official Title:

Phase I, Multicenter, Open-label, Dose-escalating, Clinical and Pharmacokinetic Study of Humanized Anti-CD47 Antibody as Single Agent in Patients With Advanced or Metastatic Solid Tumors

 

Resource links provided by NLM:

 

MedlinePlus related topics: Cancer

U.S. FDA Resources

 

Further study details as provided by Ukrainian Antitumor Center:

 

Primary Outcome Measures:

  • To evaluate the safety and tolerability of anti-CD47 antibody [ Time Frame: up to approximately 1 years ] [ Designated as safety issue: Yes ]
    • Safety profile of anti-CD47 antibody in subjects with solid tumors Subjects will be assessed for DLTs from Days 0-29. Adverse events will be reported through 30 days after the last dose
    • Safety will be evaluated by physical examinations, vital signs, laboratory assessments, ECOG PS scale, and the incidence and severity of adverse events. 
    • Secondary Outcome Measures:
    • ( Time Frame: ECOG-PS, AE's, physical examinations, vital signs, laboratory assessments will be assessed weekly)
    • Pharmacokinetics (PK) [ Time Frame: PK analyses at various time points following the 1st and 2nd doses, immediately pre and post-dose for all subsequent doses at treatment term, every 4 weeks after discontinuation of study drug or 12 weeks ] [ Designated as safety issue: Yes ]
      • Apparent half life, AUC, clearance, volume of distribution
      • For PK profile, blood samples will be collected at various time points (Time Frame: PK blood samples will be taken immediately pre-infusion then at 1, 2, 3, 4, 6, 10, 21 and 24 hours after start of infusion on Day 1 )
    • Pharmacokinetics (PK) of anti-CD47 antibody in subjects with solid tumors ( relapsed or refractory also)
    • Immunogenicity [ Time Frame: Assessed at baseline, prior to each dose, at treatment termination and every 4 weeks after the discontinuation of the study drug for 12 weeks. ] [ Designated as safety issue: Yes ] Other Outcome Measures:
       
    • Immunogenicity of anti-CD47 antibody in subjects with solid tumors (relapsed or refractory also)
  • Response Evaluation Criteria in Solid Tumors (RECIST v1.1) [ Time Frame: up to approximately 1 years ] [ Designated as safety issue: Yes ]
    • Time to Response (TTR)
    • The time interval from the date of first dose to the first documented response (complete or partial response)
    • Time to New Metastases
    • Time interval from date of first dose to first documented new metastatic lesion not reported at baseline
    • Time interval from date of first does to first documented disease progression or death from any cause (whichever occurs first) 
    •  
  • Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
   

Enrollment:

0

Study Start Date:

March 2014

Estimated Study Completion Date:

April 2014

Estimated Primary Completion Date:

March 2014 (Final data collection date for primary outcome measure)

 

Arms

Assigned Interventions

Experimental: Humanized Anti-CD47 Monoclonal Antibody

Drug:

Anti-CD47 Monoclonal Antibody monotherapy 10 mg/kg intravenously over 30-90 minutes repeats every 21 days in the absence of disease progression or unacceptable toxicity. Patients achieving response may continue treatment.

Biological: Experimental Humanized Anti-CD47 Monoclonal Antibody

Detailed Description:

This is a Phase 1 clinical study to investigate the safety, pharmacokinetics, and pharmacodynamics of anti-CD47 antibody, a fully human and humanized monoclonal antibody targeting the , in patients with advanced solid tumors. Eligible patients will have disease that is refractory or resistant to standard treatments or for which no standard therapy exists. The hypothesis for this study is that anti-CD47 antibody will be safe and well tolerated in patients with advanced solid tumors and will show initial evidence of anti-tumor activity through strengthening of apoptosis induction with activation of CD8+ T cells when macrophages covered cancer cells in the presence of CD47-blocking antibodies enables macrophage phagocytosis of cancer initiate an antitumor cytotoxic T-cell immune response and apoptosis-inducing activity and will not lead to autoimmune attack healthy tissue and organs

  Eligibility

   

Ages Eligible for Study:  

18 Years to 80 Years

Genders Eligible for Study:  

Both

Accepts Healthy Volunteers:  

No

Criteria

Inclusion Criteria:

  • Diagnosis of an advanced solid tumor malignancy or lymphoma (non-Hodgkin's or Hodgkin's lymphoma).
  • Histological or cytological evidence of malignancy.
  • Advanced malignancy, metastatic or unresectable, that has recurred or progressed following standard therapy or failed standard therapy; or for which no standard therapy currently exists, or for which subject is not a candidate for, or is unwilling to undergo, standard therapy.
  • Disease that is currently not amenable to curative surgical intervention.
  • ECOG performance status of 0-1. Subjects with performance status of 2 will be considered only after discussion between the investigator and medical monitor.
  • 18 years or older, of either sex, and of any race.
  • Subject (and/or parent/guardian for subject who otherwise is unable to provide independent consent, if acceptable to and approved by the site and/or site's IRB) must be willing to give written informed consent and be able to adhere to dose and visit schedules.
  • Female subjects of childbearing potential must have negative pregnancy test within 5 days prior to first dose of study drug.
  • Female subjects of childbearing potential and male subjects whose sexual partners are of childbearing potential must agree to abstain from sexual intercourse or to use an effective method of contraception during the study and for 60 days after the last dose of AV-299 (formerly SCH 900105). Examples of effective methods of contraception include, but are not limited to, oral contraceptives or double barrier methods such as condom plus spermicide or condom plus diaphragm.
  • Adequate hematologic function as evidenced by Hg ≥ 9g/dL, WBC ≥ 3000 per mm3, ANC ≥ 1500 per mm3 and platelet count ≥ 100,000 per mm3.
  • Adequate hepatic function as evidenced by a serum bilirubin level ≤1.5 × ULN (except with known Gilbert's Syndrome) and
  • Exclusion Criteria:
  • Women who are breast-feeding, pregnant, or intend to become pregnant.
  • Hematologic malignancies other than lymphoma
  • Any of the following within 6 months prior to administration of study drug:
  • Myocardial infarction (MI), severe /unstable angina pectoris, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack or seizure disorder.
  • Serious and/or symptomatic active infection within 14 days prior to first dose of study drug.
  • Subjects who have asymptomatic or mild infection and taking a short course of antibiotics (ie, UTI, bronchitis) may be allowed after discussion with the medical monitor.
  • Baseline QTc interval as follows per Bazett's formula: Females > 470 msec; Males > 450 msec.
  • Persistent, unresolved CTCAE v3.0 Grade 2 or higher drug-related toxicity (except alopecia, erectile dysfunction, hot flashes, and decreased libido) associated with previous treatment.
  • Inadequate recovery from any prior surgical procedure or major surgical procedure performed within 4 weeks prior to administration of first dose or major surgery within 3 weeks prior to first dose of study drug.
  • Any other medical or psychiatric condition that, in the opinion of the investigator, might interfere with the subject's participation in the trial or interfere with the interpretation of trial results.
  • Known Human Immunodeficiency Virus (HIV) infection or a known HIV-related malignancy.
  • Known active hepatitis B or C.
  • Radiotherapy within 3 weeks prior to first study drug administration.
  • Inability to comply with the protocol requirements or participation in any other clinical study.
  • Any medications listed in the table on "Prohibited Medications".
  • Active alcohol abuse.Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies. Please refer to this study by its ClinicalTrials.gov identifier: NCT02096770
  • Locations
  •   Contacts and Locations
   

Ukraine

Cancer Center

 

Dnepropetrovsk, Ukraine, 49000

Sponsors and Collaborators

Ukrainian Antitumor Center

Anticancer Research Foundation

Investigators

       

Principal Investigator:

Igor Prihoda

Cancer Centre

 

  More Information

No publications provided

   

Responsible Party:

Ukrainian Antitumor Center

ClinicalTrials.gov Identifier:

NCT02096770     History of Changes

Other Study ID Numbers:

HMA-388-58, A302388-2014

Study First Received:

March 22, 2014

Last Updated:

May 30, 2014

Health Authority:

Ukraine: Ethics Committee

Additional relevant MeSH terms:

   

Neoplasms Antibodies Antibodies, Monoclonal Immunoglobulins

Immunologic Factors Pharmacologic Actions Physiological Effects of Drugs

ClinicalTrials.gov processed this record on November 20, 2014

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por cyto às 17:51

Sábado, 22.11.14

The anti-CD47 cancer therapy clinical trials. STANFORD

The anti-CD47 cancer therapy clinical trials. STANFORD

The clinical trials of the anti-CD47 antibody are underway.

As with most FDA phase-1 safety trials, the clinical trial is small and is not currently recruiting additional patients. As the trial progresses, information about the patients in the trial and the data about how the antibody is performing are kept confidential. In accordance with the clinical trial protocol and the policy of the Stanford School of Medicine, we won’t be releasing information about the progress of the trial until the data is release by the clinical trials team at the conclusion of the study. Phase-1 clinical trials typically last about 18 months, although this particular trial may be shorter or longer than that.

If and when the clinical trial has openings for additional participants, an announcement will be made on this page. In the meantime, patients can search for currently open trials in the United States through the NIH Clinical Trials Database

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por cyto às 17:50

Sábado, 22.11.14

Power Behind “Master” Cancer Gene

 

 

MD Anderson Researchers Discover Power Behind “Master” Cancer Gene

 

shutterstock_134840537A novel study on the regulation of Myc entitled “CSN6 drives carcinogenesis by positively regulating ​Myc stability” was published in Nature Communications by Jian Chen, part of Dr. Mong-Hong Lee’s group in the Department of Molecular and Cellular Oncology at The University of Texas MD Anderson Cancer Center.

In this study, the authors showed that Myc is a target of the COP9 signalosome (CSN) subunit 6 (​CSN6)-Cullin signaling axis, and that ​CSN6 is a positive regulator of ​Myc. ​ Myc is a proto-oncogene, or master cancer gene, that stimulates tumor growth in a series of cancers including breast, lung, colon, brain, skin, leukemia, prostate, pancreas, stomach and bladder. Myc suffers ubiquitination, a process were ubiquitin molecules are attached to a protein either to lead to their degradation, alter their cellular location, or affect their activity, and promote or prevent protein interactions by Cullin-RING ubiquitin ligases (CRLs)​. The COP9 signalosome (CSN) controls neddylation, a process similar to ubiquitination, of Cullin in CRL. However, the mechanistic link between Cullin neddylation and Myc ubiquitination/degradation is not well understood. They found that overexpression of CSN6 led to aberrant expression of genes ​targeted by Myc and is a common feature observed in human cancers. Altogether, these results provide new insights into the overexpression of CSN6 and ​Myc stabilization/activation during tumorigenesis.

“We have discovered that CSN6 is a strong oncogene that is frequently overexpressed and significantly speeds up tumor growth in many types of cancer,” said Dr. Lee, in a press release. “Furthermore, CSN6 also affects the expression of Myc in tumors.”

Dr. Lee said that their findings are crucial since targeting Myc is a very difficult task due to its unique protein structure.  Although it has been studied for decades, no effective inhibitor for Myc has been successfully developed. Notably, the research team found that the inhibition of CSN6 rapidly destabilized Myc inhibiting significantly metastasis and tumor growth.

“This has the potential to unlock a promising and completely new door to effectively eliminating tumors and suppressing cancers that overexpress Myc,” concluded Dr. Lee.

This study was funded by the National Institutes of Health, the Fidelity Foundation and the Susan G. Komen Breast Cancer Foundation.

Autoria e outros dados (tags, etc)

por cyto às 17:29

Sábado, 22.11.14

Role of Telomeres in Gene Activity

UT Southwestern Scientists Make Major Discovery on the Role of Telomeres in Gene Activity

 

In a recent study entitled “Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions” the authors found that the length of telomeres is capable of silencing genes and activating them in different periods of a cell lifetime, and therefore are able to contribute to aging and disease. The study was published in the Genes and Development journal.

Telomeres are specific sequences at the end of the cells’ chromosomes that prevent them from damage and/or from fusion with neighboring chromosomes. Every time a cell divides, telomeres become shorter — a phenomena that was previously reported to be involved in human disease and mortality. While shorter telomeres were associated with aging and diseases, longer telomeres are linked to healthy aging and longevity. However, telomeres’ shortening was also related to activation or repression of genes.

Now, a team of researchers at UT Southwestern Medical Center showed that before telomeres are decreased to a length that compromises the cells, the small decreases can have an impact on the regulation of genes. Specifically, they showed a dynamic regulation of gene expression upon telomere length — a key and novel finding of their study, since a longer telomere can form a loop at the end of the chromosome and putting in contact with the telomere genes, thus enabling telomeres to regulate their expression. On the contrary, shorter telomeres prevent loop formation and as a result no interaction with other genes.

Dr. Jerry W. Shay, Professor and Vice Chairman of Cell Biology at UT Southwestern and one of the senior authors commented, “Our results suggest a potential novel mechanism for how the length of telomeres may silence genes early in life and then contribute to their activation later in life when telomeres are progressively shortened. This is a new way of gene regulation that is controlled by telomere length.”

Dr. Woodring E. Wright, Professor of Cell Biology and Internal Medicine, the other senior author added, “We have developed the concept that telomere shortening could be used as a timing mechanism to respond to physiological changes in very long-lived organisms, such as humans, to optimize fitness in an age-appropriate fashion.”

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por cyto às 17:25

Sábado, 22.11.14

Metabolic Reprogramming Leads To Tumor Regression

MD Anderson Researchers Find Metabolic Reprogramming Leads To Tumor Regression

Posted by: Daniela Semedo, PhD November 19, 2014 66 Views

In a study published this week in Nature entitled “IAPP-driven metabolic reprogramming induces regression of p53-deficient tumors in vivo,” a team of researchers led by Dr. Elsa Flores, associate professor of molecular and cellular oncology at MD Anderson Cancer Center, showed that the gene IAPP could potentially be used as therapeutics for tumors deficient in p53.

The p53 is a transcription factor with a key role in the maintenance of genetic stability, therefore preventing cancer formation. Studies have found p53 reactivation in mice to be tumor suppressive. However, this preposition has been difficult to apply for therapeutic purposes. This transcription factor belongs to a family of genes composed of p53, p63, and p73, with researchers hypothesizing that by manipulating two of the p53 family genes, p63 and p73 (isoforms lacking acid transactivation domain), they could find an alternative therapeutic-oriented strategy.

Results from this study revealed that deletion of p63 and p73 metabolic reprogrammed and regressed p53-deficient tumors through upregulation of IAPP (an amylin encoding gene related to the use of insulin).

Moreover, results indicated that IAPP is involved in tumor regression, since amylin functions through the calcitonin receptor (CalcR) and receptor activity modifying protein 3 (RAMP3) to inhibit glycolysis and induce reactive oxygen species and apoptosis. With regard to the findings, Dr. Flores stated in an MD Anderson news release “We found that IAPP is involved in tumor regression and that amylin, the protein encoded by the IAPP gene, stops a cell’s ability to metabolize glucose, leading to programmed cell death.”

Therapeutics for type 1 and type 2 diabetes includes a medication called Pramlintide (composed by a synthetic analogue of amylin) that in this study was found to regress tumors in p53-deficient thymic lymphomas, representing a novel approach to target p53-deficient cancers.

Concerning the results, Dr. Flores explained that “The p53 family interacts extensively in cellular processes that promote tumour suppression. Thus, a clear understanding of this interplay in cancer is needed to treat tumors with p53 alterations.”

This study was multi-funded by the National Cancer Institute, the Cancer Prevention and Research Institute of Texas, the Hildegardo E. and Olga M. Flores Foundation, Mr. and Mrs. Melvyn N. Klein, the Leukemia and Lymphoma Society, the Rita Allen Foundation and The V Foundation for Cancer Research.

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por cyto às 17:24

Sábado, 22.11.14

Northwest Bio: The Status Of The DCVax-L Trial

Northwest Bio: The Status Of The DCVax-L Trial

Aug. 13, 2014 6:17 PM

Summary

  • Chairman of DMC says that there has not yet been an interim analysis performed for efficacy in the phase 3 trial of DCVax-L.
  • He says that NWBO is totally blinded to the data and has no idea of how results are trending.
  • This is a serious blow to the bear thesis that maintains that the interim analysis had been performed, the results were bad and that NWBO hid the results from investors.

What a Data Monitoring Committee Does

With each clinical trial, an independent committee is formed to monitor the conduct and progression of the trial and to determine if there are any safety or efficacy issues that might necessitate stopping the trial. Members are distinguished physicians, statisticians, academics and other health care personnel knowledgeable about conducting and monitoring clinical trials. The members are not employed by companies and are not compensated by companies. This important group is called the Data Monitoring Committee (DMC).

During the conduct of a clinical trial, the Company and all other people with the exception of the DMC members are blinded to the data. If the blinding were to be broken, it would be perceived by regulatory agencies as compromising the integrity of the trial. If this were to happen, the study could not be used to file for regulatory approval. Regulatory agencies are fanatical about making sure that all people except for the DMB members are completely blinded to results.

Most trial protocols prospectively define points in the trial at which an interim analysis is done to determine safety and efficacy results. The trial can be stopped at any time if a safety reason arises, but the efficacy analysis is only done at pre-determined interim looks. The DMC at an interim look reviews the clinical data and usually makes one of four recommendations: (1) the trial should be halted because the primary endpoint of the trial has been reached; this would lead to filing for registration, (2) the data suggests that the primary outcome of the trial cannot be reached and that it would be futile to continue; the trial should be stopped, (3) because of safety issues the trial should be halted immediately, and (4) there are no issues with safety and efficacy; the trial should continue. I would note that point 4 being reached does not mean that the trial will be successful.

It is usually the case with interim looks of clinical trials that the DMC says that there are no safety or efficacy issues and that the trial should continue. Under no possible circumstances would there be any release of clinical results from the trial and under no circumstance would there be any hint given on how the data is trending. As was just noted, the release of such information would immediately compromise and ruin the trial.

The DMC is the only entity that has an insight into what is going on in a clinical trial. Their grave responsibility for making sure the trial is being safely conducted and their independence means that they are the only credible source of information on what is going on in a clinical trial.

Recent Investor Confusion

There has been a lot of speculation on what is going on with the DCVax-L trial on blogs by people holding a bearish view on the stock. Based on comments from the chairman of the DMC, key elements of their bear arguments appear to be factually incorrect. They essentially maintain that an interim look at the phase 3 trial was performed and that the interim analysis showed that DCVax-L was performing badly and they concluded that the trial was doomed to fail. They further suggested that NWBO management had seen the efficacy results and knowing that they were disappointing had changed the design of the clinical trial. I would refer you to article one and article two which express this viewpoint.

The Chairman of the DMC Speaks on the Phase 3 Trial of DCVax-L.

Some of the key conclusions reached in the above cited blogs are incorrect in the opinion of the DMC. Apparently, the comments by these authors came to the attention of the Chairman of the DMC. In a recent press release by Northwest Biotherapeutics (NASDAQ:NWBO), he explained why these authors were wrong in maintaining that an efficacy analysis had been done and that NWBO knew the results were bad. It is highly unusual for a chairman of the DMC to make a public statement, but in this case he felt compelled. Here is what he said.

"As the Company has stated clearly and specifically in its public announcements, the DMC has not conducted any efficacy analyses and the DMC has not provided any access for the Company to any clinical trial data. The DMC adheres to established clinical trial monitoring procedures and does not release any data while the trial is ongoing. This is an important issue, and it is surprising and troubling to see inaccurate claims being made by commentators who seem to lack a fundamental understanding of clinical trial monitoring. I have been on the DMCs for more than 60 clinical trials, and I have never experienced this type of attack."

There are a significant number of bears on NWBO. One of their key arguments is that the interim analysis on efficacy was performed and they question why efficacy results have not been released. They maintain that NWBO somehow buried the data. These issues are directly addressed and rebutted by the comments of the chairman of the DMC. Just to summarize, there has been no efficacy analysis performed in the trial. Also, NWBO has no knowledge of the trending of results in the trial.

Why the Confusion

Part of the confusion was caused inadvertently by the Company. The original protocol of the trial called for it to be halted and data analyzed after 110 events; i.e., 110 patients in the trial with glioblastoma multiforme either died or saw their disease progress. The first interim look for safety and efficacy was scheduled when 60% of these 110 events or 66 had occurred. In March of this year, the Company announced that it was about to reach the number of events needed to conduct the first interim look for safety and efficacy. Hence, investors were awaiting the results of this interim look.

At about this time, the Company made another decision to slightly change (they called it enhancements) the protocol of the trial. These enhancements were to allow for a statistical adjustment on dealing with the risk factor of white blood cell levels at the time that the final statistical analysis is done. I won't go into a lot of detail, but this type of analysis was previously specified in the statistical analysis plan for other risk factors in the trial including age, degree of surgical resection and performance status. Hence, the risk factor of white blood cell count was added to the list.

The size of the trial was increased from 312 patients to 348. Also, the number of events needed to halt the trial was placed at 248 up from 110. I am not a statistician and I cannot explain the statistical reason for these changes. All I can say is that the UK, US and German regulators reviewed and approved the changes. I think we can assume that the basis for these changes are statistically and clinically sound based on the approval by the regulators.

The complication and confusion about the interim look arose from the Company seeking approval for these enhancements. Remember that I previously said that regulators are fanatical about making sure that the trial is totally blinded. It was possible that the regulators could perceive that performing the interim look at 66 events had the potential to convey information about efficacy results in the trial and therefore would have potentially unblinded the trial. This might have prevented their acceptance of the enhancements to the trial design.

Because of this and as verified by the Chairman of the DMC, performing an interim efficacy look at 66 events had the potential to compromise the blinding of the new enhanced trial design. Therefore, they did not perform an interim analysis for efficacy. The first interim analysis on efficacy will now be performed at 60% of 248 events or 149 events. The DMC has not issued any information on whether the trial is close to 149 events.

The Company was in a difficult position. They could not anticipate that the enhancements to the trial would be approved and had to wait for the regulators decision. They felt that they could not directly address the issue of whether the interim efficacy analysis had been conducted until the enhancements to the trial had been approved. This left them open to the bear arguments that I previously discussed.

Investment Opinion

I can partially understand the criticism of the bears that the interim safety and efficacy data had been indicated as being imminent and never materialized. However, the extensions of their arguments that maintained that NWBO had seen the data, that the data was bad and that they were hiding the data from the public were clearly wrong from the beginning.

None of this information has much of an effect on my investment thinking on the fundamentals of NWBO. I view the potential development of DCVax-L as high risk which is the case for most paradigm changing technologies. However, there is evidence of efficacy in phase 1/2 trials and compassionate use studies of DCVax-L. There form the basis to hope for success and if confirmed in the current phase 3 trial DCVax-L could be a significant advance in the treatment of glioblastoma. However, I must emphasize that there is also a risk of failure.

The importance of this article is not what it does to my investment view as it really hasn't altered my thinking in a meaningful way. Please refer to several prior articles on Seeking Alpha for a detailed discussion of my investment thinking. However, by negating a meaningful component of the bear case, it could improve the psychology surrounding the stock and potentially its performance.

Source: Northwest Bio: The Data Monitoring Committee Addresses The Status Of The DCVax-L Trial

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por cyto às 14:57

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