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



Quarta-feira, 11.06.14

CANCER GENOMICS ELAINE MARDIS

Elaine Mardis on cancer genomics: from technological advances to clinical barriers

Posted by Biome on 23rd April 2014

The clinical impact of next-generation sequencing technology can be most keenly felt in the field of cancer. Cancer genomics continues to open up new avenues for the diagnosis and treatment of this heterogeneous disease, however there are still significant hurdles to overcome before the full potential of these new tools can be realised. In an Opinion article in Genome Medicine, Elaine Mardis from the Washington University School of Medicine, USA, discusses future applications of these tools to cancer care, as well as current barriers to clinical translation. Mardis is also a Guest Editor for the Genome Biology special issue on the genomics of cancer progression and heterogeneity. We asked Mardis what technologies she thinks hold the most promise for cancer treatment, and how advances in cancer genomics can be more readily translated to the clinic.

 

What do you think have been the most important developments in next-generation sequencing in the last five years that have contributed to a better understanding of cancer genomics?

Certainly improving kits, protocols and micro fluidic devices that help to embrace the challenging but incredibly informative aspects of clinical samples, such as limited numbers of cells, formalin fixation, and so on. Also the computational analysis breadth developed over that time frame has been remarkable and enabling.

 

What are the main hurdles to translating advances in next-generation sequencing technology to the clinic?

The challenges are numerous. Here are a few:

Firstly academic cancer centers have to commit to generating data to support the clinical benefit of these tests to patients, namely to address another challenge. Health payers have to understand why these tests and therapies help their clients so they will pay for the tests.

Coincident with these two challenges being addressed, we have got to produce data to support the argument for clinical benefit and we have to report it and share it with each other in an efficient way that largely obviates the conventional publication of results.

Lastly, pharmaceutical companies and the US Food and Drug Administration need to change the way they conduct clinical trials and approve drugs so more cancer patients benefit more rapidly, and hopefully at lower cost.

 

Whole-genome sequencing has been presented as a means to identify all of the genetic aberrations that contribute to cancer. Do you think this is the best way forward or are more targeted approaches needed?

The combination of whole genome sequencing and RNA sequencing is the best way forward at present. We have sacrificed a lot of discovery by doing large discovery projects by exome sequencing for the sake of doing it cheaply.

 

What will be needed to improve early detection of cancer using genomic and sequencing technologies?

Ideally the exciting work now happening in circulating tumor cell and nucleic acid sequencing will be applied to early detection and ultimately to prevention.

 

What will be needed to accelerate the application of cancer genomic diagnostics in primary clinical settings?

This will happen when these facilities have access to outsourced services that provide the sequencing, analysis and interpretation.

 

What new technologies across the field of cancer genomics do think hold the most promise to improve cancer treatment?

I think the most promising future therapies in cancer are happening now in the individualized immunotherapy realm. Basically, this involves a study of the most immunogenic mutant peptides in each patient’s tumor. We identify the mutations by genomic approaches, investigating only those mutations that are expressed in the RNA, and algorithmically predicting which ones are most likely to interact in a ‘non-self’ way with the patient’s HLA class I proteins. By using genomic data to identify candidate immunoantigens (also called neoepitopes), we can design personalized vaccines for patients. This is ongoing at our institution in a FDA-approved trial of melanoma patients, where several already have received their own conditioned dendritic cells as a vaccine. There are other groups also using this information to design vaccines of different types, at other institutions. I think this area holds great promise and uses our genomics capabilities in an entirely new and exciting way.

 

What role does open access and open data have to play in facilitating the progression of cancer genomics applied in clinical trials/case studies to standard clinical practice?

There’s a hugely important role played by rapid access to data around genes, mutations or other aberrations, and each patient’s response to therapy. The faster and more facile the sharing of these and other informative functional data, the faster we build the case for clinical benefit. This includes clinical trials data, acquired resistance mechanisms data and so-called ‘n of one’ results from individual patients.

 

When it comes to data sharing, what challenges do cancer researchers face in terms of the ethical implications of this?

Frankly, there are few if any ethical challenges. If we share somatic alterations only, they are unique to the tumor and not identifiable by definition. It is rare to find a cancer patient who wouldn’t want their data to contribute toward improving the disease outcome for other patients. These people are my heroes. 

Elaine Mardis is a Professor in the Department of Genetics at the Washington University School of Medicine, USA, and it also Director of Technology Development at the Genome Institute of Washington University, USA. She obtained her PhD in chemistry and biochemistry from the University of Oklahoma, USA, and went on to become a senior research scientist at Bio-Rad Laboratories, USA. Her current research interests focus on applying DNA sequencing to the characterisation of cancer genomes, and facilitating the clinical translation of basic science discoveries into human disease. Mardis is also chair of the Basic and Translational Sciences Committee for the American College of Surgeons Oncology Group, and serves on the scientific advisory boards of Pacific Biosciences, Inc. and Edge Biosciences, Inc

 

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por cyto às 19:12

Quarta-feira, 11.06.14

DCVAX clinical trial phase III Germany

DCVAX®-L PHASE III TRIAL INITIATED IN GERMANY

Tue June 10, 2014 8:15 AM|PR Newswire  | About: NWBO

   

BETHESDA, Md., June 10, 2014 /PRNewswire/ -- Northwest Biotherapeutics (NWBO) (NW Bio), a biotechnology company developing DCVax® personalized immune therapies for solid tumor cancers, announced today that it has initiated the Phase III trial of DCVax-L in Germany.  The first site to open in Germany was a medical center in Dresden, which was initiated in late May.  The Company has now scheduled the full-day site initiations for 3 more sites during June and 4 further sites in July.  

To date, the trial has been enrolling in parallel in the US and Europe (in the UK), as previously announced.  The first German site is now starting to screen patients for purposes of enrollment, and the additional German sites will begin doing so following their scheduled initiations (patients can obtain information about trial sites by contacting the Company at  patients@nwbio.com ).

The process of initiating a clinical trial site (i.e., completing the steps required to enable a site to participate in, and to open enrollment for, a clinical trial) typically takes about 6 months for each site in the US.  In Germany, there are several further steps involved beyond those in the US.  The process can be conducted at multiple clinical trial sites (i.e., medical centers) in parallel, but the steps at each individual site must be done sequentially.

In the US, the steps required to initiate a site include the following. 

  • The first step is the "site      qualification," in which both paperwork and onsite evaluations are      done (of personnel, facilities, past clinical trial experience of both the      institution and the personnel, etc.) to determine the capabilities of the medical      center to serve as a site in the clinical trial.  This step can take      a month to arrange and complete. 
  • The second step is the review and approval      of the clinical trial and all related documents (specific patient consent      forms, data collection, etc.) by that medical center's "Institutional      Review Board (IRB)."  In many medical centers, the IRB only      meets once per month.  The clinical trial package must be submitted      weeks in advance, and the IRB review, questions, further submissions,      further IRB review and decision typically take 2-3 months.   
  • The third step is the negotiation of a      business contract ("Clinical Trial Agreement") with the medical      center's legal department and clinical trial budget with the medical      center's budget department.  The contract terms and budgets can vary      substantially among medical centers within the same clinical trial.  This      process typically takes about 2 months. 
  • The fourth step is the "Site      Initiation."  This involves arranging and conducting a full-day,      detailed, joint training of all of the personnel who will be involved in      the trial:  e.g., the neurosurgeons, neuro-oncologists, head of the      hospital's pharmacy, pathologists, radiologists, nurses and others.       The lead time for arranging this joint training with so many players on      the same day is typically substantial.  The training includes all      aspects of the trial, including the patient eligibility criteria and      procedures, treatment procedures, testing and monitoring procedures, data      collection, etc.

Each of the above steps must be successfully completed before the next step at a site can be undertaken (because the sites will not proceed otherwise), and all of the steps must be successfully completed before a clinical trial can open for enrollment at that site.  This lengthy process must be accomplished at each site individually for every site that participates in a clinical trial.

In Germany, for the DCVax-L clinical trial, significant additional steps must be completed in addition to the steps for US sites described above. 

  • Each clinical trial site must obtain a      regulatory license for tumor tissue collection and use from the local      regulatory authorities in the jurisdiction where the trial site (i.e.,      medical center) is located.  The requirements of the local regulators      for these licenses vary.  The preparation of the appropriate      application package for the local regulators, and the review, decision and      issuance of the tumor collection licenses by those regulators, takes a      couple of months.
  • Similarly, each clinical trial site must      obtain a regulatory license for the leukapheresis blood draw (to collect      the immune cells) from the local regulatory authorities in the      jurisdiction where the trial site is located.  The local regulators      with the authority over leukapheresis licenses can be different than the      local regulators with authority over licenses for tumor tissue      collection.  The preparation of the appropriate application package      for the local regulators, and the review, decision and issuance of the      leukapheresis collection licenses by those regulators, takes a couple of      months.  Fortunately, unlike the other steps involved in clinical      trial site initiation, the tumor collection license and leukapheresis      license can proceed in parallel, so that these two licenses can potentially      be completed simultaneously within a couple of months.
  • At many clinical trial sites in Germany,      multiple separate business contracts must be negotiated.  Separate      contracts must be negotiated with the radiology department and with the      leukapheresis department, in addition to the Clinical Trial Agreement      described above.  The requirements and terms for these additional      contracts vary from site to site, and must be negotiated individually.

As noted above, in Germany these steps are in addition to the steps described above which take about 6 months to enable sites to open for a trial in the US.  Accordingly, the process is somewhat longer in Germany.

"We are excited to have the Phase III DCVax-L trial open for enrollment in Germany," commented Linda Powers, CEO of NW Bio.  "It has taken a major team effort to accomplish the steps required for these sites.  However, we are now ready to initiate a substantial set of clinical trial sites throughout Germany, and we have built a strong foundation for our clinical programs in Germany."

About Northwest Biotherapeutics

Northwest Biotherapeutics is a biotechnology company focused on developing immunotherapy products to treat cancers more effectively than current treatments, without toxicities of the kind associated with chemotherapies, and on a cost-effective basis, in both the United States and Europe.  The Company has a broad platform technology for DCVax® dendritic cell-based vaccines.  The Company's lead program is a 312-patient Phase III trial in newly diagnosed Glioblastoma multiforme (GBM).  GBM is the most aggressive and lethal form of brain cancer, and is an "orphan disease."  The Company is under way with a 60-patient Phase I/II trial with DCVax-Direct for all inoperable solid tumors cancers.  The Company previously received clearance from the FDA for a 612-patient Phase III trial in prostate cancer.  The Company conducted a Phase I/II trial with DCVax for metastatic ovarian cancer together with the University of Pennsylvania.  In Germany, the Company recently received approval of a 5-year Hospital Exemption for treatment of glioma (brain cancer) patients outside the clinical trial. 

 

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por cyto às 19:08

Quarta-feira, 11.06.14

INOVIO DCs VGX-3100 IMMUNOTHERAPY

Inovio Pharmaceuticals Clarifies Facts of its VGX-3100 Phase II Trial and Immunotherapy Technolo

Wed June 11, 2014 9:00 AM|PR Newswire  | About: INO

   

BLUE BELL, Pa., June 11, 2014 /PRNewswire/ -- Inovio Pharmaceuticals, Inc. (INO) wishes to clarify that a third party article published on June 10, 2014, was misrepresentative of facts and can only be taken as malicious. The referenced article does not reflect the progress, status, and potential of Inovio's active immune therapy technology and products and is rife with false and misleading conjecture.

As previously communicated on multiple earnings calls and in other public forums, Inovio has indicated that it expects to report mid-year the top-line results of its phase II clinical trial evaluating VGX-3100 for the treatment of cervical dysplasia. We designed this double blind, placebo controlled phase II study to comprehensively measure efficacy, HPV viral clearance, immunogenicity, and safety. At this time the data remains blinded. We aim to report this data by the end of July.

With respect to efficacy, we are measuring regression of disease from late stage cervical pre-cancer (CIN2/3) to early stage pre-cancer (CIN 1) or elimination of disease. The study is 80% powered to achieve a 52% response rate among vaccinated subjects versus a hypothesized 25% in the placebo group. This 25% figure was chosen based on response rates of natural regression that have ranged widely between 4% and 40% in other studies.

We are hopeful that these results could lead to a novel therapeutic option for women to avoid the invasive current surgical procedure. There exists the prospect that our immunotherapy approach may eliminate the presence of HPV virus to minimize future recurrences. 

What we are also measuring in all of these patients are T cell responses. T cells are the vital agent of oncology immunotherapies. This has been clearly validated by the recent advancements of checkpoint inhibitor products, which have achieved admirable results based on their ability to allow T cells to perform their intended function (killing targeted cells), as well as in unrelated CART technology products. 

Overall, Inovio designed a technology platform to generate antigen-specific T cells with the potential to eliminate cancers and infectious diseases. T cell data from our phase I study of VGX-3100, our DNA immunotherapy targeting pre-cancers and cancers caused by HPV, showed that our SynCon® DNA-based immunotherapy delivered with our CELLECTRA® device generated systemic T cell responses with magnitude and durability exceeding other technologies. We also measured and showed the killing effect of these T cells against the targeted cells. No other technologies have demonstrated T cell responses on par with Inovio's, including those referenced in yesterday's article. These T cell results are precisely why Inovio is executing its plans to expand Inovio's HPV therapies to treat head and neck cancer (announced June 10th) and cervical cancer this quarter.  These T cell results also provide us confidence in our plans to broadly go after other major cancers with our proprietary immune therapy products INO-5150 for prostate cancer (with Roche) and INO-1400 (breast, lung, and pancreatic cancers) in 2014.

Moreover, with this CIN 2/3 phase II study Inovio is in a position to show for the first time how the level of T cells and their specific functions in the body may be correlated to clinical efficacy in an active immunotherapy setting using a large, controlled study. The correlation between T cells and efficacy could be instrumental in guiding Inovio's development path for its technology, using different products and technology combinations to target cancers and infectious diseases. As has been pointed out by many astute investors and industry experts, the value of such T cell immune data cannot be underestimated.

It was with hesitation that we have responded to inane conjecture. However, we have received a substantial amount of communication from stakeholders and wished to reiterate the facts around our technology, products, and clinical study.

This press release contains certain forward-looking statements relating to our business, including our plans to develop electroporation-based drug and gene delivery technologies and DNA vaccines and our capital resources. Actual events or results may differ from the expectations set forth herein as a result of a number of factors, including uncertainties inherent in pre-clinical studies, clinical trials and product development programs (including, but not limited to, the fact that pre-clinical and clinical results referenced in this release may not be indicative of results achievable in other trials or for other indications, that the studies or trials may not be successful or achieve the results desired, that pre-clinical studies and clinical trials may not commence or be completed in the time periods anticipated, that results from one study may not necessarily be reflected or supported by the results of other similar studies and that results from an animal study may not be indicative of results achievable in human studies), the availability of funding to support continuing research and studies in an effort to prove safety and efficacy of electroporation technology as a delivery mechanism or develop viable DNA vaccines, the adequacy of our capital resources, the availability or potential availability of alternative therapies or treatments for the conditions targeted by the company or its collaborators, including alternatives that may be more efficacious or cost-effective than any therapy or treatment that the company and its collaborators hope to develop, evaluation of potential opportunities, issues involving product liability, issues involving patents and whether they or licenses to them will provide the company with meaningful protection from others using the covered technologies, whether such proprietary rights are enforceable or defensible or infringe or allegedly infringe on rights of others or can withstand claims of invalidity and whether the company can finance or devote other significant resources that may be necessary to prosecute, protect or defend them, the level of corporate expenditures, assessments of the company's technology by potential corporate or other partners or collaborators, capital market conditions, the impact of government healthcare proposals and other factors set forth in our Annual Report on Form 10-K for the year ended December 31, 2013, our Form 10-Q for the quarter ended March 31, 2014, and other regulatory filings from time to time. There can be no assurance that any product in Inovio's pipeline will be successfully developed or manufactured, that final results of clinical studies will be supportive of regulatory approvals required to market licensed products, or that any of the forward-looking information provided herein will be proven accurate.

CONTACTS:
Investors: Bernie Hertel, Inovio Pharmaceuticals, 858-410-3101, bhertel@inovio.com 
Media: Jeff Richardson, Inovio Pharmaceuticals, 267-440-4211, jrichardson@inovio.com

 

Inovio CEO Preps Retail Investors for Drug Study Failure

By: Adam Feuerstein | 06/10/14 - 12:23 PM EDT

Inovio Pharmaceuticals (INO) CEO Joseph Kim is walking back expectations for the phase II study of its DNA vaccine VGX-3100 in women with high-grade cervical intraepithelial neoplasia (CIN 2/3), also known as cervical pre-cancerous lesions. Results from the VGX-3100 study should be announced any day, but I suspect Inovio already has data in hand. Why else would Kim be laying the foundation for a massive spin job, if not to cushion the vaccine's failure?

The red flags flying over Inovio are there for any clear-eyed investor to see:

Inovio pushed through shareholder vote approving a 1-for-4 reverse stock split on May 23, which went into effect on June 5. Why the need for a reverse stock split? Kim explained:

Our stockholders approved a reverse split to have our price and share structure reflect our leadership position in immunotherapies and expand our potential investor audience.


Interesting spin. Drug companies in leadership positions aren't generally valued with stock prices in the $2 range. More typically, terminally depressed stock prices -- like Inovio's -- are the direct result of management incompetence and/or drug development setbacks and failures. Innovio is very good at issuing press releases and promoting its stock to retail investors, but its track record of developing DNA vaccines is abysmal.

Inovio's decision to enact a reverse stock split right before the VGX-3100 results was more likely timed purposefully to keep the stock trading above $1 if the study fails. Well played, Kim! 

Kim hints at negative VGX-3100 study results in Monday's interview conducted by a Seeking Alpha contributor.

In the interview, Seeking Alpha contributor Trevor Lowenthal asks Kim, "Inovio is expected to produce a top line data read-out for its experimental HPV immunotherapy, VGX-3100, very shortly. How crucial is this to Inovio's future?"

Kim's response:

The upcoming data will help define the potential clinical utility of this HPV immunotherapy for late-stage cervical pre-cancers. But the efficacy and immune response data together are going to help define the broad potential of the products based on our expansive DNA immunotherapy and electroporation technologies as monotherapies and as combinations with complementary technologies, such as checkpoint inhibitors. [Emphasis added.]

Later in the interview, Kim is asked, "What are the primary risks facing the company?"

Again, Kim's response:

If you are defining risk as what might negatively impact the company's market valuation, I think the obvious risk is that our upcoming Phase II efficacy data does not meet our primary goal and the market looks at the data simplistically and says INO is a sell. However, smart investors are going to be looking closely at our T cell data and making investment decisions with that as well. We have tremendous confidence that we can ultimately see clinical utility of one of our products as a monotherapy, either with one of our immunotherapies by itself or possibly with an immune activator included. But cancer is complex, and it may very well be the case that different mechanisms need to be used in conjunction to achieve the desired impact against cancer. [Emphasis added.]

Let's unpack Kim's statement. If treatment with VGX-3100 fails to shrink high-grade pre-cancerous cervical lesions more than a placebo (the study's primary endpoint), it would be "simplistic" to consider the vaccine a failure and sell Inovio. Instead, "smart investors" will disregard the miss on the study's primary efficacy endpoint and reward Inovio if VGX-3100 causes a T-cell response in patients, even though T-cell response is not listed as an endpoint in the phase II study

Don't be fooled by Inovio's smoke and mirrors. A T-cell response to VGX-3100 absent a statistically significant shrinkage in cervical lesions compared to placebo is clinically meaningless. It's a failure.

In a 2010 study published in the journal Cancer Immunology Immunotherapy which followed 50 women with high-grade cervical intraepithelial neoplasia (CIN 2/3) -- the same type of patients Inovio enrolled in the VGX-3100 phase II study -- Trimble et al found that systemic immune response (a T-cell response) did not predict regression of CIN 2/3 lesions. 

Moreover, 26% of the CIN 2/3 lesions followed in the Trimble study shrank completely on their own, without any treatment, after 15 weeks. You can find other studies in the medical literature which cite CIN 2/3 complete regression rates of approximately 35%. 

In other words, the efficacy bar for VGX-3100 is very high, which explains Kim's desire to walk back expectations.

All the 148 women enrolled in the Inovio phase II study are confirmed positive for the human papillomavirus (HPV) serotypes 16 and 18, and have a baseline diagnosis of CIN grades 2 or 3, meaning they present with abnormal cells on their cervix which carry a moderate to higher risk for progressing to cancer.

Women in the study are randomized into two groups. The first group receives injections of VGX-3100 followed by electroporation at months 0, 1 and 3. The second group receives a placebo injection followed by electroporation on the same time schedule. The study's primary endpoint is a comparison of the number of patients with regression of CIN to grade 1 or less at nine months. 

Based on the medical literature, you can expect approximately 35% of the women in the placebo arm of study to have complete regression of their CIN 2/3 cervical lesions. Keep that in mind when Inovio reports results from the VGX-3100 study. I suspect Kim knows his vaccine is in trouble, hence his need to prime retail investors with the "T-cell response" bamboozle. 

 

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por cyto às 19:01

Domingo, 08.06.14

HEAD AND NECK CANCER MD ANDERSON PROTON THERAPY

MD Anderson Proton Therapy Shows Benefit for Head and Neck Cancer

Posted by: Rafaela Relvas May 28, 2014

Researchers from the University of Texas MD Anderson Cancer Center conducted a toxicity of multifield optimization intensity modulated proton therapy (MFO-IMPT) on 15 patients with head and neck tumors. Two years after the therapy, over 93% of the patients were cancer free, suggesting that this treatment may be an effective and less toxic option for patients with certain types of cancer.

Led by Dr. Steven J. Frank, associate professor of Radiation Oncology at MD Anderson, and the medical director of the Proton Therapy Center, the study was recently published in the current issue of the International Journal of Radiation, Oncology, Biology, Physics, and follows previous MD Anderson research reported on last September by BioNews Texas, which concluded that the modulated proton therapy contributed to the decrease in 50% in the use of feeding tubes in patients with oropharyngeal carcinoma cancer.

Dr. Frank’s team worked with fifteen patients with head and neck cancer, who underwent the MFO-IMPT therapy.

For patients with squamous cell carcinoma, the treatment was extended from the base of the skull to the clavicle. Researchers also analyzed the robustness of each treatment, in order to evaluate sensitivity to uncertainties associated with variations in patient setup, as well as the effect of these uncertainties with proton beam range in patients.

The greatest advantage of MFO-IMPT, says the researchers, is that it can spare surrounding healthy tissue from the damage, while helping preserve quality of life measures such as neurocognitive function, vision, the ability to swallow, hearing, taste and speech. Currently, standard treatment for head and neck cancer destroys both cancerous and healthy cells, impairing some of the functions mentioned before.

The study’s results showed that all 15 patients were able to complete treatment with MFO-IMPT, with no need for treatment breaks and no hospitalizations. There were no treatment-related deaths and the median recovery time, for 93.3% of the patients, was 28 months. After this period, fourteen of the fifteen patients remained cancer free.

Xerostomia (dry mouth caused by reduced or absent saliva flow) was one of the symptoms that all 15 patients presented. Mucositis within the planning target was also observed during the treatment of all patients.

Steven J. Frank noted that it is still early, but believes the study provides evidence of proton therapy’s safety and effectiveness, which is particularly important, as the incidence of head and cancers are on the rise. According to Frank, ongoing research will determine if MFO-IMPT is able to reduce toxicity and improve survival.

Other MD Anderson researchers contributing to this study include James D. Cox, M.D., Michael Gillin, Ph.D., Radhe Mohan, Ph.D., Adam S. Garden, M.D., David I. Rosenthal, M.D., G. Brandon Gunn, M.D., Randal S. Weber, M.D., Merrill S. Kies, M.D., Jan S. Lewin, Ph.D., Mark F. Munsell, M.S., Matthew B. Palmer, B.S., Narayan Sahoo, Ph.D., Xiaodong Zhang, Ph.D., Wei Liu, Ph.D., and X. Ronald Zhu, Ph.D.

MD Anderson: New Intensity Modulated Proton Therapy Reduces The Use of Feeding Tubes in OPC Patients

Posted by: Anna Ishibashi September 26, 2013

Researchers at the University of Texas MD Anderson Proton Therapy Center reported that the use of feeding tubes in patients with oropharyngeal carcinoma (OPC) cancer was decreased by 50% when they are treated with intensity modulated proton therapy (IMPT) instead of intensity modulated radiation therapy (IMRT). In addition, researchers found that the toxicity levels in patients treated with IMPT were much lower than those who were treated with IMRT.

OPC cancer occurs at the back of the throat, and in most cases it is linked to human papilloma virus (HPV) infection, leading to severe disease conditions. IMPT delivers a precise dose of protons to destroy only the cancerous cells, while IMRT could damage both cancerous and healthy cells. MD Anderson has treated approximately 150 OPC patients with IMPT from 2011.

“IMPT is especially well-suited for patients with the most complicated tumors of the head and neck, precisely painting the protons onto the tumor layer by layer,” said Steven J. Frank, M.D., associate professor of Radiation Oncology at MD Anderson. “In this way, the treatment team can confine the majority of the tumor-damaging energy to target areas and work to protect normal structures such as the oral cavity and brainstem.”

In the study, researchers evaluated 25 IMPT-treated patients and 25 IMRT-treated patients. 5 IMPT-treated patients (20%) required the feeding tubes, while 12 IMRT-treated patients required the feeding tubes. IMPT-treated patients did not show side effects such as vomiting, nausea, hearing problems, and mucositis, that were observed in IMRT-treated patients. In addition, IMPT-treated patients could keep better nutrition and hydration levels, often resulting in faster recovery duting and after the treatment.

“With a recent epidemic of HPV-associated head and neck cancer among U.S. adults, there is a critical need to minimize the side effects associated with conventional IMRT that affects the patients’ courses of treatments, and, ultimately, the rest of their lives,” said Frank.  “Since radiation therapy is the main tool to treat the disease in this fairly young group of patients, we must understand if more advanced technologies will provide additional value to this patient population.”

MD Anderson is conducting a 5-year Phase II/III randomized trial of IMPT vs. IMRT, and aims to enroll 360 patients in the trial.

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por cyto às 10:28

Domingo, 08.06.14

PARKINSON DEEP BRAIN STIMULATOR

BCM and Rice Researcher Works On Advanced ‘Deep Brain Stimulator’ To Erase Tremors In Parkinson’s Patients

Posted by: Leonor Ferreira May 29, 2014

A Baylor College of Medicine and Rice Universityresearcher, Caleb Kemere, is developing a more advanced deep brain stimulator (DBS), which is designed to help erase tremors caused by Parkinson’s disease patients.

The device works by sending electrical currents deep into nerve centers close to the brain stem. Dr. Kemere is looking to improve upon the existing technology by making it automatically adjust itself many times per second, thus optimizing the operational capacity of DBS devices that are already on the market.

The technology currently in development is one of Kemere’s ongoing research initiatives that are focused on the basal ganglia, which is the part of the brain that controls movement.

“Deep brain stimulation has proven to be remarkably effective in treating Parkinson’s, and it may well turn out to be revolutionary for treating severe depression and other neurological and psychiatric disorders,” said Dr. Kemere, who serves as both an adjunct assistant professor of neurology at Baylor College of Medicine, and as an assistant professor of electrical and computer engineering, specialized in electronic devices that interact with the brain. He is also the director of Rice’s Realtime Neural Engineering Laboratory.

Current DBS systems are proven to produce significantly positive results in Parkinson’s patients, some of which have been able to walk, speak, write, and regain other movements again. The system distributes a small and continuous current to the basal ganglia and it can be thought of as a “brain pacemaker.”

However, the current DBS systems are manually adjusted by neurologists, which forces patients to attend weekly appointments. Kemere’s concept is to create a system that can automatically adjust itself many times each second, thus avoiding the need for manual recalibrations. “We want to develop deep brain stimulation technology that operates on the order of milliseconds, actively detecting what’s going on in the brain at any moment and then modulating the stimulation to optimize results. In electrical engineering terms, we call this ‘closing the feedback loop,’” he explained.

The point of departure, for Kemere, is that “today’s DBS technology is basically the same as that used in heart pacemakers.” He went on to explain that, ”the electrodes are just implanted inside the brain rather than in the heart. I’ve found that when electrical engineers like myself first hear about DBS, they generally have the same two thoughts: ‘Wow, that’s a really cool use of electronics,’ and ‘The brain doesn’t pulse like a heart; maybe we can improve this by matching the stimulation to the dynamic nature of the brain!”

Kemere believes that, though DBS is already effective, it provides only minimal therapeutic benefit “for perhaps a third” of Parkinson’s patients. With his research, he thinks it is possible to create a dynamic system that would substantially increase the effectiveness of the device.

“Also, current DBS technology has side effects, and we’d like to reduce those,” Kemere said. “For example, people with Parkinson’s have a spectrum of symptoms, including tremors, trouble initiating muscle movement, muscle rigidity and slowness of movement. Sometimes, DBS can relieve one of those symptoms but make another one worse.”

The next step of Kemere’s research is to work on the power system of the device, since the real-time computer processing required needs substantial power. The battery packs in current DBS systems last about 10 years, but it is more challenging to get the same kind of battery life in a more dynamic system.

The investigation will also involve the creation of algorithms to interpret the neural signals received from the brain. “We think we can optimize DBS stimulation and maximize its therapeutic benefit if we can better understand how information flows in the cortical-basal ganglia circuits in healthy brains, how those flows are disrupted by Parkinson’s disease and how DBS can alter those flows,” Kemere said. The experiments will be performed first with rats to create, test and refine systems.

The research was funded by a National Science Foundation (NSF) Career Award, which is only granted to 400 researchers each year, across all disciplines. Kemere will begin a five-year program to reboot DBS technology with the latest embedded processors and research analytics. The program is planned to support the research and career of young scholars. Each award consist of $400,000 in research funding.

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por cyto às 10:27

Domingo, 08.06.14

CTLA-4

 

Fighting cancer needs more of the right T cells

Angela Colmone

In immunotherapy that helps the body's fight against cancer, antibodies that block the cell surface protein CTLA-4 (cytotoxic T lymphocyte–associated antigen-4) entice the immune system to enter the ring. Cha et al. used next-generation sequencing to show that blocking CTLA-4 in cancer sufferers drives change among T cells, so that the population becomes active against a different collection of targets. However, increasing T cell diversity is not the whole story—after treatment, the patients with more favorable clinical outcomes were able to maintain certain preexisting abundant T cells, whereas poorly responding patients lost these cells. Thus, although CTLA-4 blockade induces T cell repertoire diversification, it may actually be the maintenance of particular vigorous T cell clones that helps the antitumor immune response.

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por cyto às 10:24

Domingo, 08.06.14

FDA - PEI COMMITMENT

FDA - PEI

STATEMENT OF LEGAL AUTHORITYAND COMMITMENT FROM THE UNITED STATES FOOD AND DRUG ADMINISTRATION UNITED STATES OF AMERICA NOT TO PUBLICLY DISCLOSE NON-PUBLIC INFORMATION SHARED BY THE PAUL-EHRLICH-INSTITUT GERMANY

The Paul-Ehrlich-Institut (PEI), a Senior Federal Authority reporting to the German Federal Ministry of Health, is authorized under Section 68 Paragraph 4 of the German Medicinal Products Act (§68(4) Arzneimittelgesetz - AMG) to disclose information to the U.S. Food and Drug Administration (USFDA), U.S. Department of Health and Human Services regarding PEI regulated products as part of cooperative law enforcement or cooperative regulatory activities.

The USFDA understands that some of the information it receives from the PEI may include non-public information exempt from public disclosure under the laws and regulations of Germany and/or the European Union (EU), such as confidential commercial information; trade secret information; personal privacy information; law enforcement information; or internal, pre-decisional information. The USFDA understands that this non- public information is shared in confidence, and that PEI considers it crucial that the USFDA maintains the confidentiality of the information. Public disclosure of this information by the USFDA could seriously jeopardize any further scientific and regulatory interactions between PEI and the USFDA. PEI will advise the USFDA of the non-public status of the information at the time that the information is shared.

Therefore, the USFDA certifies that it:

  1. has the authority to protect such non-public information provided to the USFDA in confidence by the PEI from public disclosure; 
  2. will not publicly disclose PEI-provided non-public information without the written authorization of the owner of the information, the written authorization from the individual who is the subject of the personal privacy information, or a written statement from PEI that the information no longer has non-public status; 
  3. will inform the PEI promptly of any effort made to obtain PEI -provided non-public information from the USFDA by judicial or legislative mandate. If such judicial or legislative mandate orders disclosure of PEI- provided non-public information, the USFDA will take all measures in an effort to ensure that the information will be disclosed in a manner that protects the information from public disclosure; and 
  4. will promptly inform the PEI of any changes to US laws, or the USFDA policies or procedures, that would affect the USFDA’s ability to honour the commitments in this document. 

Date: 23 Jan 2006 Murray M. Lumpkin, M.D., M.Sc.
Deputy Commissioner International and Special Programs Food and Drug Administration Department of Health and Human Services UNITED STATES OF AMERICA 5600 Fishers Lane Rockville, MD 20857, (301) 827-5709 (ph) (301) 443-3100 (fax)

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por cyto às 10:11

Quarta-feira, 04.06.14

DMC DCs VACCINE NW BIO Steven Giardino 4 JUN 2014

The Case Of Northwest Biotherapeutics' Missing DMC Recommendation

Jun. 4, 2014 12:25 PM ET  |  About: Northwest Biotherapeutics, Inc. (NWBO) by: Steven Giardino

Summary

  • The role of a DMC is often misconstrued by      media pundits and biotech analysts alike.
  • Above all, a DMC acts independently of the      sponsor, even though hired by them.
  • There are conditions in which a DMC      recommendation may be withheld beyond a company's power.

A well thought-out question was asked in the comment section of my last article. It is one that I have pondered long and hard over myself, which led me to research it extensively. The question is, "Where oh where has NWBO's DMC recommendation gone?"

First, it should be noted there is no aggregate efficacy or safety data available to the sponsor of a clinical trial if that trial is blinded.

The only instance in which a sponsor (in this case NWBO) of a blinded trial is unblinded to data is when a DMC has noted a stopping boundary being crossed (futility or efficacy) before the conclusion of a trial, and thus recommends to the sponsor that the trial be stopped and why (although they may not always recommend it). And if the sponsor agrees with the assessment and stops the trial, then and only then are they unblinded to data.

Otherwise, there is no available data to the sponsor, other than what is discussed in "open meetings." These include basic enrollment and treatment information, how each site is performing, etc. To allow a sponsor to view aggregate blinded data during a trial would introduce a type I error (bias) and would seriously jeopardize the validity of the results going forward.

So when someone says "interim data" regarding a blinded trial, they are referring to data the independent DMC views only. If they are implying it is something the sponsor of a blinded trial has ready access to, it is being said out of ignorance or worse (and in the above cases, I refer to the "sponsor" as executives with high public visibility and/or those in continual interaction with patients. Not select employees of the company fire-walled for such purposes).

But let's discuss the apparently missing DMC recommendation based on efficacy data from the first interim analysis of NWBO's Phase III trial.

From Guidance for Clinical Trial Sponsors:

When there is a steering committee, the sponsor may elect to have the DMC communicate with this committee rather than directly with the sponsor.

There are two CROs managing NWBO's Phase III trial (also called "steering committees"). One in the US, and one in Europe. They handle oversight and management of the clinical trial sites and collection of data. They also can serve, and often do serve, as mediators between the sponsor and the DMC, as the FDA Guidance above states. With smaller companies like Northwest Bio, it is almost always the case that a steering committee is appointed to discuss matters directly with the DMC, and not to involve the sponsor directly. To continue:

Interactions between the steering committee and the DMC consist primarily of discussions during "open sessions" (see Section 4.3) of DMC meetings and the communication of recommendations following each DMC review of the trial. More extensive interactions might occur when early termination is being considered.

The above guidance points out: "More extensive interactions (between the DMC and CRO) might occur when early termination is being considered." That is, when a DMC has viewed aggregate data, and is considering a recommendation to halt the trial early (for futility or efficacy), discussions will become more extensive. This will involve unblinding key members of the CRO to aggregate data, to make a determination on how to proceed, and will include extenuating circumstances (to halt a trial affects many variables). To continue:

In almost all cases, a DMC is advisory to the sponsor [or advisory to the steering committee who is advisory to the sponsor]; the sponsor decides whether to accept recommendations to discontinue a trial. FDA will rarely, if ever, tell a sponsor which decision to make. [brackets mine]

In most cases, and for flexibility purposes, a sponsor will design a trial with nonbinding futility and efficacy stopping boundaries. That means the trial could cross a stopping boundary for efficacy, thus resulting in the DMC recommending to the CRO (or at least opening discussions with them concerning it) to stop the trial. But due to the nature of the boundary (nonbinding), the CRO (and as per protocol laid out to the sponsor's wishes before the trial began) may choose, because of various other factors, to continue the trial instead, keeping the DMC recommendation undisclosed to the sponsor (who would be affected by such for obvious reasons, which could jeopardize the trial by introducing bias).

The same could be said of nonbinding futility recommendations. Though, in an early interim analysis of a clinical trial, if the boundary is crossed for futility, the DMC will nearly always recommend a continue anyway (especially if the treatment is an adjunct to SOC), as the data is usually too immature to make that broad of a declaration. And especially for life-threatening diseases, which is always taken into account. This can even be true in cases where OS is slightly worse in the treatment group than control (as in the 2004 corticosteroid CRASH trial).

But what will always cause a DMC to recommend a halt after an IA is toxicity. If the treatment group performs appreciably worse than the placebo group, or many toxic side effects are noted, they will recommend the trial be stopped early. This is a binding stopping boundary.

The other thing to consider is effect size. In an adjunct therapy trial (treatment in addition to SOC vs. SOC), if the treatment is non-toxic, the DMC will usually recommend a continue at the IA, even if it appears futile--unless the sponsor has given them instructions not to (in order to reallocate funds to other drugs in their development pipeline, for instance). Therefore, a futility halt is rare in these cases (and would be very rare for a company like NWBO testing DCVax-L. They would likely express the desire that the trial continue at all costs, unless deemed unsafe, even if appearing futile. And the DMC would oblige their wishes and recommend it--as a continue, if this were the case--again, so long as it's deemed safe). Even with poor or no real effect being seen, the DMC would normally issue a continue in trials like these until the second interim. But here, they haven't.

Getting back to effect size, little or no advantage of "safe treatment + SOC" vs. "SOC" is not harming patients in any way. Therefore, it is ethical to continue and see if the trend changes. The DMC, upon seeing this, would simply recommend "continue" based on efficacy data, with little deliberation (again, unless instructed otherwise by the sponsor). If, however, the effect size is large for "safe treatment + SOC" vs. "SOC," then that is a different thing. Now, it suddenly appears unethical to prevent this treatment from the rest of the patients and the rest of the world. Marked difference in dilemma.

(By the way, one of my main sources in this discussion is the book "Designs for Clinical Trials, Perspectives on Current Issues" by David Harrington. I highly recommend it).

To finish the relevant Guidance quote:

For trials that may be terminated early because a substantial benefit has been observed, however, consideration may still need to be given to the adequacy of data with regard to other issues such as safety, duration of benefit, outcomes in important subgroups and important secondary endpoints.

That was "safety, duration of benefit, outcomes in important subgroups and important secondary endpoints." These are potential causes for additional consideration, even when "substantial benefit" that warrants an early halt to a trial has been seen. This means that if there are no unresolved issues pertaining to "safety, duration of benefit, outcomes in important subgroups and important secondary endpoints," AND there is substantial benefit, a trial may be halted early. Otherwise, resolution needs to be brought to any or all of these topics first.

Regarding safety, the Company stated,

In ten years of clinical experience, there have only been a couple serious adverse events, and we believe these were due to the patient's underlying brain cancer, rather than the DCVax treatment. The broad and rapidly growing body of scientific literature about dendritic cells is consistent with the DCVax clinical experience.

Safety seems "safe" to rule out.

"Duration of benefit" is the primary factor in determining if ORR (objective response rate), which measures tumor response, ultimately leads to clinical benefit. As an aside, this marks one noticeable difference between chemotherapy and immunotherapy. Often, ORR is more dramatic with chemo, yet overall survival has been mixed. Tumor recurrence and metastases after chemo are often more aggressive than before. Immunotherapy is showing in many cases to have moderate ORRs (less of a chemical obliteration of humanity), but more substantial OS than chemos. At any rate, this would not be a factor for extensive interaction between the DMC and CRO in this particular trial (full resection prior to treatment).

"Outcomes in important subgroups" refers to the pseudoprogressive subgroup, mentioned on clinicaltrials.gov, and would broach a whole other long discussion. Suffice it to say that although it could create extensive interactions (between the CRO and DMC), immature results for this subgroup alone (set to enroll 72 total) would probably not hold back an entire trial from being halted early for efficacy. This is strictly a matter of opinion, however. And in my opinion, data on this subpopulation could be ascertained via open label studies subsequent to a halt, and such data could then be the basis for later label extension of DCVax-L. But if they WERE to hold up the entire trial to enable data on this subgroup to mature, it would most likely go to its designed end anyway (as it stands, 4 months away). The same could be said of "important secondary endpoints," namely, OS.

But can this account for the now almost 6 months without any word from the Company other than "the DMC recommendation based on efficacy data remains outstanding?" I think so. The DMC may even have recommended a halt for efficacy to executive members of the CRO, and they, because of protocol that may have insisted a halt not occur before certain provisions are reached, are not releasing it to the Company until these occur.

Another possibility is that the DMC determined that an unscheduled interim look, or two, would give them a view of more mature data that could be used as the basis for a halt for efficacy, without having to wait until the second interim was triggered to do so (or, this could have been discussed and decided between the CRO and DMC--and possibly the FDA/EMA).

Something similar to this was enacted by the DMC in a sunitinib trial. The interim look was scheduled to occur after 130 PFS events, but they unblinded efficacy data at 20, 50, and 73 PFS events instead. These correlated with safety analyses, except for the last one, which was all its own:

6.3.1 Early Study Termination

The DMC met three times to review safety data (May 2008; November 2008; and February 2009), at which times, PFS data was also reviewed (based on 20, 50, and 73 PFS events, respectively). These DMC efficacy reviews were not pre-specified and no alpha was allocated for them in the Statistical Analysis Plan (SAP). At the November 2008 meeting, when 50 PFS events had been observed, the DMC stated that "given the marked PFS difference between arms it would be reasonable to consider closure at an earlier time," and decided to meet again in 3 months, instead of 6 months.

In February 2009, at its third meeting, the DMC recommended closure of Study A6181111 based on its review of preliminary safety and efficacy data after only 73 PFS events (28.1% of planned events) had been observed. This recommendation was based on an observed median PFS of 11.1 months on sunitinib versus 5.5 months on placebo with corresponding hazard ratio of 0.397, 95% confidence interval (0.243,0.649), and 2-sided unstratified log-rank test p-value 0.0002. However, no formal alpha spending and statistical stopping boundaries were implemented. The DMC noted that if the study continued as planned and the interim analysis at 130 events was conducted, there would have been a 91% chance (conditional power) of stopping the study assuming that the true HR was 0.649 (upper limit of the 95% CI of the observed HR at 73 events). Thus, the DMC claimed that the study had met its primary endpoint in demonstrating a significant PFS advantage for sunitinib.

The sponsor agreed with the DMC and notified all investigators in March 2009 that the study would be closed and all patients (regardless of whether they had PD or not) should be offered open-label sunitinib on one of two extension studies (A6181078 or A6181114). The final PFS analysis was based on all PFS events reported by April 15, 2009 (the data cutoff date), at which time, there were 171 patients enrolled and 81 PFS events (31.2% of planned events) observed.

So we see a case where a DMC superseded protocol based on "trends in efficacy data," and made the decision to increase interim looks--especially with their final of the three decisions to unblind data 3 months after the second, where they found 73 events had occurred and the same PFS trends. In order to do this, a DMC is supposed to account for additional alpha spend, but in a well-powered trial, that would be insignificant.

Hypothetically speaking, the DMC may have decided to forgo a continue recommendation based on efficacy data in NWBO's Phase III trial. Either because the efficacy stopping boundary was close to being crossed at the first interim look (and so, calling a continue until the second interim would delay what they saw trending to occur before the second interim), or because the pseudoprogression subgroup's data or OS data was too immature in their own right, or some combination of these. They may have decided to add in unplanned interim looks perhaps in March, and then again in June, rather than wait for 88 events. This would be a clear ethical decision. It may also mean a halt could potentially occur at any moment.

In summary, these are two hypotheses:

The DMC is putting off making an offical recommendation until they conduct one or two more unplanned interim analyses, by which time they deduce they will have crossed the efficacy stopping boundary set for this trial. At that time, they may recommend a halt for efficacy.

or

The DMC recommended a halt for efficacy to the CRO, who, because of protocol, acted in the sponsor's stead, choosing to continue the trial instead, until certain provisions are in place, or data has matured. Thus, no recommendation made its way to the Company. Once these conditions are met, then they may reconvene with the DMC and remit a recommendation to halt for efficacy to the Company at that time.

The third hypothesis involves Accelerated Approval.

A recent FDA guidance states a process by which a company would file an NDA or BLA for Accelerated Approval (AA) using an interim analysis as the basis, while the trial continues to satisfy the post-AA confirmatory trial requirement.

The FDA wants to see a confirmatory trial in progress when granting AA. Why? So many of the companies granted AA drag their feet thus for many years, while taking full advantage of their newly acquired marketing capabilities. The FDA is changing the way this works. It appears they are wont to demand a confirmatory trial (Phase III) in progress before they consider AA. One way to do this is to use the interim data of a larger Phase III trial as the basis for filing a BLA or NDA for AA, while data collects as the trial continues to satisfy the post-AA confirmatory trial requirement:

When it is possible to use a later effect in a trial to verify the effect seen earlier in the same trial that supported accelerated approval, the same clinical trial(s) can be used to support accelerated approval and verify and describe the clinical benefit. In this case, the protocol and the statistical analysis plan should clearly account for an analysis of the surrogate endpoint data to provide support for accelerated approval, with continuation of the randomized trial(s) to obtain data on the clinical endpoint that will be the basis for verifying the clinical benefit. When the same trial is used to support accelerated approval and verify clinical benefit, the data to verify the clinical benefit may be, in some cases, nearly complete by the time of accelerated approval.

This is the path that was followed with Eloxatin:

In 2002, oxaliplatin (Eloxatin) was granted accelerated approval for use in combination with 5-FU/LV on the basis of data from a randomized, three-arm study of oxaliplatin plus infusional 5-FU/LV versus 5-FU/LV alone versus single-agent oxaliplatin in patients with advanced colorectal cancer refractory to first-line treatment with irinotecan and bolus 5-FU/LV (21). The study enrolled 821 patients and had a preplanned interim analysis after 450 patients were enrolled. At the time of this interim analysis, a response rate of 9% (13 of 152) was observed in the combination arm compared with a response rate of 0% (0 of 151) in the 5-FU/LV arm (P = .002). Patients in the combination arm had an approximately 2-month increase in median time-to-progression (4.6 months, 95% CI = 4.2 to 6.1 months) compared with patients in the 5-FU/LV-alone arm (2.7 months, 95% CI = 1.8 to 3.0 months).

The study was not halted early, and was granted AA after data from the interim analysis was used as the basis for their NDA application. The time in which this occurred saw the trial continue, accruing data to verify clinical benefit.

Third hypothesis: The DMC unblinded executive members of the CRO to aggregate data for the purpose of them filing a BLA for AA, according to this trial's protocol. Thus, no continue recommendation would follow.

Now considering German Hospital Exemption:

According to the FDA-PEI Confidentiality Commitment, the FDA is "authorized" to share "non-public, pre-decisional information" with the PEI, as part of "cooperative regulatory activities." Seeing as how they are both regulatory bodies overseeing the same clinical trial, it seems quite germane.

The exact timing of the Hospital Exemption approval also seemed uncanny. Ten weeks into the interim review. Hard to just ignore that detail. Hard also to ignore the 5-year term given, when HE can be granted for less. Why not 1 year, seeing as how the trial would have top line results before then? One hypothesis is they were unblinded to interim data, along with the FDA.

But how would the FDA be unblinded to interim data, to begin with?

(from FDA Guidance):

We recommend that sponsors of trials that could potentially be terminated early for efficacy reasons discuss these issues with FDA prior to implementing the trial, when the statistical monitoring plan and early stopping boundaries are being developed. In these settings, consultation with FDA may provide the sponsor with important information regarding the regulatory and scientific implications of a decision and may lead to better decisions.

Sponsors are encouraged to revisit these issues with FDA when considering DMC recommendations for early termination if new issues have arisen and/or if the regulatory implications of early termination were not adequately clarified at the outset of the trial. [emphasis mine]

The FDA may be unblinded to interim data for clarification purposes (as above), or by way of data used to apply for Fast Track designation, which may be sought "at any point during the drug development process," including following an interim review. The FDA responds in under 60 days to such requests (Fast Track also enables "rolling review," which can speed up the BLA or NDA filing and response time). The Company said it was planning to petition the FDA for Fast Track, but had not done so yet (in 2013).

Moving away from hypotheses for the moment, the DMC (or in this case more aptly called the DSMB) of course has declared the trial is safe to continue, which they delivered to the CRO, and then the CRO to the Company. That is a separate analysis, often conducted alongside efficacy analysis. Which leads me to an aside...

Why do you suppose Linda Powers, CEO of Northwest Biotherapeutics, made the decision to inform shareholders via PR that the recommendation based on efficacy data was still "pending," thenceforth revised to "outstanding?" It was not required of her or the Company to do so. They could simply have stated, "the DSMB has reviewed interim data from our Ph III GBM trial and deemed it safe to continue." There was no need to distinguish between efficacy and safety data recommendations. She was the one to bring this all up, after all. It stunned investors, who joined in chorus: "What do you mean, pending??"

Was this a faux pas? Or a seemingly clever tactic that may have backfired?

Without being of the same mind as the CEO, it is impossible to know, but I will say that it doesn't take very much investigation of the literature (Guidance) and case studies (such as in the book listed above) to reveal that such a scenario, for a trial like NWBO's Phase III, leans much more heavily towards it being due to positive rather than negative developments/data. Again, whether or not this was foresight on the Company's part, I cannot say. But it appears that way. It was intentionally said, yet not required.

The downside to putting out information that you hope is interpreted "correctly," is, of course, when it gets interpreted incorrectly instead. In biotech, every investor is afraid of his own shadow it seems, often seeing things that have no substance and making them into decisive events. It is always the lack of understanding of a thing that causes us to make it into something that it isn't. I see no difference here.

The CEO would perhaps have better served investors by leaving them in the dark on something so easily misconstrued. But I, for one, am glad she didn't.

After researching the topic exhaustively, I can honestly say that the "outstanding" nature of the DMC recommendation only increases my confidence in the Company's sponsored technology, DCVax, developed out of the prestigious UCLA Health Center, and the probability, all things considered, that it is the result of positive rather than negative efficacy data.

So there you have it: 4 hypotheses on the whereabouts of said DMC efficacy recommendation. But why not add a 5th?

The final hypothesis is that the Company, even though trying hard to keep enrollment figures undisclosed, did, in fact, give away enough timeline data to enable one to figure out that an effective current PFS range is being seen in the trial, even when conservatively figured, with reasonable accuracy. I will quote someone more knowledgeable than me on the subject:

DCVax-L Model Positive on Primary Endpoint.

Disclosure: I am long this stock; I have no inside information; I am a clinical researcher.

Hypothesis 1: The Control Patients in the DCVax-L GBM trial should relapse at a rate similar to what was shown in the Stupp trial. The Stupp trial is the best GBM data available and represents the standard of care for GBM patients. In order to compare the Stupp Trial to the current DCVax-L trial control patients, however, one must review the eligibility requirements for each trial. The DCVax-L Trial only allows patients to enter the trial, if "surgical resection with the intent of a gross total or near gross total resection" can be completed. The Stupp Trial contained 17% patient who just had a biopsy only and another 44% of the patients who only had a partial resection. Extent of surgical resection is a major prognostic factor for these tumors and historical reviews have shown the degree which the various surgical procedures can change survival rates. The Median progression free survival (PFS) for all patients in the Stupp trial was 6.9 months. When one applies algebra proportions to correct for the differences in prognosis between the trials in terms of surgical extent, the likely median PFS for the control patients in the DCVax-L trial should be around 9 months.

Hypothesis 2: Given that we know the current number of events in the total DCVax-L trial at this time (first interim analysis) is 67, then one can model the control arm PFS to be similar to the corrected Stupp trial results and thus obtain an estimate for the probable number of events required in the control arm of the DCVax-L trial to give a 9 month median PFS. When one does this with a Kaplan Meier plot, one obtains a result of a minimum of 30 events in the control arm with the total number of patients in the control arm of 57. Then one can deduce that the number of events in the experimental arm for the DCVax-L trial would be 67-30 or 37 events.

Hypothesis 3: Using the derived 37 events in the experimental arm, one can model the experimental arm to be similar to the Stupp trial results but, in this case only allow for just 37 events out of 114 total patients in the DCVax-L experimental arm. When one does this with a Kaplan Meier plot, the median PFS for the experimental arm returns > 17.5 month median PFS in the DCVax-L experimental arm. When one applies log-rank and Wilcoxon significance testing to the two curves one obtains a significant result of p=<.0001 and p =.00015 respectively.

 

 

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por cyto às 20:01

Quarta-feira, 04.06.14

DCs Vaccines Northwest Biotherapeutics, Inc. (NWBO) by: Steven Giardino

 

 

Northwest Biotherapeutics: Academic Results Create Positive Risk/Reward

Jun. 2, 2014 3:05 PM ET   |  About: Northwest Biotherapeutics, Inc. (NWBO) by: Steven Giardino

Summary

  • An extensive analysis of peer-reviewed      studies over the last 15 years shows strong evidence of effect seen with      whole tumor lysate loaded dendritic cell vaccines (such as DCVax-L).
  • Superior vetting of manufacturing      capabilities and regulatory validations make NWBO stand out from its      competitors.
  • Sales potential and risk/reward ratio of      DCVax-L provide additional impetus for investment.

A sound basis for investment in any publicly traded bio technology company should entail a thorough review of the following: veracity of technology, regulatory validations and validations from academia (peer-reviewed journals, etc.), comparison with competitors, manufacturing viability, and risk/reward ratio.

Regarding Northwest Biotherapeutics (NWBO), I shall run through each in course and offer my conclusions at the end. I will assume readers are privy to the overall technologies in question, namely DCVax-L and DCVax-Direct, NWBO's two frontline therapies. But if not, there is up-to-date information of these on its website and in its latest corporate presentation.

Veracity From Academia on Tumor Lysate-Pulsed Dendritic Cell (DC) Vaccines (analog to NWBO's DCVax-L), and Activated, Intratumorally Injected DC Vaccines (analog to NWBO's DCVax-Direct):

As DC vaccination currently has no FDA or other regulatory body approval on its use in the greater patient population, the testing of this vaccine has been limited to early-stage clinical trials and academic studies, which are often comprised of patients with very advanced, hard-to-treat cancers, with limited treatment options and near 100% mortality rates. Despite this, and where all other "effective" therapies have failed, the effectiveness and safety of DC vaccines utilizing whole tumor lysate have been repeatedly confirmed.

Cumulative data from a variety of sources has been used to verify claims in other studies. For example, in "Pseudoprogression: Relevance with Respect to Treatment of High Grade Gliomas," by Fink J, et al, their methods were noted as: "A literature review searched specifically for 'pseudoprogression' within the last 5 years (2005-2010)," whereby researchers reviewed various studies' data and gave collective demographic rates based on them.

Also, in "Advanced Therapy Medicinal Products and Exemptions to the Regulation 1394/2007: How Confident Can We Be? An Exploratory Analysis," by Van Wilder et al, their methods were noted as: "We started by checking the EMA-website (European Medicines Agency, 2012) for authorized ATMPs till December 2011. We then searched the medical literature published on 'EC authorized' and on 'non-EC authorized' ATMPs," and they likewise used various studies' data to draw conclusions on the use of the Hospital Exemption program in Europe and its possible implications.

Following their example, I likewise searched for all published scholarly articles on "tumor lysate-pulsed DC vaccine" (such as in DCVax-L) and "intratumorally injected DC vaccine" (such as in DCVax-Direct). Below is an overview of a number of these studies' findings. This will cover both "veracity of technology" and "validations from academia" above.

DCVax-L/DCVax-Direct Analogs:

In 2004, Yu et al treated 14 patients diagnosed with recurrent GBM (median OS w/ SOC is 6 months) with tumor lysate-pulsed DC vaccine. No adverse events were reported. Substantial immune responses were identified (particularly T-cell infiltration). Median OS in patients treated with DC vaccine was 133 weeks (2 years and 7 months)--more than 2 years' improvement over Standard of Care (SOC).

In 2010, Linda Liau (professor and vice chair of Neurosurgery and director of the UCLA Brain Tumor Program, founder of DCVax-L technology and principal investigator in their current Ph III DCVax-L trial) et al treated 23 patients with glioblastoma (WHO grade IV -- 15 with newly-diagnosed GBM, and 8 with recurrent GBM) with three biweekly injections of tumor lysate-pulsed DCs, followed by booster vaccinations with either imiquimod or poly-ICLC adjuvant every 3 months until tumor progression. This study has been succeeded by a current Ph II enrolling 60 patients (making it 83 total), to be completed concurrent with the DCVax-L Ph III trial, and may be used to file a supplemental BLA for use of these booster vaccinations as adjuvants.

This DC vaccine is the same that showed high efficacy in 39 patients previously in a Ph I/II trial for GBM, and which is currently being tested in NWBO's ongoing 312-patient Ph III trial. It was developed by Dr. Liau and others out of the world's premier GBM treatment and research facility (ranked #1), UCLA Health.

No adverse events were reported. Historic median time to progression (TTP) in a 2:1 ratio of newly-diagnosed and recurrent GBM patients respectively (using ratios mirroring the study) is 5.5 months. Historic median overall survival (OS) in a 2:1 ratio of newly-diagnosed and rGBM respectively (using ratios mirroring the study) is 11.8 months.

The median TTP and OS from the time of initial surgical diagnosis of GBM in these 23 patients treated with whole tumor lysate-pulsed DC vaccine and booster shot was 15.9 months and 31.4 months respectively, with a 1-, 2-, and 3-year survival rate of 91%, 55%, and 47%, respectively (nearly 3x SOC).

In 2002, Timmerman et al treated 35 patients with follicular lymphoma using dendritic cells (DC) pulsed with tumor-derived Id protein (tumor lysate). Among 10 initial patients with measurable lymphoma, 8 mounted T-cell proliferative anti-Id responses, and 4 had clinical responses -- 2 complete responses (CR) (progression-free [PF] for 44 and 57 months after vaccination), 1 partial response (PR) (PF for 12 months), and 1 molecular response (PF for 75+ months).

Subsequently, 25 additional patients were vaccinated after first chemotherapy, and 15 of 23 (65%) who completed the vaccination schedule mounted T-cell or humoral anti-Id responses.

Among 18 patients with residual tumor at the time of vaccination, 4 (22%) had tumor regression, and 16 of 23 patients (70%) remained without tumor progression at a median of 43 months after chemotherapy. Six patients with disease progression after primary DC vaccination, and tumor regression were observed in 3 of them (2 CRs and 1 PR). No adverse events were reported.

Their conclusion: "tumor lysate-pulsed DC vaccination can induce T-cell and humoral anti-Id immune responses and durable tumor regression."

In 2002, Holtl et al treated 35 patients with metastatic renal cell carcinoma with tumor lysate-pulsed autologous dendritic cells. Treatment was associated with transient flu-like symptoms (no adverse events -- fever is typical, and indicative of immune response).

In 2 of 27 evaluable patients, all evidence of disease disappeared (complete response). In both cases, metastatic tissue had been the source of tumor antigen. One patient had an objective partial response (over 30% reduction in tumor load). Seven patients had stable disease, while the remaining 17 patients had progressive disease (thus, over 50% positive response rate [positive response of "effective" therapies approved by FDA in such indications range from 5%-30% -- thus, 50% is exceptional]). No adverse events were reported.

In 2007, Ovali et al treated 18 patients with relapsed or refractory cancer. They were vaccinated with DCs pulsed with 100 μg/ml of tumor lysate. All subjects were advanced stage IV cancer patients of various indications, for whom no other treatment options were available (highly difficult responders).

8 patients showed positive response (1 complete remission, 4 near-complete remissions (>75% reduction in tumor mass, without the development of new metastatic lesions)), 2 partial remissions (>50% reduction in tumor mass w/out new lesions), and 1 stable disease (tumor reduction less than 50% w/out new lesions).

10 patients showed varying levels of response (some reduction amidst new lesions, or disease progression), and were classified as "no response." Tumor response and immune responses correlated with an increase in clinical response (overall survival).

They observed 4 (22%) objective clinical responses (one CR and one NCR, two PRs) and 8 (44%) clinical responses (4 objective clinical responses + 4 PA -- positive alteration). Objective clinical response rates of some large cancer vaccine studies range between 2.6%-32%. No adverse events were reported.

In 2002, Hernando et al treated two patients with uterine sarcoma and six patients with ovarian carcinoma with intracutaneous injections of antigen-pulsed DC vaccine. Median PFS in recurrent late-stage ovarian cancer is historically around 9 months.

Median PFS in recurrent late-stage ovarian cancer patients treated with tumor lysate loaded DC in this trial was nearly 22 months (one patient requested another round of vaccinations upon recurrence, having gone almost 4 years disease-free after treatment with the DC vaccine. She then went another 2 years before her second recurrence -- 6 years later, and was still alive by the publishing of this study). No adverse events were reported.

In 2006, Salcedo et al treated 15 patients with metastatic melanoma (stage III or IV) with four subcutaneous, intradermal, and intranodal vaccinations of DC loaded with tumor cell lysate. No adverse events were reported. Four out of nine patients who received the full treatment survived for more than 20 months.

Two patients showed signs of clinical response and received 3 additional doses of vaccine: one patient showed regression of in-transit metastases, leading to complete remission. Eighteen months later, the patient was still free of disease. The second patient experienced stabilization of lung metastases for approximately 10 months.

Overall, their results show that "vaccination with DC loaded with tumor lysate was well-tolerated and effective in this group of advanced melanoma patients."

Recently, in May 2014, Everson et al reported that Cytokine responsiveness of CD8+ T cells is a reproducible biomarker for the clinical efficacy of dendritic cell vaccination in glioblastoma patients.

28 patients were enrolled and treated in two different Phase I DC vaccination clinical trials at UCLA. They also noted that DC vaccination reproducibly induced elevated IL-2 (pSTAT-5) responsiveness, the magnitude of which was also directly associated with survival (17.25 months vs. 46.3 months).

Meta-analyses also demonstrated that vaccination with whole-tumor antigens induced higher objective clinical responses than vaccination with defined tumor antigens (such as with IMUC's ICT-107, validating again their differences regarding clinical efficacy).

CD3 + CD8+ T cells whose responsiveness to IL-2 was elevated after DC vaccination compared with before DC vaccination had significantly longer overall survival than patients whose CD3 + CD8+ T cell responsiveness to IL-2 did not change.

Based on this correlation, a one-unit increase in the ratio of the pSTAT-5 ratio (post-to-pre DC vaccination) from IL-2-stimulated cytotoxic T-cells following DC vaccination reduces the risk of death in vaccinated patients by 5.45 times over SOC (in the case of this extreme advantage over SOC, namely 5 ½ x increased OS, it is in the identified subgroup tested, which is estimated to represent 20%-30% of the GBM population)

Across the board, a 2-year median OS advantage over SOC was noted (as was seen in NWBO's early-phase trials). In specific patient analysis, it was noted that not only did this fantastically responsive subgroup receive benefit, but nearly all did (proneural, etc.).

In 2013, a private Austrian company conducting a Ph II trial testing whole tumor lysate-loaded DC vaccination (AV0113) on 100 patients with GBM reported promising ongoing results.

At 12 months, 21/33 (64%) of patients in the treatment group and 17/35 (48%) of patients in the control group were still alive. At 18 months, 8/15 (50%) of patients in the treatment and 6/18 (33%) of patients in the control group were still alive.

Being also a whole tumor lysate-loaded DC vaccine, these results would more likely mirror DCVax-L than those of IMUC's ICT-107, which utilizes only 6 synthetic "antigens," which are actually peptide fragments. DCVax-L and AV0113 have the advantage of loading DCs with the entire profile of tumor antigens (scores to hundreds). This produces a more effective vaccine (as referenced above).

In 2009, a peer-reviewed study was performed on DCVax-Brain (now termed DCVax-L) clinical data and related DC vaccines to-date. Their observations were:

"Published DC vaccine trials for high-grade glioma patients suggest favorable clinical outcomes not easily ascribed to non-treatment parameters. Evidence of possible selection bias exists in many reports, but efforts to account for this are evident in the most recent publications. Conclusion: DC vaccine trials provide evidence of low toxicity in GBM patients and effective induction of antitumor immunity in the latest publications correlate with clinical improvements. Preliminary reports on DCVax-Brain clinical outcomes seem to follow these trends."

Cutaneous T-cell lymphoma (CTCL) is a lymphoproliferative skin disease with limited therapeutic options. In 2003, Maier et al treated 10 CTCL patients with once-weekly intranodal injection of 1 × 106 mature monocyte-derived dendritic cells pulsed with 100 μg/mL tumor lysate protein.

Five of 10 (50%) patients had objective responses. Four patients had partial responses (PRs). Two are still in PR, and the other 2 patients had a mean PR duration of 10.5 months. One patient had a complete response for 19 months that is ongoing. The remaining 5 patients had progressive disease. In the 5 responder patients, 6.8 ± 1.4 vaccinations were necessary to induce an objective clinical response. Response was associated with low tumor burden. Continuation of vaccinations with new tumor lysate derived from progressive lesions reinduced treatment responses in 2 patients in PR.

Selected patients had massive infiltration of CD8+ and TIA+ cytotoxic T cells at the site of regressing lesions, and molecular remission after therapy. No adverse events were reported

Conclusion: "Intranodal injection of autologous tumor-lysate-pulsed DCs is well-tolerated and achieves immunologic and objective clinical responses in selected CTCL patients."

In 1999, Thurner et al treated 11 far advanced-stage IV melanoma patients, who were progressive despite standard chemotherapy, with DCs pulsed with Mage-3A1 tumor peptide and a recall antigen. Only minor (less than or equal to Grade II) side effects were observed. Regressions of individual metastases (skin, lymph node, lung, and liver) were evident in 6/11 patients.

Conclusion: "This study proves the principle that DC vaccines can frequently expand tumor-specific CTLs and elicit regressions even in advanced cancer and, in addition, provides evidence for an active CD8+ CTL-tumor cell interaction in situ as well as escape by lack of tumor antigen expression."

In 2005, Chi et al treated 12 patients with advanced/metastatic stage hepatoma not suitable for surgery (advanced late stage, terminally ill patients) with direct intratumoral injection of autologous immature dendritic cells. Two cycles of injections were given over 3 weeks. 10 patients had completed response evaluation 2 weeks after the second cycle of vaccination.

At that time, there were already seen two partial responses (over 30% tumor reduction) and four minor responses (10%-30% tumor reduction), showing a 60% positive response.

The AFP-specific immune response was evident in 8 patients examined by cytokine release assay and in 7 patients by ELISPOT assay.

In 2000, Triozzi et al treated 7 patients with melanoma and 3 patients with breast carcinoma with intratumoral injection of dendritic cells. Regression of the injected tumors, beginning as early as 4 days after injection, was observed in 4 patients with melanoma and in 2 patients with breast carcinoma.

Biopsies of regressing lesions showed lymphocyte infiltration associated with DCs and necrosis.

One patient (Patient 8) with melanoma manifested a complete response of the injected tumor and eight other 0.5-1.0 cm non-injected satellite lesions within a 6-cm radius of the injected tumor, showing an immune response.

6 of 10 patients showed at least 50% reduction in injected lesions - 1 of 10 had 25% reduction in injected lesion.

Taken together, these peer-reviewed, independent studies provide data on 217 patients (the size of a large Ph II trial, for which accelerated approval (AA) could very well be granted with positive results) showing marked effectiveness of therapy with whole tumor lysate-loaded DC vaccines. This further validates NWBO's technology, and leads one to the logical conclusion that the probability that DCVax-L is showing similar effectiveness in its blinded Ph III trial, coming near to completion (September 2014), is quite high.

This is in addition to the Company's earlier studies using whole tumor lysate-loaded DC vaccines (DCVax) to treat GBM, prostate, and ovarian cancers, totaling 81 patients, which showed 2-3x benefit, on average, over SOC -- even across multiple indications (a confirmation of effective therapy often required by FDA in transitioning from AA to full approval). That would bring our grand total to 298 patients in this paper alone.

A full meta-analysis of all patients treated in peer-reviewed studies with whole tumor lysate-loaded DC vaccines would easily eclipse 1,000 patients, and is beyond the scope of this paper.

As an aside, DCVax-Direct's preliminary results show the vaccine is off to an effective start in treating far advanced metastatic cancer patients for whom no other treatment options exist. In fairness, it is too soon to really comment accurately on any of the data. A better look can be had sometime late in 2015. But these preliminary results do appear compelling in their own right.

In summary, the growing body of evidence is readily apparent in academia, and only the difficulty in manufacturing has kept this therapy from being sponsored in late-stage clinical trials that may vie for regulatory approval. But what once took many months to produce for each patient can now efficiently be made with NWBO's patented manufacturing processes in only 8 days.

Manufacturing and Regulatory Validation of DCVax

Manufacturing is a key process in achieving regulatory approval of a drug, and it is especially important in receiving approval of a biologic (such as DCVax, which is an advanced therapy medicinal product, or ATMP). The process must be intensely vetted and found consistent in all applications of cell therapy production. Should any difference be noted from one manufacturing batch to the next, results based on the product's use will have been confounded and therefore difficult to interpret.

Most companies at an early stage of the drug or biologic development process have not endured the degree of vetting and validation NWBO has for its DCVax product. The Company and its partner, Fraunhofer IZI out of Germany, received manufacturing authorization for NWBO's Phase III clinical trial during the summer of 2012 as the culmination of a 1-1/2 year process of technology transfer, regulatory applications, regulatory review, and various inspections.

Geographically, the approvals for German manufacturing have enabled DCVax-L to be produced in Germany and supplied across borders to the UK for the clinical trials in both locations. Getting this important cross-border arrangement in place is a key step towards building a Europe-wide distribution network for DCVax products. Although Europe has a common market, the manufacturing and supply of medicinal products across borders must meet detailed regulatory and institutional requirements in all countries involved. They have obtained such from the MHRA of the UK and from the PEI of Germany after years of work.

NWBO's Phase III clinical trial was also "adopted" as a national priority trial in the UK under the "adoption" program managed by the National Institute for Health Research (NIHR), which is part of the UK's National Health System. This "adoption" of the Company's Phase III trial constitutes a significant validation, and also carries with it resources and operational support for the trial sites.

The NIHR maintains a portfolio of clinical trials that have been "adopted" as high priorities for the UK. In order to be selected for the NIHR Portfolio, a proposed clinical trial must go through multiple layers of review and evaluation. The evaluation includes the potential significance of the new medical technology being tested, the quality of the trial design, the feasibility of the trial, and numerous other factors.

Trials that are selected ("adopted") for inclusion in the NIHR Portfolio are monitored closely by the NIHR, and the trial sites receive several types of financial and operational support. For example, the NIHR provides resources and funding for additional staff (e.g., nurses) at the trial sites to help accelerate the trial. The NIHR also oversees the performance of the sites, and imposes penalties on the sites for shortfalls, such as lags in enrollment.

In addition to all of the above, a separate manufacturing authorization for Hospital Exemption cases (Section 4b) was approved for DCVax-L by the scrupulous PEI of Germany as one major step in the process towards approving DCVax-L for Hospital Exemption status there (very much like FDA's Accelerated Approval, but without marketing ability). The Company had entered a waiting period of nearly two years while the PEI deliberated granting DCVax-L Hospital Exemption status (it received manufacturing authorization for this about halfway through -- a process that is much more involved than manufacturing approval for use in clinical trials).

The evaluation of NW Bio's application by the German regulatory authority included detailed scrutiny of all aspects of the DCVax-L technology, all DCVax-L clinical data to-date, all manufacturing processes, all product characteristics (including potency, composition, sterility, and other aspects), all frozen storage of DCVax-L and frozen shelf life, and all distribution and handling of the DCVax-L products.

It then was granted approval under the Hospital Exemption program for its lead product, DCVax-L, for use in all newly-diagnosed GBM, recurrent GBM, and all lesser gliomas (stages I-IV). This is outside of, and much superior to, approval for use in a clinical trial setting, as well as superior to compassionate use (exclusively company-funded).

It was further granted full reimbursement from the German sickness funds (health insurers) by the German reimbursement authority. This is a first-of-its-kind, landmark achievement of the Hospital Exemption approval of a product that exerts a pharmacological (i.e., drug-like) effect in the patient's body, and a very strong validation of the technology and manufacturing capabilities for DCVax-L.

As with FDA's Accelerated Approval, German Hospital Exemption (HE) can be withdrawn, should the treatment eventually prove ineffective or prove to have non-isolated, adverse effects on patients treated. But given the above validations of the many peer-reviewed studies, this seems unlikely.

The PEI also could have granted HE to DCVax-L for a lesser term than 5 years, but instead chose to grant it for the full term. This was an individual decision from one regulatory body (PEI). There are multiple regulatory bodies involved in an international trial such as this one. NWBO is seeking approval from FDA and EMA specifically. The latter will blanket all countries in the EU, including Germany and the UK, should the product be fully approved. However, Germany vetted DCVax-L thoroughly enough to grant it HE ahead of any FDA or EMA decision. Now all patients covered under the German sickness fund (German citizens) may receive this therapy at no cost to them.

It is estimated some 10,000 German citizens have GBM or lesser gliomas. Now that they may all receive DCVax-L, none of them will be enrolling in the clinical trials also being hosted in their country. This is apparently the reason for delay in enrolling there, as the PEI most likely saw this impasse. However, the trial will continue there, and will be open to residents of other countries who can enroll. Furthermore, anyone in the world with the means who is a non-citizen of Germany may now travel to Germany to receive DCVax-L at cost (currently $110,000 for one batch, which will produce on average 3-5 years of treatment per patient).

The Company should begin receiving reimbursement from patients who can afford the vaccine immediately. This was previously unavailable to the Company. In addition, once reimbursement negotiations are finalized (imminent), German citizens may also receive this therapy, and the Company reimbursement for it. Given the number of patients in Germany that may receive subsidized DCVax-L treatments (approx. 10,000), the Company may stand to receive anywhere from $150mm-$300mm in sales in Germany alone (allowing a range of $50,000-$100,000 per patient, with a conservative 30% penetration).

This provides perhaps the greatest distinction between DCVax-L and NWBO's competitors still in the developmental process. No other product or drug being developed to treat GBM currently has such extensive vetting, manufacturing capabilities, and reimbursement agreements in place, providing overwhelming validation of the technology and the Company's eventual ability to fully market DCVax.

Comparison With Competitors

To begin with, there really are none. Taken literally, there are no companies with therapies in advanced, placebo-controlled Ph III trials for newly-diagnosed GBM with intent to treat the entire GBM population. Thus, at the moment, there are no competitors on the horizon with effective therapies that could sideline DCVax-L or get to approval before it. DCVax-L has also been granted orphan drug status in the US and EU for a DC therapy treating this indication. These carry 7- and 10-year marketing exclusivity rights respectively for first-to-market products of such status, as well as other benefits. Should DCVax-L be approved, it will have a marketing lock in newly-diagnosed GBM for that time frame.

Its various patents also prevent other DC therapy companies from producing vaccines as effectively as its own.

All other companies utilizing their version of whole tumor lysate-loaded DC therapies to treat the entire GBM population are early in the clinical trial process, or are pursuing approval in indications other than newly-diagnosed GBM.

ImmunoCellular Therapeutics (IMUC), as mentioned previously, is one company that has a different type of DC vaccine that utilizes 6 synthetic antigens. It has recently reported on updated results of its Ph II randomized trial in newly-diagnosed GBM. ICT-107 has shown effectiveness in the HLA-A2 antigen expressive population (approximately 60% of all GBM patients). It has especially shown strong effect in those expressing this antigen when the MGMT promoter methylation subgroup is also apparent (44% of total GBM patients). This would account for some 20%-30% of the entire GBM population, a significant sub population (which it has stated it will be developing a Ph III trial to treat).

However, when comparing specific targeted approaches (Rindopepimut, or CDX-110, is another -- with an ITT population below 30%) already outlined in two of the studies above, whole tumor lysate-loaded DC vaccines, which express the full array of biomarkers, show stronger effect than highly targeted antigen expressive DC vaccines, such as IMUC's ICT-107. Thus, the results with DCVax-L should exceed those of that study.

Still, there is strong evidence ICT-107 could find its way to approval, should it repeat these results in a large Ph. III trial, but that would take quite a while. By that time, DCVax-L will have long completed its Ph. III trial, and possibly have been granted full approval. Should this occur, IMUC would be required to begin anew, proving effect over the new SOC, namely Temodar + DCVax-L in newly-diagnosed GBM. That would be a much greater task for it to show than simply effectiveness over Temodar (a similar fate may befall AV0113 and CDX-110, basically wasting all of the money and research they had put into proving an advantage over Temodar alone).

It would also lose its ability to take advantage of marketing exclusivity via orphan drug status, having been beat to the punch by NWBO and DCVax-L. NWBO is much further along.

Another mention, although not exactly a competitor, is Dendreon's Provenge. Already an approved therapy for prostate cancer, Provenge has had disappointing sales to-date. The reason for this lies in Provenge's complicated manufacturing and infusion processes, the very high cost of the vaccine with limited proven ability to extend OS, and fierce competition from the cheaper, far more aggressively marketed (by JNJ), comparably effective Zytiga. Just how can any company succeed in the face of such obstacles?

DCVax is, by comparison, much less expensive ($100,000 is broken up over 3-5 years), far easier to produce and preserve (8 days and cryogenically preserved until needed), and for an indication in which no major therapeutic advances have occurred in the last 30 years. The best that has happened in all of that time was Temodar, which extended patients OS from 12 months to 14.6 months. And there are no competing therapies on the horizon.

If DCVax-L can prove to extend OS by even 6 months, it would be a mega blockbuster drug. Even extending PFS by this amount (its primary endpoint in the trial), while showing a trend towards greater OS than control, would likewise make it a mega blockbuster. Then consider what would be thought of it if it could show (as it has in a number of smaller studies conducted in academia) some 2 years' OS over SOC. It would be an unprecedented accomplishment.

Risk/Reward Ratio

The only available therapy for newly-diagnosed GBM on top of resection and later radiation therapy, is the chemotherapy Temodar, approved in 1999 and then for GBM in 2005. An estimated 150,000-180,000 people will be newly diagnosed with GBM worldwide each year. With no significantly effective therapies available, the need is high for alternatives.

From a strictly marketing vantage point, should DCVax-L be approved for first-line therapy, it is expected, as Temodar has, that it will achieve deep market penetration because of the dire need. An estimate of over 80% is reasonable.

Should the vaccine be available for $75,000/patient, which produces 3-5 years on average of vaccine, and taking a conservative approach by considering developed nations' markets only (40% of total incidents), sales could reach $4.8B/year (beyond this, label extension may allow its use in multiple indications). A typical factoring of sales x 2 for market cap would yield $9.6B.

Fully diluted, that would equate to a share price of approximately $108/share, imparting a 1,080% profit on a $10 share price, or a 1,800% profit on a $6 share price (at the time of this writing, the stock sits around $6/share, with one-year price targets between $12-$15).

The risk side of this ratio would see the stock plummet from its current share price to below $2/share, thus imparting more than a 65% loss of investment (at the time of this writing).

Given the unknown outcome of their ongoing Ph III trial, the risk is quite high. Should DCVax-L fail to show effect of therapy, the stock will unequivocally fall. And despite the possible potential in DCVax-Direct, it would likely not rebound for a very long time -- if at all.

 

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por cyto às 19:59


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