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HIV/AIDS: Great News With Enormous Promises

  Wednesday, July 14, 2010
When people began to develop acute immune deficiency syndrome and die, horror was the feeling of humans allover the world. Nobody had yet known the cause of the catastrophe and no science could deliver any explanation. When the explanation emerged, the horror became a double horror for those who found out that the culprit is a new virus that has the ability to destroy the immune system and its presence is a death sentence. For a few years, patients died by the thousands without any hope without treatments and with the first generation treatments. The side effects of the combination drugs given at the time were bitter honey that offered sweet unreliable hope and bitter devastation and despair.

It was real horror for the patients, their relatives and friends until the advancement in molecular biology and biotechnology began to yield drugs that turned the desperation into real hope. The improvement on these products by companies like Gilead (GILD) contributed to patients’ well being and to a better prognosis for the devastating disease. HIV patients are now living almost a normal life, but unfortunately, no protective vaccines and no cures have succeeded in reaching the market. All attempts to developing vaccines have failed and all promises of cures have died in experimentation. The mini HIV creature has been capable of evading all scientists’ creative means to prevent it from destroying human immune system cells.

Suddenly, and unexpectedly, last Thursday morning, we opened our eyes on breathtaking news from the National Institute of Health (NIH). The NIH announced the discovery of two natural antibodies that can prevent 90% of known HIV strains from infecting cells. A study detailing the research was published in the online edition of the journal Science. The unexpected pleasurable news made us feel, for the first time in years, that humans are finally on the most relevant path towards beating HIV at its own game. We felt that we are on the brink of winning the quarter of a century war between the human mind and the invisible mindless HIV creature, which used its built in instinctive savoir-faire in dismantling millions of human immune systems while protecting itself against all kinds of attempts to assassinate it, or prevent it from causing what medical literature call acquired immune deficiency syndrome (AIDS), killing millions of victims. The NIH news hinted that the research would probably lead to the development of far-reaching HIV preventive vaccines and treatments.

Like all stories of breakthrough achievements, the hero behind this story is the privilege restricted to humans known as curiosity. NIH’s scientists’ curiosity has led them to observe that a few HIV-infected patients have not developed AIDS. They called those patients, non-progressors. It was obvious that the lucky few must have something unique in their immune system that would prevent the virus from invading their immune system cells. Motivated still by academic curiosity, the scientists were determined to unearth the reasons behind the strange phenomenon.

Together with other scientists from various medical and research institutions, the NIH team used a novel molecular device that consists of an HIV protein they modified so it would react only with antibodies specific to the CD4 binding site of HIV. The trick worked. Two antibodies, VRC01 and VRC02 did attach to the protein. The scientists then determined the atomic-level molecular structure of VRC01 when attached to the CD4 binding site. The findings enabled them to learn the structure of the discovered natural antibodies. It is important to know that the CD4 binding site of the virus does not mutate, which explains the reason that the discovered natural antibodies are capable on neutralizing the effects of a vast majority of HIV strains. 



The information was sufficient for the scientists to begin designing components of a candidate vaccine that could stimulate the human immune system to make the natural antibodies, which would prevent infection by many HIV strains worldwide. Developing vaccines to produce the natural antibodies face some technological challenges. The leader of the research, Dr. Kwong, and his colleagues explored how this challenges might be addressed by designing vaccine components that could guide the immune system through the stepwise antibody maturation process, hence, facilitating the generation of a VRC01 antibody from its precursors. Another suggested possibility is designing gene therapy where a gene can express one of the antibodies, probably, VRC01. 



The reason for the failure of the naturally occurring antibodies in protecting the majority of patients is that the immune system usually produces them after the patients are infected. In HIV, the virus has the advantage of debilitating the immune system before the protective antibodies go into action.  



Experts’ Comments



Dr. Gary Nabel, the National Institute of Allergy and Infectious Diseases said:



"I am more optimistic about an AIDS vaccine at this point in time than I have been probably in the last 10 years. Two natural antibodies can attach to and neutralize 90 percent of the various mutations of the human immunodeficiency virus that causes AIDS. 



“We have used our knowledge of the structure of a virus—in this case, the outer surface of HIV—to refine molecular tools that pinpoint the vulnerable spot on the virus and guide us to antibodies that attach to this spot, blocking the virus from infecting cells.”

"This is an antibody that evolved after the fact. That is part of the problem we have in dealing with HIV -- once a person becomes infected, the virus always gets ahead of the immune system.  What we are trying to do with a vaccine is to get ahead of the virus."



Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, said:

“

The discovery of these exceptionally broadly neutralizing antibodies to HIV and the structural analysis that explains how they work are exciting advances that will accelerate our efforts to find a preventive HIV vaccine for global use.” In addition, the technique the teams used to find the new antibodies represents a novel strategy that could be applied to vaccine design for many other infectious diseases.”

Dr. Mascola, the deputy director of the VRC, said:

“The antibodies attach to a virtually unchanging part of the virus, and this explains why they can neutralize such an extraordinary range of HIV strains.”

Dr. Kwong who led the team at the NIH said, 



“The discoveries we have made may overcome the limitations that have long stymied antibody-based HIV vaccine design.”  



Research teams: The researchers included NIAID scientists from the VRC, the Laboratory of Immunoregulation, and the Division of Clinical Research, all in Bethesda, Md.; researchers from Beth Israel Deaconess Medical Center in Boston; Columbia University in New York; Harvard Medical School and Harvard School of Public Health in Boston; The Rockefeller University in New York City; and University of Washington in Seattle.



References:



Wu X et al. Rational design of envelope surface identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science. DOI: 10.1126/science.1187659 (2010).



Zhou T et al. Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science. DOI: 10.1126/science.1192819 (2010). 



Prohost Comments



This is good news. It offered insightful research, very promising results and suggestions for far-reaching treatments. We do not know which one of the drug designers and developers has helped design and develop the molecules used in the NIH experimentation and we do not know who will develop the therapeutic molecules or the vaccine. But we certainly know that these tasks are none of academia or government businesses. They are the specialty of drug developers that have state-of-the-art drug design and monoclonal antibody technology. There is no doubt that the NIH information has brought new possibilities for the drug developers that are interested in conquering HIV.

We take advantage to recognize the fact that the successful NIH research would not have been possible if not for the accumulated data from the previously failed attempts to develop HIV preventive and therapeutic vaccines. Some of the companies that spent a lot of effort and money on their unsuccessful attempts might have failed to survive, but their efforts have not gone to the drain. For scientists, data from failed experiments are cause for improvement. Data about failed trials are teaching treasures. They teach scientists the reasons for previous failures. They alert them against scientific mistakes that could jeopardize their efforts. They open scientists’ minds to scientific and procedural facts that are usually introduced to science after failed trials.

Before we forget, we have to admit that the firms developing the current HIV treatments have rescued millions of patients from agony and death. The world should be grateful to: Gilead (GILD), Vertex (VRTX), Abbott Laboratories (ABT), Bristol-Myers Squibb (BMY) Roche (RHHBY), GlaxoSmithKline (GSK) and any other HIV drug developer anywhere n the world that we might have omitted mentioning.

These firms will continue to offer HIV treatments for years to come and will continue to improve on them. Gilead sciences is the leader of the HIV innovative drugs. Its protease inhibitors and combination drugs have caused a tremendous transformation in HIV victims’ lives and well being.

In related news, a week ago, the U.S. decided upon a new AIDS policy that aim at finding new ways to educate people about HIV. The policy aims also at getting more patients to treatment as fast as possible, urging the FDA to consider reviewing new HIV tests a priority. The guidelines   focus on prevention and on making sure that the patients have access to care and to tests that monitor the infection so they can take their drugs at the right time.

This news is good news for HIV victims and for HIV drug developers. More...

EXELIXIS: Fear based on mind reading vs. reality.

  Monday, June 28, 2010
Following Exelixis (EXEL) press release, which announced that it has regained full rights from Bristol-Myers Squibb (BMY) to its cancer drug XL184, the firm’s stock plummeted. In the press release, Exelixis stated that BMS’ priorities made it difficult for BMS to align on the scope, breadth and pace of the ongoing clinical development of XL184 as agreed upon in the original agreement. Those who instigated the sell-off did not buy Exelixis’ explanation and were more comfortable with the notion that BMS decided to walk away from XL184, probably because of bad news about the drug. Their reasoning was that a giant pharmaceutical company like BMS, which focuses on building an impressive advanced oncology pipeline would not let a promising multi-targeted cancer drug in late phase trials slip from its hands without a significant reason. BMS did not allude to any bad reason or any reason at all for its decision. It did not comment on Exelixis’ explanation and did not deny it. 

Although investors’ speculation and their spontaneous response, instigating the selling of the stock, are not irrational, they were not supported by evidence-based knowledge, or facts. Their best speculation was that if BMS doubts the drug’s promises the least of what they can do is the same as BMS did, i.e., abandoning investing in Exelixis. The sell-off was triggered by a pyramid of suppositions that have no concrete proof.  

Now that the acute fear has subsided and Exelixis stock price bottomed, other investors and, probably, some of those who sold the stock, might like to take a deep breath and reexamine the whole situation in a more professional and rational way. It is not unreasonable for investors to try to find out good investment opportunities in bottomed stocks.

To find out whether the stock selling based on the sellers’ reading of BMS’ mind is correct, or a mistake, we resorted to history, which tells that many large pharmaceutical firms have abandoned the development of drugs that have become best sellers when other firms continued developing them. Looking at the drug itself and the history of its performance in clinical trials, we see XL184 as not only the most advanced product in Exelixis pipeline, but is also the most advanced MET inhibitor. MET pathway has long been recognized as a master switch and drug target in cancer progression. MET is mutationally activated in hereditary and sporadic papillary renal cell carcinoma and some head and neck cancers. It is either over-expressed or activated in the absence of mutation in glioblastomas, breast carcinomas, gastric cancers and other solid tumors. MET amplification has been demonstrated in some NSCLCs.

XL184 also targets and inhibits VEGFR2, which leads to starving the tumors of oxygen through the antiangiogenic effect. Expression of VEGF occurs in various cancers and has been associated with prognostic significance. Targeting the VEGF receptor has already demonstrated efficacy as anti-cancer strategy in multiple tumors. Dual targeting of MET and VEGFR2 blocks two of the major mechanisms tumors use to overcome hypoxia.

In addition, XL184 inhibits RET, which is identified in multiple endocrine tumors and familial medullary thyroid carcinoma. Activated RET is involved in regulating cell proliferation, migration, differentiation, and survival. It is activated in papillary thyroid cancer (PTC) and in both familial and sporadic forms of medullary thyroid cancer (MTC).

These unique combination of actions makes XL184 capable of causing antiangiogenic, antiproliferative, and antiinvasive effects in tumors – all have been confirmed in preclinical cancer models and in some clinical trial results. 

At ASCO 2010 Annual Meeting, the developers reported that in phase 1 trials on patients with  medullary thyroid cancer, XL184 demonstrated a 29% response rate, with a median duration of response that had not yet been reached, with a range of 4 to 35+ months. They also reported that in a phase 2 clinical trial on patients with the nasty glioblastoma, XL184 demonstrated a 30% response rate when dosed at 125 mg daily, with a median duration of response of 5.1 months. Data were presented showing that the drug demonstrated objective responses in patients with refractory melanoma, non-small cell lung cancer (NSCLC) (both as a single agent and in combination with erlotinib), hepatocellular carcinoma, prostate and ovarian cancers in an ongoing adaptive randomized discontinuation trial (RDT).

The above results were announced by the developing firms prior to their divorce. They are encouraging.  Do we have any concrete reason to doubt them? We personally don’t. All what we see now is a unique drug that targets three very important pathways of a multitude of cancers. About future plans, the drug will be in the hands of the FDA for approval of its first indication, thyroid cancer, in 2011. Exelixis expects to initiate a phase 3 pivotal trial in recurrent glioblastoma in the year-end 2010 time frame and to prioritize tumor types from the RDT in 2011 to add more cancers to the drug indications.

This is how we see the story. More...

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