News and Comments

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...

Regeneron: Arcalyst is the missing link in the treatment of gout

  Friday, June 11, 2010
Regeneron’s (REGN) Phase 3 study in gout patients initiating allopurinol therapy to lower their uric acid levels showed that the company’s drug Arcalyst (rilonacept), known as IL-1 Trap, prevented gout attacks, as measured by the primary endpoint of the number of gout flares per patient over the 16 week treatment period.

Is this s good, or bad news?

Judging from investors’ reaction to the news, one would believe the clinical trial results are a failure. However, judging based on understanding the disease, its causes, complications, symptoms and what current conventional treatments are accomplishing, or lacking would prove that Arcalyst might be the missing link in the treatment of gout. The drug neutralizes a major mediator of the severe attacks of inflammatory symptom flare up the patients suffer from after taking the uric acid lowering drugs, which is the fundamental treatment of gout. That’s what makes the bulk of patients who abandon the treatments that deal with the cause of disease, i.e., elevated uric acid. of the cause of disease. No conventional drug taken at a safe dose has been effective in preventing the flare up of the symptoms, which take their toll on patients and probably lead to worsening of the disease. It is easier for gossipers to perpetrate skepticism towards Regeneron’s drug Arcalyst if the listeners do not understand what gout is and what treatments are required for its successful management. The fact is that, gout requires more than two classes of drugs to stop the main cause of this disease, control its disabling symptoms, and prevent the attacks, thus, the consequent complications if the disease is not well treated.  

Gout occurs in patients who have elevated levels of uric acid. The uric acid is deposited in the joints and other body tissues. In the joints uric acid causes joint inflammation, joint pain, stiffness swelling, redness and heat. Deposited in soft tissues, uric acid causes the same it does the joints. Generally, patients experience flare up of symptoms that no drug is yet capable of preventing. The current management of gout aims first at lowering uric acid by either decreasing its formation or increasing its elimination from the body with uric acid-lowering drugs. Drugs exist that can tackle one or the other of the two actions. For example, the drug Allopurinol, decreases uric acid formation and  Probenecid helps the body eliminate excess uric acid through the kidneys and into the urine. The problem is that controlling the level of uric acid does not stop all the symptoms right away but the pain and suffering might increase and persist for long. The reason is that the breakup of uric acid crystals boosts inflammatory mediators, especially interleukin-1 (IL-1), which causes the flare. IL-1 is targeted for inhibition by Regeneron’s drug Arcalyst. The flare the patients experience after the treatment makes it difficult for them to adhere to uric acid-lowering therapies and discontinue the treatment within the first few months of therapy. That’s why Arcalyst is badly needed.

Currently, physicians are using the anti-inflammatory drug colchicine to calm down inflammation. In many cases, however, the dose required for the control of severe inflammatory symptoms is high and must be taken for a long time, which makes its side effects prohibiting. Patients would suffer severe diarrhea, abdominal cramps, nausea, and vomiting. Non-steroid anti-inflammatory drugs are used also, but in many cases they do not control the severe inflammatory symptoms during the flare, unless very high doses are given for a long time. Long-term use of high dose can provoke grave side effects, including peptic ulcer, kidney failure and liver failure. Steroids are resorted to, yet, again, their long-term high dose use could result in detrimental side effects, which go from immune system suppression, to osteoporosis, bone fracture, endocrine system deregulation, difficulty of wound healing, diabetes and the list goes on and on.

So, the most important results from Arcalyst phase 3 study is the one, which confirms that the concomitant use of the drug with uric acid-lowering therapy for the first several months may help avoid gout flares. The use of Arcalyst is expected to improve patients’ adherence to uric acid lowering drugs, sustain their wellbeing and improve the outcome of their disease. Is this bad news? More...

The fruits of the Human Genome Project Are Ripening

  Friday, June 04, 2010
In June 2009, Illumina announced the launch of its individual genome sequencing service. The service is built around physician-patient consultation, with a physician’s order required to initiate the process. Sequencing is performed in Illumina’s CLIA-certified, CAP-accredited laboratory, following a rigorous process that focuses on physician involvement, patient privacy and data quality. The news was big, but what makes such milestones in the medical fields achievable is individuals’ serious consideration, which is possible only through offering them explanation of the purpose of the newly suggested process. In the case of individual genome sequencing (IGS), individuals should know more about sequencing, its purpose, the results and the impact on their protection and treatment, in case they are diagnosed with a sickness. The June 2009 announcement of the sequencing service, Illumina was not crystal clear on both the clinical utility of the sequencing and its cost.    

Today, Illumina (ILMN) announced the price of IGS. The details of the clinical utility of the sequencing is mostly left for physicians to elaborte on, as they are the decision makers with regard to IGS. The price decided upon is $19,500 for individual genome sequencing service and $14,500 per genome for groups of five or more participants using the same physician. In other words, to help lower the cost for clients, a physician can order five genome sequencing at a time thus saving $5000 for each individual. This is not all. Patients who suffer from serious medical conditions for whom IGS could provide potential direct clinical value the cost will be $9,500 per genome. In all cases, the service requires individuals to follow Illumina’s physician-mediated process, which involves pre-service consultation, consent, and a seven-day cooling off period, with final genome data returned to the physician.

There is no doubt that the announced price of IGS service, especially for disease-threatened patients helps opening the door to a new era where the diagnostic procedures will not only diagnose the pathology, but also its origin, i.e., the root-cause of the disease. Also, the new cost, $9,500, will definitely be a factor in making things happen. This price is much lower than the $25,000 suggested in the past. This step will open the door to therapeutics and therapeutic procedures through emerging technologies such as gene editing through antisense, RNA interference (RNAi, microRNAi and gene switching). Serious biotech companies specialized in these disciplines include ISIS (ISIS), which uses its antisense products for gene-editing, in addition to its microRNA technology developed through a Regulus Therapeutics, a company it established through a joint venture with Alnylam (ALNY), which is also specialized in RNA interference technology. Other firms include, RXI Pharmaceuticals (RXII), which is also specialized in the same. 

We expect the price of individual genome sequencing (IGS) will further drop through more technological advancements, which have been a major factor in driving the cost down in the first place. The lowering of the price will definitely lead to increasing the number of individual genome sequences, which will be compared them to those of the public databases being populated by academia. The content of the databases will be enriched and the entire field accelerated. That’s what Illumina believes would be the case. Moreover, Illumina intends to create the World Genome Registry, a web-based resource for those who have been sequenced to record the date they were sequenced, at what coverage and with which technology platform. This web site will keep the consumer genetics community updated on the current global numbers and status of whole-genome human sequences being generated. The company intends to create this resource and then turn it over to the community once it is established.

Illumina’s (IGS) service provides valuable information regarding individual genetic makeup. Although curiosity could be a driven motive for some people to ask for sequencing their genomes, a good motive should be health-driven such as existing illnesses or family history of diseases. Once the sequencing has been completed, geneticist physicians and the patients’ physicians will review the results and help the individual formulate an action plan, which may include ordering more clinically tests to further investigate the health concerns. Once found vulnerable to developing a disease, or sick, patients will have the chance to receive a much better protective and preventive measures, or, in case of sicknesses, the treatments that work for them, not against their genetic constructs. That’s why we reiterate that the biotech firms specialized in genomics are the heart of the biotechnology industry. We expect more from the genomics group and we definitely expect much more from Illumina. 

Disclosure: No position. More...

Why Amgen’s Prolia is considered a breakthrough and a blockbuster?

  Thursday, June 03, 2010
In a surprising move, the FDA approved Amgen’s (AMGN) osteoporosis drug Prolia (denosumab) two months earlier than the scheduled date, after it had caused several months delay in the drug’s marketing. The question is, why scientists label Prolia a breakthrough and why most analysts expect it to become a blockbuster, generating billions of dollars in revenues?

Assessment of breakthrough drugs entails many intellectual practices that require knowledge of history that would confirm the absence of precedents in the same category and science that enables evaluating the drug’s structure and understanding the physiological and pathological pathways of the body system targeted for treatment. These are usually followed by a hypothetical assumption of efficacy based on the results collected from all the above studies. Confirmation of the degree of both safety and efficacy, however, comes only with the results of well-planned clinical trials. 

History confirms that being a fully human monoclonal antibody, Prolia becomes the first biological drug to be developed for osteoporosis. To understand Prolia’s action and effect, one has to know first that two kinds of cells control bone formation: The osteoclasts, which remove bone tissue mineralized matrix and break up the organic bone in a process known as bone resorption and the osteoblasts that are involved in bone formation. So, while osteoclasts resorb bone, osteoblasts make bone. These antagonistic actions enable the two cells to be in control of bone formation.

Amgen’s drug Prolia binds to and inhibits the action of the receptor activator of nuclear factor kappa B ligand, (RANKL), the principal mediator of osteoclastic bone resorption. This inhibition favors bone building by osteoblasts over bone resorption by the osteoclasts. In addition, it is known that aberrant activation of nuclear factor kappa B is observed in many cancers. The suppression of the same nuclear factor by Prolia would limit the proliferation of cancer cells, making the drug a potential therapeutic for cancer. Moreover, the same nuclear factor is also a key player in the inflammatory response. Prolia’s could also be a potential therapeutic candidate for inflammatory diseases, which are many and affect a large number of patients who are at the age of developing osteoporosis. As a matter of fact, results of clinical studies with Prolia, while confirming its efficacy and safety in treating postmenopausal osteoporosis have also demonstrated positive results in bone metastasis, rheumatoid arthritis, multiple myeloma and, giant cell tumor of bone. Confirming these results, which Amgen is in the process of doing through conducting more clinical trials, would be huge positive news for the patients, the company and for Amgen’s shareholders. 

Current good news for the sufferers of osteoporosis who are vulnerable to bone fractures is that the drug will be available within the next two weeks. Good news for investors is that the cost of the drug will be $825 per 60-milligram injection based on wholesale acquisition cost. Considering the fact that the drug will be administered only twice a year, the annual cost becomes less than that of conventional drugs. In case the drug will be used for cancer or debilitating inflammatory conditions, or other life-threatening conditions, the annual cost of the drug would become much higher, as the drug will have to be used more frequently.

It seems that many analysts estimate the product could generate for Amgen $3.3 billion in annual global sales in 2014. Some of those analysts believe that the sales will be around $700 Millions in the first year, and climb higher and higher slowly in the beginning until they reach between $3B-$4B in 2014. In case the drug will be approved for cancer and inflammatory diseases, the sales, some estimate, would reach over $7B-$8B a year.

That’s not bad. No? More...

AMGEN: Prolia’s (denosumab) Approval in Europe is Great News

  Tuesday, June 01, 2010
June 1, 2010 - Postmenopausal women at increased risk of bone fractures from osteoporosis, and men with prostate cancer who suffer bone loss associated with hormone ablation treatment will finally get Amgen’s (AMGN) drug Prolia (denosumab) in Europe. The good news for these patients and for Amgen (AMGN) has come as the European Medicines Agency’s (EMEA) Commission has granted approval for the use of Prolia in both conditions. Suddenly, Prolia has been approved in 27 European Union member states plus Norway, Iceland and Liechtenstein. The European approval of Prolia marks the first approval of the product worldwide and the first and only approval in Europe for the treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures.

If approval was expected as many Wall Street analysts are stating now, why then such expectations, which also leads to expectations for billions of dollars to be generated by the drug were not reflected on the stock price, which went south instead of flying north? In addition to the drug’s proven efficacy and fast action, as demonstrated in clinical trials, the drug is convenient to take through a subcutaneous injection given every six months. All six clinical studies have demonstrated Prolia's ability to increase bone mineral density at all skeletal sites measured.

The market for Prolia is expected to be huge. Despite widely available treatments, specialists have always been eager to have new options that can really prevent bone fractures. Prolia might be the answer, as its approach innovative. The drug has a new target, RANK Ligand and has proven to tremendously reduce the risk of fracture in both postmenopausal women and prostate cancer patients who receive hormone ablation treatment. The pivotal three-year FREEDOM (Fracture, REduction, Evaluation of Denosumab in osteoporosis) study in 7,808 women with postmenopausal osteoporosis demonstrated a 68 percent reduction in the relative risk of suffering a new vertebral fracture compared to those receiving placebo. It also demonstrated a 40 percent reduction in the relative risk of suffering a hip fracture and a 20 percent reduction in the relative risk of suffering a non-vertebral fracture at 36 months. 

The some success with Prolia was demonstrated on prostate cancer patients who received hormone treatment ablation.  Results from the pivotal HALT (Hormone Ablation Bone Loss Trial) study in 1,468 men undergoing androgen deprivation therapy (ADT) for non-metastatic prostate cancer showed a 62 percent reduction in the relative risk of suffering a new vertebral fracture with Prolia compared to placebo at 36 months, with significant reduction observed as early as month 12.  

The market for osteoporosis is huge and osteoporosis is a serious disease that can significantly impact the lives of millions of women. Despite widely available treatments, new options that could protect against fractures were lacking.  The European approval was most needed for the patients and for Amgen. The drug is expected to generate billions of dollars and to be approved for more indications, including delaying cancer metastasis in bone.  

Amgen has a collaboration agreement with GlaxoSmithKline for Prolia for the postmenopausal osteoporosis indication in Europe, Australia, New Zealand and Mexico. It will be responsible for commercializing the product for all indications where Amgen lacks marketing presence. The selection of Glaxo as a partner is excellent as per this firm’s strong marketing presence in these areas. The expected approval of Prolia in the U.S. next July 25, 2010 will be tremendous news that promises adding billions of dollars in revenues into Amgen’s coffers. Prohost believes that AMGN is undervalued and has stock in one of its portfolio that comprises top-tier biotech stocks. More...

VERTEX (VRTX) A Historical Advancement In HCV Management

  Wednesday, May 26, 2010
Better than expected results are announced from phase 3 randomized, double-blind, placebo-controlled ADVANCE study with Vertex’ hepatitis C drug telaprevir. Around 1,095 patients suffering from the genotype 1 chronic hepatitis C virus took telaprevir, which has tremendously increased the cure rate at record treatment duration. Many liver experts considered this news a historical advancement in the management of progressive disabling, life-threatening and sometimes deadly chronic hepatitis C viral infection. First, the drug deals directly with the virus and, second, it wipes it out in a short limited time. The good news will be hailed by 3 millions people infected with the virus in the U.S. and by 170 million worldwide if they hear the news. 

Telaprevir’s trial results demonstrate that 75% of chronically infected patients with genotype 1 hepatitis C virus (HCV) who had not previously been treated achieved a sustained viral response (SVR or viral cure) after receiving 12-week telaprevir-based combination regimen followed by the conventional drugs pegylated-interferon and ribavirin. A slightly smaller number, 69%, of patients,  achieved the same results after a 8-week treatment with the same regimen. On the control arm, where the conventional treatments pegylated-interferon and ribavirin were given alone without telaprevir, only 44% achieved viral cure, but only after 48 weeks duration, i.e., four times the treatment duration with telaprevir. These results are better than scientists’ expectations, including those responsible for developing the drug.  

Considering the debilitating and life-threatening nature of HCV infection, one can imagine how precious telaprevir must be regarded by liver specialists who watch their HCV infected patients suffer progressive liver deterioration and general worsening of their general health. For years they witnessed patients horrified from the possibility of developing liver failure, liver cancer and from death. That’s what HCV causes. Escalating complications beginning with liver inflammation, liver scarring, liver cirrhosis, and, possible liver failure, and sometimes, liver cancer and death.

The trial results, no doubt, have increased our confidence that telaprevir will be the first protease inhibitor to reach the HCV market. Other large pharmaceutical and small biotechnology firms are also developing HCV drugs, yet, their investigational drugs are still in early and mid-term trials. A protease inhibitor, boceprevir, developed by Merck is in late phase trials. The results are expected to be unveiled before the end of the year. (For other small biotech firms developing HCV drugs go to Prohost Letter #302.)

Reaching the market earlier than other HCV products enables Vertex to capture a large part of the market and keep it. Some financial institutions believe that telaprevir could generate $3B in 2-3 years. Others expect larger revenues from the drug sales based on the fact that physicians would like to rid their patients from the virus as soon as possible. Many are convinced that the ideal regimen will be a combination of old drugs with the new protease inhibitor from beginning to end. For a more accurate speculation, however, we believe we should wait for the guidelines when issued to telaprevir’s providers. We must also wait for Vertex to put its price tag on the drug.

Vertex expects to file a New Drug Application (NDA) to the FDA for approval in the second half of 2010 for both treatment-naïve and treatment-failure patients. Vertex plans to launch the drug in the US in 2011. 

The results and the fact that telepravir combination will be given during a shorter time than the conventional drugs are big deal for HCV patients and their physicians. The short treatment duration encourages compliance, which is extremely important for halting the progression HCV complications into liver failure and cancer. Good news also is that we have witnessed a convincing increase in compliance during the numerous trials conducted with with telaprevir. The results represent a huge victory against the nasty HCV virus. 

VRTX is selling at less than $35 with a market value of around $7B. This amount is supposed to reflect the Vertex’ expected revenues from telaprevir (drug is partnered), the royalty payments of Vertex’ marketed HIV drug, and a pipeline that has several investigational drugs, which  include: A product for cystic fibrosis in phase 3 trials; three products in phase 2 trials (not partnered ) for HCV infection, inflammatory diseases, and epilepsy; two products for cystic fibrosis (partnered) in phase 2 trials; and 2 other HCV products (not partnered) in Phase 1 trials. The pipeline has another product in early development for cancer.  We believe the stock is worth much more than its current price. We hold a long position on VRTX with a near-term target $50. More...

REGENERON (REGN): Tasting The Firm's Sweet Ripened fruits

  Friday, May 14, 2010

Things happen for reasons. Curiosity is an advantage and the ability to satisfy it is a luxury restricted to humans. Those who ignore such natural gifts miss causes and outcomes of meaningful activities and events that go around them. They miss chances to opportunities. Satisfying one’s inherent curiosity is the road to wellbeing and in some instances, life-saving. More...

COMPUGEN (CGEN): On the Road To Breakthroughs

  Tuesday, May 11, 2010

We expect to see breakthrough discoveries and treatments being made by Compugen through its far-reaching discovery and validation engines. We discussed many previous discoveries in past Prohost Letters and today news enabled us to witness an important revelation. The membrane protein, CGEN-928, which had no recognized function or potential clinical utility, could now serve as a multiple myeloma drug target thanks to Compugen’s discovery engines.  More...

Gilead (GILD) Announces $5 Billion Share Repurchase Program

  Tuesday, May 11, 2010

A Press releaseMore...

DENDREON (DNDN): Lessons from History

  Friday, April 30, 2010

Are we lovers of redundancy? No. We are lovers of fairness and the lack of it cannot be visualized unless what goes on wrong gets caught and documented by history. Dendreon’s (DNDN) history, as written in the Prohost news on Prohost website, illustrates how unfair has been Wall Street evaluation to clinical-stage firms during the past decade and how tremendous were the opportunities investors have let escape from hand by relying on misleading evaluations.If you Search Dendreon on Prohost website and start to read the articles from bottom up, you will read: More...

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