Similarities Between Two Immunotherapies in Cancer

Approval of Bristol-Myers Squibb’s (BMY) Yervoy® [ipilimumab] for melanoma in March 2011 marked the second victory for the field of immunotherapy in oncology within a year, with the first being the U.S. Food and Drug Administration [FDA] approval of Dendreon Corporation’s (DNDN) Provenge® [sipuleucel-T] for metastatic castrate-resistant prostate cancer [CRPC] in April 2010.  Ipilimumab was the first immune check point molecule and sipuleucel-T was the first active immunotherapy for cancer to demonstrate improved survival in randomized Phase 3 trials.  Both were published in the prestigious New England Journal of Medicine within one month of each other.

The similarities don’t end there, as both ipilimumab and sipuleucel-T have reignited enthusiasm for the field of active immunotherapy.  Accordingly, the purpose of this article is to highlight some of the other parallels between these two innovative agents.

Both Studied in Prostate Cancer

While ipilimumab was recently approved for the treatment of melanoma, the product has also been extensively studied in prostate cancer.  In fact, there are eight clinical studies with ipilimumab in prostate cancer according to ClinicalTrials.gov, including five that are currently active or recruiting.

One particular prostate cancer study made headlines in June 2009 when investigators at the Mayo Clinic reported in the online research magazine Discovery’s Edge that the combination of a single dose of ipilimumab [3 mg/kg] with androgen ablation therapy dramatically reduced the tumor size in two patients, making surgery possible for both patients whose prostate cancer had been previously considered inoperable. The controversial results from a handful of patients were met with skepticism and the complete Phase 2 results with 108 patients with advanced prostate cancer were later reported at the American Society of Clinical Oncology [ASCO] 2010 Genitourinary Cancers Symposium [abstract #168].  According to the ASCO abstract, patients treated with androgen ablation either alone or in combination with ipilimumab demonstrated a greater than 97% decline in testosterone levels, underscoring the possibility that the tumor reductions in a few patients could have been associated with androgen ablation.  Patients treated with ipilimumab, however, were more likely to have undetectable prostate specific antigen [PSA] by three months [55% vs. 38%].

A Phase 3 trial with ipilimumab following radiation therapy in patients with CRPC that have received prior treatment with docetaxel is ongoing [ClinicalTrials.gov identifier NCT00861614].

Two is Better than One

As the first two active immunotherapies approved for the treatment of cancer, it wouldn’t be surprising to see the products studied in combination in prostate cancer – especially in view of the fact that ipilimumab has already been studied in this disease.  Sipuleucel-T may help build an effective immune response to kill tumor cells, while ipilimumab may stimulate the immune system through T-cell activation and proliferation and stop tumor cells from growing.  Accordingly, giving vaccine therapy together with ipilimumab may be an effective treatment for prostate cancer.  Interestingly, the only such combination study listed on ClinicalTrials.gov relates to a completed Phase 1 trial with ipilimumab in combination with Bavarian Nordic’s (BAVA.CO) Prostvac®, an “off-the-shelf” therapeutic cancer vaccine moving into pivotal Phase 3 clinical development [ClinicalTrials.gov identifier NCT00124670].

Pricing Controversy

Both Dendreon’s sipuleucel-T and Bristol-Myers’ ipilimumab have been criticized as overly expensive new therapies.

The cost of sipuleucel-T is approximately $93,000 for a course of treatment, which consists of three infusions at two-week intervals.  In view of the fact that the product has been demonstrated to extend median survival by 4.1 months, this translates into an average cost of $23,000 per month of added survival.

In comparison, Taxotere® [docetaxel] by Sanofi-aventis (SNY) is indicated for the treatment of CRPC and is administered every 3 weeks for 10 cycles.  Assuming an average monthly cost of $4,000 for docetaxel [source: Cancer Res 2009;69(24 Suppl):Abstract nr 1076], this is an approximate total cost of $40,000 per patient.  In the pivotal TAX 327 study, median survival for prostate cancer patients receiving docetaxel was 18.9 months versus 16.5 months in the control arm, which results in an average cost of $16,666 per month of added survival or about 28% less than sipuleucel-T.  Updated survival analysis of the TAX 327 study demonstrates a 2.9-month survival advantage, which lowers the average cost to $13,793 per month of added survival or about 40% less than sipuleucel-T.  Unlike sipuleucel-T, however, treating common adverse reactions with docetaxel, such as infections, neutropenia, anemia, nausea, diarrhea, and others, increases the total cost of therapy – and more importantly negatively impacts the patient’s quality of life.  As such, the pricing of sipuleucel-T doesn’t appear completely out of line.

According to the prescribing information, ipilimumab is administered intravenously [3 mg/kg] over 90 minutes every 3 weeks for a total of four doses.  Bristol-Myers is pricing each dose at $30,000, which translates into a total cost of $120,000 for a full course of therapy.  In the pivotal ‘020 study, median survival for melanoma patients receiving ipilimumab was 10.1 months versus 6.4 months in the control arm.  The average cost per month of added survival is approximately $32,432, which is 41% higher than the only other active immunotherapy for cancer, sipuleucel-T.

However, on March 21, 2011, Bristol-Myers announced that the ‘024 study [ClinicalTrials.gov identifier NCT00324155] met its primary endpoint of overall survival.  Minimal details were provided, but an abstract of the ‘024 data is expected to be submitted to ASCO for potential presentation at the Annual Meeting in June 2011.  The ‘024 study is in patients with untreated Stage III [unresectable] or IV melanoma receiving dacarbazine plus 10 mg/kg ipilimumab versus dacarbazine with placebo.  If the median survival for patients in the ipilimumab arm is 5.2 months or greater than the placebo arm [versus 3.7 month difference in the ‘020 study], then the pricing of ipilimumab per month of added survival would be comparable to sipuleucel-T.

Prostate and Melanoma Highly Competitive

Melanoma and prostate cancer are the two most crowded clinical development segments within the active immunotherapy field.  As such, both ipilimumab and sipuleucel-T may face competition from other active immunotherapies in the near future.  In addition, the products may soon encounter small molecule rivals.

For example, Johnson & Johnson’s (JNJ) abiraterone acetate significantly improved overall survival for patients with metastatic advanced prostate cancer.  Based on the positive Phase 3 results, the company has filed marketing applications for abiraterone acetate with regulatory authorities worldwide for the treatment of metastatic advanced prostate cancer that has developed resistance to conventional hormonal therapies. Not far behind, Medivation, Inc. (MDVN) is evaluating its MDV3100 product candidate in collaboration with Astellas Pharma, Inc. (ALPMY.PK).  The Phase 3 AFFIRM trial with MDV3100 has completed enrollment of men with advanced prostate cancer who were previously treated with docetaxel-based chemotherapy and the Phase 3 PREVAIL trial with MDV3100 is currently enrolling men who have not yet received chemotherapy

In addition, Plexxikon, Inc. [being acquired by Daiichi Sankyo Company, Limited] and co-development partner Roche Holding (ROG.VX) are advancing PLX4032, an oral drug candidate that targets the oncogenic BRAF mutation present in about half of melanoma cancers and about eight percent of all solid tumors.  Interim data from a Phase 3 controlled study of PLX4032 in previously untreated metastatic melanoma patients with the BRAF mutation met both co-primary endpoints.  Patients treated with PLX4032 had improved overall survival (OS) and improved progression-free survival (PFS) compared to patients treated with dacarbazine, the current standard of care.  A New Drug Application [NDA] for PLX4032 is expected in 2011.

Some new agents might actually be synergistic with active immunotherapies instead of representing potential competition.  This was a central theme at the recent Cancer Immunotherapy Consortium’s 2011 Scientific Colloquium titled “Schedule and Dose for Combination Therapy.”

Summary

Both ipilimumab and sipuleucel-T represent important clinical advances for the field of active immunotherapy in oncology and for patients with melanoma and prostate cancer, respectively.  Further, with nearly 50 clinical programs currently underway, including nearly a dozen that are in pivotal Phase 3 development, we expect to see five active cancer immunotherapies approved by 2015.  Beyond these clinical accomplishments, however, industry observers will be closely monitoring the commercial success of these innovative agents in view of the product pricing, supply constraints, and competitive dynamics identified to date.

Five Key Factors Weighing on Dendreon

Shares of Dendreon Corporation (DNDN) have declined significantly from an all-time high of $57.67 in late April 2010 when the company received U.S. Food and Drug Administration [FDA] approval for Provenge® [sipuleucel-T], the first active immunotherapy approved for the treatment of cancer in the U.S.  Today, shares of Dendreon traded as low as $28.01, down more than 50% from their high, prompting us to briefly review some of the key factors weighing on the company at this time.

Product pricing and reimbursement

The cost of Provenge has been set at $93,000 for a course of treatment, which consists of three infusions at approximately two-week intervals.  In view of the fact that Provenge has been demonstrated to extend survival by 4.1 months, this translates into an average cost of $23,000 per month of added survival.

In comparison, Taxotere® [docetaxel] by Sanofi-aventis (SNY) is indicated for the treatment of patients with androgen independent [hormone refractory] metastatic prostate cancer and administered every 3 weeks for 10 cycles.  Assuming an average monthly cost of $4,000 for Taxotere [source: Cancer Res 2009;69(24 Suppl):Abstract nr 1076], this is an approximate total cost of $40,000 per patient. In the pivotal TAX 327 study, median survival for prostate cancer patients receiving Taxotere was 18.9 months versus 16.5 months in the control arm, which results in an average cost of $16,666 per month of added survival.  Unlike Provenge, however, treating common adverse reactions with Taxotere, such as infections, neutropenia, anemia, nausea, diarrhea, and others, increases the total cost of therapy – so the pricing of Provenge doesn’t appear completely out of line. [note: updated survival analysis of the TAX 327 study demonstrates a 2.9 month survival advantage, which lowers the average cost to $13,793 per month of added survival with Taxotere.  Source: Journal of Clinical Oncology, Vol 26, No 2 (January 10), 2008: pp. 242-245.]

Nonetheless, the Centers for Medicare and Medicaid Services [CMS] has initiated a National Coverage Analysis [NCA] of Provenge. In CMS’s announcement of the NCA, CMS is requesting public comments on the effects of Provenge on health outcomes in patients with prostate cancer. While the news doesn’t reflect a change in Medicare coverage policy or impact existing coverage decisions and a decision isn’t expected for a year, it does highlight sensitivity on the part of payors over the pricing of certain cancer treatments.

Supply constraints

Dendreon is making Provenge available through approximately 50 centers, all of which were approved Provenge clinical trial sites, and expects to increase capacity over the next year.  The increased capacity will be a result of the anticipated licensure of its expanded New Jersey, Georgia and California facilities in mid-2011.

In the short term, however, Dendreon officials have indicated that the company will only be able to supply 2,000 treatments to patients.  At a cost of $93,000 per treatment, this limits potential sales to approximately $186 million.

According to a June 28 article by Bloomberg reporter Tom Randall, Dendreon’s Chief Operating Officer Hans Bishop indicated that facilities will be able to churn out medicine each year valued at between $1.25 billion and $2.5 billion by the end of 2011.

Competitive landscape

In early April 2010, we published a 150-page industry report titled “Cancer Vaccine Therapies: Failures and Future Opportunities,” which included an overview of the cancer immunotherapy market, interviews with several key opinion leaders, profiles of nearly 40 companies, and a discussion of the scientific, clinical, and commercial considerations for the major industry participants.

In the report, we highlighted the fact that numerous active immunotherapies are in late-stage clinical development for prostate cancer.  In fact, nine product candidates are in clinical trials for the treatment of prostate cancer, representing the largest therapeutic area within the active immunotherapy market.  Beyond competition from other active immunotherapies, however, Provenge could also face competition from small molecule products.

For example, Johnson & Johnson (JNJ) acquired Cougar Biotechnology, Inc. for approximately $1.0 billion in cash in 2009.  Cougar Biotechnology’s oncology portfolio included abiraterone acetate [CB7630], an orally active acetate salt of the steroidal compound abiraterone.  Abiraterone acetate, which can suppress testosterone production by both the testes and the adrenals to castrate-range levels, is currently in two Phase III clinical trials for the treatment of prostate cancer according to ClinicalTrials.gov [Trial identifier numbers NCT00638690 and NCT00887198].  Both studies list a primary completion date of mid-2011.

Insider sales

Trading conducted by corporate officers, key employees, directors, or significant shareholders must be reported to the Securities and Exchange Commission [SEC], usually within a few business days of the trade.  Some investors follow the activity of insiders, believing that they might have better insights into the health of a corporation and that their trades convey important information – although this isn’t always the case.

In this regard, according to a Form 4 filed with the SEC, Dendreon’s Chief Executive Officer [CEO] beneficially owned 555,211 shares of the company’s common stock as of April 29, 2010 – the day Provenge was approved by the FDA.  The CEO sold more than half of those shares at prices ranging from $51 to $54.70, reducing his beneficial holdings to 224,359 the next day.  Other insiders also sold during the period.

Priced for perfection

Recall that Eli Lilly & Co. (LLY) purchased ImClone Systems for $6.5 billion back in 2008.  ImClone’s only product – Erbitux® [cetuximab] – had generated annual sales of approximately $1.3 billion in 2007.  Therefore, ImClone was valued at a 5x multiple to prior year sales.

At its 52-week high, Dendreon had a market capitalization of approximately $7.8 billion.  At a 5x multiple, this would imply an annual revenue run rate of $1.56 billion, which is consistent with the company’s planned manufacturing capacity by the end of 2011 and many analyst projections over the coming years.

But Dendreon isn’t generating $1.56 billion in annual sales yet and concerns over pricing, reimbursement, and competition, combined with insider selling, help explain the decrease in market valuation since the approval of Provenge.

Much Ado About Medarex

According to their website, Discovery’s Edge is the Mayo Clinic’s online research magazine that is designed to communicate the story of scientists and researchers who are bringing treatments and improved care to patients and also reports on “works–in–progress.”  Through this publication, Mayo investigators studying immunotherapy for aggressive prostate cancer reported over the past weekend that a combination therapy dramatically reduced tumor size to make surgery possible for two patients whose prostate cancer had been previously considered inoperable.  While preliminary, Mayo reported that the results were significant enough for future research.

As noted in our recent articles, investors have been “irrationally exuberant” towards biotechnology companies working in the field of prostate cancer – even those in the early stages of development.  In keeping with this theme, the Mayo news drove shares of Medarex, Inc. (MEDX) up more than 20% on Monday morning with significant volume, as the immunotherapy referenced in the investigator-sponsored study involved the company’s ipilimumab product candidate.  Ipilimumab is a fully human antibody that binds to CTLA-4, a molecule on T-cells that plays a critical role in regulating natural immune responses.

Enough has been written about the fact that the positive results were demonstrated in a mere two prostate cancer patients and the lack of information provided in the Discovery’s Edge publication (see Associated Press article), so I won’t belabor the point.

It is interesting to note, however, that Medarex included a summary of the Mayo report from two patients under the news section of the company’s website, yet the company didn’t report Phase 2 study results with ipilimumab in aggressive prostate cancer that were reported by researchers at Memorial Sloan-Kettering Cancer Center (MSKCC) during the Annual Meeting of the American Society of Clinical Oncology (ASCO) held May 29-June 2, 2009.  See abstract #5138 titled “Initial phase II experience of ipilimumab (IPI) alone and in combination with radiotherapy (XRT) in patients with metastatic castration-resistant prostate cancer (mCRPC).”

In the MSKCC study reported at ASCO, 45 patients with mCRPC received ipilimumab in 3 groups:

  1. ipilimumab alone, n=16
  2. ipilimumab + XRT, n=15, in chemotherapy naïve
  3. ipilimumab + XRT, n=14, in chemotherapy experienced patients

In the study, PSA declines ≥ 50% were seen in 10 of 45 (22%) patients.  Only one patient from Group 1 (ipilimumab alone) demonstrated a PSA ≤ 0.05 ng/ml and complete resolution of bone, nodal and prostate lesions that continued for 54+ and 84+ weeks, respectively.

While Medarex issued a press release on May 31, 2009 summarizing the results from three Phase 2 studies of ipilimumab in metastatic melanoma at ASCO, there was no such communication regarding the Phase 2 results from MSKCC in prostate cancer that certainly don’t live up to the hype generated by the results from the Mayo Clinic report.

Molecular Insight Pharmaceuticals: In the Prostate Cancer Spotlight

Prostate cancer is the most common type of cancer found in American men, other than skin cancer. In 2009, the American Cancer Society estimates that there will be nearly 200,000 new cases of prostate cancer in the United States and that about 27,000 men will die from the disease. It is estimated that there are more than 2 million American men currently living with prostate cancer.

As noted in our May 31, 2009 article, investors appear to be gravitating towards biotechnology companies working in the field of prostate cancer. Consider the following:

  • Shares of Dendreon Corporation (DNDN), which traded in the low single-digits earlier this year, currently trade above $25 following positive Phase 3 results for the company’s prostate cancer vaccine study in April 2009
  • Shares of Cougar Biotechnology, Inc. (CGRB), a development stage company with an oral prostate cancer treatment being studied in two Phase 3 clinical trials, traded as low as $16.35 over the prior 12-months before the company received a $43.00 tender offer from Johnson & Johnson (JNJ) in May 2009
  • Shares of OncoGenex Pharmaceuticals, Inc. (OGXI), which were trading around $6.00 at the end of April 2009, recently reached a 52-week high as $27.00 following the presentation of positive Phase 2 trial results for the company’s prostate cancer treatment at the Annual Meeting of the American Society of Clinical Oncology (ASCO)
  • Shares of Poniard Pharmaceuticals, Inc. (PARD), which traded as low as $1.00 in December 2008, recently reached a 52-week high of $5.50 following the presentation of positive Phase 2 data for the company’s picoplatin product candidate in patients with metastatic hormone-refractory prostate cancer at ASCO

Therefore, it may not be surprising that shares of Molecular Insight Pharmaceuticals, Inc. (MIPI) nearly doubled over the past month following the presentation of data demonstrating that the company’s investigational imaging agents can rapidly detect the spread of prostate cancer to soft tissues and bone at the recent annual meeting of the Society of Nuclear Medicine. Shares of Molecular Insight Pharmaceuticals, which traded as low as $1.15 in March 2009, nearly reached $8.00 this month on heavy volume.

Currently, simple blood tests to determine the amount of prostate-specific antigen (PSA), a protein produced by the cells of the prostate gland, are used to help initially detect prostate cancer and to monitor patients with a history of prostate cancer to see if the cancer has come back, or recurred. Unfortunately, PSA levels cannot directly identify the extent or location of disease.

Molecular Insight’s two product candidates (MIP-1072 and MIP-1095) are small molecules that target prostate-specific membrane antigen (PSMA), a protein abundantly expressed on the surface of prostate cancer cells. An imaging radioisotope (Iodine-123) is linked to the small molecules, which are administered intravenously into the patient. The small molecules travel through the bloodstream and bind to PSMA. The radioactivity from the isotope that has been attached to the small molecules can be detected from outside the body by camera equipment found in the nuclear medicine departments of most hospitals. The image captured by the camera assists in the identification of the location of the radiolabeled molecules, thus identifying the sites of tumors.

The first commercial molecular imaging agent targeting PSMA was cleared for marketing by the Food and Drug Administration (FDA) in 1996. Unlike Molecular Insight’s small molecule approach, Eusa Pharma’s ProstaScint® (capromab pendetide) consists of a monoclonal antibody directed against PSMA that is linked to the imaging radioisotope Indium-111. Publicly-reported sales of ProstaScint were $9.6 million for the year ended December 31, 2007.

Theoretically, Molecular Insight’s small molecule approach to targeting PSMA represents an advantage over monoclonal antibodies, as the imaging session can be done in a single day. In fact, the company’s compounds were able to detect metastases within one to two hours after injection. This is not possible with current monoclonal antibody approaches, which require that the patient make a second visit for imaging between 72 and 120 hours after infusion.

Molecular Insight’s product candidates may also have the potential to treat metastatic prostate cancer. The company is conducting preclinical studies for product candidates using the same small molecules attached to a therapeutic (as opposed to imaging) radioactive substance called Iodine-131.

Although investors are enthusiastic about biotech companies working in the field of prostate cancer right now, it is worth reminding readers that drug development is a long and expensive process and Molecular Insight’s prostate cancer compounds are in the early stages. According to the company, the plan for 2009 is to complete a proof of concept and dosimetry trial for imaging prostate cancer. Fortunately, Molecular Insight also has later-stage programs in development, including a molecular imaging product candidate for the diagnosis of cardiac ischemia, or insufficient blood flow to the heart.

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Disclaimer: This article contains the author’s own opinions, and none of the information contained therein constitutes a recommendation that any particular security, portfolio of securities, transaction, or investment strategy is suitable for any specific person. To the extent any of the information contained in the article may be deemed to be investment advice, such information is impersonal and not tailored to the investment needs of any specific person.

Biotech Stocks and the ASCO-effect

Investors are hoping that the spark that could reignite investor enthusiasm for biotech stocks is taking place right now. Approximately 30,000 participants are gathering from May 29-June 2, 2009, in Orlando, Florida, for the year’s largest cancer conference. Attendees of the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO) will exchange ideas and hear about the latest breakthroughs in cancer therapeutics and diagnostics from over 4,000 scientific abstract presentations during the four day event.

It is no wonder that ASCO is closely watched by biotechnology industry observers. According to the Pharmaceutical Research and Manufacturers of America (PhRMA), there are 633 medicines and vaccines developed through biotechnology in human clinical trials – the majority of them (254) for the treatment of cancer. Even more impressive, all of these products are either in human clinical trials or under review by the Food and Drug Administration (FDA).

The need for new cancer treatments and diagnostics is compelling. This year alone, the American Cancer Society estimates nearly 1.5 million new cases of cancer will be diagnosed with more than 562,000 Americans expected to die from the disease. Not only is cancer the second leading cause of death in the US (exceeded only by heart disease), the economic impact is massive. University of Chicago economists Kevin Murphy and Robert Topel reported that a permanent one percent reduction in mortality from cancer alone has a present value to current and future generations of Americans of nearly $500 billion and that a cure would be worth about $50 trillion.

For biotechnology companies working in the field of cancer, double or triple-digit stock price increases from the end of April through the ASCO meeting (usually held in late May or early June) are not unprecedented. I first dubbed this the “ASCO-effect” in May 2000 while presenting a review of the top five performing stocks from companies issuing ASCO-related news from 1996 through 1999. Ironically, more than a decade has passed, but some of the same companies are once again benefiting from the ASCO-effect.

For example, Peregrine Pharmaceuticals, Inc. (PPHM), known as Techniclone Corporation at the time, saw its stock price nearly triple as a result of the ASCO-effect back in 1998. The stock, which was trading below $0.40 at the end of April 2009, recently traded as high as $1.13 on news that preliminary data from a Phase 2 clinical trial evaluating the company’s bavituximab in combination with docetaxel in advanced breast cancer patients would be the subject of an oral presentation at ASCO.

In addition, the stock of Poniard Pharmaceuticals (PARD), known as NeoRx Corporation at the time, nearly doubled as a result of the ASCO-effect in 1998. The stock, which was trading around $3.00 at the end of April 2009, recently traded as high as $5.19 on news that data from two Phase 2 clinical trials evaluating the company’s picoplatin in metastatic prostate and colorectal cancer would be presented at ASCO.

Since there are over 4,000 scientific abstracts being presented during ASCO 2009, it would be impossible to detail all of them in this setting. However, following recent positive Phase 3 results from Dendreon Corporation (DNDN) regarding its prostate cancer vaccine study; it is not surprising that investors appear to be gravitating towards companies working in the field of prostate cancer treatment. This enthusiasm only increased when Johnson & Johnson (JNJ) announced that it would acquire Cougar Biotechnology, Inc. (CGRB), a development stage company with an oral prostate cancer treatment being studied in two Phase 3 clinical trials, for approximately $1.0 billion.

With this in mind, OncoGenex Pharmaceuticals, Inc. (OGXI) appears to be one of the early beneficiaries of the ASCO-effect in 2009. The company’s stock, which was trading around $6.00 at the end of April 2009, recently traded as high as $22.00 on news that the company will be presenting final results of a Phase 2 trial of its prostate cancer treatment at ASCO. On Monday, investors will react to the data presented over the weekend.

At the start of the year I provided a positive outlook for the biotechnology industry in 2009, citing the sector’s defensive characteristics, favorable technical aspects, and improving fundamentals, such as the number of new product approvals, products in clinical trials and the brisk pace of industry consolidation and licensing transactions. With these fundamental and technical characteristics intact, it is possible that this year’s ASCO meeting could be the spark that reignites investor enthusiasm for the sector.

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Disclaimer: This article contains the author’s own opinions, and none of the information contained therein constitutes a recommendation that any particular security, portfolio of securities, transaction, or investment strategy is suitable for any specific person. To the extent any of the information contained in the article may be deemed to be investment advice, such information is impersonal and not tailored to the investment needs of any specific person.