Dr. Sharman's Post: How expensive are new drugs?

I just got through reading Dr. Sharman's blog post and wanted to share it with you. It is a continuation of my conversation about the out-of-control costs of cancer drugs. I will let his words speak to you...

http://www.cll-nhl.com/2013/05/how-expensive-are-new-drugs.html?utm_source=feedburner&utm_medium=email&utm_campaign=Feed%3A+DrSharmansCllNhlBlog+%28Dr.+Sharman%26%2339%3Bs+CLL+%26amp%3B+NHL+Blog%29

Paying to Survive: The Cost of Leukemia Drugs

My husband Carl and I have worked hard all of our lives. We both went to college, earned a living, raised a family, contributed to society, and hoped to leave the world a better place because we were here. Cancer reared its ugly head when we least expected it, and it took a financial and emotional toll on us. Becoming a proactive patient has helped me to personally deal with my diagnosis of 17p deleted leukemia.

As you all know, I have just completed nine months in a clinical trial with an experimental drug Ibrutinib, which will not cure the leukemia, but seems to be keeping it at bay, until a cure can be found. Hurrah! It looks like the FDA will approve of the drug in a year or so. This will be my lifeline and has changed my chances for survival. Hurrah! Now the next obstacle in our lives… How much am I going to have to pay to survive?

Here is a quote from the Blood Journal Report, which was prepublished April 25, 2013:

“Of the 12 drugs approved by the FDA for various cancer indications in 2012, 11 were priced above $100,000 per year. Cancer drug prices have almost doubled from a decade ago, from an average of $5,000 per month to more than $10,000 per month.”

If the cost of Ibrutinib follows in suit with today’s cost of Imatinib, more commonly known as Gleevac, which is a drug for chronic myeloid leukemia, the drug company will probably price it about $100,000 per year. Hmmm… My husband is retired. I am not working now. I don’t believe we have an extra $100,000 per year laying around to pay for my survival. I wonder if my insurance will help me pay for this? We are not alone in this situation. I guess we will cross that road when we get there.

All I can say is “Thank God for compassionate and sensible physicians.” Dr. Hagop Kantarjian from M.D. Anderson in Houston is taking the lead with a paper in the Blood Journal Report:

“The Price of Drugs for Chronic Myeloid Leukemia (CML); A Reflection of the Unsustainable Prices of Cancer Drugs: From the Perspective of a Large Group of CML Experts.”

Dr. Kantarjian states:

“As a group of more than 100 experts in chronic myeloid leukemia (CML), we draw attention to the high prices of cancer drugs, with the particular focus on the prices of approved tyrosine kinase inhibitors for the treatment of CML. This editorial addresses the multiple factors involved in cancer drug pricing, their impact on individual patients and healthcare policies, and argues for the need to lower the prices of cancer drugs to allow more patients to afford them and to maintain sound long-term healthcare policies.”

Blood Journal Report full article:

http://bloodjournal.hematologylibrary.org/content/early/2013/04/23/blood-2013-03-490003.full.pdf

The New York Times article, published April 25, 2013, states that physicians in more than 15 countries on more than five continents have joined together to suggest “… that charging high prices for a medicine needed to keep someone alive is profiteering, akin to jacking up the prices of essential goods after a natural disaster.”

New York Times full article

http://www.nytimes.com/2013/04/26/business/cancer-physicians-attack-high-drug-costs.html?_r=1

Stay tuned for the next adventure of “Dr. La Verne’s Awesome Adventure: Slaying the Leukemia Dragon.”

Dedicated to Dr. Mohammed Farooqui

This painting is on display at Banner Hospital for the next few months. When it is returned to me, I will give it to Dr. Farooqui as a gift of appreciation.

Novel Antibody Directed at Chronic Lymphocytic Leukemia

By Anna Azvolinsky, PhD¹ | April 3, 2013

¹Freelance Science Writer and Cancer Network Contributor.

Researchers have identified a novel monoclonal antibody directly targeted against a receptor found in abundance on chronic lymphocytic leukemia (CLL) cells, but not normal B cells. The humanized antibody can directly kill CLL cells, according to Thomas Kipps, MD, PhD, professor of medicine and deputy director for research at the University of California, San Diego Moores Cancer Center, and colleagues. The results of the study are published in the online edition of Proceedings of the National Academy of Sciences.

In contrast to normal B cells, CLL cells express a high level of CD44, a cell-surface glycoprotein receptor. CD44 is thought to mediate one of the important survival signals for leukemia cells. CLL cells receive survival signals from its tumor environment, including cells that are present in the lymph nodes and the bone marrow of CLL patients. Previous work from Kipps and colleagues has shown that CLL cells can undergo drug-induced or spontaneous cell death when removed from a patient and cultured in the laboratory. Because the RG7356 antibody induces cell death of the CLL cells by binding to CD44, the drug is a potential new therapy for treatment of at least a subset of CLL patients.

Ibrutinib on a Fast Tract for FDA Approval for 17p Deleted Patients

EXTRA! EXTRA!

April 8, 2013 it was announced that the FDA granted breakthrough therapy designation for ibrutinib (Janssen and Pharmacyclics) as a monotherapy for patients with CLL/SLL (chronic lymphocytic leukemia or small lymphocytic lymphoma) with deletion of the short arm of chromosome 17. This genetic mutation is associated with poor prognosis and is one of the worst prognostic factors in patients with CLL. This is what I have.

This is the third breakthrough designation the FDA granted for ibrutinib an investigational Bruton’s tyrosine kinase inhibitor. One was as a monotherapy for previously treated patients with relapsed or refractory mantle cell lymphoma, and the other was as a monotherapy for patients with Waldenström’s macroglobulinemia.

The breakthrough therapy designation was created in 2012. It enables the development and review of drugs shown in preclinical studies to offer potentially substantial improvements over existing therapies for patients with serious or life-threatening diseases to be expedited.

Patients like me with 17p deletion generally do not respond well to chemoimmunotherapy, and are limited on their treatment options. In my case, because I am bi-racial, I have less than a 1% chance of finding a bone marrow donor match. Ibrutinib has the potential to improve the outcome in this serious and life-threatening disease, and is much less risky than a bone marrow transplant.

A Phase II global study of ibrutinib in patients with CLL deletion 17p, will be available this year and Pharmacyclics plans to enroll 111 patients worldwide. The study called “RESONATE™ -17” is a single-arm, open-label, multi-center trial using ibrutinib as a monotherapy in previously-treated patients who have deletion 17p, who did not respond or who relapsed (a high unmet need population). The purpose of the study will be to determine overall response rate.

Those of you following my blog know that I have just completed my 9-month milestone as “a little white laboratory mouse” in the clinical trial with ibrutinib. Dr. Adrian Wiestner, M.D., PhD, of the National Institutes of Health is the lead investigator in the clinical study. Dr. Wiestner just presented the findings from this clinical trial at the American Association for Cancer Research (AACR) in Washington, D.C. Here is an excerpt from Pharmacyclics’ press release from April 8, 2013. Please note that this is a fast track to FDA approval, and applies to 17p deleted CLL/SLL patients like me. :-)

Phase II Ibrutinib Monotherapy Study Shows CLL Patients Achieved Rapid and Sustainable Disease Control Irrespective of Age or High Risk Prognostic Factor

SUNNYVALE, Calif., April 8, 2013 /PRNewswire/ -- Pharmacyclics, Inc. (Nasdaq: PCYC) today announced results from a Phase II trial of the investigational oral agent ibrutinib which demonstrated rapid and sustained disease control as a monotherapy in untreated, relapsed and refractory chronic lymphocytic leukemia (CLL) patients, irrespective of characteristics that predict poor outcomes to chemoimmunotherapy.

This study was discussed at today's American Association for Cancer Research (AACR) annual meeting in Washington, DC together in addition to 8 other presentations covering advances in clinical and pre-clinical research with ibrutinib. The Phase II study, which was sponsored by the National Heart, Lung and Blood Institute, included an analysis of two CLL patient cohorts: the elderly, above 65 years of age, (n=24, of which 8 were treatment naive) and the high risk genetic group with a deletion of chromosome 17p (del 17p) (n=29, of which 15 were treatment naive). Many elderly patients with CLL are unable to tolerate aggressive therapies. Patients with deletion of chromosome 17p typically are poor responders to chemoimmunotherapy and have limited treatment options with no standard of care defined. Of all CLL patients enrolled in this trial, 72% had been characterized as Rai stage 3-4, indicating an advance stage, high-risk patient population.

The results of the study were presented by lead investigator Adrian Wiestner, M.D., PhD, Hematology Branch, NHLBI, National Institutes of Health. "Ibrutinib was highly efficacious as a single agent in patients with untreated, relapsed and unresponsive CLL, irrespective of their del 17p status," Dr. Wiestner said. "Responses in this study appear to be durable, and results indicate the drug is effective against the disease in lymph nodes, spleen and bone marrow. This is important because existing therapies often fail to effectively eliminate cancer cells in these tissue sites. Targeted therapy for CLL is becoming a reality, and this new approach may greatly improve the lives of patients with this disease."

The study also evaluated in vivo effects of ibrutinib using blood and tissue samples collected before and during treatment. Ibrutinib demonstrated rapid and sustained disease control in blood, lymph nodes, spleen and bone marrow. After 6 months, 95 percent of patients experienced a reduction in lymph node size and all showed reduction in spleen enlargement, with a median reduction of 55 percent. In 26 patients, for whom a bone marrow biopsy was done, tumor infiltration decreased by 82 percent.

The Progression Free Survival probability for these patients at 12 months was estimated to be 94 percent. Most adverse events were mild and manageable and included diarrhea, fatigue and rash, severe events occurred in less than 13 percent of patients. 

"We are very pleased with the continued research that is being demonstrated at AACR across 9 different presentations. These advances show the potential breadth of the ibrutinib program and provide further opportunities for us to pursue. We are grateful for the continued support of our collaborators, investigators, patients and shareholders," said Bob Duggan, CEO and chairman of the board.

Ibrutinib has been designated as a FDA Breakthrough Therapy in CLL patients with deletion 17p, based on data from completed Phase I/II clinical studies, where ibrutinib as a monotherapy was used to treat patients with this disease. Ibrutinib has the potential to improve the outcome in this serious and life-threatening disease, and may provide a substantial improvement over existing therapies for this indication.

The Ibrutinib story

Forbes Magazine

April 5, 2013

http://www.forbes.com/sites/davidshaywitz/2013/04/05/the-wild-story-behind-a-promising-experimental-cancer-drug/

The Wild Story Behind A Promising Experimental Cancer Drug

Today, Pharmacyclics is a $5.3B company, a value attributable largely to its promising lead compound, ibrutinib, currently in late clinical development for chronic lymphocytic leukemia (CLL) and mantle cell lymphoma, and under investigation for a range of other B-cell malignancies.  A joint development and marketing deal with J&J was announced in late 2011, valued at nearly $1B, including $150M upfront plus significant milestone payments.  Analysts are already pegging future sales in the billions.

Ibrutinib’s emergence as a promising oncology drug – “The Gleevec of CLL,” as one oncologist described it to me – is an almost absurdly improbable story embracing the Human Genome Project on the one hand, and Scientology on the other.

A “Most Wondrous Map”

In 1998, a radically inventive biologist, J. Craig Venter, founded a company called Celera, with the goal of sequencing the human genome within three years.  He was competing against a much larger, well-funded public effort, led by Human Genome Project Director Dr. Francis Collins, who is now Director of the National Institutes of Health.

Both efforts succeeded; the initial draft map of the human genome was famously announced on June 26, 2000 by President Clinton, joined by Venter and Collins.  Clinton said, “Today the world is joining us here in the East Room to celebrate the completion of the first survey of the entire human genome. Without a doubt, this is the most important, most wondrous map ever produced by humankind.”

In 2002, Venter stepped down as President of Celera, and over the next four years, its promise progressively evaporated.  Turning information into value – arguably the key challenge of the genomic era – proved elusive.  The company’s attempts to try its hand at drug development — kick-started by the acquisition of Axys Pharmaceuticals in 2001 — had largely fallen short.  Electing to focus on diagnostic testing, the company unloaded its early stage assets – a phase 1 HDAC inhibitor and a few other preclinical molecules, which in 2006 were picked up for a pittance by a small struggling company called Pharmacyclics.

A Useful Tool

Included among the preclinical assets were small molecules targeting a signal transduction molecule called Bruton’s trysosine kinase – BTK – an enzyme that sits downstream of the B-cell receptor, and was targeted by Celera because of its putative role in autoimmune diseases such as rheumatoid arthritis (a thoughtful discussion of “immunokinase” drug discovery can be found here).  The BTK gene itself — tied through “classical” genetics to the disorder X-linked agammaglobulinemia (XLA) — was first identified in 1993.

As part of their efforts to screen candidate BTK inhibitors, Celera researchers created a “tool compound,” a molecule that would bind BTK permanently (i.e. covalently), and could also be fluorescently labeled.  This tool would help the company identify compounds that could bind BTK tightly, but not covalently, since drug developers traditionally shy away from compounds that permanently bind their target, concerned about their “potential for off-target reactivity,” as a recent review nicely summarizes.  That said, many drugs, both ancient– such as aspirin – and recent – such as clopidogrel (Plavix) and esomeprazole (Nexium) – work through a covalent mechanism.

As Celera researchers pursued BTK inhibitors, they made two important discoveries: first, they learned that their molecules seemed to show activity in arthritis models; second, they progressively appreciated that their tool compound seemed more promising than any of the other molecules emerging from their screens.  It was at this point that Celera’s assets were sold to Pharmacyclics.

Developing Science

Meanwhile, elegant experiments in mice by Harvard immunologist Klaus Rajewsky highlighted the importance of B-cell receptor signaling for B-cell development, stimulating cancer researchers to wonder whether inhibiting B-cell receptor signaling might help treat B-cell cancers.  In rapid succession, scientists from Stanford, Harvard, and other universities reportedly reached out to a small Bay-area biotechnology company called Rigel to request permission to study one of their lead compounds, fostamitinib, an inhibitor of the Syk kinase which is also in the B-cell receptor signal transduction pathway.

The initial results were promising but not stellar, although encouraging responses were seen in some patients, according to Dr. Jeff Sharman, who at the time was a Stanford oncology fellow in the legendary lab of Ronald Levy, and an early proponent of inhibiting B-cell receptor signaling in B-cell cancers.  (In 2010, Rigel partnered fostamitinib with AstraZeneca, and it is currently in late-phase development for rheumatoid arthritis).  Sharman (disclosure: we trained together at MGH) recalls that a frequent visitor to the Levy lab was Dr. Richard Miller, an oncologist and entrepreneur who at the time was CEO of a local drug development company: Pharmacyclics.

Local Hero

Richard Miller was already a bit of a legend in the Bay area; in 1984, he co-founded IDEC with Stanford colleague Levy, UCSD immunologist Ivor Royston, San Diego bioentrepreneur Howard Birndorf, and a trio of top-tier VC investors led by Brook Byers of KPCB (he’s the “B”), and including Tony Evnin of Venrock and Pitch Johnson of Asset Management; IDEC integrated an existing company, Biotherapy Systems, that Miller and Levy had founded in Mountain View.   In 1997, IDEC delivered rituximab, the first monoclonal antibody approved by the FDA for cancer treatment; it is also used for the treatment of rheumatoid arthritis.  IDEC merged with Biogen in 2003.

Miller ultimately left IDEC, and in 1991 teamed up with chemist Jonathan Sessler to co-found Pharmacyclics, a collaboration that reportedly began when Miller was treating Sessler for cancer at Stanford in the early 1980’s.  The company was initially focused on a class of molecules called “texaphyrins,” synthesized by Sessler (who had moved on to the University of Texas); the name may reflect either the UT origins or the resemblance of the structure to the five-point star of Texas.

While initially promising, the lead molecule,  motexafin gadolinium (Xcytrin), was unfortunately not panning out in clinical studies of brain metastases (eventually leading to a much-publicized dispute between Miller and the FDA), prompting Pharmacyclics to start thinking about a Plan B.  Enter Celera.

A Prepared Mind

The opportunity to pick up potentially promising assets from Celera – essentially, acquire an early-stage pipeline – was appealing to Pharmacyclics; while the deal apparently was initially focused only on the Phase 1 HDAC asset, Miller reportedly was keen for the BTK inhibitor program to be included as well; it was an easy request to grant, as its perceived value at the time was just about zero.

Additional studies of autoimmune disease seemed to confirm the potential of the “tool” BTK inhibitor, now designated PCI-32765; however, Miller was eager to explore its potential in B-cell cancers.  The problem was that it was hard to find appropriate models to use, either cell lines or animal models, as it was felt essential to find a model in which growth was explicitly dependent upon B-cell receptor activation, rather than bypassing it as was more commonly the case in model systems.  Ultimately, the team decided their only option was to study the drug in spontaneously occurring lymphomas in dogs, and obtained results that were suggestive, but not overwhelming.  A partial response was observed in several animals, stable disease was seen in several others.

The team struggled with what to do next.  For starters, they had reached the limits of what they felt they could learn from preclinical studies, and needed to decide, in the words of a researcher, “whether it was worth $1M” to figure out whether the promising but shaky preclinical results would translate into patients.

In addition, the team was also agonizing about whether to move forward with a molecule that worked by forming an irreversible, covalent bond; perhaps it would make more sense to go back to the chemistry lab, and try to identify a BTK inhibitor that worked by a more traditional, non-covalent mechanism.

“I Have Patients Who Are Dying”

Reportedly, Miller asked the team what were the risks of moving ahead with the covalent mechanism, and when he received vague responses, he reportedly told his colleagues, “I have patients in clinic who are dying, and need something right away.  I can’t tell them they’ll need to wait around for another year because we have a concern we can’t even articulate.”

Hence, the clinical study was initiated, and while at first it was slow to recruit, it ultimately was completed and viewed as strikingly successful.  The drug – now in phase 3, and called ibrutinib — is not a magic bullet, but may emerge as a promising option for some patients with some B-cell cancers.

On The Road Again

In another strange twist, Miller hasn’t been around to see this; he was dismissed in 2008 by the chairman of the board, Robert Duggan, who is perhaps best known as Scientology’s biggest donor.  While a Bloomberg report seems to suggest Miller’s departure reflected Duggan’s disappointment in the Xcytrin program, and his preference for focusing on B-cell cancers, I’ve also heard a very different account, suggesting it was Duggan who was keen to pursue Xcytrin, and Miller who refused, preferring instead to focus on the promising BTK inhibition program.

Miller promptly teamed up with UCSF chemist Jack Taunton to co-found Principia Biopharma, a company that focuses on “reversible covalent” molecules – drugs that form covalent bonds that release when the target protein denatures; VC backers include New Leaf, OrbiMed, Morgenthaler, SR One, and the UCSF early stage fund Mission Bay Capital.

In 2010, Miller signed on with the University of Texas as “Chief Commercialization Officer.”  However, according to reports, this role ended abruptly with his resignation less than two years later “after UT officials insisted that Miller divest his ownership interest in three startup companies that intended to license tech discoveries from the school.”   He is said to be working on a new company focused on a novel drug delivery technology.

Lessons Learned?

1.Limitations of experimental models.   In this case, the team had the insight, and the confidence, to recognize that available model systems for the study of B-cell cancers wouldn’t accurately enable assessment of their B-cell receptor-dependent mechanism, and rather than force the molecules through traditional assays (and get a false negative result), they tried to use a less traditional approach (e.g. spontaneous lymphoma model in dog), and then proceed rapidly to the clinic.

2.            Value of a translational champion: This is evident on both the academic side (e.g. inquisitive physicians such as Sharman) and on the industry side (e.g. Miller’s ability to see the clinical potential of research compound developed for different indications).

3.            Courage to value clinical need over conventional wisdom, and empiricism over theory.   Miller challenged traditional pharmaceutical reticence about covalent mechanisms in order to speed an important new drug to patients.

4.            It helps to be lucky.  For each of the lessons here – and particularly, for each of the “brave” and “bold” choices — I can easily envision how following this exact approach might have led to a far less favorable outcome, and a very different narrative (e.g. “cavalier physician imperils patients in reckless pursuit of flawed vision”).

Bottom Line: Discovering impactful new drugs is far more difficult – and far less linear – than is typically recognized.  It’s wonderful to celebrate success; our challenge is finding a way to repeat it.

9-month milestone on Ibrutinib

My son is running the Rock ‘n’ Roll San Diego Marathon to raise money for research for the Leukemia & Lymphoma Society on June 2, 2013. This event funds clinical trials for leukemia and lymphoma. Please read his story.

http://pages.teamintraining.org/az/rnr13/rharrisiij

I am personally grateful every day that I have had an opportunity to participate in a clinical trial, and I am grateful every day for the wonderful people who have funded all the clinical trials through their donations.

On another note, I just returned from the National Institutes of Health in Bethesda, Maryland last night about midnight. It was my 9-month milestone on Ibrutinib. I got the best blood work report I have had in a long while. My white blood count has gone down from 53,000 to about 35,000 in the last three months. (approximately 4,000 to 10,000 is normal). I am where I was shortly after I was diagnosed. Nothing would make me happier than to become “normalized.” Dr. Farooqui said for me NOT to expect that I will be within the normal range at my next appointment at the end of June. But as long as I am headed in the right direction, I am okay with that.

I am not anemic. My kidney function, LDH, and other organs appear normal. Hemoglobin and platelets are stable. Absolute lymphocytes are coming down. Nutriphils are normal now (They were not last time). Bone marrow does not show anything suspicious.

I am off Acyclovir, since I have not had infections. Hurrah!

My only issue is on-and-off cramping when I get in an odd position. My thumbs, my middle toes, my ankles, my shoulder blades… Strange places to be cramping. My electrolytes are not low and I am apparently drinking enough water. It happens at the oddest times. It only lasts a short while until I pull my muscle the opposite direction. Other participants have had the same side effect.

NIH doctors are keeping an eye on the unusual trisomy 13 that has cropped up in my genetics, since it has nothing to do with CLL/SLL, and may or may not develop into another blood disorder. It is not related to the trisomy 13 (Patau syndrome) in which some babies are born, involving physical and mental disorders. Trisomy 13 in adults usually doesn’t occur until people are in their 80s or 90s. I have always been told I am an “old soul,” so now I have proof. LOL.

Another strange thing is the presence of the protein CD34 on my baby platelets. Usually those are found on baby white blood cells. Doctors are researching this odd phenomena. There I go again… being an anomaly.

I am happy with the medical report. I am happy with my son and our dear friend Tyler running a marathon. And now I am off selecting the new tile for my house …