Source: Medical Progress Today 12/14/12 http://bit.ly/1sPO1WU

In our September 16, 2014 article on this blog, we announced the publication by Cambridge Healthtech Institute’s (CHI’s) Insight Pharma Reports of a new book-length report, Cancer Immunotherapy: Immune Checkpoint Inhibitors, Cancer Vaccines, and Adoptive T-cell Therapies, by Allan B. Haberman, Ph.D.

As we said in that blog article, “cancer immunotherapy is a ‘hot’, fast-moving field”. Thus—inevitably—in the short time since the publication of our report, a great deal of late-breaking news has come in.

This article is a discussion of several key late-breaking news items, which were not published in the report.

Pricing of checkpoint inhibitor agents

As discussed in the report, two PD-1 inhibitors have been recently approved. Bristol-Myers Squibb (BMS)/Ono’s nivolumab was approved in Japan (where it is know by the brand name Opdivo) in July 2014 for treatment of unresectable melanoma. Pembrolizumab (Merck’s Keytruda) was approved in the U.S. for treatment of advanced melanoma on September 5, 2014. The very first checkpoint inhibitor to reach the market, the CTLA-4 inhibitor ipilimumab (Medarex/BMS’s Yervoy), was approved in the U.S. in 2011.

At the same time as the news of the approval of the PD-1 inhibitors nivolumab and pembrolizumab came out, information on the pricing of these agents also became available. However, because of the need to complete the report for publication, there was no time to discuss the issue of pricing adequately.

As discussed in a September 4, 2014 article in FiercePharma, the cost of nivolumab in Japan (according to the Wall Street Journal) is $143,000. According to the FierceBiotech article, this was greater than the introductory price for any other cancer drug, especially in Japan, where prices tend to be somewhat lower than in the U.S.

Meanwhile, as reported in a September 4, 2014 article in FierceBiotech, the cost of pembrolizumab in the U.S. will be $12,500 a month, or $150,000 a year.

For comparison, the launch price of BMS’ ipilimumab was $120,000. As we discussed in the report, the PD-1 inhibitors nivolumab and pembrolizumab—as seen in early clinical trials—appear to be more efficacious and have fewer adverse effects in treatment of melanoma.

As discussed in our report, checkpoint inhibitors such as ipilimumab, nivolumab and pembrolizumab are eventually likely to be used in combination with other drugs, including other immuno-oncology drugs, targeted therapies, and others. The price per month or per year of these potentially life-saving and at least in some cases curative combination therapies may thus be expected to go still higher. However, if cancers are pushed into long-term remission or even cure, then it might be possible to discontinue treatment with these expensive drug combinations. In such cases, the cost of treatment may even be less than current therapeutic regimens.

There are no analyses of the costs of specific immunotherapy drugs or cellular therapies in our report. However, we do discuss the issue of drug costs in the survey and interviews that are part of the report.

The issue of the costs of expensive drugs for life-threatening cancers is under discussion in the cancer community. For example, the American Society of Clinical Oncology (ASCO) has initiated an effort to rate oncology drugs not only on their efficacy and adverse effects, but also on their prices. ASCO’s concern is that pricing be related to the therapeutic value of drugs. And commentators such as Peter Bach, MD, MAPP (the Director of the Memorial Sloan Kettering Cancer Center’s Center for Health Policy and Outcomes) have been weighing in with their analyses. As additional immunotherapy drugs and cellular therapies reach the market, these discussions will certainly continue.

The Bristol-Myers Squibb-Merck lawsuit over PD-1 inhibitors

Another late-breaking news item that came out at the time of the publication of our report is the lawsuit between BMS and Merck over PD-1 inhibitors. Specifically, as soon as Merck gained FDA approval for pembrolizumab, BMS and its Japanese partner Ono sued Merck for patent infringement.

The patent in question is U.S. patent number 8,728,474. It was filed on December 2, 2010, granted to Ono on May 20, 2014, and licensed to BMS. The patent covers the use of anti-PD-1 antibodies to treat cancer. According to BMS and Ono’s claims, Merck started developing pembrolizumab after BMS and Ono had already filed their patent and were putting it into practice by developing their own PD-1 inhibitor, nivolumab.

The lawsuit asks for damages, and for a ruling that Merck is infringing the BMS/Ono PD-1 patent. Such a ruling may mean that BMS and Ono are owed royalties on sales of all rival PD-1 drugs, not just Merck’s. BMS/Ono and Merck are involved in parallel litigation in Europe.

Merck acknowledges Ono’s method patent, but says that it is invalid. Merck also said the lawsuit will not interfere with the U.S. launch of pembrolizumab.

We shall have to watch the proceedings in the U.S. District Court for the District of Delaware to see the outcome of this case. Although this lawsuit was not discussed in our report, the report does include a discussion of the fierce race between PD-1 inhibitor developers Merck and BMS to be the first to market, and to gain the largest market share. The lawsuit is clearly one element in this race.

Merck Serono discontinues development of the cancer vaccine tecemotide

On September 18, 2014, Merck KGaA (Darmstadt, Germany; also known as Merck Serono and EMD Serono) announced that it has discontinued development of the cancer vaccine tecemotide. Tecemotide is a peptide vaccine that was formerly known as Stimuvax. It was originally developed by Oncothyreon (Seattle, WA) and licensed to Merck Serono in 2007.

We covered tecemotide in our report, both as an example of a cancer vaccine that had failed in Phase 3 clinical trials, and as an example of a vaccine that was nevertheless still under development. As discussed in our report, in a Phase 3 trial known as START in non-small cell lung cancer (NSCLC) patients, researchers found no significant difference in overall survival between administration of tecemotide or placebo. However, a subsequent analysis suggested that there was a statistically significant survival advantage for tecemotide compared with placebo in a pre-defined subset of patients. Based on these results, Merck Serono began a second Phase 3 trial in that subset.

However, as the result of a failure in a Phase 3 trial in Japan sponsored by Oncothyreon (reported on August 19, 2014), Merck Serono decided to discontinue development.

As stated by Merck Serono’s Executive Vice President and Global Head of R&D Luciano Rossetti, “While the data from the exploratory subgroup analysis in the START trial generated a reasonable hypothesis to warrant additional study, the results of the recent trial in Japanese patients decreased the probability of current studies to reach their goals.”

As we discussed in our report, the cancer vaccine field has been rife with clinical failures—from its beginnings in the 1990s to the present day. This has especially included late-stage failures, not only that of Merck Serono’s tecemotide, but also, for example, GlaxoSmithKline’s (GSKs) MAGE-A3 vaccine. Only one anticancer vaccine—sipuleucel-T (Dendreon’s Provenge) for treatment of metastatic castration-resistant prostate cancer—has ever reached the market, and its therapeutic effects appear to be minimal.

Despite these poor results, researchers and companies persist in their efforts to develop cancer vaccines. Our report discusses why cancer vaccine R&D continues despite the overwhelming history of failure, the hypothesized reasons for these failures, and what researchers and companies can do and are doing to attempt to obtain better results.

Conclusions

As a fast-moving, important field, cancer immunotherapy will continue to generate scientific, medical, and market news. There will continue to be periodic meetings, such as the 2014 European Society for Medical Oncology (EMSO) meeting (September 26-30, Madrid, Spain), in which positive results of small, early-stage trials of several checkpoint inhibitors were presented. Our report—an in-depth discussion of cancer immunotherapy—can enable you to understand such future developments, as well as current ones. It is also designed to inform the decisions of leaders in companies and in academia that are involved in cancer R&D and treatment.

For more information on Cancer Immunotherapy: Immune Checkpoint Inhibitors, Cancer Vaccines, and Adoptive T-cell Therapies, or to order it, see the Insight Pharma Reports website.

As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

T cells attached to tumor cell. Source: MSKCC. http://bit.ly/1uPr5nl

On September 9, 2014, Cambridge Healthtech Institute’s (CHI’s) Insight Pharma Reports announced the publication of a new book-length report, Cancer Immunotherapy: Immune Checkpoint Inhibitors, Cancer Vaccines, and Adoptive T-cell Therapies, by Allan B. Haberman, Ph.D.

As attested by the torrent of recent news, cancer immunotherapy is a “hot”, fast-moving field. For example:

• On September 5, 2014, the FDA granted accelerated approval to the PD-1 inhibitor pembrolizumab (Merck’s Keytruda, also known as MK-3475) for treatment of advanced melanoma. This approval was granted nearly two months ahead of the agency’s own deadline. Pembrolizumab is the first PD-1 inhibitor to reach the U.S. market.

• On July 4, 2014, Bristol-Myers Squibb’s rival PD-1 inhibitor nivolumab was approved for treatment of advanced melanoma in Japan, where it will be marketed as Opdivo by Ono Pharmaceuticals. Nivolumab is the first PD-1 inhibitor to reach the Asian market.

• On May 8, 2014, the New York Times published an article about a woman in her 40’s who was treated with adoptive immunotherapy with autologous T cells to treat her cancer, metastatic cholangiocarcinoma (bile-duct cancer). This deadly cancer typically kills the patient in a matter of months. However, as a result of this treatment, the patient lived for over 2 years, with good quality of life, and is still alive today.

These and other recent news articles and scientific publications attest to the rapid progress of cancer immunotherapy, a field that only a few years ago was considered to be impracticable.

Our report focuses on the three principal types of therapeutics that have become the major focuses of research and development in immuno-oncology in recent years:

• Checkpoint inhibitors
• Therapeutic anticancer vaccines
• Adoptive cellular immunotherapy

The discussions of these three types of therapeutics are coupled with an in-depth introduction and history as well as data for market outlook.

Also featured in this report are exclusive interviews with the following leaders in cancer immunotherapy:

• Adil Daud, MD, Clinical Professor, Department of Medicine (Hematology/Oncology), University of California at San Francisco (UCSF); Director, Melanoma Clinical Research, UCSF Helen Diller Family Comprehensive Cancer Center.

• Matthew Lehman, Chief Executive Officer, Prima BioMed (a therapeutic cancer vaccine company with headquarters in Sydney, Australia).

• Marcela Maus, MD, PhD, Director of Translational Medicine and Early Clinical Development, Translational Research Program, Abramson Cancer Center, University of Pennsylvania in Philadelphia.

The report also includes the results and an analysis of a survey of individuals working in immuno-oncology R&D, conducted by Insight Pharma Reports in conjunction with this report. The survey focuses on market outlook, and portrays industry opinions and perspectives.

Our report is an in-depth discussion of cancer immunotherapy, an important new modality of cancer treatment that may be used to treat as many as 60% of cases of advanced cancer by the late 2010s/early 2020s. It includes updated information from the 2014 ASCO (American Society of Clinical Oncology) and AACR (American Association for Cancer Research) meetings. The report is designed to enable you to understand current and future developments in immuno-oncology. It is also designed to inform the decisions of leaders in companies and in academic groups that are working in areas that relate to cancer R&D and treatment.

For more information on Cancer Immunotherapy: Immune Checkpoint Inhibitors, Cancer Vaccines, and Adoptive T-cell Therapies, or to order it, see the Insight Pharma Reports website.

As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Happy New Year! Source: Roblespepe. http://bit.ly/1cpkyHX

As it does every year, Science published its “Breakthrough of the Year” for 2013 in the 20 December 2013 issue of the journal.

Science chose cancer immunotherapy as its Breakthrough of the Year 2013.

In its 20 December 2013 issue, Science published an editorial by its Editor-in-Chief, Marcia McNutt, Ph.D., entitled “Cancer Immunotherapy”. The same issue has a news article  by staff writer Jennifer Couzin-Frankel, also entitled “Cancer Immunotherapy”.

As usual, the 20 December 2013 issue of Science contains a Breakthrough of the Year 2013 news section, which in addition to the Breakthrough of the Year itself, also contains articles about several interesting runners-up, ranging from genetic microsurgery using CRISPR (clustered regularly interspaced short palindromic repeat) technology to mini-organs to human cloning to vaccine design.

In the Science editorial and news article, the authors focus on the development and initial successes of two types of immunotherapy:

• Monoclonal antibody (MAb) drugs that target T-cell regulatory molecules, including the approved CTLA4-targeting MAb ipilimumab (Bristol-Myers Squibb’s Yervoy), and the clinical-stage anti-PD-1 agents nivolumab (Bristol-Myers Squibb) and lambrolizumab (Merck).
• Therapy with genetically engineered autologous T cells, known as chimeric antigen receptor (CAR) therapy, such as that being developed by a collaboration between the University of Pennsylvania and Novartis.

The rationale for Science’s selection of cancer immunotherapy as the breakthrough of the year is that after a decades-long process of basic biological research on T cells, immunotherapy products have emerged and–as of this year–have achieved impressive results in clinical trials. And–as pointed out by Dr. McNutt–immunotherapy would constitute a new, fourth modality for cancer treatment, together with the traditional surgery, radiation, and chemotherapy.

However, as pointed out by Dr. McNutt and Ms. Couzin-Frankel, these are still early days for cancer immunotherapy. Key needs include the discovery of biomarkers that can help predict who can benefit from a particular immunotherapy, development of combination therapies that are more potent than single-agent therapies, and that might help more patients, and means for mitigating adverse effects.

Moreover, it will take some time to determine how durable any remissions are, especially whether anti-PD1 agents give durable long-term survival. Finally, although several MAb-based immunotherapies are either approved (in the case of  ipilimumab) or well along in clinical trials, CAR T-cell therapies and other adoptive immunotherapies remain experimental.

In addition to the special Science “Breakthrough 2013” section, Nature published a Supplement on cancer immunotherapy in its 19/26 December 2013 issue. This further highlights the growing importance of this field.

Cancer immunotherapy on the Biopharmconsortium Blog

Readers of our Biopharmconsortium Blog are no strangers to recent breakthroughs in cancer immunotherapy. In the case of MAb-based immunotherapies, we have published two summary articles, one in 2012 and the other in 2013. These articles noted that cancer immunotherapy was the “star” of the American Society of Clinical Oncology (ASCO) annual meeting in both years.

Our blog also contains articles about CAR therapy, as being developed by the University of Pennsylvania and Novartis and by bluebird bio and Celgene. Moreover, the Biopharmconsortium Blog contains articles on other types of cancer immunotherapies not covered by the Science articles, such as cancer vaccines.

We look forward to further progress in the field of cancer immunotherapy, and to the improved treatments and even cures of cancer patients that may be made possible by these developments.

As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Eastern Bluebird

The Biopharmconsortium Blog includes several articles that are–in whole or in part–about adoptive T-cell immunotherapy [or adoptive cell transfer (ACT)] for cancer. In particular, we have produced two blog articles that discuss the Novartis/University of Pennsylvania (Penn) collaboration, which is aimed at finally commercializing adoptive immunotherapy for cancer.

• “Is Novartis Building A Viable Business Model For Adoptive Immunotherapy For Cancer?” (September 28, 2012)
•  “Leukemia–Going For The Cure!” (July 29, 2013 )

The Novartis/Penn collaboration focuses on a particular technology for ACT, known as chimeric antigen receptor (CAR) technology. In this technology, autologous T cells isolated from patient blood are engineered with retroviral vectors carrying a gene for a tumor antigen-specific CAR. The CAR enables the engineered cells to recognize specific surface proteins on tumor cells, and to go on to kill the cells.

Now we find out that at least one more company–one a lot closer to home (at least for us folks in Greater Boston)–is involved in a collaboration to develop and commercialize CAR technology for ACT. This company is bluebird bio (Cambridge, MA). As of June 24, 2012, bluebird successfully completed its initial public offering.

On March 21, 2013, bluebird announced in a press release that it had entered into a multi-year strategic collaboration with Celgene (Summit, NJ) to discover new disease-modifying gene therapies for cancer. The collaboration is to focus on applying bluebird’s gene therapy technology to the design and development of CAR T cells.

According to the news release, the bluebird/Celgene collaboration may lead to the development and commercialization of multiple CAR T-cell products. Celgene has an option to license products that result from the collaboration after the completion of a Phase 1 clinical trial for each product. bluebird bio will be responsible for R&D through Phase 1 clinical trials, and Celgene will be responsible for clinical studies beyond Phase 1 for any product that it licenses, as well as commercialization of any such product.

As also announced in the March 21, 2013 press release, Celgene has entered into a separate strategic collaboration that focuses on CAR T-cell technology with the Center for Cell and Gene Therapy at Baylor College of Medicine, Texas Children’s Hospital and The Methodist Hospital (Houston, TX). The work on CAR T-cell technology in Houston is led by Malcolm Brenner, M.D., Ph.D. (Director, Center for Cell and Gene Therapy Baylor College of Medicine). Dr. Brenner and his colleagues, for example, showed that T cells expressing a CAR specific for the GD2 tumor antigen on neuroblastoma cells produced tumor responses in over half of 19 neuroblastoma patients with refractory or active disease. Three of 11 patients with active disease achieved complete remission.

According to the March 21, 2013 news release, bluebird bio, Celgene and Dr. Brenner’s team will work collaboratively to advance and develop existing and new CAR T-cell products and programs.

Our October 2012 discussion of bluebird bio and adoptive cell transfer in the Biopharmconsortium Blog

On  October 11, 2012, we published an article on this blog entitled “Is Gene Therapy Emerging From Technological Prematurity?” This article included a section on bluebird bio, which represented the very first time we mentioned bluebird on this blog.

In this section–over 5 months before bluebird announced its agreement with Celgene–we discussed the relationship between bluebird’s technology and ACT:

bluebird bio’s platform..represents both a gene therapy technology and an adoptive cellular transfer (ACT) technology. We have discussed ACT technologies (in this case, for immunotherapy for cancer) in a previous article on this blog.  Since some of these technologies involve genetically-engineered autologous T cells, they may also be thought of as representing both ACT and a kind of gene therapy.

We are happy to learn that bluebird also realized (independent from us) the potential utility of their “gene therapy” technology for adoptive immunotherapy/ACT for cancer. We are also happy that bluebird entered into an agreement with Celgene to develop and commercialize such therapies, with the potential to give at least some cancer patients the durable complete responses that they yearn for.

As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or an initial one-to-one consultation on an issue that is key to your company’s success, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Chronic Myeloid Leukemia. Source: Paulo Mourao. http://bit.ly/14ZLZqA

Both the 28 June 2013 issue of Science and the 27 June 2013 issue of Nature have articles or sections that feature discussions of new ways to treat or even cure various types of leukemia.

The human interest story about T-cell immunotherapy researchers in Science

The 28 June 2013 issue of Science contains an article by Science staff writer Jennifer Couzin-Frankel entitled “The Dizzying Journey to a New Cancer Arsenal”. It focuses on researchers who have been working in the engineered T cell adoptive immunotherapy project at the Perelman School of Medicine of the University of Pennsylvania. We featured a discussion of this project, which since August 6, 2012 has involved a collaboration with Novartis, in our September 12, 2012 article on this blog.

Ms. Couzin-Frankel’s article is a human interest story which especially focuses on Carl June, MD, and how he came to work on T-cell immunotherapy. This included how cancer had touched his own life, with the death of his first wife, Cynthia, in 2001. The article also focused on patients who were successfully treated with the therapy, including biotech company scientist Douglas Olson, and Emily Whitehead, who is now eight years old and achieved remission from what had been end-stage leukemia over a year ago.

As we discussed in our September 2012 article, the Penn group has been developing adoptive immunotherapy based on autologous T cells engineered with chimeric antigen receptors (CARs). Specifically, this involved a CAR with specificity for the B-cell antigen CD19, coupled with the T cell costimulatory receptor CD137 and CD3-zeta (a signal-transduction component of the T-cell antigen receptor) signaling domains. (In the Science article, CD19 is referred to by its alternative name, 4-1BB.) These engineered T cells are designed for the treatment of B-cell leukemias, such as B-cell chronic lymphocytic leukemia (CLL). As discussed both in our 2012 blog article and in the 2013 Science article, Novartis has been collaborating with the Penn group in order to industrialize production of the autologous engineered T cells and their use in treatment of patients. Via the ability of Penn to patent and license its technology, the Novartis collaboration also provides a potential means to conduct clinical trials under FDA regulation, and thus to commercialize a form of adoptive cellular immunotherapy for the first time.

Nature’s special supplement on leukemia

The 27 June 2013 issue of Nature includes an entire Nature Outlook supplement on “Leukaemia”. The supplement–or at least the portion of it that consists of articles produced under Nature’s “full responsibility for all editorial content” is available free online to all.

The general theme of the special supplement is stated in the introductory article by science writer and editor Apoorva Mandavilli “While survival rates for some types of leukaemia have improved dramatically, this family of blood cancers remains a potentially fatal disease. Research in epigenetics, immunotherapy, and cell transplants offers hope. And leukaemia is proving a testing ground for the theory of cancer stem cells — leading to knowledge that could advance cancer research overall.”

The Nature Perspective on adoptive T-cell immunotherapy by Penn researchers Levine and June

Included in the supplement is a short Perspective on CAR-based adoptive T-cell immunotherapy by Drs. Bruce L. Levine and Carl H. June of the Perelman School of Medicine at the University of Pennsylvania. It is entitled “Assembly line immunotherapy”. According to this Perspective, CAR technology [unlike the earlier tumor infiltrating lymphocyte (TIL) technology] enables researchers to ” efficiently produce large populations of T cells, approximating the mass of T cells in the human immune system”.

Drs. Levine and June further assert that by “using equipment and facilities developed for blood banks and stem-cell laboratories, and by automating production”, it will be possible to make CAR-based adoptive cellular immunotherapies (ACTs) widely available. Thus leukemia treatment may be on the brink of a revolution such as the auto industry experienced in recent years in moving from manual assembly lines to robotic automation.

Despite the issue of the pharmaceutical industry and regulatory agencies such as the FDA and the European Medicines Agency being geared to developing drugs, not individually-prepared cellular therapies, Drs. Levine and June cite the case of  organ, bone-marrow, and stem-cell transplants. These modalities were seen as exotic a few decades ago, but are now utilized in treatment of tens of thousands of people. The authors thus envision that ACT may also eventually be scaled up to treat the large numbers of patients who might benefit from this type of therapy. However, this will require innovation in regulatory agency oversight, and in the means by which the pharmaceutical industry might commercialize such individualized technologies. As we discussed in our September 2012 Biopharmconsortium Blog article, Novartis and Penn are leading the way.

Moving toward cures for chronic myeloid leukemia–Dr. Charles Sawyers’ Perspective

Another Perspective in the special supplement is authored by Charles L. Sawyers, M.D. [Chair, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer (New York, NY), and Howard Hughes Medical Institute]. The Perspective, entitled “Combined forces”, focuses on chronic myeloid leukemia (CML). The first targeted kinase inhibitor for cancer, imatinib (Novartis’ Gleevec/Glivec) was initially approved for treatment of CML.

In our October 25, 2010 article on this blog, we discussed the classic proof-of-concept clinical trial that helped launch imatinib toward FDA approval. As we discussed in that article, Dr. Sawyers was a key leader of that trial. He was a co-recipient–with Drs.  Brian J. Druker and Nicholas B. Lydon, of the 2009 Lasker~DeBakey Award for Clinical Medical Research for his work on treatment of CML.

As we discussed in our Octotber 2010 article, imatinib is highly specific for the BCR-ABL fusion protein [which is generated as the result of the translocation that produces the Philadelphia (Ph) chromosome, the characteristic genetic abnormality of CML], as well as two other protein kinases. CML patients who are initially successfully treated with imatinib may experience resistance to that drug. As a result, two second-generation kinase inhibitors–dasatinib (Bristol-Myers Squibb’s Sprycel) and nilotinib (Novartis’ Tasigna) were developed to target imatinib-resistant mutated BCR-ABL proteins, and thus successfully treat imatinib-resistant CML. More recently–in September 2012–as mentioned in Dr. Sawyers’ Perspective, another second-generation agent, bosutinib (Pfizer’s Bosulif), has reached the market. A still newer agent, ponatinib (Ariad’s Iclusig) was approved in December 2012, under the FDA’s Accelerated Approval Program. Ponatinib is of special interest, since it  targets the T315I mutation, which confers resistance to all the other four targeted CML drugs.

In Dr. Sawyers’ Perspective, he discusses how oncologists might use the current armamentarium of targeted drugs for CML to move toward a cure for the disease. Resistance to imatinib occurs because of selection for resistant mutants of BCR-ABL . Second-generation agents inhibit BCR-ABL kinases with these mutations, thus restoring disease remission. The current armamentarium of kinase inhibitor drugs for CML covers all known resistance mutations; however, no single drug can prevent all forms of resistance.

The current paradigm for treatment of CML has been to start with imatinib, and keep treating with that agent until the patient develops resistance to that drug and disease recurs. Then the physician treats with one of the second-generation agents, which typically produces disease remission. However, this sequential treatment can select for cells with BCR-ABL molecules that contain multiple mutations, which will be resistant to all kinase inhibitors. (See a 2007 report by Dr. Sawyers and his collaborators demonstrating the hazard of sequential therapy with imatinib followed by dasatinib.)

Because the second-generation agents dasatinib and nilotinib are more potent than imatinib, they were approved for frontline therapy of CML instead of imatinib, subsequent to the publication of Dr.Sawyers’ 2007 article. They were approved for frontline therapy because of their superior clinical outcomes in head-to-head comparisons against imatinib. (Bosutinib and ponatinib are newer, and have not yet received frontline therapy approval.) However, Dr. Sawyers counsels caution, since  dasatinib and nilotinib have been studied for only 3–4 years compared with the 8–10 years of data that have amassed for imatinib. Thus replacing imatinib with one of these agents might still result in development of resistance down the road.

Dr. Sawyers postulates that Instead of focusing on which individual drug is best as a monotherapy, it is time for researchers to consider whether it might be better to use combination therapy with multiple kinase inhibitors instead of sequential therapy. Extrapolating from the experience with single- versus multi-agent therapy for tuberculosis and HIV/AIDS, a combination of two or three ABL inhibitors with non-overlapping BCR–ABL mutation resistance profiles would almost certainly prevent the emergence of drug resistance. This is particularly true in the light of ponatinib’s success against T315I.

In a recent French study cited by Dr. Sawyers, researchers found that patients with the best responses to treatment with imatinib alone (no BCR–ABL detectable for more than two years) may no longer need any kinase inhibitor drugs at all. In this study, 40% of patients had not relapsed after 18 months. This raises the possibility that these patients may be cured of their disease.

Dr. Sawyers hypothesizes that since next-generation BCR-ABL inhibitors have greater potency in clinical trials, and since two-drug combinations are superior to monotherapies in preclinical studies, upfront therapy with either a second-generation inhibitor or with a combination therapy may result in even higher percentages of patients who experience elimination of all CML cells.

Even though these more potent treatments would be even more costly than imatinib therapy, if these treatments are curative, their long-term cost will be lower than the current treatment. Therefore, they might be both medically and economically advantageous, as well as giving cancer patients what they really want–a cure.

Meanwhile, in the 18 July 2013 issue of Nature, Drs. Natalia L. Komarova (University of California Irvine, Irvine CA) and C. Richard Boland (Baylor University Medical Center, Dallas TX) published a News and Views article discussing recently published mathematical models that predict that combination therapy is more effective than sequential treatment in preventing drug resistance in cancer. These mathematical models were developed especially for treatment of CML and the solid tumors melanoma, pancreatic cancer, and colorectal cancer. But these types of models may apply to all cancers for which targeted therapies have been or are being developed.

Moving toward cures for chronic myeloid leukemia–the Novartis 27 June 2013 white paper

Bound with the Nature Outlook supplement on leukemia–immediately following the Levine & June article on adoptive immunotherapy–is a white paper by Novartis researchers (Szczudlo et al.), entitled “The Novartis research vision and approach for treating patients with chronic myeloid leukaemia”. Unfortunately, since this “sponsor feature” was not written under Nature’s “full responsibility for all editorial content”, this white paper is treated almost as an advertisement. It is not available in the online version of Nature, or anywhere else online. Perhaps Novartis will make this valuable white paper available online in the near future. As with other published reviews in scientific journals (and unlike advertisements), this white paper is signed by its authors, and has reference citations.

The subject of the white paper is developing approaches that will enable CML patients on tyrosine kinase inhibitor (TKI) therapy to safely and effectively suspend their drug therapy, while maintaining minimal residual disease (MRD) levels that are either undetectable or below the level at which there is a risk of progression to more advanced phases of disease. Such a condition is known as “treatment-free remission” (TFR).

The research that is the focus of the Novartis white paper does not involve treatment with combination therapies, but monotherapy with nilotinib (Novartis’ Tasigna). The TFR-focused clinical trials with nilotinib are made possible not only by the potency of this agent, but also the development of new diagnostic assays for level of residual disease. Traditional diagnostics for CML have been based on achieving a “complete cytogenetic response” (CCyR). A CCyR is defined as the state in which there are so few Philadelphia chromosome positive (Ph+) cells in a patient’s blood or marrow that they are undetectable by this assay.

The new diagnostic assays involves measuring levels of BCR-ABL messenger RNA (mRNA) transcripts using a real-time quantitative polymerase chain reaction (RQ-PCR). The results of these sensitive assays are reported as major molecular response [MMR–a 3-log reduction in BCR-ABL levels from the international scale (IS) baseline; molecular response ≥ 4.0 logs (MR4); and molecular response ≥ 4.5 logs (MR4.5)].

Using these assays, researchers are participating in new Novartis-sponsored clinical studies of

1. patients who had previously been treated with imatinib, without achieving MR4.5, and who were then switched to nilotinib.
2. patients treated do novo with nilotinib.

The strategy is to maintain patients on nilotinib who have achieved MR4.5 for one year at that level, and then discontinue drug treatment. These patients continue to be monitored, and must maintain ≤ MR4 in order to remain free of nilotinib treatment. Those who exceed this threshold will be put back on nilotinib. So far, in earlier studies, patients on imatinib or niolotinib who were ≤MR4 off-drug and who then exceeded this level, when put back on their drug went back to deeper levels of molecular response to therapy, and showed no drug resistance. These clinical trial protocols therefore appear to be safe.

For more information about the above clinical trials, see ClinicalTrials.gov, clinical trial number NCT01784068 and NCT01698905. Both of these trials are recruiting patients.

The Novartis white paper does discuss a different kind of combination therapy than the ones proposed by Dr. Sawyers–combination therapy with a potent TKI such as nilotinib and an agent that specifically targets leukemic stem cells (LSCs). TKI-insensitive leukemia stem cells have been implicated in the persistence of MRD, and LSCs could contribute to the re-emergence of disease following suspension of TKI treatment.

Novartis and its collaborators are now testing TKIs in combination with Novartis’ experimental agent sonidegib (LDE225). Sonidegib is an inhibitor of the hedgehog (Hh) pathway. Aberrant activation of the Hh pathway has been implicated in the activity of LSCs and of other types of cancer stem cells. A poster session that described an in vitro study of a combination of sonidegib and nilotinib in CML was presented at a scientific meeting in 2010. Sonidegib (which is also known as erismodegib) has also been undergoing preclinical studies as a potential inhibitor of prostate cancer stem cells.

Conclusions

We recommend the 28 June 2013 Science article by Jennifer Couzin-Frankel, and the special supplement on leukemia in the 27 June 2013 issue of Nature for your late summer reading. It is heartening to see that at least some researchers are moving towards cures for various types of leukemia–with potential implications for development of cures for other types of cancer.

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