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.

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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.

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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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.

On June 28, 2012 we published an article on this blog entitled “Cancer Immunotherapy: The Star Of The 2012 ASCO Annual Meeting”. Now comes the American Society of Clinical Oncology (ASCO) 2013 Annual Meeting, which took place from May 30 to June 3, 2013.

As in 2012, cancer immunotherapy was the star of the meeting.

In our June 2012 article, we focused on experimental monoclonal antibody (MAb) drugs that target the cell surface receptors programmed cell death-1 (PD-1) and programmed cell death-1 ligand (PD-L1). PD-1 is a member of the CD28/CTLA4 family of T cell regulators. Like CTLA4, the target of ipilimumab, PD-1 is a negative regulator of T-cell receptor signals. When PD-L1, which is a protein on the surface of some tumor cells, binds to PD-1 on T cells that recognize antigens on these tumor cells, this results in the blockage of the ability of the T cells to carry out an anti-tumor immune response. Anti-PD-1 MAb binds to PD-1 on T cells, thus preventing PD-L1 on tumor cells from binding to the PD-1 and initiating an inhibitory signal. Anti-tumor T cells are then free to initiate immune responses against the tumor cells. This mechanism of action is completely analogous to that of ipilimumab, which binds to CTLA4 and thus prevents negative signaling from that molecule.

Anti-PD-L1 therapeutics bind to PD-L1 on tumor cells. Ira Mellman (vice-president of research oncology at Genentech), believes that anti-PD-L1 might have fewer adverse effects than anti-PD-1. That is because anti-PD-L1 would target tumor cells while leaving T cells free to participate in immune networks that work to prevent autoimmune reactions.

Three experimental drugs in this area of immunotherapy were a main focus at ASCO in 2013. They are:

• BMS’ anti-PD-1 agent nivolumab (BMS-936558, MDX-1106), which we had discussed in our 2012 ASCO article.
• Merck’s anti-PD-1 agent lambrolizumab (MK-3475)
• Roche/Genentech’s anti-PD-L1 agent MPDL3280A

We shall focus on these three agents in this article.

Competition between BMS’ nivolumab and Merck’s lambrolizumab

As highlighted in the 2013 ASCO meeting and in reports by industry commentators such as FierceBiotech, there is a keen race between BMS and Merck to be the first to market an anti-PD-1 agent.

At the ASCO 2013 meeting, BMS researchers and their colleagues reported that a third of the patients in a Phase 1 trial of nivolumab saw tumors shrink at least 30%. They also reported that patients with solid tumors [metastatic melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC)] showed high rates of 2 year overall survival–44% for melanoma, 32% for NSCLC, and 52% for RCC (clinical trial NCT00730639).

In a first Phase 1 study of a combination therapy of nivolumab with ipilimumab in metastatic melanoma, BMS researchers and their colleagues reported that the two agents could be administered in combination safely. Clinical activity for the combination therapy appeared to exceed that of published monotherapy data for each of the two agents, with greater or equal to 80% tumor reduction at 12 weeks in 30% (11/37) of patients. In addition to the ASCO 2013 presentation, the results of this combination therapy trial were published online in the New England Journal of Medicine.

According to Fierce Biotech, BMS has 6 late-stage studies under way for nivolumab, with fast-track status in place for melanoma, lung cancer and kidney cancer.

Meanwhile, Merck announced in a June 2, 2013 press release the presentation at ASCO 2013 of interim data from a Phase 1B study evaluating its anti-PD-1 agent lambrolizumab in patients with advanced melanoma. The data was presented by Antoni Ribas, M.D., Ph.D. (Jonsson Comprehensive Cancer Center, University of California, Los Angeles). in addition to the ASCO 2013 presentation, this study was published online in the New England Journal of Medicine.

A total of 135 patients with advanced melanoma were treated. Most of the adverse events seen in the study were low grade. The confirmed response rate across all dose cohorts was 38%. The highest confirmed response rate (52%) was seen in the cohort that received the highest dose (10 mg per kilogram every 2 weeks). Ten percent of the patients in the highest-dose group achieved a complete response, with response duration ranging from 28 days to 8 months.

Response rates did not differ significantly between patients who had received prior ipilimumab treatment and those who had not. Responses were durable in the majority of patients; 81% of the patients who had a response (42 out of of 52 total) were still receiving treatment at the time of analysis in March 2013. The overall median progression-free survival among the 135 patients was over 7 months.

According to Fierce Biotech, Merck now has four clinical studies under way for lambrolizumab, including a  Phase 2 trial in melanoma and Phase 1 trials in ipilimumab-naïve patients with triple-negative breast cancer, metastatic bladder cancer and head and neck cancer. The company, which has won breakthrough drug designation from the FDA for lambrolizumab, believes that the ongoing 500-patient Phase 2 melanoma study could provide enough positive data to win FDA approval. Merck is also preparing applications for late-stage clinical trials in melanoma and non-small cell lung cancer, which are planned to launch in the third quarter of 2013.

Roche/Genentech’s anti-PD-L1 agent MPDL3280A

Genentech researchers and their collaborators presented data on a clinical study of MPDL3280A in patients with metastatic melanoma at ASCO 2013. In addition to the ASCO 2013 presentation and abstract, The Angeles Clinic and Research Institute (Los Angeles, CA) published a press release about the study. Omid Hamid, M.D. of The Angeles Clinic and Research Institute made the oral presentation at the ASCO meeting.

This study was a Phase 1, multicenter, first in human, open-label, dose escalation study (clinical trial NCT01375842), which is still ongoing. It was primarily designed to assess  safety, tolerability, and pharmacokinetics of MPDL3280A in patients with metastatic melanoma. The drug was found to be well tolerated. 35 patients who began treatment at doses of 1-20 mg/kg and were enrolled prior to Jul 1, 2012 were evaluable for efficacy. An overall response rate of 26% (9/35) was observed, with all responses ongoing or improving. Some responding patients experienced tumor shrinkage within days of initial treatment. The 24-week progression-free survival was 35%. Several other patients had delayed antitumor activity after apparent tumor progression. Of three initial patients treated with a combination of MPDL3280A and vemurafenib (Daiichi Sankyo/Genentech’s Zeboraf, a targeted kinase inhibitor), two experienced tumor shrinkage, including 1 complete response. The researchers concluded that further assessment of MPDL3280A as monotherapy and combination therapy is warranted. A Phase 1 study (NCT01656642) of a combination therapy of MPDL3280A and vemurafenib in patients with previously untreated BRAFV600-mutation positive metastatic melanoma is ongoing.

Data was also presented at ASCO 2013 on the efficacy of MPDL3280A in other solid tumors. According to Roy S. Herbst, M.D. Ph.D., (Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven) MPDL3280A showed significant anti-tumor activity and was well tolerated in patients with such cancers as NSCLC, melanoma, colorectal cancer, gastric cancer, and RCC. 29 of 140 evaluable patients (21%) exhibited tumor shrinkage, with the highest overall responses in patients with NSCLC and melanoma. Of the 29 responders, 26 patients continued responding as of their last assessment.

Researchers have also been studying PD-L1 expression levels as a potential biomarker to identify likely responders. As outlined by Dr. Herbst, responses appeared to be better among patients with higher levels of PD-L1 expression. The response rate among PD-L1-positive patients was 36% (13 of 36 patients), compared with 13% (9 of 67 patients) who were PD-L1-negative. The role that PD-L1 expression might play as a biomarker is still being explored, including attempting to determine the best way to measure the protein and other related criteria.

In addition to the Phase 1 trial of MPDL3280A/vemurafenib combination therapy in melanoma, Genentech is sponsoring a Phase 1 trial of MPDL3280A in combination with bevacizumab (Genentech/Roche’s Avastin, an angiogenesis inhibitor that targets vascular endothelial growth factor) or with bevacizumab plus chemotherapy (clinical trial NCT01633970). Genentech is also sponsoring a Phase 2 clinical trial (NCT01846416) of MPDL3280A in patients With PD-L1-positive advanced NSCLC.

Conclusions

The field of immunotherapeutic MAbs for cancer, which target negative regulators of T-cell receptor signals, continues to advance. The approval and marketing of ipilimumab provides an important proof-of-principle for this approach. Now the field is advancing to include agents that target PD-1 and its negative regulator PD-L1. Studies of BMS’ PD-1 inhibitor nivolumab have advanced as far as Phase 3, and of Merck’s lambrolizumab as far as Phase 2. Meanwhile, Roche/Genentech’s PD-L1 inhibitor MPDL3280A has reached Phase 2.

However, the in terms of clinical trial data, it is still too early to meaningfully determine the efficacy of any of the PD-1 and PD-L1 inhibitor drugs. The meaningful data will come from randomized Phase 3 trials, based on overall survival rather than tumor response rate as in currently reported trials (with the exception of the Phase 1 results of clinical trial NCT00730639 of nivolumab described earlier, which included measures of overall survival).

Nevertheless, this is an extremely exciting field, and researchers, companies, and patient communities have high expectations of success.

__________________________________________

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.

On June 11, 2013, Agios Pharmaceuticals (Cambridge, MA) filed with the U.S. Securities and Exchange Commission for an Initial Public Offering (IPO). The company plans to raise up to $86 million through this IPO. This news was reported by Fierce Biotech, the Boston Business Journal, and Xconomy, among others.

The Biopharmconsortium Blog has been following Agios since December 31, 2009, and we have posted three additional articles since. Our newest article, posted on December 28, 2012, announced the publication of an article  in the November 19, 2012 issue of Chemical & Engineering News (C&EN) by senior editor Lisa M Jarvis, in which I was quoted. More recently, Agios posted a reprint of that article on its website, which it retitled “Built to Last”. I had used that phrase in my quote in Ms. Jarvis’ article.

Agios specializes in the field of cancer metabolism. The company is working on multiple potential targets, with the goal of dominating that field, using its strong proprietary technology platform. Its financing strategy is aimed at building a company with the potential to endure as an independent firm over a long period of time–hence “built to last”. This contrasts with the recent trend toward “virtual biotech companies”–lean companies with only a very few employees that outsource most of their functions, and that are designed for early acquisition by a Big Pharma or large biotech company. Agios’ ambition to dominate the field of cancer metabolism requires a “built to last” strategy.

As Agios’ CEO David Schenkein said in the C&EN article, “You’re never going to get that with a one-target deal”. In support of that strategy, Agios has raised over a quarter of a billion dollars in funding. This has included two rounds of venture capital funding that raised a total of $111 million, and a partnership with Celgene that brought in a total of $141 million in upfront payments. According to the Fierce Biotech article, Celgene has committed to invest in Agios’ IPO.

As of yet, Agios has no drugs in clinical trials. However, the company has several drug candidates in early development. And according to the Fierce Biotech article, Agios intends to use the proceeds of the IPO to fund its first clinical trials. One of the company’s lead candidates, AG-221, which targets mutant isocitrate dehydrogenase 2 (IDH2), may reach the clinic soon, according to the Fierce Biotech article. Another Agios compound, AG-120, which targets mutant IDH1, is expected to enter the clinic in early 2014.

Recent developments in Agios’ research

The Biopharmconsortium Blog has been reporting on Agios’ research on mutant forms of IDH1 and IDH2, and their roles in human cancer, beginning with our December 31, 2009 article. Briefly, wild-type IDH1 and IDH2 catalyze the NADP+-dependent oxidative decarboxylation of isocitrate to α-ketoglutarate. However, mutant forms of IDH1and IDH2, which are found in certain human cancers, no longer catalyze this reaction, but instead catalyzes the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2-HG). The researchers have hypothesized that 2HG is an oncometabolite, and that developing mutant-specific small molecule inhibitors of IDH1 and IDH2 might inhibit the growth or reverse the oncogenic phenotype of cancer cells that carry the mutant enzymes.

As we reported in our December 28, 2012 article, Agios researchers and their collaborators reported a series of compounds that selectively inhibit the mutant form of IDH1. These compounds were found to lower tumor 2-HG in a xenograft model. More recently, on May 3, 2013, Agios researchers and their collaborators published two research reports in the journal Science, and the company also announced the results of these studies in a April 4, 2013 press release. According to that press release, the two reports are the first publications to show the effects of inhibiting mutant IDH1 and IDH2 in patient-derived tumor samples. These results constitute preclinical support for the hypothesis that the two mutant enzymes are driving disease, and that drugs that target the mutant forms of the enzymes can reverse their oncogenic effects.

In the first of these papers (Wang et al.), the researchers reported the development of the small-molecule compound AGI-6780 (a tool compound, not a clinical candidate), which potently and selectively inhibits the tumor-associated mutant IDH2/R140Q. AGI-6780 is an allosteric inhibitor of this mutant enzyme. Treatment with AGI-6780 induced differentiation of two IDH2-bearing tumors in vitro: a TF-1 erythroleukemia genetically engineered to express IDH2, and primary human acute myelogenous leukemia (AML) carrying the IDH2 mutation. These data provide proof-of-principle that inhibitors targeting mutant IDH2/R140Q could have potential applications as a differentiation therapy for AML and other IDH2-driven cancers.

In the second paper (Rohle et al.), Agios researchers and their collaborators focused on a selective mutant IDH1 (R132H-IDH1) inhibitor, AGI-5198 (also a tool compound), which is one of the mutant IDH1 inhibitors that we referred to in our December 28, 2012 article. The researchers studied the effects of AGI-5198 on human glioma cells with endogenous IDH1 mutations. AGI-5198 inhibited, in a dose-dependent manner, the ability of the mutant IDH1 to produce 2-HG. Under conditions of near-complete inhibition of 2-HG production, AGI-5198 induced demethylation of histone H3K9me3 in chromatin, and also induced expression of genes associated with differentiation to glial cells (specifically astrocytes and oligodendrocytes). Blockade with AGI-5198 also impaired the growth of IDH1-mutant—but not IDH1–wild-type—glioma cells. Oral administration of AGI-5198 to mice with established R132H-IDH1 glioma xenografts resulted in impaired growth of the tumors. Treatment of mice with AGI-5198 was well-tolerated, with no signs of toxicity during 3 weeks of daily treatment.

It is possible that Agios’ IDH1/2 inhibitors do not inhibit tumor growth by inducing differentiation, at least in the case of AGI-5198 in glioma. Rohle et al. noted that although high-dose (450 mg/kg) AGI-5198 induced demethylation of histone H3K9me3 and induced gliogenic differentiation markers, a lower dose of AGI-5198 (150 mg/kg) did not. Nevertheless, the lower dose of AGI-5198 resulted in a similar tumor growth inhibition as did the the higher dose. This suggests that in glioma cells, mutant IDH1 regulates cell proliferation and cell differentiation via distinct pathways. These pathways may have different sensitivities to levels of 2-HG, with the differentiation-related pathway requiring increased inhibition of levels of 2-HG than the proliferation-related program.

Is differentiation therapy with IDH1/2 inhibitors sufficient to provide efficacious treatment of AML and/or glioma?

A companion Perspective, authored by Jiyeon Kim and Ralph J. DeBerardinis (Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX), was published in the same issue of Science as Wang et al and Rohle et al. Kim and DeBerardinis note that the selective mutant IDH1 and IDH2  inhibitors produced cytostatic rather than cytotoxic effects. Specifically, they induced cancer cell differentiation rather than cell death.

It is possible that inducing a permanent state of differentiation may be sufficient for therapeutic efficacy. However, the survival (in a differentiated, nontumor state) of viable cells still containing potentially oncogenic mutations may eventually give rise to cancer. Therefore, it is important to determine whether the therapeutic effects of these compounds will persist over long periods of time.

In discussing AGI-6780 as a differentiation therapy in hematopoietic malignancies, Wang et al. compared their results to the action of all-trans retinoic acid (ATRA) on acute promyelocytic leukemia (APL). ATRA has be used to treat APL, and it apparently works via relieving a block in differentiation present in these leukemic cells. The use of ATRA in APL has thus been taken as a paradigm of differentiation therapy, and it is used as such a paradigm by Wang et al.

We discussed the case of ATRA treatment of APL in our April 15, 2010 article on this blog. APL patients whose leukemia is due to a PML-RARα translocation in their promyelocytes (who constitute the vast majority of APL patients) initially respond to differentiation therapy with ATRA, but eventually develop resistance to the drug. Combination therapy of ATRA and arsenic trioxide (As 2O 3) cures the majority of patients, rendering a cancer that was once uniformly fatal 90% curable. As discussed in our 2010 article, this was first modeled in transgenic mice, and then applied to human patients. APL patients whose leukemia is due to a PLZF-RARα translocation in their promyelocytes are unresponsive to both ATRA and As 2O 3. However, as discussed in our 2010 article, the corresponding mouse model does respond to a combination of ATRA and a histone deacetylase (HDAC) inhibitor such as sodium phenylbutyrate.

When this combination therapy was tested in one patient in 1998 (presumably the first patient in a clinical trial), she achieved a complete remission. Presumably, clinical trials of newer, approved HDAC inhibitors [e.g., suberoylanilide hydroxamic acid (SAHA), Merck’s Vorinostat] in combination with ATRA could be carried out.  (The SAHA/ATRA combination has been tested in a mouse model of PLZF-RARα APL.)

As in the case of Agios’ AGI-5198, ATRA may work in part via a different mechanism than induction of differentiation in APL. This is despite this case being taken as a paradigm of differentiation therapy. We referred to this briefly in our April 19, 2010 blog post. ATRA appears to produce cancer cell growth arrest at least in part via inducing degradation of the PML-RARα fusion protein. Growth arrest and differentiation appear to be uncoupled in the case of the action of ATRA on PLZF-RARα-bearing cells. [The issue of the uncoupling of RARα transcriptional activation (which induces differentiation) and RARα degradation was investigated further in a study published in April 2013.]

Is it possible–as in the case of ATRA in APL–that Agios’ therapies for targeting mutant forms of IDH1/2 will require combination with another agent to achieve long-term therapeutic efficacy? Only clinical trials can answer this question. However, perhaps it might be possible to design animal models to test this issue, and to use these models to identify agents that may be productively used in combination with the IDH1/2 inhibitors.

Conclusions

Agios IPO comes amidst a boom in biotech IPOs–especially Boston biotech IPOs. In addition to Agios, recent Boston-area IPOs include Epizyme (Cambridge, MA), TetraPhase Pharmaceuticals (Watertown, MA) and Enanta Pharmaceuticals (Watertown, MA). According to a June 14 2013 article in the Boston Business Journal, bluebird bio (Cambridge, MA) is also expected to complete its IPO during the week of June 17, 2013. We discussed bluebird bio in our October 11, 2012 Biopharmconsortium Blog article.

As with Agios, neither Epizyme, TetraPhase, Enanta, nor bluebird has any revenues from approved and marketed therapeutics. However, unlike Agios, all of these four companies have drug candidates that have reached the clinic. In addition, TetraPhase and Enanta have compounds that have completed Phase 2 clinical trials, and thus have presumably achieved proof-of-concept in humans. Thus the stock of these two companies appear to be lower risk investments than that of Agios, despite Agios’ very compelling scientific and strategic rationale. At least until its compounds achieve proof-of-concept in human studies, investing in Agios is mainly for sophisticated investors who have a high tolerance for risk. ____________________________________________________

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.

 

I was quoted in an article in the November 19, 2012 issue of Chemical & Engineering News (C&EN) by senior editor Lisa M Jarvis. The article is entitled

The article focuses on Agios Pharmaceuticals’ (Cambridge, MA) strategy for building a company that can endure as an independent firm over a long period of time, and that can also demonstrate sustained performance.

This contrasts with the recent trend toward “virtual biotech companies”–lean companies with only a very few employees that outsource most of their functions, and that are designed for early acquisition by a Big Pharma or large biotech company. The virtual company strategy is designed to deal with the inability of most young biotech companies to go public in the current financial environment. Without the ability to go public, young companies cannot provide early-stage venture capital investors with a profitable exit within a few years after launching the company. Virtual companies typically have a few assets, such as molecules that are ready for preclinical studies or early clinical trials. The goal is to obtain enough evidence that their compounds can become drugs to interest a Big Pharma.

In contrast, there are a few young  “platform companies” that are built on a broad technology platform, which aim to address important areas of biology and potentially to develop numerous products with the potential to address important areas of unmet medical need. One of these is Agios.

“Built to Last” in the current biotech ecosystem

In the C&EN article, I was quoted as saying that only a few platform companies have been launched in recent years. In the Boston area, in addition to Agios, such companies include Forma Therapeutics and Aileron Therapeutics. I was further quoted as saying “These companies are built to last.”

That brings up the old business paradigm from the 1990s and early 2000s–“Built to Last” versus “Built to Flip”. Those involved in building virtual biotech companies–especially venture capitalists and angel investors–do not like the use of “Built to Flip” to characterize their companies. And there are some fine virtual biotechs–some, such as Energesis and Zafgen–which we have covered in our blog.

(Plexxikon, the developer of targeted melanoma drug vemurafenib, also operated as a virtual company. However, it had a technology platform, and had the potential to become an independent biotech with marketed products. Thus Plexxikon did not fit the usual “virtual biotech model”. Nevertheless, it was acquired by Daiichi Sankyo in 2011.)

However, some industry commentators believe that “Built to Flip” is an appropriate designation for virtual biotech companies, and that the virtual model is likely to be detrimental to drug discovery and to the biotech/pharma industry as a whole.

Meanwhile, the 2012 BIO International Convention in Boston had a session entitled “Moving the Goal Posts: How to Build a Free-Standing Biotech from Scratch in Today’s Environment.” This session focused on how to build the “next Vertex or even the next Genentech” (i.e., a “Built to Last” biotech company) in today’s environment. John Evans, the Vice President of Business Development & Operations of Agios was a speaker at that session. The session was moderated by Bruce Booth of Atlas Ventures. Thus, despite the preference for lean virtual biotech companies in the current funding environment, there is an interest in the entrepreneurial and venture capital communities for how free-standing biotechs might emerge under current conditions.

How to build a young platform biotech company

The Biopharmconsortium Blog has included three articles about Agios:

• Cancer metabolism as a target for drug discovery: Agios Pharmaceuticals (December 31, 2009)
• Agios Pharmaceuticals partners with Celgene (April 23, 2010)
• Cancer metabolism specialist Agios Pharmaceuticals continues its spectacular fundraising success (November 30, 2011)

These articles, as well as the November 19 2012 C&EN article, outline how Agios has been building a free-standing biotech in today’s unfavorable environment. Agios’ strategy is based on three elements:

• A stellar group of scientific founders–Drs. Craig B. Thompson, Tak W. Mak, and Lewis C. Cantley.
• A strong proprietary technology platform based on cancer metabolism
• A financing strategy that includes both venture capital and partnerships with established companies. In the case of Agios, their partner is Celgene. The Agios/Celgene partnership provides Agios with $150 million, and allows Agios to maintain control over the direction of its early stage research.

As stated in the C&EN article, the financial security gained via Agios’ funding by its venture investors and by Celgene enables Agios to work on multiple potential targets, with the goal of dominating the field of cancer metabolism. Agios focuses on two types of targets: metabolic enzyme species that are found only in cancer cells, and enzyme species on which a cancer cell has become dependent. Agios researchers intend to develop drugs against targets for which their are predictive biomarkers that identify the right patients for clinical studies.

New developments outlined in the November 19, 2012 C&EN article

Both the November 19, 2012 C&EN article and our Bipharmconsortium Blog articles outline Agios’ program to target a mutated form of isocitrate dehydrogenase 1 (IDH1), which together with mutated IDH2 has been implicated in 70% of human brain cancers. As stated in the C&EN article, Agios researchers have recently reported a series of compounds that selectively inhibit the mutant form of IDH1. This research had been carried out in collaboration with researchers from Ember Therapeutics (Watertown, MA). As we stated in another Biopharmconsortium Blog article, Ember specializes in targeting beige adipocytes for treatment of metabolic diseases.

As we noted in our November 30, 2011 Biopharmconsortium Blog article, Agios had slated a portion of the $78 million that it raised in its Series C financing to expand its R&D efforts into inborn errors of metabolism (IEMs). IEMs comprise a large class of inherited disorders of metabolism, most of which are defects in single genes that code for metabolic enzymes. These rare metabolic diseases have a high level of unmet medical need.

As outlined in the C&EN article, Agios’ work with mutant IDH1 and IDH2 is serving as a bridge to the company’s programs in IEMs. IDH2 mutations have been found in a class of children with 2-hydroxyglutaric aciduria, a rare inherited neurometabolic disorder that can cause developmental delay, epilepsy, and a set of other pathologies.

According to the C&EN article, IEMs are of special strategic interest to Agios. Agios CEO David Schenkein stated that expanding the company’s R&D efforts into IEMs helps the company to manage the risk profile of its portfolio. In the case of cancer, Agios researchers must identify and validate targets involved in the pathobiology of these diseases, and then to find drugs that modulate these targets. In the case of IEMs, disease biology is already validated by genetics.

Moreover, IEMs have small patient populations. Thus only small clinical trials are needed to bring a drug to market. Agios therefore believes that it can bring drugs for these diseases to market on its own, without the need for a larger partner such as Celgene or a Big Pharma.

As we discussed in a Biopharmconsortium Blog article on improving the clinical trial system, although rare diseases only require small clinical trials, finding and recruiting patients for the trials is made more difficult because of the very small number of patients with a particular disease. One solution is to work with patient advocates and “disease organizations”, some of which have patient registries. In the case of 2-hydroxyglutaric aciduria and other organic acidemias, a “disease organization” exists–the Organic Acidemia Association (OAA). Perhaps Agios will find it fruitful to work with the OAA in its patient recruitment efforts.

Currently, Agios is focused on getting compounds into the clinic–both for IEMs and for cancer. Looking down the road, the company’s $180 million war chest should enable Agios to put several compounds through proof-of-concept studies, according to Dr. Schenkein. (This is besides any cancer drug candidates that are licensed by Celgene.) Despite Agios’ strategy of conducting small trials for IEM drug candidates, Dr. Schenkein said that the company will eventually need to go public to achieve its strategic goal of dominating the cancer metabolism field.

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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