Biopharmconsortium Blog

Expert commentary from Haberman Associates biotechnology and pharmaceutical consulting.

Posts filed under: Monoclonal Antibodies

Can adoptive cellular immunotherapy successfully treat metastatic gastrointestinal cancers?

 

Dr. Steven Rosenberg

Dr. Steven Rosenberg

On September 6, 2014, we published an article on this blog announcing the publication of our book-length report, Cancer Immunotherapy: Immune Checkpoint Inhibitors, Cancer Vaccines, and Adoptive T-cell Therapies, by Cambridge Healthtech Institute (CHI).

In that article, we cited the example of the case of a woman with metastatic cholangiocarcinoma (bile-duct cancer), which typically kills the patient in a matter of months. The patient, Melinda Bachini, was treated via adoptive immunotherapy with autologous tumor-infiltrating T cells (TILs) resulting in survival over a period of several years, with a good quality of life.

Our report includes a full discussion of that case, as of the date of the May 2014 publication of a report in Science by Steven A. Rosenberg, M.D., Ph.D. and his colleagues at the National Cancer Institute (NCI). Ms. Bachini’s story was also covered in a May 2014 New York Times article.

Now comes the publication, in Science on December 2015, of an update from the Rosenberg group on their clinical studies of TIL-based immunotherapy of metastatic gastrointestinal cancers. This article discusses the results of TIL treatment of ten patients with a variety of gastrointestinal cancers, including cancers of the bile duct, the colon or rectum, the esophagus, and the pancreas. The case of Ms. Bachini (“patient number 3737”) was included.

Ms. Bachini, a paramedic and a married mother of six children, and a volunteer with the Cholangiocarcinoma Foundation, was 41 years old when first diagnosed with cancer. She remains alive today—a five-year survivor—at age 46.

The Foundation produced a video, dated March 13, 2015, in which Ms. Bachini gives her “patient perspective”. This video includes her story “from the beginning”—from diagnosis through surgery and chemotherapy, and continuing with adoptive immunotherapy at the NCI under Dr. Rosenberg. Although her tumors continue to shrink and she remains alive, she still is considered to have “Stage 4” (metastatic) cancer. Ms. Bachini is a remarkable woman.

The Cholangiocarcinoma Foundation has also produced an on-demand webinar (dated October 21, 2014) on the adoptive cellular therapy trial in patients with various types of metastatic gastrointestinal cancers, led by Drs. Eric Tran and Steven Rosenberg. Ms. Bachini is also a presenter on that webinar. The December 2015 Science article is an updated version of the results of this trial.

The trial, a Phase 2 clinical study (NCT01174121) remains ongoing, and is recruiting new patients.

The particular focus of Dr. Tran’s and Dr. Rosenberg’s study in TIL treatment of gastrointestinal cancers is whether TILs derived from these tumors include T-cell subpopulations that target specific somatic mutations expressed by the cancers, and whether these subpopulations might be harnessed to successfully treat patients with these cancers. Of the ten patients who were the focus of the December 2015 publication, only Ms. Bachini had a successful treatment. In the case of Ms. Bachini, she received a second infusion of TILs that were enriched for CD4+ T cells that targeted a unique mutation in a protein known as ERBB2IP. It was this second treatment that resulted in the successful knockdown of her tumors, which continues to this day.

Despite the lack of similar successes in the treatment of the other nine patients, the researchers found that TILs from eight of these patients contained CD4+ and/or CD8+ T cells that recognized one to three somatic mutations in the patient’s own tumors. Notably, CD8+ TILs isolated from a colon cancer tumor of one patient (patient number 3995) recognized a mutation in KRAS known as KRAS G12D. This mutation results in an amino acid substitution at position 12 in KRAS, from glycine (G) to aspartic acid (D). KRAS G12D is a driver mutation that is involved in causation of many human cancers.

Although two other patients (numbers 4032 and 4069, with colon and pancreatic cancer, respectively) had tumors that expressed KRAS G12D, the researchers did not detect TILs that recognized the KRAS mutation in these patients. The researchers concluded that KRAS G12D was not immunogenic in these patients. The TILs from patient 3995 were CD8+ T cells that recognized KRAS G12D in the context of the human leukocyte antigen (HLA) allele HLA-C*08:02. [As with all T cells, TILs express T-cell receptors (TCRs) that recognize a specific antigenic peptide bound to a particular major histocompatibility complex (MHC) molecule—this is referred to as “MHC restriction”.] The two patients for whom KRAS G12D was not immunogenic did not express the HLA-C*08:02 allele.

The results seen with KRAS G12D-expressing tumor suggest the possibility of constructing genetically-engineered CD8+ T cells that express a TCR that is reactive with the KRAS mutation in the context of the HLA-C*08:02 allele. The KRAS G12D driver mutation is expressed in about 45% of pancreatic adenocarcinomas, 13% of colorectal cancers, and at lower frequencies in other cancers, and the HLA-C*08:02 allele is expressed by approximately 8% and 11% of white and black people, respectively, in the U.S. Thus, in the U.S. alone, thousands of patients per year with metastatic gastrointestinal cancers would potentially be eligible for immunotherapy with this KRASG12D-reactive T cell.

Although only Ms. Bachini (“patient number 3737”) was a long-term survivor, the researchers were able to treat three other patients with enriched populations of TILs targeting predominantly one mutated tumor antigen. Patient 4069 experienced a transient regression of multiple lung metastases of his pancreatic adenocarcinoma, but patients 4007 and 4032 had no objective response. Whereas 23% of circulating T cells at one month after treatment were adoptively transferred mutation-specific TILs in the case of Ms. Bachini, the other three patients treated with enriched populations of mutation-specific TILs showed no or minimal persistence. The researchers concluded that they will need to develop strategies designed to enhance the potency and persistence of adoptively transferred mutation-specific TILs. Nevertheless, the researchers concluded that nearly all patients with advanced gastrointestinal cancers harbor tumor mutation-specific TILs. This finding may serve as the basis for developing personalized adoptive cellular therapies and/or vaccines that can effectively target common epithelial cancers.

Conclusions

Dr. Rosenberg pioneered the study and development of adoptive cellular immunotherapy, beginning in the 1980s. Most studies with TIL-based adoptive immunotherapy have been in advanced melanoma. Adoptive cellular immunotherapy is the most effective approach to inducing complete durable regressions in patients with metastatic melanoma.

As we discussed in our cancer immunotherapy report, melanoma tumors have many more somatic mutations (about 200 nonsynonymous mutations per tumor) than most types of cancer. This appears to be due to the role of a potent immunogen—ultraviolet light—in the pathogenesis of melanoma. The large number of somatic mutations in melanomas results in the infiltration of these tumors by TILs that target the mutations. As discussed in our report, Dr. Rosenberg and his colleagues cultured TIL cell lines that addressed specific immunodominant mutations in patients’ melanomas. Treatment with these cell lines in several cases resulted in durable complete remissions of the patients’ cancers.

Dr. Rosenberg and his colleagues used the same strategy employed in identification of TIL cell lines that targeted specific mutations in melanomas to carry out the study in gastrointestinal cancers, as discussed in our report. However, the small number of somatic mutations and of endogenous TILs in gastrointestinal cancers and in most other epithelial cancers has made studies in these cancers more difficult than studies in melanoma.

in addition, the susceptibility of melanoma to treatment with checkpoint inhibitors such as the PD-1 blockers pembrolizumab (Merck’s Keytruda) and nivolumab (Bristol-Myers Squibb’s Opdivo) correlates with the large number of somatic mutations in this type of cancer. As we discussed in our December 15, 2014 article on this blog, immune checkpoint inhibitors work by reactivating endogenous tumor-infiltrating T cells (TILs). In the case of melanoma, these endogenous TILs target the numerous somatic mutations found in these cancers, and—as suggested by Dr. Rosenberg’s studies with cultured TIL cell lines—those endogenous TILs that target immunodominant mutations can induce durable compete remissions. As discussed in our December 15, 2014 blog article, the three major types of immuno-oncology treatments—immune checkpoint inhibitors, cancer vaccines, and adoptive T-cell therapies, work via related mechanisms.

In 2015, researchers showed that other types of cancers that have numerous somatic mutations are especially susceptible to checkpoint inhibitor treatment. These include, for example, non-small cell lung cancers (NSCLCs) that have mutational signatures that indicate that the cancers were caused by smoking, and cancers that have mutations in genes involved in DNA repair. (Mutations in genes involved in DNA repair pathways result in the generation of numerous additional mutations.)

Moreover, as discussed in our December 15, 2014 blog article, cancer immunotherapy researchers have been expanding the types of tumors that can be treated with checkpoint inhibitors. Genentech/Roche’s PD-L1 inhibitor that was discussed in that article, MPDL3280A, is now called atezolizumab. The clinical trials of atezolizumab discussed in that article and in our report have continued to progress. In a pivotal Phase 2 study in locally advanced or metastatic urothelial bladder cancer (UBC), atezolizumab shrank tumors in 27 percent of people whose disease had medium and high levels of PD-L1 expression and had worsened after initial treatment with platinum chemotherapy. These responses were found to be durable. According to Genentech, these results may represent the first major treatment advance in advanced UBC in nearly 30 years. Atezolizumab also gave positive results in Phase 2 clinical trials in patients with NSCLC that expresses medium to high levels of PD-L1.

Meanwhile, NewLink Genetics (Ames, IA) has entered Phase 3 clinical trials in pancreatic cancer with its HyperAcute cellular immunotherapy vaccine therapy. A Phase 2 trial of the company’s HyperAcute cellular immunotherapy algenpantucel-L in combination with chemotherapy and chemoradiotherapy in resected pancreatic cancer (clinical trial number NCT00569387) appears to be promising.

Dr. Rosenberg’s studies of TIL therapies of gastrointestinal cancers represent another approach to moving immuno-oncology treatments beyond melanoma, based on mutation-specific targeting. The types of cancers that form the focus of these studies—gastrointestinal epithelial cancers—have proven difficult to treat. Moreover, several of them are among the most common of cancers. The researchers and patients involved in these and other immuno-oncology studies are heroes, and oncologists appear to be making measured progress against cancers that have been until recently considered untreatable.

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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.

Our new website, and continuing R&D on antibody drugs for cancer immunotherapy

OX40 Protein Source: Emw http://bit.ly/1Fww0kP

OX40 Protein Source: Emw http://bit.ly/1Fww0kP

Haberman Associates has a new website, with the same URL as previously but with many improvements. This article is the first Biopharmconsortium Blog post to be posted after the new website has gone online. Please explore the new site, and send any comments on the site to us.

In addition to announcing our new website, this article is designed to outline several new areas of cancer immunotherapy R&D.

Research and development of novel checkpoint inhibitors for cancer immunotherapy

Our September 2014 book-length Insight Pharma Report, “Cancer Immunotherapy: immune checkpoint inhibitors, cancer vaccines, and adoptive T-cell therapies” focused on agents that had reached the clinic. In the case of checkpoint inhibitors, the report did not cover the universe of immune checkpoints, but only those that have been addressed with late-stage agents, some of which had entered—or were about to enter—the market. However, as we stated in the report, researchers expect new experimental products to emerge from immune checkpoint research in the next 5-10 years.

In the report, we mentioned research on agents to target the lymphocyte-activation gene 3 (LAG-3, CD223) pathway. In a published study in mice, Bristol-Myers Squibb (BMS) researchers and their academic collaborators obtained evidence that dual treatment with an anti-PD-1 (such as BMS’ nivolumab) and an anti-LAG-3 monoclonal antibody (MAb) cured most mice of established tumors that were largely resistant to single antibody treatment. They concluded that dual blockade of PD-1 and LAG-3 might constitute a viable strategy for cancer immunotherapy, which might be superior to blocking PD-1 alone.

At the time of our report’s publication, BMS had initiated two Phase 1 safety studies with an investigational anti-LAG-3 MAb. These are a study of anti-LAG-3 with and without anti-PD-1 in treatment of solid tumors (clinical trial number NCT01968109), and a study of anti-LAG-3 in relapsed or refractory chronic lymphocytic leukemia (CLL), Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) (clinical trial number NCT02061761). Both of these studies are still ongoing and recruiting patients.

Another checkpoint inhibitor target that is begin investigated (in preclinical studies) for potential use in cancer immunotherapy is TIM-3 (T-cell immunoglobulin domain and mucin domain 3). TIM-3 is is co-expressed on PD-1+ CD8 T cells in mouse models with solid tumors or hematologic malignancies. In a preclinical mouse melanoma model, combined blockade of TIM-3 and PD-1, or TIM-3 and CTLA4, was more effective in prolonging survival than blocking either protein alone. Moreover, the combination of anti-CTLA4, anti-TIM-3 and anti-LAG-3 produced further suppression of growth of the melanoma tumor. These data suggest that blockade of multiple inhibitory receptors—including TIM-3 and LAG-3—results in synergistic antitumor activity.

Research and development of agonist antibodies for use in cancer immunotherapy

Another approach to antibody-based cancer immunotherapy—in addition to targeting checkpoint inhibitors—is development of agonist antibodies. This is the subject of an upcoming conference in Boston—sponsored by Cambridge Healthtech Institute (CHI), on May 7-8, 2015. This conference is part of CHI’s annual PEGS Boston (Essential Protein Engineering Summit). Agonist antibodies target certain cell surface proteins on T cells, resulting in stimulation of the activity of the T cells. This contrasts with checkpoint inhibitors, which are designed to overcome blockages to T cell activity mediated by immune checkpoints.

Among the targets for agonist antibodies are two members of the tumor necrosis receptor (TNFR) superfamily—CD27 and OX40.

Celldex Therapeutics’ fully-human monoclonal antibody (MAb) agent varlilumab (CDX-1127) targets CD27. As discussed in our cancer immunotherapy report, activation of naïve T-cells requires both T-cell receptor (TCR) signaling and costimulation by a “second signal”. In our report, we used the example of CD28 (present on the surface of T cells) interacting with B7 [present of the surface of an antigen-presenting cell (APC) such as a dendritic cell] to deliver a “second signal”. CD27 is a member of the CD28 superfamily, and it interacts with CD70 to deliver a “second signal”. Varlilumab can substitute for CD70, and deliver a costimulatory signal to T cells whose TCRs are engaged. This can change a weak immune response into a strong, prolonged response. In preclinical models, immunostimuation by varlilumab has been shown to mediate antitumor effects.

In addition to the immunostimulatory activity of varlilumab, this agent may also exert direct therapeutic effects against tumors that express CD27 at high levels, such as human B and T cell lymphomas. Varlilumab has shown potent anti-tumor activity against these lymphomas in preclinical models. In these models, varlilumab may exert its therapeutic activity both via “second-signal” immune activation, and via direct antitumor activity against CD27-bearing lymphoma cells.

Varlilumab is now in ongoing Phase 1 clinical trials against solid and hematological tumors (clinical trial number NCT01460134), and in ongoing Phase 1 and Phase 2 trials in combination with the anti-PD-1 MAb agent nivolumab (BMS’ Opdivo) against advanced refractory solid tumors (clinical trial number NCT02335918). Reports of interim data from clinical trials of varlilumab at scientific meetings in 2013 and in 2014 indicate that this agent was very well tolerated and demonstrated biological activity and signs of clinical activity against advanced, treatment-refractory lymphoid malignancies and metastatic melanoma and renal cell carcinoma.

On March 17, 2015 Celldex announced that it had entered into an agreement with Roche to evaluate the safety, tolerability and preliminary efficacy of varlilumab in combination with Genentech/Roche’s investigational anti-PDL1 agent MPDL3280A in a Phase 1/2 study in renal cell carcinoma. This is based on preclinical studies that suggest that the combination of these two agents may be synergistic, and enhance anti-tumor immune response as compared to either agent alone. In Celldex’s Phase 1 study of varlilumab in multiple solid tumors, promising signs of clinical activity had been seen in patients with refractory renal cell carcinoma. This included a durable partial response (11.0+ months) with decreases in tumor volume over time, and 4 patients with stable disease over periods ranging from 5.3 to 30.7+ months.

Another target for agonist MAbs in immuno-oncology is OX40. MedImmune (the global biologics R&D arm of AstraZeneca) is testing the OX40 agonist MAb MEDI6383 in an ongoing Phase 1 clinical trial (clinical trial number NCT02221960) against recurrent or metastatic solid tumors. MedImmune’s OX40 program is based on technology developed by AgonOx (Portland, OR). The two companies entered into an exclusive global partnership to develop OX40 agonists in 2011.

OX40 is a costimulatory receptor that can potentiate TCR signaling in T cells, leading to the activation of these cells by antigens recognized by their TCRs. Engagement of OX40 by its natural ligands on dendritic cells, or by anti-OX40 antibodies initiates a signal transduction cascade that enhances T cell survival, proliferation, and cytokine production, and can augment immune responses to tumors. Preclinical studies have shown that OX40 agonist antibodies increase antitumor immunity and improve tumor-free survival. A Phase 1 clinical study of an mouse anti-OX40 agonist MAb in patients with advanced cancer was carried out by researchers at the Providence Portland Medical Center in Portland, OR. (AgonOx is a spin-off of the Providence Portland Medical Center.) The study (clinical trial number NCT01644968), whose results were published in 2013, found that treatment with one course of the anti-OX40 MAb induced regression of at least one tumor metastasis in 12 of 30 patients, and exhibited an acceptable toxicity profile. Treatment with the agent also increased the antitumor reactivity of T and B cells in patients with melanoma.

In the upcoming CHI agonist antibody conference, Scott A. Hammond, Ph.D., Principal Scientist, Oncology Research at MedImmune will discuss the preclinical characterization of MedImmune’s OX40 agonists now in clinical trials.

Conclusions

The studies on novel immune checkpoint inhibitors and agonist antibodies illustrate that researchers are continuing to advance the frontiers of immuno-oncology beyond the late-stage MAb agents described in our report. Moreover, many of these studies involve clinical trials of combination therapies of the novel agents with other therapeutics discussed extensively in our report, including the CTLA-4 inhibitor ipilimumab (Medarex/BMS’s Yervoy), the PD-1 inhibitors nivolumab (BMS’ Opdivo) and pembrolizumab (Merck’s Keytruda), and the PD-L1 inhibitor MPDL3280A (Genentech/Roche). This is consistent with the idea that “the future of cancer immunotherapy is combination therapy”. In the survey that Insight Pharma Reports conducted in conjunction with our report, 80% of respondents agreed with this statement.


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.

Immune checkpoint inhibitors work by reactivating tumor-infiltrating T cells (TILs)

cancer cell

Cancer Cell

The 27 November issue of Nature contains a wealth of new studies on how immune checkpoint inhibitors target various types of cancer, and how researchers and physicians might be able to identify the patients who are most likely to benefit from treatment with these agents.

These studies are described in five papers published in that issue of Nature. This issue also contains a “News & Views” commentary on these articles by Drs. Jedd D. Wolchok and Timothy A. Chan (both at the Memorial Sloan Kettering Cancer Center). This article serves as an introduction to the five research articles.

In addition, Science Magazine published a commentary on these articles, entitled “Multiple boosts for cancer immunotherapy”, by contributing correspondent Mitch Leslie.

Checkpoint inhibitors can be used to treat several types of cancer

One important result of these studies is the expansion of the range of cancers that can be treated via immunotherapy beyond melanoma, kidney cancer, and non-small cell lung cancer (NSCLC). The papers by Powles et al. and Herbst et al. contain results from a Phase 1 clinical trial of Genentech’s monoclonal antibody (MAb) PD-L1 blocker MPDL3280A. Herbst et al. reported that MPDL3280A showed therapeutic responses in patients with NSCLC, melanoma, renal cancer, and head and neck cancer. Powles et al. focused on the effects of this agent in a larger group of patients with metastatic urothelial bladder cancer (UBC). In both reports, researchers documented that a subset of patients experienced durable responses, and that the treatment showed low toxicity.

We discussed earlier presentations of the results of the Phase 1 trial of MPDL3280A in our Insight Pharma Report (IPR), Cancer Immunotherapy: Immune Checkpoint Inhibitors, Cancer Vaccines, and Adoptive T-Cell Therapies. As we discussed in this report, the FDA granted breakthrough therapy designation for MPDL3280A for treatment of UBC. Roche/Genentech has initiated a Phase 2 clinical trial (clinical trial number NCT02108652) of MPDL3280A in UBC. UBC is the ninth most common cancer in the world. Metastatic UBC is associated with a poor prognosis, and has few treatment options. There have been no new treatment advances in nearly 30 years.

Checkpoint inhibitors work by reactivating tumor-infiltrating T cells (TILs)

Perhaps the most important finding of the research published in the November 27th issue of Nature is that checkpoint inhibitors work via reactivating endogenous tumor-infiltrating T cells. (These T cells are often called “TILs”, which is an acronym for “tumor-infiltrating lymphocytes”.)

For example, as described in the Powles et al. report, Genentech’s PD-L1 blocker MPDL3280A was found to be especially effective in treating patients whose tumors contained PD-L1-positive TILs. As we discussed in our IPR report, Genentech researchers found that MPDL3280A not only targets PD-L1 on the surface of tumor cells, but also PD-L1 on the surface of TILs. PD-L1 on activated T cells interacts not only with PD-1, but also with B7 on the surface of antigen presenting cells, sending a negative signal to the T cells. MPDL3280A targets the PD-L1-B7 interaction, thus enabling reactivation of PD-L1-bearing TILs so that they can attack the tumor.

As we also discuss in our report, targeting PD-1, PD-L1, and CTLA-4 may also be important in reversing immunosuppression by regulatory T cells (Tregs), which typically heavily infiltrate tumors. This provides another mechanism by which checkpoint inhibitors can reactivate TILs and thus induce anti-tumor immune responses.

As described in Powles et al, MPDL3280A was engineered with a modification in the Fc domain that eliminates antibody-dependent cellular cytotoxicity (ADCC). Genentech researchers did this because PD-L1 is expressed on activated T cells, and they wanted an anti-PD-L1 MAb agent that would reactivate these T cells, not destroy them via ADCC.

In the studies described by Herbst et al., researchers showed that Genentech’s PD-L1 blocker MPDL3280A gives antitumor response across multiple types of cancer, in tumors that expressed high levels of PD-L1. These responses especially occurred when PD-L1 was expressed by TILs. The studies suggest that MPDL3280A is most effective against tumors in which endogenous TILs are suppressed by PD-L1, and are reactivated via anti-PD-L1 MAb targeting.

In the Tumeh et al. study, the researchers found that patients responding to treatment with Merck’s MAb PD-1 blocker pembrolizumab (Keytruda) showed proliferation of intratumoral CD8+ T cells that correlated with reduction in tumor size. Pretreatment tumor samples taken from responding patients showed higher numbers of CD8, PD-1, and PD-L1 expressing cells at the invasive tumor margin and within tumors, with a close proximity between PD-1 and PD-L1, and a clonal TCR repertoire.

Based on this information, the researchers developed a predictive model based on CD8 expression at the invasive tumor margin. They validated this model in an independent 15-patient cohort. The researchers concluded that tumor regression due to treatment with the PD-1 blocker pembrolizumab requires preexisting CD8+ T cells whose activity has been blocked by PD-1/PD-L1 adaptive resistance. This study, like those of Powles et al. and Herbst et al., thus indicate that checkpoint inhibitors work against cancer by reactivating TILs. The Tumeh et al. study also indicates that CD8 expression at the invasive tumor margin is a predictive biomarker for sensitivity of patient tumors to treatment with anti-PD-1 checkpoint inhibitors.

The Powles, Herbst, and Tumeh reports all involved studies in human patients. However, the other two papers—Yadav et al. and Gubin et al. involve studies in mouse tumor models.

In the study of Yadav et al., the researchers used their mouse model to develop a method for discovering immunogenic mutant peptides in cancer cells that can serve as targets for T cells. They sequenced the exomes of two mouse cancer cell lines, and looked for differences with the corresponding normal mouse exomes. They also identified which of the neoantigens that they identified via exome sequencing could bind to histocompatibility complex class I (MHCI) proteins, and thus could be presented to T cells. They then modeled the MHC1/peptide complexes, and used these models to predict which of these neoantigens were likely to be immunogenic.

These methods identified only a few candidate neoantigens. Vaccination of tumor-bearing mice with these neoantigens resulted in therapeutically active T-cell responses. In addition, the researchers developed methods for monitoring the antitumor T cell response to peptide vaccination.

In the study of Gubin et al., the researchers used similar genomic and bioinformatic approaches to those of Yadav et al., and identified two neoantigens that were targeted by T cells following therapy with anti-PD-1 and/or anti-CTLA-4 antibodies. [Human CTLA-4 is the target of the checkpoint blockade inhibitor ipilimumab (Medarex/ Bristol-Myers Squibb’s Yervoy).] As with PD-1 and PD-L1 blockers, we discussed this agent in our IPR report. T cells specific for these neoantigens (in the context of MHCI proteins expressed by the mice) were present in the tumors. These T cells were reactivated by anti-PD-1 and/or anti-CTLA-4 antibodies, enabling the mice to reject the tumors.

As in the study of Yadav et al., the Gubin et al. researchers performed experiments in which they vaccinated tumor-bearing mice with peptides that incorporated the mutant epitopes. This vaccination induced specific tumor rejection that was comparable to treatment with checkpoint blockade inhibitors. As in the case of Yadav et al, the Gubin et al. researchers concluded that specific mutant antigens were targets of checkpoint inhibitor therapy in their mouse models, and that the mutant antigens could also be used to develop personalized cancer vaccines.

Since the studies of Yadav et al. and Gubin et al. were carried out using mouse tumor models, the results are not directly applicable to cancer in human patients. However, the studies suggest that immune checkpoint inhibitors work by reactivating endogenous TILs, and that anti tumor TILs work by attacking specific neoantigens on the tumors.

As we discussed in our IPR report, Dr. Steven Rosenberg (National Cancer Institute, Bethesda, MD) identified specific antigens that were the targets of TILs, both in metastatic melanoma and in metastatic cholangiocarcinoma (a type of epithelial bile duct cancer). However, these target antigens were from human cancers, and they were targets of TILs that has been isolated from patient tumors, cultured and expanded ex vivo, and used in adoptive cellular immunotherapy.

Moreover, the antigens were targets of TIL therapies that resulted in a durable compete remission in the case of the melanoma patient, and long-term tumor regression in the case of the metastatic cholangiocarcinoma patient. The metastatic cholangiocarcinoma case was highlighted in our September 16, 2014 Biopharmconsortium Blog article.

The Yadav et al. paper referenced the Rosenberg group’s work. However, this paper stated that “few mutant epitopes have been described because their discovery required the laborious screening of patient tumour-infiltrating lymphocytes for their ability to recognize antigen libraries constructed following tumour exome sequencing.”

The methods of Yadav et al. (and of Gubin et al.) are thus designed to simplify and accelerate the discovery of immunogenic mutant peptides. They carried out their studies in mouse models, which helped these researchers to develop methods that could potentially discover greater numbers of neoantigens more efficiently. However, it remains to be seen to what extent they can apply their methods to human patients.

Unifying the field of immuno-oncology

As can be seen, for example, from the title of our IPR report, the three major approaches to immuno-oncology in 2014/2015 are development of immune checkpoint inhibitors, of cancer vaccines, and of adoptive T-cell therapies.

In the immuno-oncology papers published in the 27 November issue of Nature, researchers show that checkpoint inhibitors work via reactivating of endogenous TILs. They also (in mouse tumor models) identified neoantigens that are targets of these reactivated TILs, and designed peptide vaccines that were as effective as checkpoint inhibitor therapy in the mouse models. In principle, one can isolate TILs that are reactive to particular neoantigens in the mouse tumors, culture and expand them ex vivo, and infuse them back into the mice to target their tumors. Thus the studies in the 27 November issue of Nature serve as a template for the unification of the immuno-oncology field as it now exists.

However, it will be necessary to apply the methodologies developed by Yadav et al. and Gubin et al. to human patients. And at least so far, peptide vaccines have not been very successful in treating patients, as compared to TIL therapy (in the subset of patients in whom TIL therapy can be done). It is thus possible that once these methods of neoantigen identification are applied to human patients, it will be found that targeting the neoantigens with ex vivo-expanded TILs will be more successful than therapy with peptide vaccines. However, whether this is true awaits the application of the new methodologies to neoantigen identification in human tumors.

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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.

Late-breaking cancer immunotherapy news

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

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.

Cancer Immunotherapy Report Published By CHI Insight Pharma Reports

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

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 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.

Breakthrough of the year 2013–Cancer Immunotherapy

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

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.

Chemokine receptors and the HIV-1 entry inhibitor maraviroc

Maraviroc

Maraviroc

In April 2012, Informa’s Scrip Insights published our book-length report, “Advances in the Discovery of Protein-Protein Interaction Modulators.” We also published a brief introduction to this report, highlighting the strategic importance of protein-protein interaction (PPI) modulators for the pharmaceutical industry, on the Biopharmconsortium Blog.

The report included a discussion on discovery and development of inhibitors of chemokine receptors. Chemokine receptors are members of the G-protein coupled receptor (GPCR) superfamily. GPCRs are seven-transmembrane (7TM) domain receptors (i.e. integral membrane proteins that have seven membrane-spanning domains). Compounds that target GPCRs represent the largest class of drugs produced by the pharmaceutical industry. However, in the vast majority of cases, these compounds target GPCRs that bind to natural small-molecule ligands.

Chemokine receptors, however, bind to small proteins, the chemokines. These proteins constitute a class of small cytokines that guide the migration of immune cells via chemotaxis. Chemokine receptors are thus a class of GPCRs that function by forming PPIs. Direct targeting of interactions between chemokines and their receptors (unlike targeting the interactions between small-molecule GPCR ligands and their receptors) thus involves all the difficulties of targeting other types of PPIs.

However, GPCRs–including chemokine receptors–appear to be especially susceptible to targeting via allosteric modulators. Allosteric sites lie outside the binding site for the protein’s natural ligand. However, modulators that bind to allosteric sites change the conformation of the protein in such a way that it affects the activity of the ligand binding site. (Direct GPCR modulators that bind to the same site as the GPCR’s natural ligands are known as orthosteric modulators.) In the case of chemokine receptors, researchers can in some cases discover small-molecule allosteric modulators that activate or inhibit binding of the receptor to its natural ligands. Discovery of such allosteric activators is much easier than discovery of direct PPI modulators.

Chemokines bind to sites that are located in the extracellular domains of their receptors. Allosteric sites on chemokine receptors, however, are typically located in transmembrane domains that are distinct from the chemokine binding sites. Small-molecule allosteric modulators that bind to these sites were discovered via fairly standard medicinal chemistry and high-throughput screening, sometimes augmented with structure-based drug design. This is in contrast to attempts to discover small molecule agents that directly inhibit binding of a chemokine to its receptor, which has so far been extremely challenging.

Our report describes several allosteric chemokine receptor modulators that are in clinical development, as well as the two agents that have reached the market. One of the marketed agents, plerixafor (AMD3100) (Genzyme’s Mozobil), is an inhibitor of the chemokine receptor CXCR4. It is used in combination with granulocyte colony-stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for autologous transplantation in patients with non-Hodgkin lymphoma and multiple myeloma. The other agent, which is the focus of this blog post, is maraviroc (Pfizer’s Selzentry/Celsentri).

Maraviroc is a human immunodeficiency virus-1 (HIV-1) entry inhibitor. This compound is an antagonist of the CCR5 chemokine receptor. CCR5 is specific for the chemokines RANTES (Regulated on Activation, Normal T Expressed and Secreted) and macrophage inflammatory protein (MIP) 1α and 1β.  In addition to being bound and activated by these chemokines, CCR5 is a coreceptor (together with CD4) for entry of the most common strain of HIV-1 into T cells. Thus maraviroc acts as an HIV entry inhibitor; this is the drug’s approved indication in the U.S. and in Europe. Maraviroc was discovered via a combination of high-throughput screening and optimization via standard medicinal chemistry.

New structural biology studies of the CCR5-maraviroc complex

Now comes a report in the 20 September 2013 issue of Science on the structure of the CCR5-maraviroc complex. This report was authored by a mainly Chinese group led by Beili Wu, Ph.D. (Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai); researchers at the University of California at San Diego and the Scripps Research Institute, San Diego were also included in this collaboration. A companion Perspective in the same issue of Science was authored by P. J. Klasse, M.D., Ph.D. (Weill Cornell Medical College, Cornell University, New York, NY).

As described in the Perspective, the outer surface of the HIV-1 virus displays numerous envelope protein (Env) trimers, each including the outer gp120 subunit anchored in the viral membrane by gp41. When gp120 binds to the cell-surface receptor CD4, this enables interaction with a specific chemokine receptor, either CCR5 or CXCR4. Interaction with both CD4 and the chemokine receptor triggers complex sets of changes in the Env complex, eventually resulting in the fusion of the viral membrane and the cell membrane, and the entry of the virus particle into the host cell.

HIV-1 gp120 makes contact with CCR5 at several points. The interactions between CCR5 and the variable region of gp120 called V3 are especially important for the tropism of an HIV-1 strain, i.e., whether the virus is specific for CCR5 (the “R5 phenotype”) or CXCR4 (the “X4 phenotype”). In the case of R5-tropic viruses, the tip of the V3 region interacts with the second extracellular loop (ECL2) of CCR5, while the base of V3 interacts with the amino-terminal segment of CCR5. Modeling of the interactions between the V3 domain of gp120 of either R5 or X4-tropic viruses with CCR5 or CXCR4 explains coreceptor use, in terms of forming strong bonds or–conversely–weak bonds and steric hindrance.

Monogram Biosciences (South San Francisco, CA) has developed and markets the Trofile assay. This is a molecular assay designed to identify the R5, X4, or mixed tropism of a patient’s HIV strain. If a patient’s strain is R5-tropic, then treatment with maraviroc is appropriate. However, a patient’s HIV-1 strain may undergo a tropism switch, or may mutate in other ways to become resistant to maraviroc.

Dr Wu and her colleagues determined the high-resolution crystal structure of the complex between maraviroc and a solubilized engineered form of CCR5. This included determining the CCR5 binding pocket for maraviroc, which was determined both by Wu et al’s X-ray crystallography, and by site-directed mutagenesis (i.e., to determine amino acid residues that are critical for maraviroc binding) that had been published earlier by other researchers.

The structural studies of Dr. Wu and her colleagues show that the maraviroc-binding site is different from the recognition sites for gp120 and for chemokines, as expected for an allosteric inhibitor. The X-ray structure shows that maraviroc binding prevents the helix movements that are necessary for binding of g120 to induce the complex sequence of changes that result in fusion between the viral and cellular membranes. (These helix movements are also necessary for induction of signal transduction by binding of chemokines to CCR5.)

Structural studies of CXCR4 and its inhibitor binding sites

In addition to their structural studies of the CCR5-maraviroc complex, Dr. Wu and her colleagues also published structural studies of CXCR4 complexed with small-molecule and cyclic peptide inhibitors in Science in 2010. These inhibitors are IT1t, a drug-like orally-available isothiourea developed by Novartis, and CVX15, a 16-residue cyclic peptide that had been previously characterized as an HIV-inhibiting agent. IT1t and CVX15 bind to overlapping sites in CXCR4. Other researchers have found evidence that the binding site for plerixafor also overlaps with the IT1t binding site.

As discussed in Wu et al’s 2013 paper, CCR5 and CXCR4 have similar, but non-identical structures. The binding site for IT1t in CXCR4 is closer to the extracellular surface than is the maraviroc binding site in CCR5, which is deep within the CCR5 molecule. The entrance to the CXCR4 ligand-binding pocket is partially covered by CXC4’s N terminus and ECL2, but the CCR5 ligand-binding pocket is more open.

Mechanisms of CXCR4 and CCR5 inhibition, and implications for discovery of improved HIV entry inhibitors

The chemokine that specifically interacts with the CXCR4 receptor is known as CXCL12 or stromal cell-derived factor 1 (SDF-1). Researchers have proposed a hypothesis for how CXCL12 interacts with CXCR4; this hypothesis appears to be applicable to the interaction between other chemokines and their receptors as well. This hypothesis is know as the “two-step model” or the “two-site model” of chemokine-receptor activation. Under the two-site model, the core domain of a chemokine binds to a site on its receptor (known as the “chemokine recognition site 1” or “site 1”) defined by the receptor’s N-terminus and its ECLs. In the second step, the flexible N-terminus of the chemokine interacts with a second site (known as “chemokine recognition site 2” or “site 2” or the “activation domain”) deeper within the receptor, in transmembrane domains. This result in activation of the chemokine receptor and intracellular signaling.

Under the two-site model, CXCR4 inhibitors (e.g., IT1t, CVX15, and  plerixafor), which bind to sites within the ECLs of CXCR4, are competitive inhibitors of binding of the core domain of CXCL12 to CXCR4 (i.e.., step 1 of chemokine/receptor interaction). They are thus orthosteric inhibitors of CXCR4. (This is contrary to the earlier assignment of plerixafor as an allosteric inhibitor of CXCR4.)  The CCR5 ligand maraviroc, however, binds within a site within the transmembrane domains of CCR5, which overlaps with the activation domain of CCR5. Dr. Wu and her colleagues propose two alternative hypotheses: 1. Maraviroc may inhibit CCR5 activation by chemokines by blocking the second step of chemokine/chemokine receptor interaction, i.e., receptor activation. 2. Maraviroc may stabilize CCR5 in an inactive conformation. It is also possible that maraviroc inhibition of CCR5 may work via both mechanisms.

Dr. Wu and her colleagues further hypothesize that the interaction of  HIV-1 gp120 with CCR5 (or CXCR4) may operate via similar mechanisms to the interaction of chemokines with their receptors. As we discussed earlier in this article, the base (or the stem region) of the gp120 V3 domain interacts with the amino-terminal segment of CCR5. The tip (or crown) of the V3 domain interacts with the ECL2 of CCR5, and–according to Dr. Wu and her colleagues–also with amino acid residues inside the ligand binding pocket; i.e., the activation site of CCR5. The HIV gp120 V3 domain may thus activate CCR5 via a similar mechanism to the two-step  model utilized by chemokines.

Based on their structural biology studies, Dr. Wu and her colleagues have been building models of the CCR5-R5-V3 and CXC4-X4-V3 complexes, and are also planning to determine additional structures needed to fully understand the mechanisms of HIV-1 tropism. The researchers will utilize their studies in the discovery of improved, second-generation HIV entry inhibitors for both R5-tropic and X4-tropic strains of HIV-1.

The bigger picture

The 17 October 2013 issue of Nature contains a Supplement entitled “Chemistry Masterclass”. In that Supplement is an Outlook review entitled “Structure-led design”, by Nature Publishing Group Senior Editor Monica Hoyos Flight, Ph.D. The subject of this article is structure-based drug design of modulators of GPCRs.
This review outlines progress in determining GPCR structures, and in using this information for discovery of orthosteric and allosteric modulators of GPCRs.

According to the article, the number of solved GPCR structures has been increasing since 2008, largely due to the efforts of the Scripps GPCR Network, which was established in that year. Dr. Wu started her research on CXCR4 and CCR5 as a postdoctoral researcher in the laboratory of Raymond C. Stevens, Ph.D. at Scripps in 2007, and continues to be a member of the network. The network is a collaboration that involves over a dozen academic and industrial labs. Its goal has been to characterize at least 15 GPCRs by 2015; it has already solved 13.

Interestingly, among the solved GPCR structures are those for the corticotropin-releasing hormone receptor and the glucagon receptor. Both have peptide ligands, and thus work by forming PPIs.

One company mentioned in the article, Heptares Therapeutics (Welwyn Garden City, UK), specializes in discovering new medicines that targeting previously undruggable or challenging GPCRs. In addition to discovering small-molecule drugs, Heptares, working with monoclonal antibody (MAb) leaders such as MorphoSys and MedImmune, is working to discover MAbs that act as modulators of GPCRs. Among Heptares’ targets are several GPCRs with peptide ligands.

Meanwhile, Kyowa Hakko Kirin Co., Ltd. has developed the MAb drug mogamulizumab (trade name Poteligeo), which is approved in Japan for treatment of relapsed or refractory adult T-cell leukemia/lymphoma. Mogamulizumab targets CC chemokine receptor 4 (CCR4).

Thus, aided in part by structural biology, the discovery of novel drugs that target GPCRs–including those with protein or peptide targets such as chemokine receptors–continues to make progress.

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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.

Novartis’ breakthrough therapy for a rare muscle-wasting disease

skeletal muscle

Skeletal muscle. http://bit.ly/15BgVYY

On August 20, 2013, Novartis announced in a press release that the FDA had granted breakthrough therapy designation to its experimental agent BYM338 (bimagrumab) for treatment of the rare muscle wasting disease sporadic inclusion body myositis (sIBM).

sIBM is a rare–but increasingly prevalent–disease. It is the most common cause of inflammatory myopathy in people over 50. sIBM has a yearly incidence of 2 to 5 per million adults with a peak at ages 50 to 70, with male predominance. Muscle wasting caused by sIBM is superimposed upon the sarcopenia (degenerative loss of muscle mass) that typically occurs with aging.

sIBM is characterized by a slowly progressive asymmetric atrophy and weakness of muscles. Typically, patients become wheelchair bound within 10 to 15 years of onset. Death may occur due to falls, respiratory infection, or malnutrition.

The causes of sIBM are not well-understood. In sIBM, an autoimmune process and a degenerative process appear to occur in muscle cells in parallel. In the autoimmune process, T cells that appear to be driven by specific antigens invade muscle fibers. In the degenerative process, holes appear in muscle cell vacuoles, and inclusion bodies containing abnormal proteins are deposited in muscle cells.

Despite the lack of understanding of the causes of sIBM, in recent years researchers have developed potential therapeutic approaches to this disease. These therapeutic strategies are based on the hypothesis that enhancing muscle regeneration can be beneficial in treating muscle-wasting diseases regardless of their cause. Researchers have thus been working on several approaches, principally 1. developing drugs that stimulate myofiber regeneration, and 2. cell-mediated therapies to replace damaged myofibers (e.g., autologous stem cell therapy). It is the first approach that led to the discovery of Novartis’ bimagrumab.

The myostatin pathway

Myostatin is a regulator of muscle growth in mammals and other vertebrates. It is a secreted protein that is a member of the transforming growth factor beta (TGF-β) family. It is secreted in an inactive form, and must be activated via cleavage by a metalloproteinase. The activated myostatin then binds to its receptor, activin receptor type IIB (ActRIIB). The binding of myostatin to ActRIIB on myoblasts initiates an intracellular signaling cascade, which (as with other members of the TGF-β family), includes activation of transcription factors of the SMAD family. The SMADs (SMAD2 and SMAD3) in the myostatin pathway go on to induce myostatin-specific gene regulation, which inhibits the proliferation of myoblasts and their differentiation into mature muscle fibers.

Bimagrumab, the myostatin pathway, and muscle-wasting diseases

Bimagrumab is a novel, fully human monoclonal antibody (MAb), which was developed by the Novartis Institutes for Biomedical Research (NIBR), in collaboration with the human MAb specialist company MorphoSys (Martinsried, Germany). MorphoSys’ HuCAL (Human Combinatorial Antibody Library) technology was used to identify bimagrumab.

Bimagrumab binds with high affinity to the ActRIIB receptor, thus blocking myostatin binding. The researchers working on development of bimagrumab hypothesized that treatment with the drug would have the same physiological result as myostatin deficiency. For example, myostatin knockout mice have a two-fold to three-fold increase in muscle mass, without other abnormalities. Humans with a loss-of-function mutation in myostatin exhibit marked increase in muscle mass, as well as increased strength. These findings suggest that a myostatin receptor antagonist such as bimagrumab would be a potent stimulator of muscle growth.

According to Novartis’ press release, this hypothesis has been borne out in human studies. The FDA granted breakthrough status for bimagrumab based on the results of a Phase 2 proof-of-concept (POC) study that showed that the drug substantially benefited patients with sIBM compared to placebo. The results of this study will be presented at the American Neurological Association meeting on October 14, 2013. Novartis also expects to published the results of the study in a major medical journal later in 2013.

In addition to sIBM, Novartis is developing bimagrumab for the common muscle-wasting disease of aging sarcopenia, as well as for cachexia in cancer and in chronic obstructive pulmonary disease (COPD) patients, and for muscle wasting in mechanically ventilated patients. In particular, the company is sponsoring a Phase 2 POC study (Clinical Trial Number NCT01601600) of bimagrumab in older adults with sarcopenia and mobility limitations. The study is designed to determine the effects of the drug on skeletal muscle volume, mass, and strength and patient function (gait speed). It will also generate data on the safety, tolerability, and pharmacokinetics of bimagrumab in older adults, as well as (via an extended study duration) the stability of drug-induced changes in skeletal muscle and patient function.

As we discussed in the Conclusions section of our August 15, 2013 blog article on aging, aging-related sarcopenia is a major causes of disability and death. We also said in that section that sarcopenia is not normally a target for drug development. At that time, we did not know about Novartis’ development of bimagrumab. We are happy to be proven wrong about drug development for sarcopenia.

Another approach to myostatin pathway-based drug development

A fully-human anti-myostatin MAb, Regeneron/Sanofi’s REGN1033 (SAR391786), is in Phase 1 clinical development for treatment of sarcopenia. Unlike bimagrumab, which binds to the myostatin receptor ActRIIB, REGN1033 binds directly to myostatin. REGN1033 thus represents an alternative approach to treatment of sarcopenia and other muscle-wasting conditions via the myostatin pathway.

Attempts to address the causes of muscle degeneration in sIBM directly

Despite the evidence from early clinical trials that therapies that enhance muscle regeneration may be effective in treating sIBM, some researchers believe that it will be necessary to identify the causes of muscle degeneration in sIBM and to address them. For example, there is evidence that in some patients, autoantibodies may recognize antigens that are enriched in regenerating muscle fibers. Some researchers therefore hypothesize that treating such patients with therapies that enhance muscle regeneration without addressing the autoimmune pathology may be counterproductive. Therefore, continuing research on the causes of muscle degeneration in sIBM and on potential therapies to slow this degeneration may still be important, despite the apparent progress of clinical trials of such drugs as bimagrumab.

For example, some researchers hypothesize that sIBM is a primary degenerative disease, like Alzheimer’s and Parkinson’s disease. As with these neurodegenerative diseases, some researchers have found evidence that misfolded proteins may be involved in the pathogenesis of sIBM. This avenue of research has led to the hypothesis that agents that enhance correct protein folding may slow muscle degeneration in sIBM patients. One such agent, CytRx’ arimoclomol has been in clinical trials in sIBM patients. [Arimoclomol is also in clinical trials in patients with amyotrophic lateral sclerosis (ALS)].  Arimoclomol appears to act as a coinducer of chaperone proteins such as heat shock protein 70 (Hsp70). Chaperone proteins promote the correct folding of intercellular proteins.

In a small POC Phase 2a clinical trial in Europe, arimoclomol showed early signs of efficacy, in addition to being well tolerated. There was a trend toward slower degeneration in physical function, muscle strength, and right-hand grip muscle strength in arimoclomol-treated patients as compared to placebo over an 8-month period.

Other researchers are attempting to address the inflammatory aspects of sIBM. For example, there are early clinical trials in progress of  the-anti-lymphocyte agent alemtuzumab (Genzyme’s Campath/Lemtrada) and the anti-tumor necrosis factor agent etanercept (Amgen/Pfizer’s Enbrel).

Meanwhile, additional basic research on the causation of sIBM continues. Some of these approaches may eventually lead to additional drug discovery strategies for this disease.

However, whether or not muscle-enhancing therapies such as bimagrumab might provide adequate treatment for at least some classes of sIBM patients (without addressing the autoimmune and/or degenerative aspects of the causation of the disease) will depend on the results of late-stage clinical trials now in the planning stage.

Conclusions

The development of bimagrumab represents an example of Novartis’ pathway-based rare disease strategy. We discussed this strategy in our July 20, 2009 Biopharmconsortium Blog article. Novartis researchers note that in many cases rare diseases are caused by disruptions of pathways that are also involved in other rare diseases and/or in more common diseases. The researchers therefore develop drugs that target these pathways, and obtain POC for these drugs by first testing them in small populations of patients with a specific rare disease. Drugs that have achieved POC in this rare disease may later be tested in other indications (especially including more common diseases) that involve the same pathway.

As we discussed in our July 20, 2009 article, the first drug that Novartis developed by using this strategy is the interleukin-1β inhibitory MAb drug Ilaris (canakinumab). The company conducted its first clinical trials in patients with cryopyrin-associated periodic syndromes, (CAPS), a group of rare inherited auto-inflammatory conditions that are characterized by overproduction of IL-1β. In 2009, the FDA and the European Medicines Agency approved Ilaris for treatment of CAPS. Since that time, Novartis has been conducing clinical trials of canakinumab in such conditions as systemic juvenile idiopathic arthritis (SJIA), gout, acute gouty arthritis, type 2 diabetes, and several others. Canakinumab had also been tested in rheumatoid arthritis, but these trials have been discontinued.

In the case of bimagrumab, Novartis researchers are targeting the myostatin pathway. The strategy is to first target the rare disease sIBM, and to obtain POC in human studies in that disease. Novartis claims (and the FDA concurs with them) that they have obtained POC in sIBM, and the company plans to present the results of its POC clinical trial later this year, both in a scientific meeting and in a publication. Novartis then plans to complete development of bimagrumab for sIBM, while also developing the drug for other muscle-wasting conditions, especially the more common aging-related condition sarcopenia, which is becoming a major public health problem.

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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.

Cancer immunotherapy: the star of the ASCO Annual Meeting two years in a row!

PD-L1

PD-L1

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.

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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.

Haberman Associates in “Pink Sheet” article on the cystic fibrosis drug market

 

Lumacaftor (Vertex' VX-809)

Lumacaftor (Vertex’ VX-809)

I was quoted in an article in the March 11, 2013 issue of Elsevier Business Intelligence’s The Pink Sheet by senior writer Joseph Haas. The article is entitled “Cystic Fibrosis Market Snapshot: Disease-Modifying Drugs Elusive 24 Years After Discovery Of Root Cause”. A subscription is required to view the full text of this article.

The article focused on the newly-approved disease modifying drug ivacaftor (Vertex’ Kalydeco), as well as programs in drug discovery and development of disease-modifying drugs for cystic fibrosis (CF) at Vertex, PTC Therapeutics, Proteostasis Therapeutics, Pfizer, and Genzyme. It also discussed pipeline products aimed at treating or preventing life-threatening infections in CF patients at such companies as KaloBios, Insmed, and Savara.

Mr. Haas interviewed me for this article. Most of the content of our interview is available in our February 15, 2013 article on the Biopharmconsortium Blog. One company whose R&D program we did not cover in that article is Proteostasis. Proteostasis’ CF program, which is being carried out in collaboration with the Scripps Research Institute, is aimed at discovery and development of compounds that promote CFTR ΔF508 folding and trafficking. This program is in the research and lead optimization stage. We discussed R&D programs at other companies (Vertex, Pfizer) that are also aimed at correction of improper CFTR ΔF508 folding and trafficking in our February 15, 2013 article.

KaloBios’ KB001-A, a bacterial virulence factor-targeting agent

Among the agents aimed at ameliorating life-threatening infections in CF patients that were discussed in the Pink Sheet article is KB001-A, a monoclonal antibody (MAb) agent being developed by KaloBios (South San Francisco, CA). KB001-A is now in Phase 2 development for prevention of Pseudomonas aerguinosa infections in the lungs of CF patients. KB001-A targets an extracellular component of the bacterium’s type III secretion system. This system enables the bacteria to kill immune cells by injection of protein toxins into these cells.

The type III secretion system is an example of a virulence factor. Virulence factors are not expressed by a strain of pathogenic bacteria in vitro, but are expressed only when the bacteria infect a host. Once expressed, they enable the bacteria to colonize the host and cause disease.

In our June 11, 2012 article on this blog, we discussed an antibacterial drug discovery strategy aimed at targeting two related physiological systems that are important in the ability of pathogenic bacteria to cause disease, but are not essential for bacterial proliferation or survival. These systems are virulence factors and quorum sensing. At least by hypothesis, agents that disrupt these systems will prevent pathogenic bacteria from causing disease without selecting for resistant strains of the bacteria. This will give such agents an advantage over conventional antibiotics, which notoriously generate resistant strains when used to treat infections. According to the Pink Sheet article, KaloBios believes that P. aerguinosa bacteria will not develop resistance to KB001-A, which is in accord with this hypothesis.

Another issue with anti-infectives used to treat CF that is discussed in the Pink Sheet article is the definition of a “disease-modifying” agent for CF. We define disease-modifying agents as drugs that ameliorate or cure a disease by targeting the root cause of that disease. However, KaloBios considers KB001-A to be a disease-modifying agent. That is because the company believes that most CF patients die of the effects of P. aerguinosa infection, which causes deterioration of the patients’s lungs. Thus an effective anti-P. aerguinosa agent may produce dramatic increases in patients’ lifespans.

Perhaps the real issue is that one should not classify CF drugs as “disease-modifying” agent and agents that merely treat “symptoms” (as is done in the Pink Sheet article) but should define infections of CF patients as “complications” of the disease. Thus anti-infectives such as KB001-A may effectively treat a major life-threatening complication of CF, without modifying the underlying disease. Such an agent would result in increased lifespans (and improved quality of life) for CF patients, without affecting their underlying disease. As KaloBios asserts, anti-infective agents like KB001-A would be complementary to such disease-modifying agents as ivacaftor.

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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.