Biopharmconsortium Blog

Expert commentary from Haberman Associates biotechnology and pharmaceutical consulting.

Posts filed under: Personalized medicine

Strimvelis (GSK2696273), a gene therapy for a deadly immunodeficiency in children, expected to reach the European market in mid-2016

Adenosine deaminase

Adenosine deaminase

Our recent book-length report, Gene Therapy: Moving Toward Commercialization was published by Cambridge Healthtech Institute in November 2015. As indicated by its title, the report focuses on clinical-stage gene therapy programs that are aimed at commercialization, and the companies that are carrying out these programs.

Until recently, gene therapy was thought of as a scientifically-premature field with little prospect of near-term commercialization. However, as outlined in our report, numerous companies have been pursuing clinical programs aimed at regulatory approval and commercialization. These efforts have attracted the interest of investors and of large pharma and biotech companies. As a result, several gene therapy specialty companies have gone public, and some companies in this sector have attracted large pharma or biotech partnerships.

A key question addressed in our report is whether any gene therapies might be expected to reach the U.S. and/or European markets in the near term. In the last chapter (Chapter 9) of the report, we included a table (Table 9.1) of eight gene therapy products that we deemed to be likely to reach the market before 2020.

One of these products, uniQure/Chiesi’s Glybera (alipogene tiparvovec), a treatment for the ultra-rare condition lipoprotein lipase deficiency (LPLD), was approved in Europe in 2012. It is thus the “first commercially available gene therapy” in a regulated market. However, uniQure has dropped plans to seek FDA approval for Glybera.

As we discussed in our December 17, 2015 article on this blog, another product listed in Table 9.1, Spark Therapeutics’ SPK-RPE65, is expected to reach the U.S. market by 2017. SPK-RPE65 is a gene therapy for the rare retinal diseases Leber congenital amaurosis and retinitis pigmentosa type 20. As of March 9, 2016, Spark is preparing to file a Biologics License Application (BLA) for SPK-RPE65 in the second half of 2016. SPK-RPE65 may be the first gene therapy approved in the U.S. Spark also plans to file a marketing authorization application (MAA) in Europe in early 2017.

Now comes an announcement of the impending European marketing of a third product listed in Table 9.1, GlaxoSmithKline/San Raffaele Telethon Institute for Gene Therapy (TIGET)’s GSK2696273, now called Strimvelis. On April 1, 2016, the The European Medicines Agency (EMA) recommended the approval of Strimvelis in Europe, for the treatment of children with ADA severe combined immune deficiency (ADA-SCID) for whom no matching bone marrow donor is available. ADA-SCID is a type of SCID caused by mutations in the gene for adenosine deaminase (ADA).

Approximately 15 children per year are born in Europe with ADA-SCID, which leaves them unable to make certain white blood cell that are involved in the immune system. ADA-SCID is an autosomal recessive condition that accounts for about 15% of cases of SCID. ADA deficiency results in the intracellular buildup of toxic metabolites that are especially deleterious to the highly metabolically active T and B cells. These cells thus fail to mature, resulting in life-threatening immune deficiency. Children with ADA-SCID rarely survive beyond two years unless their immune function is rescued via bone marrow transplant from a compatible donor. Thus Strimvelis is indicated for children for whom no compatible donor is available.

As we discussed in our report, the development of therapies for ADA-SCID goes back to the earliest days of gene therapy, in 1990. Interestingly, Strimvelis (GSK2696273) is based on a Moloney murine leukemia virus (MoMuLV) gammaretrovirus vector carrying a functional gene for ADA. In other applications (for example, gene therapy for another type of SCID called SCID-X1), the use of MoMuLV vectors resulted in a high level of leukemia induction. As a result, researchers have developed other types of retroviral vectors (such as those based on  lentiviruses) that do not have this issue. Nevertheless, Strimvelis Mo-MuLV-ADA gene therapy has been show to be safe over 13 years of clinical testing, with no leukemia induction. As discussed in our report, researchers hypothesize that ADA deficiency may create an unfavorable environment for leukemogenesis.

Delivery of Strimvelis requires the isolation of hematopoietic stem cells (HSCs) from each patient, followed by ex vivo infection of the cells with the MoMuLV-ADA construct. The transformed cells are then infused into the patient, resulting in restoration of a functional immune system.

With the EMA recommendation of approval for Strimvelis, it is expected that the therapy will be approved by the European Commission approval in July 2016.

Strimvelis is the result of a 2010 partnership between GSK and Italy’s San Raffaele Telethon Institute for Gene Therapy (TIGET), and the biotechnology company MolMed, which is based at TIGET in Milan. MolMed is currently the only approved site in the world for production of and ex vivo therapy with Strimvelis. However, GSK is looking into ways of expanding the numbers of sites that will be capable of and approved for administration of the therapy. GSK’s plans will include seeking FDA approval for expansion into the U.S. market.

Moreover, as discussed in our report, under the GSK/TIGET agreement,  GSK has exclusive options to develop six further applications of ex vivo stem cell therapy, using gene transfer technology developed at TIGET. GSK has already exercised its option to develop two further programs in two other rare diseases. Both are currently in clinical trials. Because of the issue of leukemogenesis with most gammaretrovirus-based gene therapies, these other gene therapy products are based on the use of lentiviral vectors.

Given the tiny size of the market for each of these therapies, pricing is an important—and tricky—issue. For example, treatment with UniQure’s Glybera, as of 2014, cost $1 million. As of now, GSK is not putting a price on Stremvelis, but reportedly the therapy will cost “very significantly less than $1 million” if and when it is approved.

Conclusions

The success of researchers and companies in moving three of the eight gene therapies listed in Table 9.1 toward regulatory approval suggests that gene therapy will attain at least some degree of near term commercial success. However, Glybera and Strimvelis are for ultra-rare diseases, and are thus not expected to command large markets.

However, as discussed in our previous blog article, SPK-RPE65 may achieve peak sales ranging from $350 million to $900 million. And as discussed in our report, some of the remaining therapies listed in Table 9.1, especially those involved in treatment of blood diseases or cancer, may achieve sales in the billions of dollars. Thus, depending on the timing and success of clinical trials and regulatory submissions of these therapies, gene therapy may demonstrate a degree of near-term commercial success that few thought was possible just five years ago.

Meanwhile, even therapies that address rare or ultra-rare diseases will be expected to save the lives or the sight of patients who receive these products.

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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.

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.

Gene editing technology used to treat infant with leukemia

 

Baby_Face Source: http://bit.ly/1OjMOyo

Baby_Face Source: http://bit.ly/1OjMOyo

In November 2015, the use of gene editing technology to treat an 11-month-old child with leukemia was reported in news articles in Nature and in Science. Because of the human-interest value of this story, it was also reported in Time magazine and in the New York Times.

Data from this first-in-humans clinical use of the therapy will be presented at the 57th American Society of Hematology (ASH) Annual Meeting in Orlando, FL in early December 2015.

The young patient was treated with a complex cellular immunotherapy regimen developed by Cellectis (Paris, France and New York, NY). Cellectis’ platform involves production of allogeneic (rather than autologous) chimeric antigen receptor (CAR) T-cells to create an “off-the-shelf solution” to cellular immunotherapy for cancer, potentially simplifying manufacturing and standardization of therapies.

We have discussed CAR T-cell therapies on this blog, and—in more detail—in two book-length reports published by Cambridge Healthtech Institute (CHI). These are our 2014 Cancer Immunotherapy report, and our new November 2015 report, Gene Therapy: Moving Toward Commercialization.

CAR T-cell therapies directed against the B-cell antigen CD19, being developed by Novartis/University of Pennsylvania, Juno Therapeutics, and Kite Pharma, have demonstrated impressive clinical results against B-cell leukemias and lymphomas. However, in order to avoid immune incompatibility, CAR T-cell must be constructed and manufactured using autologous T-cells derived from the patient to be treated. This is an expensive and laborious process. Hence the rationale for allogeneic CAR T-cell therapy.

Cellectis uses gene editing in construction of its allogeneic CAR T-cells. Specifically, the company first modifies T-cells from healthy donors with an anti-CD19 CAR gene construct, similar to the methods used by other companies that are developing anti-CD19 CAR cellular immunotherapies. Cellectis then uses gene editing based on transcription activator-like effector nucleases (TALENS) to disrupt expression of the T-cells’ TCR (T-cell receptor) genes. It is the TCRs of the transplanted T cells that recognize the patient’s own cells as foreign, and thus attack them. Cellectis also uses TALENS gene editing to disrupt expression of a gene for another cell-surface protein, CD52. CD52 is present on mature lymphocytes, and is the target of the monoclonal antibody drug alemtuzumab (Genzyme’s Lemtrada). Researchers can then use alemtuzumab to prevent host-mediated rejection of the HLA mismatched CAR19 T cells. Cellectis’ “Talen engineered universal CAR19 T cells” can thus in principle be used to treat any patient with B-ALL (B-cell acute lymphoblastic leukemia), instead of autologous anti-CD19 CAR T-cells.

The treatment of the young patient, Layla Richards of London, was on a compassionate use basis. She had refractory relapsed B-ALL, and was expected to die shortly. Meanwhile, Cellectis had a universal CAR19 (UCART19) cell bank in the same hospital in which Layla was being treated. The cell bank had been characterized in detail, in preparation for submission for regulatory approval and Phase 1 testing.

Prior to administration of the UCART19 cells, the patient received lymphodepleting chemotherapy (including administration of alemtuzumab). After getting the UCART19 cells in June 2015 (near her first birthday), Layla went into remission, and has no trace of leukemia. After about three months she had a bone marrow transplant to help her immune system recover, and is now at home. However the follow-up period since her treatment has only been 5 months. Therefore, Layla’s doctors do not yet know how durable the remission will be. The key question is how long the UCART19 cells can survive in the body and prevent recurrence of leukemia.

Gene editing companies and their technologies discussed in our November 2015 report

Our November 2015 gene therapy report includes a chapter (Chapter 8) that focuses on gene-editing technologies and on companies that are developing therapies based on these technologies. The gene-editing technology that has been getting the most attention from the scientific and financial communities is known as CRISPR/Cas9. The other two technologies discussed in Chapter 8 are TALENS and zinc-finger nucleases (ZFN). The basic principle of these gene-editing technologies is that a “molecular scissors” makes a specific double-strand break in a deleterious DNA sequence. This break is either repaired in such a way as to disrupt the gene by forming deletions or mutations, or—if a suitable donor DNA is provided—the deleterious gene is replaced with a desired, functional gene sequence.

Gene-editing specialty companies discussed in our report based on CRISPR/Cas9 technology include Editas Medicine (Cambridge, MA) (which also utilizes TALENS), Intellia Therapeutics (Cambridge MA), CRISPR Therapeutics (Basel, Switzerland; Stevenage, U.K.; and Cambridge MA), and Caribou Biosciences (Berkeley, CA). Sangamo BioSciences (Richmond, CA), which is also discussed in our report, is a pioneer in ZFN technology.

Despite the predominant focus on CRISPR/Cas9 technology and companies in the biotechnology and venture capital communities, the first clinical studies involving gene editing have used Sangamo’s ZFN technology. These studies are in the field of HIV/AIDS. They involve ex vivo treatment of HIV-infected patients’ T-cells with a specific ZFN-based vector, in order to render the patients resistant to further manifestations of the disease.

Meanwhile, Editas has developed a vector designed to enable the company to move its CRISPR/Cas9 technology into the clinic. Editas’ first clinical program will be a potential treatment for a form of the genetically-driven retinal disease, Leber congenital amaurosis (LCA). (This is a different form of LCA than the one being targeted by Spark Therapeutics, which we discussed in our November 16, 2015 article on this blog).

bluebird bio (Cambridge, MA) is also pursuing a gene-editing technology program based on homing endonucleases and MegaTAL enzymes. This research and preclinical-stage program came to bluebird via its 2014 acquisition of Precision Genome Engineering Inc. (Seattle WA).

Cellectis is not the only company that is combining CAR T-cell therapies with gene-editing technology. In May 2015, Editas formed a collaboration with Juno Therapeutics to pursue research programs that combine Editas’ genome editing technologies with Juno’s CAR and TCR T-cell technologies.

Conclusions

Despite the great deal of excitement about gene-editing technologies and companies (especially CRISPR/Cas9) these are early days for development of therapies based on these technologies. Despite the almost miraculous results in the treatment of Layla Richards, it is only one case, and the follow-up period has been short. Nevertheless, this one case may open the way for this therapy to be used in other “desperate situations” where there is no time, or it is not possible, to use a patient’s own T cells. And researchers are already speculating that a similar technique may be used to treat people with other blood cancers, and eventually people with solid tumors.

For more information on our November 2105 gene therapy report, or to order it, see the CHI Insight Pharma Reports website.

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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.

Gene Therapy Report Published By CHI Insight Pharma Reports

 

Adeno-associated virus, a common gene therapy vector. Source: http://bit.ly/1NR7tf4

Adeno-associated virus, a common gene therapy vector. Source: http://bit.ly/1NR7tf4

On November 6, 2015, Cambridge Healthtech Institute (CHI) announced the publication of a new book-length report, Gene Therapy: Moving Toward Commercialization, by Allan B. Haberman, Ph.D.

As demonstrated by several late-breaking news items that appeared as our report was in the process of publication, gene therapy is a “hot”, fast-moving field. For example:

On October 5, 2015, Spark Therapeutics (Philadelphia, PA) announced positive top-line results from the Phase 3 pivotal trial of SPK-RPE65, a gene therapy for treatment of inherited retinal diseases (IRDs) caused by mutations in the gene for RPE65. This trial met its primary endpoint, and there were no serious adverse events related to treatment with the therapy. In results presented at a scientific meeting later in October, SPK-RPE65 was found to give durable improvements in vision over a three-year period.

SPK-RPE65 is not only Spark’s most advanced gene therapy in development, but is the most advanced gene therapy for retinal disease of any company. It is covered in our report.

bluebird’s LentiGlobin BB305—including the company’s strategy for commercializing this product—is also discussed in our report. In bluebird’s November 5, 2015 presentation at the American Society of Hematology (ASH) Annual Meeting, it was revealed that in Phase 1/2 clinical trials, LentiGlobin BB305 rendered the few sickle-cell disease patients in the trials transfusion-free and hospitalization-free for at least six months. Among patients with severe beta-thalassemia, all except for those with the β0/β0 genotype were rendered transfusion-free for at least 90 days, with a median of 287 days transfusion-free. Two of the β0/β0 patients (who made no hemoglobin at baseline) received a single transfusion post-discharge, and the third β0/β0 patient remains transfusion-dependent.

The stock market had focused on the negative results with the β0/β0 patients, and thus bluebird stock lost over 20% of its value after the ASH abstracts were released. However, the β0/β0 patients represent only one-third of the beta-thalassemia market, and sickle-cell disease is a larger market than beta-thalassemia. Thus, provided further clinical trials are positive, LentiGlobin BB305 can still be a successful product. bluebird is increasing the number of patients who will be enrolled in the trial from eight to 20, so more data should be forthcoming in 2016.

In corporate gene therapy news, Spark Therapeutics recently opened a new satellite office in the Boston area, joining Boston-area gene therapy companies bluebird bio, Dimension Therapeutics, and Voyager Therapeutics. All are discussed in our report. Spark and bluebird are public companies, and Dimension and Voyager recently went public. In addition, uniQure, the company that developed the first approved gene therapy product, opened a Lexington MA office and manufacturing facility in 2013. Boston has thus become Gene Therapy Central. As discussed in our report, Boston is also the most important center for companies that focus on gene editing, based on CRISPR/Cas9 technology.

These and other recent news articles and scientific publications attest to the progress of gene therapy, which only a few years ago was considered to be a “premature technology”.

Our gene therapy report looks at how researchers have been working to overcome critical barriers to development of safe and efficacious gene therapy, from 1990 to 2015. It then focuses on clinical-stage gene therapy programs that are aimed at commercialization, and the companies that are carrying out these programs. A major theme of the report is whether gene therapy can attain near-term commercial success, and what hurdles still need to be overcome.

Topics covered in the report:

  • Development of improved vectors (integrating and non-integrating vectors)
  • Gene therapy for ophthalmological diseases
  • Gene therapy for hemophilias and other rare diseases
  • Gene therapy for more common diseases (e.g., Parkinson’s disease, osteoarthritis, and heart failure)
  • Companies whose central technology platform involves ex vivo gene therapy
  • Gene editing technology
  • Outlook for gene therapy
  • Outlook for eight gene therapy products expected to reach the market before 2020

The report also includes:

  • An exclusive interview with Sam Wadsworth, Ph.D., the Chief Scientific Officer of Dimension Therapeutics and former Head of Gene Therapy R&D at Genzyme
  • The results and an analysis of a survey of individuals working in gene therapy, conducted by Insight Pharma Reports in conjunction with this report.
  • Companies profiled: uniQure, Spark Therapeutics, GenSight, Dimension Therapeutics, Voyager Therapeutics, Oxford BioMedica, bluebird, Juno Therapeutics, Kite Pharma, Editas, and others.

Our report is designed to enable you to understand current and future developments in gene therapy. It is also designed to inform the decisions of leaders in companies and in academic groups that are working in gene therapy R&D and in development of gene therapy enabling technologies.

For more information on the report, or to order it, see the CHI 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.

Our New Year’s 2015 article: Notable researchers and breakthrough research of 2014

 

Pre-1917 Russian Happy Christmas and Happy New Year card

Pre-1917 Russian Happy Christmas and Happy New Year card

As is their customary practice, both Nature and Science ran end-of-year specials. The Nature special (in their 18 December issue) is entitled “365 days: Nature’s 10. Ten people who mattered this year.” The Science special (in their 19 December issue) is entitled, as usual “2014 Breakthrough of the Year.” As is also usual, there is a section for “Runners Up” to the year’s “Breakthrough”.

From the point of view of a consulting group—and a blog—that focuses on effective drug discovery and development strategies, we were disappointed with both end-of-year specials. Most of the material in these articles was irrelevant to our concerns.

Science chose the Rosetta/Philae comet-chasing mission as the “Breakthrough of the Year”, and its “runners up” included several robotics and space-technology items, as well as new “letters” to the DNA “alphabet” that don’t code for anything.

Nature also focused on comet chasers, robot makers, and space technologists, as well as cosmologist and mathematicians, and a fundraising gimmick—“the ice-bucket challenge”. Moreover, Nature was much too restrictive in titling its article “Ten people who mattered”. Every human being matters!

Nevertheless, these two special sections do contain a few gems that are both relevant to effective drug discovery and development, and are worthy of highlighting as “notable researchers of 2014” and “breakthrough research of 2014”. We discuss these in the remainder of this article.

Suzanne Topalian, M.D.

Suzanne Topalian is one of the researchers profiled in “Nature’s 10”. She is a long-time cancer immunotherapy clinical researcher who began her career in 1985 in the laboratory of cancer immunotherapy pioneer Steven Rosenberg at the National Cancer Institute (Bethesda MD). In the early days of the field, when cancer immunotherapy was scientifically premature, there was a great deal of skepticism that these types of treatments would even work. However, both Dr. Rosenberg and Dr. Topalian persevered in their research.

In 2006, Dr. Topalian moved to Johns Hopkins University (Baltimore, MD) to help launch clinical trials of Medarex/Bristol-Myers Squibb/Ono’s nivolumab, a PD-1 inhibitor. As noted in the Nature article, her work “led to a landmark publication in 2012 showing that nivolumab produced dramatic responses not only in some people with advanced melanoma but also in those with lung cancer [specifically, non–small-cell lung cancer, NSCLC].” We also discussed that publication on the Biopharmconsortium Blog, and in our recently published book-length Insight Pharma Report, Cancer Immunotherapy: immune checkpoint inhibitors, cancer vaccines, and adoptive T-cell therapies. Our report also includes discussions of Dr. Rosenberg’s more recent work in cellular immunotherapy.

As discussed in our report, nivolumab was approved in Japan as Ono’s Opdivo in July 2014 for treatment of unresectable melanoma, and a competitive PD-1 inhibitor, pembrolizumab (Merck’s Keytruda) was approved in the United States for advanced melanoma on September 5, 2014. More recently, on December 22, 2014, the FDA also approved nivolumab (BMS’ Opdivo) for advanced melanoma in the U.S. There are thus now two FDA-approved PD-1 inhibitors [in addition to the CTLA-4 inhibitor ipilimumab (BMS’ Yervoy)] available for treatment of advanced melanoma in the U.S.

Meanwhile, researchers continue to test both nivolumab and pembrolizumab for treatment of NSCLC and other cancers. And some analysts project that both of these agents are likely to be approved by the FDA for treatment of various populations of patients with NSCLC before the middle of 2015. Researchers are also testing combination therapies that include nivolumab or pembrolizumab in various cancers. And clinical trials of Genentech/Roche’s PD-L1 blocking agent MPDL3280A are also in progress.

Science’s 2013 Breakthrough of the Year was cancer immunotherapy, as we highlighted in our New Year’s 2014 blog article. Science could not make cancer immunotherapy the Breakthrough of the Year for 2014, too. Thus it chose to give physical scientists a turn in the limelight by highlighting the comet-chasing mission instead. Nevertheless, 2014 was the year in which cancer immunotherapy demonstrated its maturity by the regulatory approval of the two most advanced checkpoint inhibitor agents, pembrolizumab and nivolumab.

Implications for patients with terminal cancers

The clinically-promising results of cancer immunotherapy in a wide variety of cancers, coupled with the very large numbers of clinical trials in progress in this area, has also changed the situation for patients who have terminal cancers. Researchers who are conducting clinical trials of immunotherapies for these cancers are actively recruiting patients, of whom there are limited numbers at any one time. For example, there are now numerous clinical trials—mainly of immunotherapies—in pancreatic cancer, and most of these trials are recruiting patients. There are also active clinical trials of promising immunotherapies in the brain tumor glioblastoma. These are only two of many examples.

Recently, a 29-year-old woman with terminal glioblastoma ended her life using Oregon’s physician-assisted suicide law. Prior to her suicide, she became an advocate for “terminally ill patients who want to end their own lives”. We, however, are advocating that patients with glioblastoma and other types of terminal cancer for which there are promising immunotherapies seek out clinical trials that are actively recruiting patients. There is the possibility that some of these patients will receive treatments that will result in regression of their tumors or long-term remissions. (See, for example, the case highlighted in our September 16, 2014 blog article. There are many other such cases.) And it is highly likely that patients who participate in these trials will help researchers to learn how to better treat cancers that are now considered “incurable” or “terminal”, and thus help patients who contract these diseases in the future. From our point of view, that is a lot better than taking one’s own life via assisted suicide, and/or becoming an euthanasia advocate.

Masayo Takahashi, M.D., Ph.D.

Another researcher profiled in “Nature’s 10” is Masayo Takahashi, an ophthalmologist at the RIKEN Center for Developmental Biology (CDB) in Kobe, Japan who has been carrying out pioneering human stem cell clinical studies. We also discussed Dr. Takahashi’s research in our March 14, 2013 article on this blog.

At the time of our article, Dr. Takahashi and her colleagues planned to submit an application to the Japanese health ministry for a clinical study of induced pluripotent stem cell (iPS)-derived cells, which would constitute the first human study of such cells. They planned to treat approximately six people with severe age-related macular degeneration (AMD). The researchers planned to take an upper arm skin sample the size of a peppercorn, and transform the cells from this sample into iPS cells by using specific proteins. They were then to add other factors to induce differentiation of the iPS cells into retinal cells. Then a small sheet of these retinal cells were to be placed under the damaged area of the retina, where they were expected to grow and repair the damaged retinal pigment epithelium (RPE). Although the researchers would like to demonstrate efficacy of this treatment, the main focus of the initial studies was to be on safety.

According to the “Nature’s 10” article, such an autologous iPS-derived implant was transplanted into the back of a the damaged retina of one patient in September 2014. This patient, a woman in her 70s, had already lost most of her vision, and the treatment is unlikely to restore it. However, Dr. Takahashi and her colleagues are determining whether the transplant is safe and prevents further retinal deterioration. So far, everything has gone smoothly, and the transplant appears to have retained its integrity. However, the researchers will not reveal whether the study has been a success until a year after the transplantation.

The “Nature’s 10” article discusses how this technology might be moved forward into clinical use if the initial study is successful. It also discusses how Dr. Takahashi has been carrying her research forward in the face of a major setback that has plagued stem cell research at the CDB in 2014, as the result of the withdrawal of two once highly-regarded papers and the suicide of one of their authors.

Generation of insulin-producing human pancreatic β cells from embryonic stem (ES) cells or iPS

Another stem cell-related item, which was covered in Science’s end-of-2014 “Runners Up” article, concerned the in vitro generation of human pancreatic β cells from embryonic stem (ES) cells or iPS. For over a decade, researchers have been attempting to accomplish this feat, in order to have access to autologous β cells to treat type 1 diabetes, in which an autoimmune attack destroys a patient’s own β cells. In vitro generated β cells might also be used to screen for drugs that can improve β cell function, survival, and/or proliferation in patients with type 2 diabetes.

As reported in the Science article, two research groups—one led by Douglas A. Melton, Ph.D. (Harvard Stem Cell Institute, Cambridge, MA), and the other by Alireza Rezania, Ph.D. at BetaLogics Venture, a division of Janssen Research & Development, LLC.–developed protocols to produce unlimited quantities of β cells, in the first case from IPS cells, and in the other from ES cells.

However, in order to use the β cells to treat type 1 diabetes patients, researchers need to develop means (for example, some type of encapsulation) to protect the cells from the autoimmune reaction that killed patients’ own natural β cells in the first place. For example, Dr. Melton is collaborating with the laboratory of Daniel Anderson, Ph.D. (MIT Koch Institute for Integrative Cancer Research). Dr. Anderson and his colleagues have developed a chemically modified alginate that can be used to coat and protects clusters of β cells, thus forming artificial islets. Dr. Melton estimates that such implants would be about the size of a credit card.

The 2014 Boston biotech IPO boom

Meanwhile, the Boston area biotechnology community has seen a boom in young companies holding their initial public offerings (IPOs). 17 such companies were listed in a December 24 article in the Boston Business Journal. Among these companies are three that have been covered in the Biopharmconsortium Blog—Zafgen, Dicerna, and Sage Therapeutics.

We hope that 2015 will see at least the level of key discoveries, drug approvals, and financings seen in 2014.


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.

Vertex cystic fibrosis therapeutics update


CFTR protein: A. normal B. gating mutant. Source: Lbudd14 http://bit.ly/1rGrzJ1

CFTR protein: A. normal B. gating mutant.
Source: Lbudd14 http://bit.ly/1rGrzJ1

As we said in our September 10, 2014 article, we intended to post updates on companies that we had been following on our blog, and that have achieved significant progress in recent months. So far, we have covered Agios and Zafgen. Both of these companies were featured in Boston-area meetings in October—Zafgen in Xconomy Xchange: Boston’s Life Science Disruptors on October 8, and Agios in the New Approaches to Cancer Drug Discovery symposium at Harvard Medical School on October 14.

Now we turn to the small-molecule cystic fibrosis (CF) therapeutics program at Vertex Pharmaceuticals (Boston, MA).

We covered Vertex’ CF program in our articles of January 24, 2013 and February 15, 2013. As a result of the publication of these articles, I was interviewed for and quoted in an article in the March 11, 2013 issue of Elsevier Business Intelligence’s The Pink Sheet 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.)

To summarize our discussions of CF in these earlier articles, CF causes a suite of symptoms that affect the skin, the lungs and sinuses, and the digestive, endocrine, and reproductive systems. The most important results of CF is that patients accumulate thick, sticky mucus in the lungs. This results in clogging of the airways with mucus. This leads to inflammation and bacterial infections. Lung transplantation is often necessary as the disease worsens. With proper management, patients can live into their late 30s or 40s.

The gene that is affected in cystic fibrosis encodes the cystic fibrosis transmembrane conductance regulator (CFTR).  CFTR is an ion channel that regulates the movement of chloride and sodium ions across epithelial membranes, including the epithelia of lung alveoli. CF is an autosomal recessive disease, which is most common in Caucasians. The most common mutation that causes CF, ΔF508, is a deletion of three nucleotides that causes the loss of the amino acid phenylalanine at position 508 of the CFTR protein. The ΔF508 mutation accounts for approximately two-thirds of CF cases worldwide and 90% of cases in the United States. However, there are over 1500 other mutations that can cause CF.

Ion channels constitute an important class of drug targets, which are targeted by numerous currently marketed drugs. These compounds were developed empirically by traditional pharmacology before knowing anything about the molecular nature of their targets. However, discovery of novel ion channel modulators via modern molecular methods has proven to be challenging.

The ΔF508 mutation results in defective cellular processing, and the mutant CTFR protein is retained in the endoplasmic reticulum. Some other mutations in CTFR (which affect a small percentage of CF patients) result in mutant proteins that reach the cell membrane, but are ineffective in chloride-channel function.

After a long discovery and development program (which we outlined in our February 15, 2013 article), Vertex identified two types of candidate small-molecule CF therapeutics:

  • CFTR potentiators, which potentiate the chloride channel activity of mutant CFTR molecules at the cell surface;
  • CFTR correctors, which partially correct the folding and/or trafficking defect of such mutant CFTRs as ΔF508, thus enabling a portion of these mutant proteins to exit from the endoplasmic reticulum and to deposit in the cell membrane.

Vertex’ CTFR potentiator ivacaftor (Kalydeco, formerly known as VX-770) was approved by the FDA in January 2012, and approved in Europe in July 2012. At that time, ivacaftor was only indicated for treatment of CF patients age 6 and over carrying the CFTR G551D mutation (Gly551Asp). Although the G551D mutation only affects approximately 4% of CF patients, it is the most common CFTR gating mutation (i.e., a mutation that affects transport of sodium and chloride ions across epithelial membranes).

New indications for ivacaftor (Kalydeco)

On July 31, 2014, Vertex announced that the European Commission had approved ivacaftor for treatment of CF patients age 6 and over who have one of eight non-G551D gating mutations in the CFTR gene. The eight additional gating mutations included in the new approval affect approximately 250 people ages 6 and older in the European Union.

The approval was based on data from a Phase 3 randomized, double-blind, placebo-controlled study of 39 people with CF ages 6 and older who have a non-G551D gating mutation.

The European approval followed the February 21, 2014 announcement that the FDA had approved ivacaftor for treatment of CF patients 6 and older who have one of the same additional eight mutations in the CFTR gene. In the U.S., approximately 150 people ages 6 and older have one of the additional eight mutations.

On October 21, 2014, the FDA’s Pulmonary Allergy Drugs Advisory Committee (PADAC) voted 13-2 to recommend approval of ivacaftor in CF patients age 6 and older who have the R117H mutation in the CTFR gene. This new indication is now under review by the FDA.

Thus Vertex has been pursuing a strategy of testing and seeking approval of ivacaftor for treatment of CF patients with gating mutations in the CTFR gene other than the G551D mutation, in a systematic, step-by-step fashion. As a result of this strategy, ivacaftor is currently approved to treat over 2,600 people ages 6 and older in North America, Europe and Australia.

Vertex’ development of the CFTR correctors lumacaftor (VX-809) and VX-661

Meanwhile, Vertex has also been pursuing approval for its CFTR correctors lumacaftor (VX-809) and VX-661. We have discussed these agents in our February 15, 2013 blog article.

As we discussed in that article, as of February 2013 Vertex had completed Phase 2 studies of a combination of ivacaftor and lumacaftor in CF patients who were homozygous for the CFTR ΔF508 mutation. They then planned pivotal phase 3 trials of the combination therapy in this patient population. The rationale for the combination treatment was that VX-809 potentates the deposition of CFTR ΔF508 in the cell membrane, and invacaftor potentiates the function of cell-surface CFTR ΔF508.

As of February 2013, Vertex was also conducting Phase 2 trials of another CTFR corrector, VX-661, alone and in combination with ivacaftor in CF patients homozygous for CFTR ΔF508.

On June 24, 2014, Vertex announced that results from two Phase 3 studies of lumacaftor in combination with ivacaftor showed statistically significant improvements in lung function in people ages 12 and older with cystic fibrosis (CF) who were homozygous for CFTR ΔF508. All four 24-week combination treatment arms in the studies, known as TRAFFIC and TRANSPORT, met their primary endpoint of mean absolute improvement in lung function from baseline compared to placebo at the end of treatment. The combination treatments were also generally well tolerated.

Data from a pre-specified pooled analysis also showed improvements in multiple key secondary endpoints, including lowering pulmonary exacerbations.

On October 9, 2014, Vertex announced updates of the results of the TRAFFIC and TRANSPORT studies, in conjunction with the company’ presentations at the 28th Annual North American Cystic Fibrosis Conference (NACFC). Patients who completed 24 weeks of treatment in TRAFFIC or TRANSPORT were eligible to enter a Phase 3 rollover study to receive a combination regimen of lumacaftor and ivacaftor. The first interim data from the rollover study (presented at NACFC) showed that the improvements in lung function observed in the 24-week TRAFFIC and TRANSPORT studies were sustained through 48 weeks of treatment with the combination treatment. At the time of the interim analysis, safety and tolerability results were also consistent with those observed in the initial Phase 3 TRAFFIC and TRANSPORT studies.

In the October 9, 2014 press release, Vertex also announced the submission of an NDA in the U.S. and an MAA in Europe for the approval of ivacaftor in children with CF ages 2 to 5 with one of the same 9 CTFR gene mutations for which the drug is approved in patients 6 or older. These line extension submissions are based on further Phase 3 studies, which were also presented at the NACFC.

On November 5, 2014, the company announced that it had submitted an NDA to the FDA and an MAA to the European Medicines Agency (EMA) for a fully co-formulated combination of lumacaftor and ivacaftor for CF patients age 12 and older who are homozygous for CFTR ΔF508. There are approximately 22,000 people with CF ages 12 and older who are homozygous for CFTR ΔF508 in North America, Europe and Australia. This includes approximately 8,500 people in the United States and 12,000 people in Europe. These new submissions are based on data from TRAFFIC and TRANSPORT, and on the first interim data from the subsequent rollover study.

Meanwhile, as also announced on October 9, 2014, clinical studies of VX-661 are continuing. Vertex presented data from Phase 2 studies of VX-661 in combination with ivacaftor at the 2014 NACFC. In the October 9 press release, Vertex announced that it plans to initiate a pivotal Phase 3 development program for VX-661 in combination with ivacaftor in CF patients who have one or two copies of the CFTR ΔF508 mutation, including patients with a second CFTR mutation that causes a defect in the gating of the CFTR protein. The initiation of this study is pending regulatory discussions and data from a fully enrolled 12-week Phase 2b study of VX-661 in combination with ivacaftor in patients who are homozygous for CFTR ΔF508.

The high cost of Kalydeco causes controversy

Kalydeco (ivacaftor) costs nearly $300,000 a year. These costs are usually borne by insurers and governments, and Vertex has pledged to provide the drug free to any U.S. patient who is uninsured or whose insurance won’t cover it.

However, the high cost of this drug—and the anticipated higher cost of combination therapies for treatment of CF—has generated controversy in some circles. This issue has been discussed, for example, in 2013 articles in the M.I.T. Technology Review and in MedPage Today. (MedPage Today is a peer-reviewed online medical news service for clinicians, which provides breaking medical news, professional medical analysis and continuing medical education (CME) credits to its physician readers.)

According to the Technology Review article, by Barry Werth, doctors and patients enthusiastically welcomed Kalydeco because it offers life-saving health benefits and there is no other treatment. Insurers and governments readily paid the cost. However, commentators quoted in the MedPage Today article said that the price of Kalydeco is exorbitant, and the increasing numbers of high-priced life-saving drugs to treat rare diseases (although nor usually borne directly by patients themselves) is unsustainable. Vertex—as quoted in the MedPage Today article—said that the price of Kalydeco reflects its high degree of efficacy, the time and cost [and risk] it took to develop the drug, and the company’s commitment to reinvest in continued development of newer drugs to help other CF patients.

The discussions of the high cost of Kalydeco echoes the discussions of the cost of novel drugs for life-threatening cancers, as mentioned in our October 2, 2014 article, “Late-breaking cancer immunotherapy news”, on this blog.

With respect to the development of Kalydeco and other small-molecule CF drugs, the publicly-funded—and successful—research to determine the molecular cause of CF was of little help in enabling researchers to develop disease-modifying drugs. (See our January 24, 2013 blog article, “Determining the molecular cause of a disease does not necessarily enable researchers to develop disease-modifying drugs”.) As outlined in our February 15, 2013 blog article, Vertex’ own drug discovery and development program (partially funded by the nonprofit Cystic Fibrosis Foundation, which now receives royalties on sales of Kalydeco) was long (beginning in 1998), expensive, risky, and involved considerable ingenuity.

Given the high barrier between the knowledge of the molecular biology of CF and its use in discovering and developing safe and efficacious small-molecule drugs, the development of such agents as ivacaftor, lumacaftor, and VX-661 is almost miraculous. Vertex’ arguments that justify the high cost of the drug thus have considerable merit. However, discussions in the medical community and beyond on how the costs of novel life-saving drugs for rare diseases and cancer may be sustained will and should continue.

Conclusions

The goal of Vertex’ CF program as a whole is the development, approval and marketing of multiple combinations of small-molecule therapeutics that will have disease-modifying efficacy in the great majority of CF patients. Especially with the recent progress with clinical studies of the ivacaftor/lumacaftor combination in patients with CFTR ΔF508 mutations, and with line extensions of ivacaftor, Vertex appears to be well on its way to accomplishing this, pending regulatory approvals.

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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 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.

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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.

Agios Pharmaceuticals continues to progress

Agios Kirykos, Ikaria, Greece. Source: http://commons.wikimedia.org/wiki/File:Agios_Kirikos,_Ikaria.jpg

Agios Kirykos, Ikaria, Greece. Source: http://commons.wikimedia.org/wiki/File:Agios_Kirikos,_Ikaria.jpg

Because of being very busy with other projects, we have not posted an article on this blog since April 10, 2014. However, the Biopharmconsortium Blog is still here. More importantly, Haberman Associates biotech/pharma consulting is still here, and we’re still accepting new clients.

Thanks to the many readers who have continued to follow our website and blog during our blogging hiatus, and who have linked to our blog on Twitter and on other social media.

During the hiatus, several of the companies that we have been following on our blog have been progressing. Over the next several months, we shall be blogging about some of these companies, as well as about other notable industry events that have occurred in recent weeks and that will occur during the remainder of 2014.

The first company that we are writing about is cancer metabolism specialist Agios Pharmaceuticals (Cambridge, MA). Our most recent three articles about Agios on this blog are:

In our September 23, 2013 article, we noted that Agios had initiated its first clinical study—a Phase 1 clinical trial of AG-221 in patients with advanced hematologic malignancies bearing an isocitrate dehydrogenase 2 (IDH2) mutation. AG-221 is a first-in-class, orally available, selective, potent inhibitor of the mutated IDH2 protein. It is thus a targeted (and personalized) therapy for patients with cancers with an IDH2 mutation.

On June 14, 2014, Agios reported on new clinical data in its ongoing Phase 1 trial of AG-221, which was presented at the 19th Congress of the European Hematology Association (EHA) in Milan, Italy by Stéphane de Botton, M.D. (Institut de Cancérologie Gustave Roussy, Villejuif, France).

The presentation reported on the results of AG-221 treatment of 35 patients with IDH2 mutation positive hematologic malignancies. The researchers observed objective responses in 14 out of 25 evaluable patients, and stable disease in an additional 5 patients. Six patients experienced complete remissions which lasted from one to four months, and are still ongoing. AG-221 has shown favorable pharmacokinetics at all doses tested, with large reductions in serum levels of the oncometabolite 2-hydroxyglutarate (2HG). AG-221 was also well tolerated.

The new data confirms and builds upon previously results. The favorable safety and efficacy data supports Agios’ plan to initiate four expansion cohorts in the second half of 2014. Agios also expects to submit additional data from the ongoing Phase 1 trial for presentation at a later scientific meeting in 2014.

Meanwhile, as announced on June 13, 2014, Agios’ partner Celgene exercised its option to an exclusive worldwide license for AG-221. It exercised this option early, based on the Phase 1 data generated so far.

On June 16, 2014, Agios announced that the FDA granted orphan drug designation for AG-221 for treatment of patients with acute myelogenous leukemia (AML). On August 13, 2014, the FDA also granted Fast Track designation to AG-221 for the treatment of patients with AML that carry an IDH2 mutation.

Thus development of Agios’ lead compound, AG-221, continues to progress. Several other Agios R&D programs are also progressing, as detailed in the company’s report for the second quarter of 2014.

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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.

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.
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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.