Tsarevich Alexei of Russia

The boy pictured above is Tsarevich Alexei Nikolaevich of Russia, who lived between 1904 and 1918, and was the heir to the throne of Imperial Russia. He is arguably the most famous hemophiliac in history.

Alexei suffered from hemophilia B, a form of hemophilia that was passed from Queen Victoria of Britain through two of her five daughters to the royal families of Spain, Germany, and Russia. He inherited the disease—which is X-linked and recessive—from his mother, the Empress Alexandra Feodorovna, a granddaughter of Queen Victoria.

During Alexei’s lifetime, there was no good treatment for hemophilia. So Empress Alexandra turned to the charlatan Grigori Rasputin, a supposed “holy man” whom she thought had the power to heal the boy. The relationship between the Empress and Rasputin, and the disastrous rule by the two during September 1915—February 1917, led to the fall of the Romanov dynasty and the eventual rise of Bolshevism. In July 1918, the Bolsheviks murdered Tsar Nicholas II and his entire family, including Tsarevich Alexei, who was one month shy of his 14th birthday.

Current treatments for hemophilia

In 2016, there are much better approved therapies for hemophilia than in Alexei’s day. Hemophilias include hemophilia A and B. Both are X-linked recessive disorders, which thus affect mainly males. Hemophilia A involves a deficiency in factor VIII (FVIII),  and hemophilia B involves a deficiency in factor IX (FIX). Both of these are clotting factors made in the liver. Hemophilia occurs in approximately one in 5,000 live births, and hemophilia A is four times as common as hemophilia B.

Management of hemophilia—from the early 1990s to today—is based on the use of recombinant FVIII or recombinant FIX, for the treatment of hemophilia A and B, respectively. Examples of these products include Baxalta’s Advate and Pfizer’s Xyntha (both recombinant FVIII products), and Pfizer’s BeneFix and Biogen’s Alprolix (both recombinant FIX products). (Baxalta was spun off from Baxter International in July 2015, and then acquired by Shire in January 2016.)

To avoid joint damage and other complications, patients with severe hemophilia need regular infusions, lasting 30 minutes or more, of relatively short-acting and expensive recombinant clotting factors. The cost of these products per patient could total more than $300,000 in 2014.

In recent decades, clotting factor replacement therapy has reduced the morbidity and mortality of hemophilia. However, compared with individuals with normal coagulation, deaths still occur at higher rates due to bleeding episodes. Prophylactic therapy via regular intravenous infusions of factor two to three times per week is now the standard of care for children and increasingly for adults, especially for patients with severe hemophilia. With the expense of current therapies, and the need for frequent infusions, compliance is difficult. Moreover, convenient access to peripheral veins is often a problem. Many children require use of central venous access devices, with the risks of infection and thrombosis.

As a result, pharmaceutical and biotechnology companies have been attempting to develop longer-acting recombinant clotting factor products, with some success. Example of recently-developed products include Biogen/Swedish Orphan Biovitrum’s Alprolix (recombinant factor IX Fc fusion protein, approved by the FDA in March 2014 for treatment of hemophilia B) and Biogen/Swedish Orphan Biovitrum’s Eloctate (recombinant factor VIII Fc fusion protein, approved by the FDA in June 2014 for treatment of hemophilia A). Both of these products are fusion proteins between recombinant clotting factors and Fc immunoglobulin domains. The use of Fc domains is designed to prolong the half-life of the recombinant fusion proteins in the circulation. Other companies that have been active in developing longer-acting recombinant FIX and FVIIII products include Bayer and Novo Nordisk.

The new longer-acting recombinant clotting factors can reduce the frequency of infusion needed for control of a patient’s hemophilia. However, some patients, especially children under 12, may require higher doses or more frequent infusions than most adults.

Gene therapies for hemophilia under development

The ideal therapies for hemophilia A and/or B would be gene therapies. Gene therapies would potentially eliminate the need for lifelong, frequent infusions of clotting factors, with improved quality of life and reduced risk of death due to bleeding episodes.

As discussed in our recently published book-length report, Gene Therapy: Moving Toward Commercialization (published by Cambridge Healthtech Institute), hemophilia A and B have been extensive researched as candidates for gene therapy. This research has included development and use of animal models, development of coagulation assays that can be used in quantitating the results of treatment, and development of actual candidate gene therapies, especially in the case of hemophilia B.

Development of gene therapies for hemophilia B (the disease that afflicted Tsarevich Alexei and other European royals) enjoys the advantage of the relatively small size of the coding region of the gene for FIX. It is approximately 1.4 kB of cDNA (complementary DNA) coding sequence. This allows researchers to insert this coding element into many different gene transfer vectors, especially adeno-associated virus (AAV) vectors. (AAV is the most commonly used vector in gene therapy today.) The small size of the FIX coding region also allows for the addition of transcriptional regulatory elements to modulate the expression of an FIX transgene into small vectors such as those based on AAV.

In contrast, FVIII cDNA is over 8kB in size. Thus, it is not as readily accommodated in small gene transfer vectors such as AAV.  Researchers and companies have been employing several strategies to overcome this difficulty. Although R&D efforts aimed at making gene therapy for hemophilia A possible are underway, commercial development of gene therapy for hemophilia B is far ahead of that for hemophilia A.

As discussed in our report, an important factor that favors the use of gene therapy in treatment of hemophilias is that there is a relatively low threshold for success. In a hemophilia patient, If long-term expression of 2-3% of wild-type (or normal) levels of a functional clotting factor (FIX for hemophilia B or FVIII for hemophilia A) could be achieved, then a substantial reduction in the clinical manifestations of the disease could be attained. Expression of over 30 percent of the wild-type level of the clotting factor could restore a patient to phenotypic normality, although higher levels may be required in the case of hemostatic challenge.

Preliminary results of uniQure’s clinical trial of its hemophilia B gene therapy, AMT-060

In our report, we discuss four programs for development of hemophilia B gene therapies that have reached the clinic. All are based on AAV vectors. One of these four therapies, AMT-060, is being developed by uniQure (Amsterdam, The Netherlands). uniQure has the distinction of having developed the first, and currently (as of January 2016) the only, gene therapy product that has received regulatory approval in a regulated market. This is Glybera (alipogene tiparvovec), a treatment for the ultra-rare genetic disease lipoprotein lipase deficiency (LPLD). uniQure’s hemophilia B gene therapy candidate, AMT-060, is being developed in Europe in collaboration with Chiesi (Parma, Italy).

On January 7, 2016 uniQure announced preliminary results from the low-dose cohort of an ongoing Phase 1/2 clinical trial (clinical trial number NCT02396342) being conducted in adult hemophilia B patients treated with uniQure’s novel AAV5-FIX gene therapy, AMT-060. At the time of their enrollment in the trial, all five patients in the low-dose cohort had FIX levels of less than 1-2% of normal levels, and required chronic treatment with prophylactic recombinant FIX (rFIX) therapy.

The first two patients out of the five have completed 20 and 12 weeks of follow-up and had FIX expression levels of 5.5% and 4.5% of normal, respectively, as of the cutoff date of December 16th, 2015. The three other patients have been dosed, but had not achieved the full 12 weeks of follow-up at the cutoff date. However, as of January 6, 2016, four of the five patients, including the first two patients enrolled in the study, have been able to fully discontinue prophylactic rFIX. The first patient in the low-dose cohort experienced a mild, transient and asymptomatic elevation of liver transaminase levels in serum at 10 weeks after treatment; this was easily resolved by treatment with prednisolone. No elevated transaminase levels have been observed in the other four patients so far.

As outlined in our report, AMT-060 consists of an AAV5 vector carrying a gene cassette encoding a codon-optimized (i.e., using codons most frequently found in highly expressed eukaryotic genes) wild-type human FIX (hFIX), under the control of a liver-specific promoter. The gene cassette has been exclusively licensed by uniQure from St. Jude Children’s Research Hospital (Memphis, Tenn.). It is the same gene cassette that has been successfully tested in published Phase 1 trials. AMT-060 is manufactured using uniQure’s proprietary insect cell based technology. The therapy is administered, without the use of immunosuppressants, through a peripheral vein in one treatment session for approximately 30 minutes. The study includes a low-dose and a high-dose cohort. So far, there have been no issues with pre-existing neutralizing antibodies against AAV5 or with development of inhibitory FIX antibodies.

This early data suggests that AMT-060 is well-tolerated, and is able to successfully transduce the liver, and thus to produce clinically meaningful levels of serum FIX.

uniQure and its collaborators are continuing the study. The investigators intend to present a more complete analysis of the data from the low-dose cohort at a scientific conference in the second quarter of 2016. uniQure also anticipates initiating enrollment of the high-dose cohort in the first quarter of 2016.

The hemophilia gene therapy field will be competitive

Among the clinical-stage hemophilia B programs covered in our report, Spark Therapeutics expects to report initial efficacy data in mid-2016 for its Phase 1/2 clinical trial of SPK-FIX, which it is developing in collaboration with Pfizer. As discussed in our report, only Baxalta has reported early clinical trials for its therapy, AskBio009/BAX335. These results were reported in July 2015. As in many early studies of hemophilia gene therapies, there were issues with neutralizing antibodies that led to decreased FIX expression. Baxalta continues to work to address the observed immune responses, while maintaining target levels of FIX expression. As uniQure continues with its clinical trial of AMT-060 and treats more patients with higher doses, it remains to be seen to what extent immune reactions might affect results with its hemophilia B gene therapy.

The other hemophilia B program discussed in our report is at Dimension Therapeutics. At the time of our report’s publication, Dimension’s first clinical trial was to commence in the second half of 2015. As reported by Dimension, the Phase 1/2 study for its AAVrh10-FIX product DTX101 was actually initiated on January 7, 2016.

Other companies that are entering the hemophilia B or A gene therapy field include Biogen, Sangamo in collaboration with Shire, and Biomarin. Biomarin’s program is in hemophilia A, and all the companies mentioned in this article and in our report that have hemophilia B programs also are developing hemophilia A gene therapies. At least some commentators believe that “hemophilia could prove to be the most competitive gene therapy race to date.”

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.

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.

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.

Spark! Source: http://bit.ly/1Obw4Nk

As we discussed in our November 16, 2015 article on this blog, Spark Therapeutics (Philadelphia, PA) recently 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.  At a later scientific meeting, the company presented data that showed that SPK-RPE65 gave durable improvements in vision over a three-year period.

SPK-RPE65 is the most advanced gene therapy in development for retinal disease of any company, as discussed in our November 2015 book-length gene therapy report, Gene Therapy: Moving Toward Commercialization, published by Cambridge Healthtech Institute. Our report includes detailed discussions of SPK-RPE65, Spark Therapeutics, and other companies developing gene therapies for ophthalmologic diseases.

Now comes a recent online article in “Seeking Alpha” by ONeil Trader, which discusses Spark’s commercialization plans for SPK-RPE65, based on the positive Phase 3 results. Spark is planning to file a Biologics License Application (BLA) for SPK-RPE65 in 2016, as also stated on the company’s website. According to the “Seeking Alpha” article, SPK-RPE65 should reach the U.S. market in 2017, and should be the first FDA-approved gene therapy product in the United States.

The “Seeking Alpha” article also gives a projected range of peak sales for SPK-RPE65: from $350 million to $900 million. The article also reminds investors (the primary audience of “Seeking Alpha”) that Spark has a rich pipeline beyond SPK-RPE65. We have discussed the two clinical stage products mentioned by “Seeking Alpha”—SPK-CHM for the IRD choroideremia and SPK-FIX for hemophilia B (partnered with Pfizer) in our report. We have also discussed Spark’s first neurodegenerative disease gene therapy, SPK-TPP1 for Batten disease, in the December 7, 2015 article on this blog.

Might other gene therapies reach the U.S. market in 2017?

The “Seeking Alpha” article predicts that SPK-RPE65 will be the first gene therapy to reach the US. market, in 2017. However, there are several other gene therapies discussed in our report that might also reach the U.S. market by 2017, perhaps beating SPK-RPE65 for the honor of being first-to-U.S.-market.

Despite its already being approved in Europe, uniQure’s Glybera, the “first commercially available gene therapy”, will not be the first to reach the U.S. market. That is because uniQure has dropped plans to seek FDA approval for Glybera.

As discussed in our gene therapy report, the products most likely to reach the U.S. market at the same time or before SPK-RPE65 are all CD19-targeting CAR T-cell therapies for treatment of various B-cell leukemias and lymphomas. These products include Novartis/Penn’s CTL019, Juno’s JCAR015, and Kite’s KTE-C19. At least as a “stretch goal”, CTL019 might even reach the U.S. market for treatment of acute lymphoblastic leukemia (ALL) in 2016. In addition to these products, our report includes discussions of other gene therapies that might reach the U.S. and/or European market before 2020, and achieve revenues equal to or greater than those projected for SPK-RPE65.

Importantly, none of these other products will compete with SPK-RPE65, except for the honor of being “the first gene therapy to reach the U.S. market”. And the prospect of several gene therapy products reaching the U.S. and/or European market before 2020 suggests that gene therapy is moving beyond the “premature technology” stage, and into commercial success.

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

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.

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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