Biopharmconsortium Blog

Expert commentary from Haberman Associates biotechnology and pharmaceutical consulting.

Posts filed under: Gene therapy

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.

Gene therapy for hemophilia—an update

 

Tsarevich Alexei of Russia

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.”

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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.

Spark Therapeutics’ retinal disease gene therapy SPK-RPE65 may reach the U.S. market in 2017

 

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

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.

“Our Promise to Nicholas”, Batten disease, and gene therapy

 

Wayland MA Source: http://bit.ly/1N1TyRk

Wayland MA Source: http://bit.ly/1N1TyRk

Russell’s Garden Center, on Route 20, a family-owned business established in 1876, is a unique Wayland MA institution. When you shop at Russell’s and approach the check-out counter with your plants, flowers, or other purchases, you will see a donation box for a rare-disease charity called “Our Promise to Nicholas Foundation”.

This charity is named for Nicholas R. Dainiak, a Bedford MA boy who died on his 11th birthday in 2014, after “a courageous six year battle with Batten’s disease”. The primary mission of the foundation is to raise funds and create partnerships aimed at promoting awareness, providing education, and developing translational research in Batten disease.

One of the events that the Foundation sponsors in order to raise funds and awareness is the John Tanner Memorial 5-K Run and Walk, which this year took place on October 4, 2015 in Wayland. This event memorializes both Nicholas and John Tanner. John Tanner was a competitive runner who devoted all of his races over 5 years to raising awareness about Nicholas and Batten disease. He was also a long-time employee of Russell’s Garden Center—hence the Russell’s and Wayland connection to the Foundation. John Tanner died unexpectedly while running the NYC half marathon in the spring of 2013.

Batten disease

Batten disease is a very rare, fatal, autosomal recessive neurodegenerative disorder that usually begins in childhood. Juvenile Batten disease is one of a group of disorders known as neuronal ceroid lipofuscinoses (NCLs). NCLs may be caused by one of over 400 different mutations. They affect the nervous system with vision loss, seizures, movement disorders, slow learning, altered thought processes, and cognitive decline.

Although Batten disease was originally used to describe only the juvenile form of NCL the term “Batten disease” is now widely used to refer to all forms of NCL, including adult-onset disease. Juvenile NCL, the most prevalent form of Batten disease, has been linked to mutations in the CLN3 gene. Late infantile NCL has been linked to mutations in NCL2.

Batten disease is a type of lysosomal storage disease. The CLN3 gene codes for a protein called battenin, which is found principally in lysosomes and in endosomes. The protein’s function is currently unknown. The CLN2 gene codes for a lysosomal enzyme called tripeptidyl peptidase 1 (TPP1), which is an acid protease.

Mutations in CLN2, CLN3, and other Batten disease genes result in the accumulation of lipofuscins in the tissues of the body. Lipofuscins are lipoproteins that form autofluorescent ceroid (i.e., waxy) deposits throughout the body of Batten disease patients.  Lipopfuscin deposits can sometimes be detected visually in the back of the eye. As the disease progresses, the deposits in the retina appear more pronounced, and ophthalmologists see circular bands of different shades of pink and orange in the patient’s optic nerve and retina. Ceroid lipofuscins are a hallmark of Batten disease, and appear to cause disease symptoms.

Juvenile Batten disease has an estimated incidence between 0.5 – 8 per 100,000 live births, with an average of 1.2. Despite its rarity, juvenile Batten disease appears to be the most common form of pediatric neurodegenerative disease. In addition to Batten disease patients, there are approximately 440,000 asymptomatic people in the United States who are carriers of juvenile Batten disease who have one copy of a mutated version of the CLN3 gene.

As with other rare diseases, a typical Batten disease patient may visit 8 physicians and receives 2 to 3 misdiagnoses before being correctly diagnosed. This may take many years. In the case of Nicholas, he had several misdiagnoses and mis-treatments over the early course of his disease, from age 4 to age 5. It was a ophthalmologist who finally correctly diagnosed Nicholas with Batten disease.

Relationship between Batten disease and more common neurodegenerative diseases

The written material next to the donation box for “Our Promise to Nicholas” in Russell’s Garden Center claims that study of Batten disease may lead to a greater understanding of such neurodegenerative diseases of aging as Alzheimer’s and Parkinson’s disease. Some of the symptoms and consequences of Batten disease resemble those of Alzheimer’s and Parkinson’s. Nevertheless, Batten disease is classified as a lysosomal storage disease, while Alzheimer’s and Parkinson’s are thought to be caused via other mechanisms.

However, some researchers see common mechanisms in the pathobiology of neurodegenerative lysosomal storage diseases such as Batten and of other neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Specifically, these include impairment of autophagy and increase in cytoplasmic protein aggregation. For example, some researchers have found relationships between mutations in the Alzheimer’s disease-related protein presenilin 1 and lysosomal dysfunction.

Since clinical trials of drugs for Alzheimer’s disease have so far been unsuccessful, study of alternative mechanisms for the pathogenesis of Alzheimer’s may be useful in developing new ways of addressing drug discovery for this devastating and all-too-common disease.

Discovery and development of gene therapies for Batten disease

The “Our Promise to Nicholas” website has a page entitled “Where your donations go”. According to that Web page, Nicholas’ disease was caused by a splice mutation in CLN2, which blocked production of TPP1. This is the most common mutation in children with the late infantile subtype of Batten Disease.

The same Web page discusses a gene therapy program led by Beverly Davidson, Ph.D. (then at the University of Iowa, Iowa City, IA), which had been supported by Our Promise To Nicholas Foundation. As of April 2014, Dr. Davidson joined the Children’s Hospital of Philadelphia (CHOP). At that time, Dr. Davidson became the director of CHOP’s Center for Cellular and Molecular Therapeutics. She has also continued her research on gene therapy for neurodegenerative diseases, including Batten disease, other neurologic lysosomal storage disorders, Huntington’s and Alzheimer’s diseases, and others.

While at Iowa, and continuing at CHOP, Dr. Davidson and her colleagues were investigating the use of adeno-associated virus (AAV) vectors carrying a functional TPP1 gene in treatment of late infantile Batten disease in animal models.

On November 11, 2015, Spark Therapeutics (Philadelphia, PA) announced that its first gene therapy program targeting a central nervous system (CNS) disease will target late infantile Batten disease. In that press release, it also announced that a report published in the 11 November issue of Science Translational Medicine provides preclinical proof of principle for Spark’s gene therapy, known as SPK-TPP1. The preclinical study, in a naturally occurring dog model, was led by Dr. Davidson at CHOP.

The study demonstrated the potential of a one-time administration of SPK-TPP1 to delay onset and progression of Batten disease in the dog model. SPK-TPP1 consists of Spark’s AAV2 vector carrying a functional TPP1 gene. The preclinical study showed that one-time administration of SPK-TPP1 to the ependymal cells of the brain ventricular system produced steady expression of the enzyme in the cerebrospinal fluid, and throughout the CNS. It also resulted in delayed onset of clinical symptoms and disease progression, protection from cognitive decline and extension of lifespan, as compared to untreated controls.

Based on these results, Spark plans to initiate Investigational New Drug Application (IND)-enabling studies in 2015.

Our November 2015 book-length report, Gene Therapy: Moving Toward Commercialization (published by Cambridge Healthtech Institute), contains a discussion of gene therapy vectors, including AAV. It also highlights Spark Therapeutics as a leader in AAV-based gene therapy and in gene-therapy treatments for retinal diseases. Spark’s technology platform had been developed over a 20-year period at CHOP.

As also discussed in our November 16, 2015 article on this blog, Spark has recently completed a 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. SPK-TPP1 uses the same AAV2 vector as SPK-RPE65, and will utilize the same manufacturing processes. AAV2 has a neural tropism. Since the retina is an extension of the brain, researchers can utilize AAV2 vectors to target both tissues.

Conclusions

On the Web page “Where your donations go”, Dr. Davidson says that funding from “family foundations such as Our Promise to Nicholas Foundation” has provided much needed support. Their donations have allowed cutting-edge research to be conducted in a timely manner, rather than months or years after researchers develop the ideas for these studies. Moreover, interacting with Batten disease families is especially motivating, and the advisory role of scientists who review grant proposals for family foundations is valuable as well.

Our Promise to Nicholas is far from the only Batten disease “family foundation”. Other families of patients with juvenile and adult-onset Batten disease have formed foundations to fund research and awareness. For example, there are Nathan’s Battle Foundation and the Batten Disease Support and Research Association (BDSRA). Our Promise to Nicholas participated in the 2015 BDSRA Annual Conference, and worked together with other Batten disease family foundations to provide nursing care and childcare for the event. Thus when Dr. Davidson refers to “family foundations”, she is referring to several such organizations.

Dr. Davidson also pointed out that grant funding from the National Institutes of Health (NIH) has dramatically decreased in recent years due to Federal budget constraints. This has especially affected research on rare diseases such as Batten disease. Dr. Davidson believes that “family foundation support is being increasingly relied upon to fill a growing void in NIH funding”.

Funding of Dr. Davidson’s research by Our Promise to Nicholas Foundation and other family foundations has resulted in a gene therapy R&D program that has been adopted by one of the world’s leading gene therapy companies, Spark Therapeutics. Spark (in collaboration with Dr. Davidson’s group at CHOP) is taking its Batten disease program into the clinic, and intends to commercialize SPK-TPP1. Spark is also using its Batten disease program as the basis for its larger neurodegenerative disease program. Thus Our Promise to Nicholas Foundation has much to be proud of.

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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.

_________________________________________________________________________________________________

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.

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.

Bluebird Bio, Celgene, and Adoptive Immunotherapy for Cancer

Eastern Bluebird

Eastern Bluebird

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

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

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

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

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

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

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

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

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

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

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

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

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

Determining the molecular cause of a disease does not necessarily enable researchers to develop disease-modifying drugs

 

NBD1 of human CFTR. Source: PDBbot http://bit.ly/11UmpkS

NBD1 of human CFTR. Source: PDBbot http://bit.ly/11UmpkS

A major objective of research in genomics is to identify mutations that cause genetic diseases. However, doing so does not necessarily directly enable researchers to discover and develop drugs to treat these diseases.

Two examples of genetic diseases whose causes were identified decades ago, without directly enabling the development of any disease-modifying drug, are sickle cell disease (SCD) (also known as sickle cell anemia) and cystic fibrosis (CF).

Sickle cell disease

The causative mutation of SCD was identified by protein researchers, decades before the era of genomics. Vernon M. Ingram, Ph.D. showed in 1957 that a glutamic acid to valine mutation at position 6 of the β-chain of hemoglobin was the sole abnormality in SCD. For this discovery, Dr. Ingram has been called The Father of Molecular Medicine. Dr. Ingram’s work was made possible by a 1949 study by Linus Pauling and his colleagues, which showed that SCD hemoglobin had a different electrophoretic mobility than normal hemoglobin. Thus the sickle cell trait was likely to be due to a mutation in the β-hemoglobin gene that changed its amino acid composition, as confirmed by Dr. Ingram.

Yet to this day, although SCD (which occurs in individuals who are homozygous for the sickle-cell mutation) can be managed by various treatments (such as hydroxyurea and blood transfusions and bone marrow transplants) that can result in survival into one’s fifties, there is no mechanism-based therapy for this disease. Thus the identification of the causative mutation of SCD has not led to any treatments.

The reason why discovery and development of drugs for SCD has been so very difficult is that the mutation that causes this disease affects an intracellular protein, hemoglobin, which is neither a receptor nor an enzyme. Unlike secreted proteins such as insulin, it is not possible to develop protein drugs to replace missing or defective hemoglobin. It is also not possible to replace the missing function of normal hemoglobin by treatment with a small molecule drug.

Diseases such as SCD–in which the function of an essential intracellular protein is defective or missing–have often been cited as candidates for gene therapy.

However, as we discussed in our October 11, 2012 and our November 8, 2012 Biopharmconsortium Blog articles, it is only this past fall that the first gene therapy was approved for marketing in a regulated market. As we discussed in the first of these articles, gene therapy has a history going back to at least the early 1970s. However, gene therapy has displayed the characteristics of a premature technology. Several notable failures, including some that caused the deaths of patients, put a severe damper on the gene therapy field. Only recently–between around 2003 and 2012–have researchers been developing more advanced gene therapy technologies and conducting clinical studies, with some success. Entrepreneurs have also been building gene therapy specialty companies to commercialize this research.

As also we discussed in our October 11, 2012 article, among the many companies that are developing gene therapies, bluebird bio (Cambridge, MA) has been singled our for special attention lately. Among the diseases being targeted by bluebird bio are SCD, and beta-thalassemias, which are also genetic diseases that affect hemoglobin. bluebird bio is in Phase 1/2 trials for its beta-thalassemia therapy, and in Phase 1 for its SCD program.

Cystic fibrosis

CF causes a number of symptoms, which affect the skin, the lungs and sinuses, and the digestive, endocrine, and reproductive systems. Notably, people with CF accumulate thick, sticky mucus in the lungs, resulting in clogging of the airways due to mucus build-up. This leads to inflammation and bacterial infections. Ultimately, lung transplantation is often necessary as the disease worsens. With proper management, patients can live into their late 30s or 40s.

The affected gene in CF and the most common mutation that causes the disease (called ΔF508 or F508del) were identified by Francis S Collins, M.D., Ph.D. (then at the Howard Hughes Medical Institute and Departments of Internal Medicine and Human Genetics, University of Michigan, Ann Arbor, MI) and his colleagues in 1989. Dr. Collins was subsequently the leader of the publicly-funded Human Genome Project and is now the Director of the U.S. National Institutes of Health, Bethesda, MD.

The gene that is affected in cystic fibrosis encodes a protein known as the cystic fibrosis transmembrane conductance regulator (CFTR).  CFTR 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; one in 2000–3000 newborns in the European Union is found to be affected by 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.

In the case of CF, the affected protein, CFTR, is an ion channel–specifically a chloride channel.

Ion channels constitute an important class of drug targets, which are targeted by numerous currently marketed drugs, e.g., calcium channel blockers such as amlodipine (Pfizer’s Norvasc; generics) and diltiazem (Valeant’s Cardizem; generics). These compounds were mainly 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, mainly because of the difficulty in developing assays suitable for drug screening. In addition, development of suitable assays for assaying chloride channel function has lagged behind the development of assays for the function of cation channels (e.g., sodium and calcium channels).

Moreover the most common CFTR mutation that causes CF, ΔF508, results in defective cellular processing, and the mutant CTFR protein is retained in the endoplasmic reticulum. In the case of some other mutant forms of CTFR (accounting for perhaps 5% of CF patients), the mutant proteins reach the cell membrane, but are ineffective in chloride-channel function.

Given these difficulties, researchers first attempted to develop gene therapies for CF. Genzyme (a Sanofi company since 2011) has been a leader in developing gene therapy for CF, and has been conducting research in this area since the 1990s. However, as with most gene therapies, development of treatments capable of reaching the market has been elusive.

Genzyme is still researching gene therapies for CF, as are others. An academic group in the U.K., known as the U.K. Cystic Fibrosis Gene Therapy Consortium is working to develop CF gene therapies, using Genzyme’s nonviral cationic lipid vector GL67 (Genzyme lipid 67) as the delivery vehicle. GL67 is the current “gold-standard” for in vivo lung gene transfer. Recently, the Consortium received funding from the U.K. Medical Research Council and National Institute of Health Research to continue its Phase 2B trial of its CF gene therapy product,GL67A/pGM169. This is a combination of GL67 and plasmid DNA expressing CFTR (pGM169).

Very recently, R&D on disease-modifying small-molecule drugs for CF has begun to bear fruit. In January 2012, the FDA approved the first such drug, ivacaftor (Vertex’ Kalydeco.) In July 2012, Vertex received European approval for this drug. Ivacaftor only works in patients with the G551D  (Gly551Asp) mutation in CFTR, which only accounts for around 4% of CF patients. Vertex and other companies–including Genzyme–are working on development of other small-molecule disease-modifying drugs with the potential to treat greater numbers of CF patients.

We shall discuss the new wave of disease-modifying CF drugs, including ivacaftor, in a later post on this blog.

Conclusions

SCD and CF are two examples of cases in which the identification of the genetic or molecular cause of a disease did not directly lead to new treatments. In the case of SCD, even though over 55 years have elapsed since the identification of the genetic cause of the disease, no therapy had yet emerged from this discovery. In the case of CF, it took over two decades from the identification of the molecular cause of the disease to the approval of the first disease-modifying drug.

Many other cases in which molecular targets involved in disease have been identified also lack disease-modifying treatments because the targets are “undruggable”. This especially applies to protein-protein interactions (PPIs). However, PPIs have assumed increasing strategic importance in drug discovery and development in recent years, and researchers and companies have been developing new technologies and strategies to discover  developable drugs that address PPIs.

Back in the early 2000s, researchers and commentators hailed the sequencing of the human genome as heralding a new era in drug discovery and development. However, the “industrialized biology” approach that grew out of the genomics of that era gave very few successes in terms of drug development. Now–a decade later–we have next-generation sequencing and  are approaching the “$1000 genome.” Once again, at least some commentators are expecting immediate breakthroughs in therapeutic development to come out of these breakthroughs in sequencing technology. Others, such as CFTR gene discoverer Francis Collins, believe that we can “speed the development of genetic advances into treatments” by more rapidly weeding out “what turn out to be..nonviable compounds.”

However, in the case of CF there were barriers to drug discovery, such as limited understanding of disease biology and difficulties in assay development, that were the true causes of lack of progress in developing disease-modifying genes. Moreover, once they had good assays, researchers needed to come up with effective strategies to develop small-molecule drugs for CF. In the case of SCD, because of the nature of the target, only gene therapy–with its manifold difficulties–had any hope of addressing the disease. In the case of PPIs, there was the need to discover new breakthrough strategies to address these “undruggable” targets.

Thus, despite breakthroughs in sequencing technologies, determining of disease-related sequences is likely to only be the first step in effective discovery of disease-modifying drugs. And there may continue to be a considerable time lag between sequence determination and drug development.

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