20 March 2019

Gene therapy company buyouts are making the news

By |2019-04-16T21:56:50+00:00March 20, 2019|Business, Drug Development, Eye Diseases, Gene Therapy, Hemophilia, Personalized Medicine, Rare Diseases, Strategy and Consulting|

Adeno-associated virus. Source: https://commons.wikimedia.org/wiki/File:Adeno-associated_virus_serotype_AAV2.jpg

In recent weeks, buyouts of gene therapy companies by Big Pharmas or Big Biotechs—as well as other major gene therapy deals—have been making the news. Specifically, on February 25, 2019, leading gene therapy company Spark Therapeutics (Philadelphia, PA) announced that it had entered into a merger agreement with Roche. Under this agreement, Roche will fully acquire Spark for $4.3 billion.

Roche will keep Spark as a independent entity, similar to Roche’s Genentech. This should enable the type of innovation that has been demonstrated by Spark since its founding in 2013.

Meanwhile, Biogen is buying gene therapy company Nightstar Therapeutics (London, UK) for $800 million in order to gain access to its suite of gene therapies for rare retinal diseases. According to “Endpoints News”, the Biogen/Nightstar deal is the result of a bidding war for Nighrstar by Biogen and three other (unnamed) companies.

And Johnson & Johnson has signed a deal with MeiraGTX (London and New York) for rights to its experimental gene therapies for rare retinal diseases. The two companies also will collaborate on improving gene therapy manufacturing. J&J paid Meira $100 million in cash upfront, and Meira could get up to $340 million in additional downstream payments plus royalties on sales if its products reach the market. J&J will be paying for clinical development of the therapies.

Our previous discussions of Spark and Nightstar

We discussed Spark and Nightstar and their gene therapy programs in our 2015 book-length report, Gene Therapy: Moving Toward Commercialization. We also updated our discussion of Spark’s lead ophthalmological gene therapy product Luxturna (voretigene neparvovec-rzyl) (formerly known as SPK-RPE65), in our December 21, 2017 article on this blog.

As we discussed in these publications, Spark’s Luxturna is a one-time gene therapy designed to treat patients with an inherited retinal disease (IRD) caused by mutations in both copies of the RPE65 (retinal pigment epithelium-specific 65 kDa protein) gene. It consists of a version of the human RPE65 gene delivered via an adeno-associated virus 2 (AAV2) viral vector, and is administered via subretinal injection. Luxturna is the first FDA-approved gene therapy for a genetic disease, the first FDA-approved pharmacologic treatment for an IRD, and the first AAV-vector gene therapy approved in the USA.

Nightstar is clinical stage company whose initial focus is treatment of the IRD choroideremia (CHM). CHM is an X-linked genetic disease caused by mutations in the X-CHM gene. These mutations interfere with the production of Rab escort protein-1 (REP1). REP1 is involved in intracellular protein trafficking, and the elimination of waste products from retinal cells.

Nightstar’s lead product is NSR-REP1 (formerly known as AAV2-REP1). This gene therapy consists of an AAV2 vector containing recombinant human complementary DNA, (cDNA), that is designed to produce REP1 inside the eye. NSR-REP1 is currently in a Phase 3 registrational clinical trial, known as the STAR trial. It is thus the most clinically advanced candidate for choroideremia in the world.

In addition to discussing gene therapies under development (including the above-mentioned Spark and Nightstar programs, as well as many others), our 2015 gene therapy report also discusses development and use of gene therapy vectors, especially AAV. It thus continues to be a valuable reference for understanding the gene therapy field.

MeiraGTX

MeiraGTX focuses on AAV-based gene therapies. Its five programs in clinical development include three ophthalmological therapies, as well as gene therapies for a salivary gland condition, and for Parkinson’s disease. The company’s most advanced programs are in Phase 1/2 clinical development, and include treatments for achromatopsia and X-linked retinitis pigmentosa.

Spark is also developing gene therapies for hemophilia

As discussed in a February 23, 2019 “Endpoints News” article on the Roche/Spark merger, Roche’s interest in Spark is not only because of its leadership position in ophthalmological gene therapies, but also because of its broad product portfolio. Notably, among Spark’s product candidates is SPK-8011, one of the leading clinical-stage gene therapies for hemophilia A. SPK-8011 is a novel AAV vector containing a codon-optimized human factor VIII gene under the control of a liver-specific promoter. As the result of promising Phase 2 data, SPK-8011 is now in a lead-in study (NCT03876301) for phase 3 clinical trials. Also in a lead-in study for Phase 3 trials (sponsored by Spark’s partner for this therapy, Pfizer) is Spark’s hemophilia B candidate, fidanacogene elaparvovec (SPK-9001).

The hemophilia gene therapy field is highly competitive. Other companies with clinical-stage hemophilia gene therapies include BioMarin, uniQure, and Sangamo/Pfizer.

Roche’s acquisition of Spark’s SPK-8001 may enable Roche/Genentech to strengthen its leading competitive position in the hemophilia A market. Roche received FDA approval for its blockbuster prophylactic Hemlibra for hemophilia A without factor VIII inhibitors in October 2018.

Pfizer enters the gene-therapy buyout arena

In late-breaking (March 20, 2019) news, Pfizer has taken an exclusive option to acquire Vivet Therapeutics (Paris, France).

Vivet focuses on the development of gene therapies for inherited liver diseases with high unmet medical need. Under the new agreement, Pfizer has acquired 15% of Vivet’s equity, and an exclusive option to acquire all outstanding shares. Initially, the two companies will collaborate on the development of Vivet’s VTX-801, a preclinical-stage gene therapy for Wilson disease.

Wilson disease is a rare and potentially life-threatening liver disorder involving impaired copper transport, resulting in severe copper poisoning. The Wilson’s disease mutation disables the excretion pathway for copper via the bile. This results in excess copper accumulation in the liver and other organs, including the central nervous system. Untreated, Wilson disease results in severe copper toxicity, which can be fatal. It can only be cured by liver transplantation. Existing therapies for Wilson disease are of low efficacy and/or result in significant side effects.

VTX-801, like other therapies discussed in this article, is an AAV-based gene therapy. It is Vivet’s first gene therapy, and the most advanced in development.

Under the terms of the agreement, Pfizer paid approximately €45 million (US$51 million) upon signing and may pay up to €560 million (US$635.8 million) in milestone payments. Pfizer also has an option to acquire 100% of Vivet, based on the results of a Phase 1/2 clinical trial for VTX-801. Pfizer senior executive Monika Vnuk, M.D., Vice President, Worldwide Business Development, is also joining Vivet’s Board of Directors.

Vivet’s earlier-stage preclinical liver-directed gene therapies include a program for progressive familial intrahepatic cholestasis (PFIC) for bile excretion defects and in citrullinemia for defects in the urea cycle.

The Pfizer/Vivet agreement is yet another example of the recent Large Pharma/Biotech enthusiasm for buying up small gene-therapy companies.

Concerns about cost and patient selection for “one and done” gene therapies

As we discussed in our December 21, 2017 article on this blog, Luxturna, as the first FDA-approved gene therapy for an inherited disease, is expected to be a one-time (“one and done”) therapy for its targeted condition. It is expensive, priced at $850,000 ($425,000 per eye affected by an RPE65 gene mutation). This made Luxturna the highest priced therapy in the U.S. to date. Other “one and done” gene therapies are also expected to be expensive. Pricing and related issues with “one and done” gene therapies thus affect the prospects for gene therapy companies and for larger companies that are planning to acquire or partner with them.

In our December 21, 2017 article, we discussed payer programs designed to enable patient access to treatment with Luxturna. These include an outcomes-based rebate plan with a long-term durability measure, and a proposal under which payments for Luxturna would be made over time. Such programs are designed to reduce risk and financial burden for payers and treatment centers. As we discussed, pricing and payer programs that become established for Luxturna may have a wide impact on the entire gene therapy field.

A March 5, 2019 article on gene therapy by Jeremy Schafer, PharmD, MBA of Precision for Value was published in Clinical Leader. This article focused on designing gene therapy clinical trials to meet the concerns of payers and health systems.

At the recent annual meeting of the Academy of Managed Care Pharmacy, the results of a survey that included the perceptions of gene therapy among health plans and health system stakeholders were presented. Among these respondents, 35% stated that their primary concern with gene therapy was “selecting appropriate patients.” Another 30% named “the potential need for retreatment” as their main concern. The major concern of 5% of respondents was that patients treated with gene therapy would still need conventional treatment for their condition. A total of 88 percent of respondents felt that information on appropriate patient selection as well as durability of response would be extremely valuable. Another 60 percent would like to have an economic model on the long-term value of the gene therapy.

Dr. Schafer’s article discussed how clinical trial design might help address these concerns. For example, gene therapy clinical trials might include a long-term follow-up plan to capture data on an ongoing basis. This might help address the question as to whether a gene therapy is truly “one and done”. Ongoing data from these trials might be shared in peer-reviewed publications. The long-term data might be used in economic models by health plans.

In terms of identifying appropriate patients for gene therapies, clinical trial design might include clearly-defined inclusion and exclusion criteria, based on good scientific rationales. Preplanned subgroup analyses might show which groups respond well or not so well to a gene therapy. Clinical trials could also be designed to determine whether and to what extent gene-therapy patients will still need ongoing therapy with conventional drugs.

All these issues in structuring payer programs and in clinical trials designed to meet the concerns of payers and health plans (and of partner and acquiring companies) may enable the development and acceptance of gene therapies as this field moves beyond the release of the first few 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.

21 December 2017

FDA approves Spark Therapeutics’ retinal disease gene therapy Luxturna, a month ahead of schedule

By |2018-09-12T21:33:46+00:00December 21, 2017|Drug Development, Eye Diseases, Gene Therapy, Haberman Associates, Personalized Medicine, Rare Diseases, Recent News|

Interface of retinal pigment epithelium and photoreceptor cells. Source: NIH Open-i

 

As we discussed in our December 17, 2015 article on this blog, Spark Therapeutics’ (Philadelphia, PA) SPK-RPE65 had achieved positive Phase 3 results at that time. It was expected to reach the U.S. market in 2017.

As announced by Spark in a press release, SPK-RPE65, now known as Luxturna (voretigene neparvovec-rzyl), was approved by the FDA on Dec. 19, 2017. This was ahead of the FDA’s PDUFA date for the therapy (i.e., the deadline for action by the FDA) in mid-January 2018.

Luxturna is a one-time gene therapy designed to treat patients with an inherited retinal disease (IRD) caused by mutations in both copies of the RPE65 (retinal pigment epithelium-specific 65 kDa protein) gene who have sufficient viable retinal cells as determined by their treating physicians. Luxturna consists of a version of the human RPE65 gene delivered via an adeno-associated virus 2 (AAV2) viral vector. It is administered via subretinal injection.

As outlined in the Spark December 19, 2017 press release, Luxturna is first FDA-approved gene therapy for a genetic disease, the first FDA-approved pharmacologic treatment for an inherited retinal disease (IRD), and first adeno-associated virus (AAV) vector gene therapy approved in the United States. However, two gene therapies, uniQure/Chiesi’s Glybera (alipogene tiparvovec) (an expensive money-losing therapy that has only been used once) and GlaxoSmithKline’s Strimvelis, were approved in Europe prior to the FDA approval of Luxturna. Moreover, the CAR-T (chimeric antigen receptor  T-cell) cellular immunotherapies Kymriah (tisagenlecleucel) (Novartis) and Yescarta (axicabtagene ciloleucel) (Gilead/Kite), which are ex vivo gene therapies, were approved in 2017—prior to the approval of Luxturna. Thus although Luxturna is a pioneering gene therapy that represents a number of “firsts”, it is only one of several of the first gene therapies that have reached regulatory approval in recent years.

Pricing and patient access issues with Luxturna

On January 3, 2018, Spark announced that it has set an $850,000 wholesale acquisition cost for Luxturna — $425,000 per eye affected by an RPE65 gene mutation. This makes Luxturna—which is intended as a one-time treatment—the highest priced therapy in the U.S. to date. Some 2,000 patients (fewer than 20 new patients per year) may be eligible for treatment with Luxturna, provided that Spark can persuade payers to cover the treatment.

Also on January 3, 2018, Spark announced a set of three payer programs designed to enable patient access to treatment with Luxturna. These include “an outcomes-based rebate arrangement with a long-term durability measure, an innovative contracting model and a proposal to CMS [The Centers for Medicare & Medicaid Services] under which payments for Luxturna would be made over time.” Spark has reached agreement in principle with Harvard Pilgrim Health Care to make Luxturna available under the outcomes-based rebate program, and under the contracting model that is designed to reduce risk and financial burden for payers and treatment centers. Spark has also reached an agreement in principle with affiliates of Express Scripts to adopt the innovative contracting model.

Spark’s proposal to CMS is based on enabling the company to offer payers the option to spread payment over multiple years, as well as greater rebates tied to clinical outcomes.

As pointed out by John Carroll of Endpoints News, pricing and payer programs that become established for Luxturna may have a wide impact on the whole gene therapy field, in particular gene therapies for hemophilia. As we discussed in our February 2, 2016 blog article, several companies—including Spark—are developing one-time gene therapies for hemophilias A and B. Hemophilia could prove to be the most competitive area of gene therapy in the near future.

Our gene therapy report

Our book-length report, Gene Therapy: Moving Toward Commercialization, contains extensive information on the development of improved gene therapy vectors (especially including AAV vectors). It also contains detailed information on SPK-RPE65/Luxturna and its mechanism of action, as well as on other gene therapies in clinical development (such as those for hemophilia). In addition, it contains information on leading gene therapy companies including Spark. It is an invaluable resource for understanding clinical development of gene therapies, and the academic groups and companies that are carrying out this development.

To order our report, Gene Therapy: Moving Toward Commercialization, please go to the Insight Pharma Reports website.

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

7 December 2017

”Improving Candidate Selection: Translating Molecules into Medicines.”

By |2018-12-28T23:31:34+00:00December 7, 2017|Cancer, Drug Development, Drug Discovery, Gene Therapy, Haberman Associates, Immunology, Monoclonal Antibodies, Oligonucleotide Therapeutics, Recent News, RNAi, Strategy and Consulting|

Bromodomain. A chromatin “reader” that is a target of PPI drug development. Source: WillowW at the English language Wikipedia.

 

Allan B. Haberman, Ph.D. was one of about 25 experts from pharmaceutical, biotechnology, and consulting firms who attended Aptuit’s  one-day think-tank event, ”Improving Candidate Selection: Translating Molecules into Medicines”. This was the third and final such networking and discussion symposium, which was held in downtown Boston, on December 4, 2017. The previous two events in this series had been held in San Francisco (18th & 19th Sept 2017) and in Hertfordshire, UK (22nd & 23rd Oct 2017). The Boston discussion session was preceded by a relaxed networking dinner on the evening of the 3rd.

Attendees and presenters at the Boston meeting were from Shire, Celgene, Forma Therapeutics, Roche, Amgen, Novartis, the Broad Institute, Warp Drive Bio, Mass General Hospital, EnBiotix, Yumanity, and Ra Pharma—among others—as well as from Aptuit and its parent company Evotec.

The focus of the meeting was on improving drug candidate selection in order to improve development success. Only about 10% of drug candidates make their way from first-in-humans trials to regulatory approval. The greatest amount of attrition occurs in Phase 2. Approximately half of candidates fail at that stage, mainly due to lack of efficacy.

One of the key issues discussed in the symposium was the role of the Lipinski Rule of Five—a set of physico-chemical properties that determine the “drug-likeness” of a clinical candidate; i.e., whether a compound is likely to be an orally active drug in humans. Some participants stated that these guidelines had been interpreted too rigidly, and have excluded many potentially good drugs from further development. They stated that the Lipinski rules are only guidelines, and do not replace thinking. (For a similar point of view, see Paul Leeson’s 2012 News and Views article in Nature.) For example, researchers should measure physical properties empirically, rather than inferring them.

The Lipinski rules also exclude whole classes of drug candidates—such as natural products and macrocyclic compounds—from consideration. Before the era of combinatorial chemistry and high-throughput screening, natural products were the mainstay of drug discovery and development.

The Haberman Associates website contains reports, articles, and links to reports that are useful in understanding the issues discussed in the Aptuit symposia. Links to most of these publications can be found on our Publications page. Notably, there is a 2009 report entitled Approaches to Reducing Phase II Attrition, which is available from Insight Pharma Reports. There is also a 2009 article (available on our website at no cost) based on that report, entitled “Overcoming Phase II Attrition Problem.”

Drug attrition numbers have not changed since our 2009 publications. However even back in 2009, pharmaceutical company researchers attributed high attrition rates due to lack of efficacy to companies’ addressing more complex diseases, with the need to discover and develop drugs that have novel mechanisms of action and/or address unprecedented targets. At the December 4 Aptiut symposium, participants similarly attributed high attrition rates to researchers’ tackling new classes of drugs. These included drug classes whose development involves working with premature technologies—e.g., protein-protein interactions (PPIs), gene therapy, RNAi, CAR-T therapies, cancer vaccines, , and combination immuno-oncology therapies.

Working on development of drugs based on premature technologies involves development of enabling technologies that will allow researchers to “move up the technology development curve” and thus to achieve increasing success in drug development. R&D in some of these fields—notably development of checkpoint inhibitors for use in immuno-oncology—has been moving up the technology curve, resulting in notable successes.

Although attrition rates have not changed since 2009, drug developers have been working with increasingly newer classes of drugs. Attrition thus continues to be a moving target.

Among the publications available on our website is our 2012 report—Advances in the Discovery of Protein-Protein Interaction Modulators. As the result of corporate restructuring, this report has not be available anywhere in recent years. However, with the permission of the publisher, Datamonitor Healthcare (a division of Informa), we are now hosting it on our website.

Aptuit’s “Translating molecules into medicines” symposia and improving drug discovery and development

The purpose of Aptuit’s symposia was “to discuss and learn from the experiences of those involved in working at the interface of discovery and development. These meetings were designed to give attendees the chance to build meaningful relationships, challenge their understanding of certain subjects and learn from leading members of their peer group in a non-commercialized setting.”

The organizers of the symposia ask whether “having the flexibility to think beyond established rules and adopting more collaborative development strategies will be just as important as the innovative science and technologies for drug discovery and development.” We at Haberman Associates look forward to assisting you in your efforts to move your drug discovery and development programs forward.

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.

21 April 2016

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

By |2018-09-12T21:33:49+00:00April 21, 2016|Cancer, Drug Development, Eye Diseases, Gene Therapy, Immunology, Personalized Medicine, Rare Diseases, Stem Cells|

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.

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.

2 February 2016

Gene therapy for hemophilia—an update

By |2018-12-28T22:59:41+00:00February 2, 2016|Drug Development, Gene Therapy, Rare Diseases|

photo of 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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