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.

_____________________________________________________________________________________________________

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.

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.

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.

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.