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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