Keeping Tabs On Gene Therapy? Big Pharma Is Closing In

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

Some good news for Big Pharma in recent weeks was GSK’s filing with the European Medicines Agency for approval of its gene therapy for ADA Severe Combined Immune Deficiency (ADA-SCID), also known as “bubble boy disease.” This treatment is the fruit of a collaboration the company formed with Fondazione Telethon and Fondazione San Raffaele in 2010 (TIGET) to uncover new gene therapies for rare genetic disorders. Though the treatment is for a very small patient population — 350 children worldwide — this therapy, should it win approval from the EMA, could be a more effective alternative to the expensive and tricky standard-of-care, bovine enzyme replacement therapy.

If you don’t count the partnerships springing up in this space as of late, GSK’s latest news is the biggest step Big Pharma has taken toward approving a gene therapy since 2012 when the Netherlands-based biotech UniQure won approval for Glybera, its lipoprotein lipase deficiency (LPLD) therapy. Glybera is the only approved gene therapy in the West, according to PM Live, though it followed in the footsteps of Gendicine, created by Shenzhen SiBiono GeneTech, which was approved in China in 2004.

Big Pharma is venturing more boldly into gene therapy these days after more than a decade of being haunted by a past failure in which a young patient died after receiving gene therapy treatment in 1999. The approval of Glybera in 2012 was a big win for the therapeutic area, and, given the number of big players entering into gene therapy collaborations these days, it would seem the space is encountering a renaissance.

Indeed, at the CALBIO conference in March, experts said gene therapy was in the “second honeymoon” phase. According to Edward Lanphier, CEO of Sangamo BioSciences, “The regulatory environment for gene therapy has definitely improved. It’s more defined. It’s more informed. Now we are hitting a physical facilities/infrastructure roadblock versus a technical roadblock.” The solution to the manufacturing infrastructure roadblock, said one expert, is garnering the appropriate amount of funding for the indication.  

However, given payer drug pricing concerns shaking the industry, these treatments, which are rumored to potentially cost upwards of $1 million in the future, might see a short honeymoon period. In November 2014, UniQure slapped a $1.4 million price tag on Glybera. Granted, the treatment is only indicated for the 150 to 200 LPLD patients throughout Europe and, according to Reuters, would likely have a small impact on healthcare budgets despite the high price. But the real concern here is the fact that drug makers are paying close attention to the prices of new treatments on the market and pricing their new and older meds accordingly. Glybera’s million-dollar price tag will be the reference point for any future candidates hitting the market, and, frankly, I’m betting that’s not going to go over well (or maybe at all?) given recent uprisings over cancer treatments in the realm of $100,000 and more.

Besides cost concerns, recent bad news about a high-profile gene therapy candidate emphasizes the risky nature of the gene therapy space, and indeed, of drug development in general. Most recently, Celladon announced that its Mydicar, which was the first gene therapy to receive Breakthrough Therapy Designation (BTD) from the FDA last year, performed poorly in a recent clinical trial. In the CUPID2 trial in advanced heart failure, the therapy failed to meet primary (heart failure-related hospitalizations or ambulatory treatment for worsening heart failure) and secondary endpoints (all-cause death).

But this disappointment aside, there is an impressive line-up of Big Pharma and biotech players, all of which are worth keeping your eyes on. There are upwards of 500 gene therapy candidates in development, 40 percent of which are aimed at cancer, PM Live reports. Between 1999 and 2014, $503.5 million was invested in gene therapies for brain diseases, followed by $224.8 million for blood diseases and $211.6 million for eye disorders. Given GSK’s recent news, as well as the number of big names at work in the space, we might just find it’s becoming Big Pharma’s time to shine. Some of the ongoing efforts by biotechs and Big Pharma in gene therapy include: 

• Juno Therapeutics: In a Phase 1 clinical trial, 91 percent of pediatric patients taking Juno’s JCAR017 for relapsed/refractory CD19-positive acute lymphoblastic leukemia (ALL) achieved complete remission. In even more recent news, the company launched a research collaboration with Fate Therapeutics to bolster the therapeutic potential of Juno’s T-cell immunotherapies, as well as acquired Stage Cell Therapeutics. 
• Novartis: One researcher from Novartis, in partnership with an expert from GenVec, is exploring a gene therapy treatment for patients with hearing loss, Bloomberg reported in February. These two researchers are attempting to regrow the sound-sensing hair cells within the ear that have been destroyed by excessive loud noise. A trial enrolling 45 U.S. patients received NIH approval and is currently underway, with results expected by 2017. In addition, the company made headlines at the beginning of 2015 for its deals with Intellia Therapeutics and Caribou Biosciences which will provide Novartis with CRISPR  (clustered regularly interspaced short palindromic repeats) technology to edit the genes of targeted cells and boost drug discovery efforts. Novartis is also currently in a collaboration with the University of Pennsylvania, which led to the development of CTL019 for pediatric and adult patients with r/r ALL. This treatment earned a BTD from the FDA last summer for this indication, and, in a clinical trial, led to complete remission of the disease in 36 of the 39 patients receiving the therapy.
• Sanofi: In February, Sanofi’s subsidiary Genzyme launched an $845 million partnership with Voyager to collaborate on gene therapy programs in Parkinson’s disease (VY-AADC01), Friedreich’s ataxia (VY-FXN01), and Huntington’s disease (VY-HTT01). In particular, the two are working to accelerate the Parkinson’s candidate through Phase 1, as it promises to be able to treat those who don’t respond to standard-of-care levodopa and carbidopa. Voyager, with Sanofi’s help, is also planning preclinical programs for the other candidates. 
• Spark Therapeutics: In January, the gene therapy company expanded its pipeline of inherited retinal dystrophy treatments by initiating a Phase 1/2 clinical trial of its SPK-CHM candidate for choroideremia, an inherited retinal dystrophy (IRD) affecting male children. The company’s lead candidate, SPK-RPE65, is currently in Phase 3 trials for IRDs.
• Bristol-Myers Squibb (BMS): In April, BMS signed an agreement with UniQure for the rights to UniQure’s lead heart failure candidate, S100A1. According to the agreement, BMS will also gain the rights to three other UniQure candidates in the upcoming months.
• Biogen Idec: Following in GSK’s footsteps, Biogen Idec has joined forces with Fondazione Telethon and Ospedale San Raffaele against hemophilia A and B. The partners will explore liver-targeting lentiviral gene transfer technology. This step followed the company’s decision to hire Olivier Danos as VP of its burgeoning gene therapy operation.
• Pfizer: Adding to the pool of companies exploring hemophilia gene therapy treatments, Pfizer jumped aboard with Spark Therapeutics in December 2014 to accelerate development of the AAV vector SPK-FIX and launch Phase 1/2 clinical trials this year.
• bluebird bio: In October 2014, the company launched a trial for its primary gene therapy candidate, LentiGlobin BB305, indicated for sickle cell disease. The first patient dosed was enrolled in the Phase 1/2 HGB-205 study being conducted in Paris, while a separate Phase 1 trial, HGB-206, enrolling upwards of eight sickle cell disease patients is currently underway in the U.S. LentiGlobin also recently demonstrated its ability to boost hemoglobin production in patients with beta-thalassemia major in the HGB-204 study — an indication for which the treatment recently was awarded an FDA BTD. The company has also been in a partnership with Celgene since 2013 to explore new and develop existing chimeric antigen receptor T-cell (CART) therapies in cancer.
• UniQure: In a Phase 1 dose-escalation clinical trial, the company’s AAV5-PBGD candidate for Acute Intermittent Porphyria, AMT-021, was found to be a safe method of inserting the porphobilinogen deaminase gene (PBGD) into patients liver cells.
• Bayer: Last summer, Bayer teamed up with Dimension Therapeutics to come up with a gene therapy treatment for hemophilia A.