Abstract
Established in 2011, genSight said it will use the funds to develop a gene replacement therapy for Leber's hereditary optic neuropathy (LHON) and an optogenetic therapy for retinitis pigmentosa (RP). genSight expects its lead therapy, rAAV2/2_ND4, to enter the clinic in 2013 with LHON patients.
The vector—which targets the mitochondria in LHON and contains the human ND4 gene—is based on research at the Vision Institute, where genSight is located, by Marisol Corral-Debrinsky, Ph.D., now leader of a research team at Fondation Voir et Entendre, and Jose-Alain Sahel, M.D. The therapy also relies on exclusive access to key intellectual property from Novartis for using optogenetics to treat RP patients.
“Our outstanding links to leading ophthalmology physicians and scientists on both sides of the Atlantic, our strong link with the Foundation Fighting Blindness, our partnership with AFM/Genethon and our experienced management team are key to successfully moving our products through clinical developments to proof of efficacy,” genSight's cofounder and executive chairman Bernard Gilly, Ph.D., said in a statement. Genethon is a nonprofit created by the Association Contre les Myopathies to design, develop, and manufacture gene therapy products.
Joining Dr. Gilly as cofounders of genSight are Dr. Sahel, the Vision Institute's chairman; Botond Roska, M.D., Ph.D., a specialist in the structure and function of neural circuits at the Friedrich Miescher Institute (FMI) in Basel and a pioneer in optogenetics; Jean Bennett, M.D., Ph.D., the F.M. Kirby professor of ophthalmology and cell and developmental biology and a senior investigator at the University of Pennsylvania; Connie Cepko, Ph.D., principal investigator and professor of genetics at Harvard Medical School; Ernst Bamberg, professor at The Max Planck Institute; Luk Vandenberghe, Ph.D., principal investigator at the Schepens Eye Research Institute; and Serge Picaud, Ph.D., director of research at the Vision Institute.
Three representatives of investors will join genSight's board of directors—Florent Gros of Novartis Venture Fund; Genghis Lloyd-Harris, Ph.D., a partner at Abingworth; and Guido Magni, M.D., Ph.D., a venture partner at Versant.
“The emergence of tumor cells that no longer contain the target protein suggests that in particular patients with high-risk ALL, we may need to broaden the treatment to include additional T cells that may go after additional targets,” the case report's co-first author Stephan A. Grupp, M.D., Ph.D., said in a statement. Dr. Grupp is director of translational research for the Center for Childhood Cancer Research at CHOP and a pediatrics professor at the Perelman School of Medicine at the University of Pennsylvania. “However, the initial results with this immune-based approach are encouraging, and may later even be developed into treatments for other types of cancer,” Dr. Grupp added.
Researchers removed some of each patient's T cells, transduced them with anti-CD19 antibody and a T-cell signaling molecule, then infused the resulting CTL019 cells into their patients' bodies, where they multiplied and circulated throughout the body. While the CTL019 cells eliminated leukemia, they also generated a cytokine release syndrome that proved especially severe in the 7-year-old, requiring her doctors to blunt the immune overresponse while still preserving the modified T cells' anti-leukemia activity.
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Dr. Grupp has maintained an ongoing collaboration with the Penn Medicine scientists who developed the modified T cells. The Penn team used the therapy in three adult chronic lymphocytic leukemia (CLL) patients in August of 2011. Two have remained in remission more than 2.5 years following their treatment, while seven out of ten adult patients had responded as of December.
In another study (Brentjens et al., 2013), an experimental cell therapy that manipulated the immune system to treat the normally deadly recurrent B-cell ALL showed success in Phase I of an ongoing clinical trial. By genetically modifying a patient's lymphocytes to attack the tumor cells causing ALL, researchers killed those cells in all five patients studied, enabling their cancers to go into rapid and complete remission, according to the study published in Science Translational Medicine.
All five patients underwent the cell therapy following the failure of chemotherapy. Four of the five patients received an additional bone marrow transplant. Of those, three have remained in remission for between 5 and 24 months. A fourth died while in remission, 2 months after the transplant, from complications unrelated to the cancer therapy. The fifth, who was ineligible for the transplant because of health risks, died after relapsing.
Yet, those results offered dramatic improvements from what researchers in the study said were the usual dismal prognosis of patients with ALL. Nearly 6,100 people will be diagnosed with ALL this year, of which more than 1,400 are expected to die, according to figures from the National Cancer Institute. Current treatments can cure an estimated 80–90%.
“This is a very exciting finding for patients with B-cell ALL, and a major achievement in the field of targeted immunotherapy,” Michel Sadelain, M.D., Ph.D., director of the Center for Cell Engineering at Memorial Sloan-Kettering Cancer Center, said in a statement. Dr. Sadelain led the study along with Renier J. Brentjens, M.D., Ph.D., a medical oncologist specializing in the treatment of acute and chronic leukemias at Memorial Sloan-Kettering, and the study's corresponding author.
All but one of the study's 25 coauthors were from Memorial Sloan-Kettering. Lindsay G. Cowell, Ph.D., is based at University of Texas Southwestern Medical Center in Dallas. The team is now pursuing a larger trial of more than 50 patients toward further study of the effects of the experimental treatment.
A stability of improvement in visual and retinal function was achieved following months after treatment of gene therapy, with maximum improvement achieved within 6 months after treatment at The Children's Hospital of Philadelphia in conjunction with Italy's Seconda Universita degli Studi di Napoli (Second University of Naples), and visual improvement stable through the last observed time, the team added.
In a study published March 20 in Opthalmology 2013 (Testa et al., 2013), the team, led by Francesca Simonelli, M.D., of Second University of Naples, detailed the results of a 3-year follow-up study of the LCA2 gene therapy clinical trial. Patients showed improvement in best-corrected visual acuity (BCVA) as well as in kinetic visual field, which remained stable in all patients through three years after their injection. Also remaining stable during that period was the ability of patients to navigate an obstacle course. However, the percentage of pupillary constriction of treated eyes versus untreated eyes showed a statistically significant difference persisting during the 3 years.
“The visual function improvements, achieved within a few months after a single unilateral injection, remained stable up to three years after the treatment in all the patients independent of age, vector dose, surgical procedure, and baseline retinal status,” the team concluded, adding that the surgical procedure “yielded no clinically significant damage to macular photoreceptors up to 3 years after treatment.”
The team noted several limitations to their results: Their study design did not involve randomization of eyes. An inherent imbalance exists between eyes since the injected eyes by definition had worse vision. And examiners and patients knew which eyes were control eyes and which were study eyes.
The study also suggested for future studies the inclusion of multifocus electroretinography (ERG) and microperimetry as sensitive secondary clinical tests for assessing gene therapy efficacy for ocular disease in particular LCA patients.
Researchers focused on camptodactyly-arthropathy-coxa vara-perricardituis syndrome, a genetic disorder in children characterized by a deficiency in PRG4. In results published in Science Translational Medicine (Ruan et al., 2013), the team led by Brendan H. L. Lee, M.D., Ph.D., professor of molecular and human genetics at Baylor College of Medicine, used gene therapy to inject PRG4 once into the joints of mice through an engineered adenovirus, after first studying mice that produced higher levels of the protein in cartilage in a more traditional mouse transgenic model. At first, those mice acted and grew normally, suggesting that increased amounts of the protein were not harmful. Even when those mice developed knee injuries, they did not develop traumatic or injury-induced OA.
Using phase contrast ultra–high resolution microcomputed tomography (micro-CT), an imaging technique developed by Merry Z. C. Ruan, a graduate student in Dr. Lee's lab, the team determined that the mice did not have cartilage changes typically associated with OA. As the mice that made extra lubricin aged, their cartilage resembled that of young mice, without the disease—suggesting the protein may protect against both injury- and age-related OA.
In finding that PRG4 affects the metabolism of the cartilage by preventing its breakdown, the researchers elevated the importance of PRG4 well beyond its traditionally understood role of acting as a lubricant between bones in a joint. “The lubricin protein was expressed for the life of the mouse after a single injection into the joint,” Dr. Lee said in a statement.
Dr. Lee said he and colleagues next plan to test the gene therapy in large animals, such as horses, that suffer from forms of OA similar to those in humans. If the therapy proves successful in horses, it would then be tested in humans, with the eventual goal of treating OA that develops after sports- or work-related injuries.
In addition, bluebird bio will receive an undisclosed upfront payment and up to $225 million per product in potential option fees and payments tied to clinical and regulatory milestones. Also, bluebird bio has the right to participate in development and commercialization of any licensed products resulting from the collaboration through a 50/50 codevelopment and profit share in the United States, in return for reduced milestone payments. Royalties would also be paid in regions where there is no profit share, including in the United States, if bluebird bio declines to exercise its codevelopment and profit-sharing rights.
Celgene has an option to license any products from the collaboration after completion of a Phase I clinical study for each such product; bluebird bio will be responsible for research activity through Phase I studies.
“We believe that our recent advances in the industrialization of our gene therapy platform will drive improvements in the potency, purity, efficiency, and scalability of our lentiviral gene therapy programs. These advances provide us with an opportunity to apply our platform, intellectual property, and know-how to the development of additional product candidates in indications such as CAR T cells for cancer,” Nick Leschly, bluebird bio's president and CEO, said in a statement.
Separately, Celgene entered into a strategic collaboration in the CAR T-cell field with the Center for Cell and Gene Therapy at Baylor College of Medicine (BCM), Texas Children's Hospital, and The Methodist Hospital in Houston. The collaboration will be led by Malcolm Brenner, M.D., Ph.D., director of BCM's Center for Cell and Gene Therapy and a professor in the medical college's Department of Molecular and Human Genetics. Dr. Brenner's team will work with Celgene and bluebird bio to advance and develop existing and new CAR T-cell products and programs.
“The genetic manipulation of autologous T-cells is a new frontier in oncology, one that shows early promise in emerging clinical trials,” said Tom Daniel, president, research & early development at Celgene.
“RNAi therapeutics hold great promise for the treatment of ATTR since they have demonstrated rapid, potent, and durable knockdown of TTR, the disease-causing protein,” said Akshay Vaishnaw, M.D., Ph.D., Alnylam's executive vice president and CMO.
The Phase I trial is being conducted in the United Kingdom as a randomized, double-blind, placebo-controlled, single- and multidose dose-escalation study, enrolling up to 40 healthy volunteer subjects. The primary objective is to evaluate the safety and tolerability of single and multiple doses of subcutaneously administered ALN-TTRsc. Secondary objectives include assessment of clinical activity of the drug as measured by serum TTR levels. Alnylam expects to present data from this trial later this year.
Upon completion of the Phase I trial, Alnylam plans to start a Phase II clinical study of ALN-TTRsc in FAC patients by year's end. Should that trial also yield positive results, the company expects to start a pivotal trial for ALN-TTRsc in FAC patients in 2014.
Preclinical studies have shown that injection of ALN-TTRsc resulted in potent and sustained suppression of TTR. In nonhuman primates, ALN-TTRsc administration resulted in an approximately 80% reduction of TTR at doses as low as 2.5 mg/kg.
In single- and multidose preclinical safety studies in rodents and nonhuman primates, ALN-TTRsc was found to be generally safe and well tolerated. Specifically, at doses as high as 300 mg/kg in nonhuman primates, ALN-TTRsc was well tolerated with no clinical signs, no adverse laboratory or histopathologic findings, no elevations in cytokines or complement, and no significant injection-site reactions.
Last October, Alnylam and Sanofi's Genzyme subsidiary entered into an exclusive alliance to develop and commercialize RNAi therapeutics, including ALN-TTRsc for ATTR, in Japan and the broader Asian-Pacific region. Alnylam plans to develop and commercialize the ALN-TTR program in the United States and the rest of the world.
The company's ATTR effort also includes ALN-TTR02 for familial amyloidotic polyneuropathy (FAP), which is now enrolling patients in a Phase II trial. Alnylam's pipeline includes ALN-AT3 for hemophilia and rare bleeding disorders, ALN-AS1 for acute intermittent porphyria, ALN-PCS for hypercholesterolemia, and ALN-TMP for hemoglobinopathies.
The company expects to have five RNAi therapeutic products for genetically defined diseases in clinical development, on its own or with a partner, by the end of 2015 through its “Alnylam 5x15TM” strategy. Alnylam has additional partnered programs in clinical or developmental stages, including ALN-RSV01 for respiratory syncytial virus (RSV) infection and ALN-VSP for liver cancers.