As the news emerged of Richmond, CA-based Sangamo Biosciences’s progress toward a gene therapy treatment for HIV infection, the media buzzed and investors boosted the company’s share price by 17 percent Thursday.
For the first time, Sangamo (NASDAQ: SGMO) had tried its gene-editing platform on human subjects, and it found encouraging signs in small early stage trials that the treatment could be adapted to push down the population of HIV virus to low or even undetectable levels.
The grabber in the story is that such a treatment might someday allow HIV-infected patients to stop taking antiviral drugs daily for the rest of their lives—eliminating both side effects and a big expense for the healthcare system.
So it’s natural to wonder how such developments would affect the companies taking in billions of dollars a year from sales of those HIV drugs.
The improved prospects for an HIV “functional cure” might have led some investors to turn around and shed shares in Foster City, CA-based Gilead, the world’s largest maker of HIV drugs, whose share price dropped more than 3 percent to $79.92 on Thursday and lost a bit more ground to wrap up the week at $79.58 on Friday. Antiviral drugs made up $9.34 billion of Gilead’s $10.8 billion in product sales in 2013. Gilead’s slide coincided with an overall decline in biotech indexes. It also came amid news from a Boston HIV/AIDS conference, including data from other HIV drug developers as well as Sangamo, that may have affected trading.
But some investors who have been closely following Gilead might have seen the price dip as an opportunity to snap up more shares in the company, which is also one of the industry’s most broad-based and well-funded new developers of cancer therapies.
While Gilead has continued to nurture its HIV and antiviral franchise—in December it gained FDA approval of the new chronic hepatitis drug sofosbuvir (Sovaldi), and won expanded FDA approval of its once-daily HIV combination drug, Complera—the company has also been buying up oncology companies and assets since at least 2010. And the acquisitions are beginning to bear fruit. Gilead announced in October that a late-stage trial of one of its leading cancer compounds, idelalisib, was halted early because the drug was already showing significant efficacy as a treatment for chronic lymphocytic leukemia. Even with last week’s price dip, Gilead shares are still up more than 75 percent over the past 12 months.
Gilead’s forward-looking moves to become a diversified pharmaceutical company may insulate it from an erosion of HIV drug revenue—if and when an effective gene therapy becomes approved, and accessible. Sangamo’s promising results came from tiny, early stage trials, and the company has said it needs to refine its ZFN gene-editing treatment procedures in future studies to enhance the chance of a cure.
But Sangamo’s moment in the spotlight is one recent reminder that gene therapy is finally emerging as a viable technology that could transform the treatment of HIV, cancer, and a host of other conditions. If the method proves out, it could shoulder aside some maintenance drug therapies by attacking genetic mechanisms closer to the root causes of a range of diseases. Sangamo is trying to do this with its proprietary toolkit of zinc finger proteins for altering the sequences of targeted genes. ZFN stands for zinc finger nucleases, which are molecular tools for homing in on specific small sections of genes and clipping them out.
“Our goal is to use this powerful technology to engineer genetic cures for diseases that have thus far been treated as chronic conditions, including HIV and a wide range of monogenic diseases,” said Sangamo CEO Edward Lanphier in a company release on the first of several studies unveiled this week.
The first paper, published in the New England Journal of Medicine on Wednesday, detailed the results of Sangamo’s inaugural trial of its ZFN gene-editing platform in HIV patients. Through genetic engineering of blood cells called T-cells, Sangamo is trying to mimic the natural immunity to a common HIV strain that a few rare individuals are fortunate enough to inherit with their own genes.
To create its treatment, Sangamo disabled a gene called CCR5 in T-cells from blood samples withdrawn from 12 HIV-positive trial participants. In most people, the CCR5 gene makes the cells susceptible to HIV infection. The modified T-cells with disrupted CCR5 genes were then infused back into the trial subjects.
In such Phase I trials, the first goal is to establish that previously untested treatments are safe. Sangamo reported that its treatment, called SB-728-T, was generally well tolerated. The next step was to track the fate of the genetically modified, transplanted T-cells by exposing them to the HIV virus during a temporary interruption of antiretroviral drug treatment. Six of the trial participants suspended their HIV drug regimens. The T-cells with disabled CCR5 genes survived better than the unmodified T-cells, Sangamo announced. A key aim of current HIV drugs is to maintain T-cell population numbers at normal levels.
Sangamo also revealed later tweaks to its SB-728-T therapy in data presented at an HIV/AIDS conference on Thursday. In another small early stage trial, investigators used a preconditioning treatment before the trial participants received the infusion of their genetically modified T-cells. The pre-treatment with the drug cyclophosphamide (Cytoxan), which is typically used against cancer or autoimmune diseases, helped the modified T-cells establish themselves in the body, and also enhanced the control of viral levels once antiretroviral drug treatment was suspended in some trial subjects for several weeks, investigators found.
The much-discussed star participant in Sangamo’s trials has ceased taking HIV drugs for about seven months while maintaining undetectable counts of HIV virus. In that individual, however, one of the two original copies (or alleles) of the CCR5 gene is the rare, natural variation that makes T-cells resistant to the entry of the most common form of the HIV virus. After Sangamo’s treatment, it’s assumed, both copies of the CCR5 gene were inactive in many of that individual’s T-cells—and this may be the reason why HIV levels became undetectable.
Sangamo is now planning to alter its ZFN method of editing genes to increase the chances that it can disable both copies of the CCR5 gene in future trial participants. (Every cell in the body, except for eggs and sperm, carries two sets of genes, one set inherited from each parent.)
“To make a therapy, we’ll need to knock out both alleles,” Lanphier told me Thursday during a day of back-to-back media interviews.
While gene therapy may seem to move forward by such inches, tweaks, and increments, the wider story in the Sangamo announcements this week is the growth of a set of technologies shared among a community of scientists and companies working on genetic modifications to treat a variety of different diseases.
A senior author of the New England Journal of Medicine paper about Sangamo’s first HIV trial is Carl June, a professor of immunotherapy at the University of Pennsylvania, who also drew attention at the annual meeting of the American Society of Hematology in December with the favorable results of an experimental gene therapy treatment for two blood cancers, chronic lymphocytic leukemia and acute lymphoblastic leukemia. The Swiss drug giant Novartis (NOVN) has licensed the method, Bloomberg reported from the conference.
Sangamo itself is crossing the jurisdictional lines of disease. Its pipeline includes experimental therapies for the genetically based blood disorders beta-thalassemia and sickle cell disease; in January it announced a partnership on that work with Cambridge, MA-based Biogen Idec (NASDAQ: BIIB). Sangamo is also working on potential gene-altering treatments for hemophilia A, hemophilia B, and Huntington’s Disease in a collaboration with Shire.
“ZFN could be applied to whatever gene we want,” Lanphier says.
Sangamo also isn’t alone in its pursuit of a gene therapy for HIV. Both Sangamo and Los Angeles, CA-based Calimmune have received grants from California’s stem cell research funding agency, the California Institute for Regenerative Medicine, for their work on experimental HIV therapies involving stem cells. Using different techniques, each company is genetically modifying the hematopoietic stem cells that circulate in the blood and give rise to a stable of blood and immune system cells.
In Sangamo’s treatment, the re-engineered stem cells would be re-introduced into the body through a “low-intensity bone marrow transplant,” says Geoff Nichol, Sangamo’s executive vice president of research and development. Theoretically, the modified stem cells would then produce a range of different types of blood-borne cells protected from HIV infection—not only the T-cells that are the targets of Sangamo’s completed trials using modified T-cell infusions. Other immune cells generated by genetically modified stem cells might be enabled to kill the virus, Nichol says. Sangamo plans to seek FDA permission this year for clinical trials of that method.
However, the gene therapy company that succeeds in developing a functional HIV cure may some day face competition from a longtime rival: Gilead. The kingpin of antiretroviral HIV drug sales is conducting its own research programs on potential cures for HIV infection that don’t rely on gene modification. Gilead is studying drug compounds with the potential to eradicate all vestiges of HIV in the human tissues that serve as reservoirs where the deadly virus can hide out.
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