5:49 PM
Sep 08, 2017
 |  BioCentury  |  Strategy

Some of the parts

Can Gilead apply its combination chops to make Kite CAR Ts work in solid tumors?

The acquisition of Kite Pharma Inc. by Gilead Sciences Inc. could put the industry-leading CAR T pipeline in the hands of the company best-suited to expand the cell therapies into the as-yet-elusive solid tumor space.

The deal’s $11.9 billion valuation was driven largely by axicabtagene ciloleucel (KTE-C19), a chimeric antigen receptor T cell (CAR T) therapy under review to treat refractory aggressive non-Hodgkin’s lymphoma (NHL). Response rates have been in the neighborhood of 80% in that and other blood cancers.

But the holy grail for CAR Ts is in solid tumors, where data have underwhelmed.

Current opinion holds that combination therapy will be the key to improving response rates because of factors expressed in the microenvironment that prevent CAR Ts from infiltrating solid tumors.

There are few if any companies better at combination strategies than Gilead. The company built its multibillion-dollar virology franchises through the methodical and swift development of combination therapies that iterate on an initial agent developed as monotherapy, expanding both the efficacy and the exclusivity of that agent.

Gilead also has been pursuing a combination strategy in building its nascent pipeline in non-alcoholic steatohepatitis (NASH).

The company could be expected to apply this expertise to Kite’s pipeline of CAR T products, but will have to fill out its cancer pipeline with additional programs that have complementary mechanisms of action. Prior to the acquisition, the pipeline contained one approved cancer drug and five cancer candidates, at least two of which could make sense in a CAR T combo.

Gilead, which declined to provide an interview, did tell investors that it plans to acquire or license additional molecules that could be used in combinations. It did not elaborate on what mechanisms or classes might be its targets.

“If you think about our HIV portfolio, it’s been a process of continuous innovation.”

John Milligan, Gilead

Multiple targets and mechanisms have been hypothesized for helping CAR Ts overcome the tumor microenvironment. While many of these approaches are in their infancy, Gilead’s cancer deals to date show a willingness to acquire early stage programs before proof of concept has been established.

All the programs in Gilead’s clinical pipeline were acquired when the candidates were still in preclinical development. The company gained its sole marketed cancer drug, Zydelig idelalisib, when it was in Phase II testing.

The company’s new head of oncology, Alessandro Riva, brings with him experience at identifying new technologies that could be used to improve the efficacy of CAR Ts in solid tumors. Riva, who is SVP, hematology and oncology therapeutic area head at Gilead, was head of global oncology development at Novartis AG from 2005 to 2016. When he departed, he also was head of medical affairs.

Riva was responsible for the clinical development of Novartis’ Kymriah tisagenlecleucel, which late last month became the first approved CAR T. And between the 2012 deal with the University of Pennsylvania that brought in Kymriah and Riva’s departure, Novartis acquired or licensed several programs that could boost immune responses, block suppressors in the microenvironment and improve antigen presentation when added to CAR T therapies.

Even after adding Kite’s extensive pipeline of CAR T and T cell receptor (TCR)-based therapies and additional pipeline deals, investors will likely be looking for Gilead to keep shopping. Gilead has not provided long-term revenue guidance but has guided for HCV sales to decline by as much as $6.3 billion (43%) in 2017, reaching $8.5-9.5 billion vs. $14.8 billion in 2016 (see “After HCV”).

By 2020, analysts expect HCV revenues to be $6.9 billion, $7.9 billion less than the 2016 figure.

New products, including axicabtagene ciloleucel, will fill in some of the gap.

Analysts estimate axicabtagene ciloleucel will bring in $947 million by 2020. However, the consensus estimate includes forecasts made before Novartis announced a price for Kymriah far below expectations (see “About Price”).

Sidebar: About price

Figure: After HCV

HCV revenues from Gilead Sciences Inc. (NASDAQ:GILD) have already declined to $14.8 billion in 2016 from a peak of $19.1 billion in 2015. Analysts estimate a further decline to $6.9 billion by 2020, driven by the competitive landscape, more patients being cured and fewer patients starting therapy. More than half the $7.9 billion HCV shortfall is expected to be filled by new HIV products and the cell therapy gained from the proposed acquisition of Kite Pharma Inc. (NASDAQ:KITE).

An estimated $3.1 billion is expected for a fixed-dose combination of bictegravir/emtricitabine/tenofovir alafenamide, an HIV product with a Feb. 12, 2018, PDUFA date. The recently approved Vosevi sofosbuvir/velpatasvir/voxilaprevir is expected to chip in $2.4 billion as an HCV salvage regimen. And consensus estimates for Kite call for $947 million in total sales of axicabtagene ciloleucel by 2020.

2020 revenue projections are compiled using separate consensus estimates for Gilead and Kite and include projected sales of pipeline products. “Other products” includes Letairis ambrisentan for pulmonary arterial hypertension, Ranexa ranolazine for chronic angina, AmBisome amphotericin B for fungal infections, Phase III autoimmune candidate filgotinib and unspecified “other products” in Gilead’s 10-K. Source: Gilead SEC filings, FactSet

Laying the foundation 

Gilead has been signaling since at least the start of the year that it wanted to go deep in oncology.

It announced Riva’s appointment on Jan. 3 and in February said he would help seek new assets.

“We’ve brought in a new head of oncology and we’re reconfiguring how we’re thinking about oncology and what kinds of things we might want to bring in to augment some of the pipeline programs we have,” Gilead President and CEO John Milligan said at the Feb. 22 RBC Capital Markets Global Health Care Conference.

According to an SEC filing, Gilead signed a confidentiality agreement with Kite that same month, and by May had started preliminary discussions with Kite about potential collaborations or partnerships.

“It’s going to take that kind of continuous investment and innovation to be successful in this field.”

John Milligan, Gilead

On Gilead’s 1Q17 earnings call May 2, the big biotech stated its intent to build a sustainable long-term cancer business. “It’s clear we’ve been focusing on oncology, where the question is, is there an area where we can use our resources to accelerate products to market and build a meaningful franchise,” Milligan said.

Gilead disclosed in an SEC filing that it made its first offer to acquire Kite for $127 per share, or $8.4 billion, on July 16. That offer, and a second of $160 per share on July 28, were rebuffed by Kite as insufficient. Gilead’s third offer on Aug. 18 of $180 per share was accepted. The filing did not say whether there were any other bidders.

On an Aug. 28 investor call to discuss the deal, Gilead said it sees Kite as a foundation for growth.

“Our oncology efforts have been fairly nascent and we have had few real successes in those areas,” said Milligan, adding, “This is a pivot to cell therapy as our main strategy going forward.”

Gilead noted that data in NHL suggest axicabtagene ciloleucel could have broad applicability in CD19-positive lymphomas and leukemias.

Kite announced top-line data from the Phase II portion of the Phase I/II ZUMA-1 trial in February showing an objective response rate (ORR) of 82% vs. 20% for historical controls in 101 patients with refractory aggressive NHL, including diffuse large B cell lymphoma (DLBCL), transformed follicular lymphoma or primary mediastinal B cell lymphoma (PMBCL).

Median OS had not been reached at a median follow-up of 8.7 months. In April, the biotech announced the six-month survival rate was 80%.

“We really became convinced that the broader population of CD19-positive lymphomas and leukemias had an excellent chance of being treated by axi-cil cell therapy,” Milligan said.

The therapy is also being studied in earlier lines of treatment, including a Phase II trial in indolent NHL. A Phase I trial in second-line DLBCL, the most common form of NHL, is expected to start this year. Kite also has ongoing studies of axicabtagene ciloleucel in mantle cell lymphoma (MCL) and adult and pediatric acute lymphoblastic leukemia (ALL).

Milligan added that Gilead has “great expectations” for the Kite platform to treat a broader group of patients across solid and hematologic malignancies.

Kite has six other CAR T or T cell receptor (TCR) programs in the clinic, including four in solid tumors (see “Gilead’s Cancer Pipeline”).

Kite’s lead solid tumor program is a TCR targeting melanoma-associated antigen A3 (MAGEA3) in Phase I/II testing. MAGEA3 is expressed on a variety of solid tumors. In August researchers at the National Cancer Institute reported that in 17 patients with metastatic tumors, the therapy led to four objective responses (23%) while avoiding off-target toxicity.

Gilead did not comment on the data in solid tumors. However, when asked by analysts about the company’s expectations to build on the cell therapy platform Milligan said Gilead would look for ways to “enhance the activity of some of these products either through engineering or perhaps in combinations.”

Figure: Gilead’s cancer pipeline

With its proposed acquisition of Kite Pharma Inc. (NASDAQ:KITE), Gilead Sciences Inc. (NASDAQ:GILD) will more than double the size of its clinical cancer pipeline, taking it to 13 from six. Kite also has six disclosed preclinical CAR T and TCR programs, including two that are expected to enter the clinic next year. The combined pipeline is below, with programs from Kite in blue, and those from Gilead in green. Only lead indications are shown. (A) In-licensed from Ono Pharmaceutical Co. Ltd. (Tokyo:4528); (B) In Phase I/II testing; (C) Kite pipeline lists “HPV-16 E6 & E7” as a single program with trials run by the National Cancer Institute (NCI), plus an additional preclinical HPV-16 E7 product; the biotech has not disclosed which are included in its partnership with bluebird bio Inc. (NASDAQ: BLUE) to develop TCR product candidates against HPV-16 E6; Source: BCIQ: BioCentury Online Intelligence, ClinicalTrials.gov, Gilead and Kite websites

Internal enhancers 

Gilead declined to name specific combinations it had in mind. However, the company has said it would start by looking at its own pipeline.

“We’re quite interested in things that would augment cellular therapy and so we’re going to take some time to look at our own portfolio to determine what, if any other things, we should do,” Milligan said.

One potential combination partner is andecaliximab (GS-5745). The matrix metalloproteinase 9 (MMP9) inhibitor is in Phase III testing to treat gastric cancer

MMP9 is a regulator of the tumor microenvironment, where it facilitates tumor vascularization via activation of cytokines such as transforming growth factor (TGF) beta.

TGF beta expression by tumor cells limits effector T cell function and activates regulatory T cells -- both of which would limit the effectiveness of CAR Ts.

Gilead described Phase I data at the JPMorgan Healthcare Conference in January. In 30 patients with gastric cancer, about 45% had more than a 50% response rate and a progression-free survival (PFS) of about 14 months vs. 6 months for historical controls.

The company has not presented data on whether administration of andecaliximab led to an increase in T cell infiltration and/or a reduction in Tregs, which would suggest combining the mAb with CAR Ts could improve their efficacy.

Gilead’s GS-5829 is another option for combinations. The small molecule inhibitor of BET bromodomain proteins is in Phase I/II trials in ER-positive, HER2-negative breast cancer, as well as in metastatic castration-resistant prostate cancer (CRPC).

Epigenetic modulators including BET inhibitors reduce Treg expression and increase tumor antigen expression in solid tumors. The exact BET protein targeted by GS-5829 is undisclosed, and there are limited data for the program. However, researchers at Roche’s Genentech Inc. unit and Constellation Pharmaceuticals Inc. published results in 2016 showing multiple different bromodomain inhibitors synthesized by the companies down-regulated Tregs and dampened Treg suppression of naïve T cell proliferation.

Kite is already investigating combining CAR Ts with PD-L1 inhibition. Last September, Kite started a Phase Ib/II trial of axicabtagene plus Tecentriq atezolizumab from Roche and Genentech. The ZUMA-6 trial is assessing the combination in patients with refractory DLBCL.

In March, researchers at Baylor College of Medicine showed that a HER2-targeted CAR T in combination with a PD-1 inhibitor decreased cancer cell numbers and increased CAR T cell proliferation in cell culture. In mouse models of HER2-positive prostate and cervical cancer, the combination decreased tumor growth and increased survival compared with either agent alone.

A look at cancer deals done during Riva’s tenure at Novartis may provide insight into the types of approaches he thinks could improve the activity of CAR T therapies.

Representative deals include the February 2014 acquisition of CoStim Pharmaceuticals Inc. to gain a portfolio of late-stage discovery programs focused on immune checkpoint proteins.

Novartis also partnered with Aduro Biotech Inc. in 2015 to generate receptor agonists of STING (transmembrane protein 173; TMEM173) and acquired Admune Therapeutics LLC.

STING agonists stimulate immunity in distal tumors. The STING receptor has aroused interest in the immunotherapy space because it is located on dendritic cells and other immune cells and can produce long-lasting T cell antitumor responses by activating multiple immune cell types.

Admune’s technologies boost the immune system’s response to cancer immunotherapies by increasing the number of antitumor lymphocytes overall and in the vicinity of tumors.

In 2016, Novartis gained rights to an undisclosed program from Surface Oncology Inc., which is developing preclinical compounds against cancer immunotherapy targets that aim to improve the effectiveness of antigen presentation, block activity of suppressor cells in the tumor microenvironment and counter the impact of undisclosed cytokines and metabolites.

Honed in virology 

While cell therapy is a different beast than small molecules, much of Gilead’s skill set in matching combination partners and designing clinical programs to test them should translate to work quickly and adaptively to make combinations successful.

“We’ve been very successful in HIV and HCV by offering products that are at the forefront of science, starting with once-daily pills and then going to the single-tablet regimen. If you think about our HIV portfolio, it’s been a process of continuous innovation since the launch of Viread in 2001. We’ve brought out product after product, each improving upon the generation before and offering better long-term options,” Milligan told investors.

Gilead is now on its eighth iteration of Viread tenofovir with a fixed-dose combination of bictegravir/emtricitabine/tenofovir alafenamide. The addition of bictegravir, an unboosted integrase inhibitor, should reduce resistance. The combination is under review in the U.S. and Europe.

Similarly, in HCV, Sovaldi sofosbuvir was launched in December 2013 as the first interferon-sparing regimen in HCV. It was approved for some but not all HCV genotypes and showed cure rates in excess of 90%. A year later, Gilead launched Harvoni ledipasvir/sofosbuvir, an interferon-free regimen with 100% cure rates after 12 weeks of therapy.

In June 2016, FDA approved the first-ever pan-genotypic HCV regimen, Gilead’s Epclusa sofosbuvir/velpatasvir. In clinical trials, the single-tablet, once-daily therapy resulted in SVR12 rates of 83-98%, depending upon the genotype.

“Gilead has to be the company that makes meaningful advances in the space.”

Brad Loncar, Loncar Investments

Milligan said he sees the same kind of need for continuous innovation in CAR T. “First-generation products have complete response rates that are very impressive given the kinds of patients [they’re treating], but we’re far from curing everybody,” he said.

“We see a great deal of similarity between the way we approach the diseases and the way Kite is approaching disease, and I think it’s going to take that kind of continuous investment and innovation to be successful in this field,” Milligan added.

Other must-haves 

Brad Loncar, portfolio manager of Loncar Investments, thinks Gilead will have to bring the competitive, cutting-edge mentality it honed in virology to cell therapy.

“Gilead wants to be a leader in whatever they do,” Loncar said. To maintain Kite’s position in CAR T, “Gilead has to be the company that makes meaningful advances in the space. Given how fast this field is evolving, that is no small feat.”

Loncar thinks gene editing could be a necessary tool to make the cell therapies work in solid tumors.

“What I think it will take to succeed in solid tumors could be gene editing approaches because right now, one of the limitations is that you can only program one thing into the T cell,” he told BioCentury.

Under Riva, in 2015, Novartis in-licensed rights to use gene editing technology from Intellia Therapeutics Inc. to conduct ex vivo engineering of CAR Ts.

David Epstein, former CEO of the Novartis Pharmaceuticals unit and head of the pharma’s oncology business before that, said combinations with tumor-targeted small molecules or biologicals will be the most near-term approach to improving the efficacy of CAR Ts. However, next-generation technologies are starting to add more than one antigen onto T cells, which could be a more long-term solution. “Second-generation cellular therapies like those at Rubius will be multitargeted, thus obviating the need for such combinations,” he told BioCentury.

Epstein is chairman of Rubius Therapeutics Inc. and an executive partner at Flagship Pioneering. Rubius’ Red-Cell Therapeutics platform genetically engineers hematopoietic progenitors to produce therapeutic proteins when the progenitor differentiates into a red blood cell (RBC). The programs are in preclinical development.

Retaining Kite’s team and keeping the current programs on track will also be important.

“If they had a brain drain or any sort of slowdown while they integrated this, they could very easily be leapfrogged,” Loncar told BioCentury.

Added Epstein, “If Gilead can keep the Kite unit intact, it should be in good shape. It’s not smart to think you can develop a cell therapy like a small molecule.”

Gilead has said it will retain Kite as a distinct unit. “Kite will become Gilead’s cell therapy unit and we hope that the vast majority of people stay to become part of the combined companies,” Milligan said.

Epstein also noted that Riva’s experience at Novartis equips him with the skills to help Gilead manage the platform going forward.

“Rivas was intimately involved in CTL019 [Kymriah] development, so he understands this all well in terms of recognizing the intimate connection of every decision between the clinical development, manufacturing and regulatory teams,” Epstein told BioCentury.

Novartis is Gilead’s closest competitor. In addition to the spate of programs gained during Riva’s tenure, the pharma has disclosed at least two CAR Ts in clinical testing for solid tumors: CAR-T-EGFRvIII to treat glioblastoma multiforme (GBM) and CAR-T-Meso to treat ovarian cancer and mesothelioma. Both programs are being developed under the collaboration with the University of Pennsylvania and are in Phase I testing.

Celgene Corp. also has its eye on CAR T combinations. In 2015, the company partnered with Juno Therapeutics Inc. in a 10-year collaboration to develop CAR T combinations, though it’s currently focused on hematologic malignancies.

In July 2016, Celgene announced a collaboration with Jounce Therapeutics Inc. in which Celgene gained options to JTX-2011 and up to five preclinical programs. Jounce’s antibodies target Tregs, tumor-associated macrophages and B cells that can block immunosuppressive effects of solid tumors.

Companies and Institutions Mentioned 

Aduro Biotech Inc. (NASDAQ:ADRO), Berkeley, Calif.

Baylor College of Medicine, Houston, Texas

Celgene Corp. (NASDAQ:CELG), Summit, N.J.

Centers for Medicare & Medicaid Services (CMS), Baltimore, Md.

Constellation Pharmaceuticals Inc., Cambridge, Mass.

Genentech Inc., South San Francisco, Calif.

Gilead Sciences Inc. (NASDAQ:GILD), Foster City, Calif.

Harvard Pilgrim Health Care Inc., Boston, Mass.

Intellia Therapeutics Inc. (NASDAQ:NTLA), Cambridge, Mass.

Jounce Therapeutics Inc. (NASDAQ:JNCE), Cambridge, Mass.

Juno Therapeutics Inc. (NASDAQ:JUNO), Seattle, Wash.

Kite Pharma Inc. (NASDAQ:KITE), Santa Monica, Calif.

National Cancer Institute (NCI), Bethesda, Md.

Novartis AG (NYSE:NVS; SIX:NOVN), Basel, Switzerland

Real Endpoints LLC, Westport, Conn.

Roche (SIX:ROG; OTCQX:RHHBY), Basel, Switzerland

Rubius Therapeutics Inc., Cambridge, Mass.

Surface Oncology Inc., Cambridge, Mass.

University of Pennsylvania, Philadelphia, Pa.

U.S. Food and Drug Administration (FDA), Silver Spring, Md.


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