Seattle, WA, United States

Calistoga Pharmaceuticals
Seattle, WA, United States
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Subramaniam P.,Columbia University | Whye D.,Columbia University | Efimenko E.,Columbia University | Chen J.,Columbia University | And 12 more authors.
Cancer Cell | Year: 2012

Constitutive phosphoinositide 3-kinase (PI3K)/Akt activation is common in T cell acute lymphoblastic leukemia (T-ALL). Although four distinct class I PI3K isoforms (α, β, γ, δ) could participate in T-ALL pathogenesis, none has been implicated in this process. We report that in the absence of PTEN phosphatase tumor suppressor function, PI3Kγ or PI3Kδ alone can support leukemogenesis, whereas inactivation of both isoforms suppressed tumor formation. The reliance of PTEN null T-ALL on the combined activities of PI3Kγ/δ was further demonstrated by the ability of a dual inhibitor to reduce disease burden and prolong survival in mice as well as prevent proliferation and promote activation of proapoptotic pathways in human tumors. These results support combined inhibition of PI3Kγ/δ as therapy for T-ALL. © 2012 Elsevier Inc.

Lannutti B.J.,Calistoga Pharmaceuticals | Meadows S.A.,Calistoga Pharmaceuticals | Herman S.E.M.,Ohio State University | Kashishian A.,Calistoga Pharmaceuticals | And 10 more authors.
Blood | Year: 2011

Phosphatidylinositol-3-kinase p110δ serves as a central integration point for signaling from cell surface receptors known to promote malignant B-cell proliferation and survival. This provides a rationale for the development of small molecule inhibitors that selectively target p110δ as a treatment approach for patients with B-cell malignancies. We thus identified 5-fluoro-3-phenyl-2-[(S)-1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one (CAL-101), a highly selective and potent p110δ small molecule inhibitor (half-maximal effective concentration [EC50] = 8nM). Using tumor cell lines and primary patient samples representing multiple B-cell malignancies, we have demonstrated that constitutive phosphatidylinositol-3-kinase pathway activation is p110δ-dependent. CAL-101 blocked constitutive phosphatidylinositol-3-kinase signaling, resulting in decreased phosphorylation of Akt and other downstream effectors, an increase in poly(ADP-ribose) polymerase and caspase cleavage and an induction of apoptosis. These effects have been observed across a broad range of immature and mature B-cell malignancies, thereby providing a rationale for the ongoing clinical evaluation of CAL-101. © 2011 by The American Society of Hematology.

Herman S.E.M.,Ohio State University | Lapalombella R.,Ohio State University | Gordon A.L.,Ohio State University | Ramanunni A.,Ohio State University | And 8 more authors.
Blood | Year: 2011

In patients with chronic lymphocytic leukemia (CLL), lenalidomide can promote humoral immune responses but also induces a distinct disease-specific toxicity of tumor flare and cytokine release. These CLL-specific events result from increased expression of costimulatory molecules on B cells. Here we demonstrate that lenalidomide activation of CLL cells depends on the phosphatidylinositol 3-kinase p110δ (PI3K-δ) pathway. Inhibition of PI3K-δ signaling by the PI3K-δ-inhibiting drug, CAL-101, or by siRNA knockdown of p110δ, abrogates CLL cell activation, costimulatory molecule expression, and vascular endothelial growth factor and basic fibroblast growth factor gene expression that is induced by lenalidomide. In addition, CAL-101 attenuates lenalidomide-mediated increases in immunoglobulin M production by normal B cells. Collectively, these data demonstrate the importance of PI3K-δ signaling for lenalidomide immune modulation. These findings may guide development of strategies for the treatment of CLL that combine lenalidomide with CAL-101, with other inhibitors of the PI3K-δ pathway, or with other agents that target downstream kinases of this signaling pathway. © 2011 by The American Society of Hematology.

Herman S.E.M.,Ohio State University | Gordon A.L.,Ohio State University | Wagner A.J.,Ohio State University | Heerema N.A.,Ohio State University | And 11 more authors.
Blood | Year: 2010

Targeted therapy with imatinib in chronic myeloid leukemia (CML) prompted a new treatment paradigm. Unlike CML, chronic lymphocytic leukemia (CLL) lacks an aberrant fusion protein kinase but instead displays increased phosphatidylinositol 3-kinase (PI3K) activity. To date, PI3K inhibitor development has been limited because of the requirement of this pathway for many essential cellular functions. Identification of the hematopoietic-selective isoform PI3K-δ unlocks a new therapeutic potential for B-cell malignancies. Herein, we demonstrate that PI3K has increased enzymatic activity and that PI3K-δ is expressed in CLL cells. A PI3K-δ selective inhibitor CAL-101 promoted apoptosis in primary CLL cells ex vivo in a dose- and time-dependent fashion that was independent of common prognostic markers. CAL-101-mediated cytotoxicity was caspase dependent and was not diminished by coculture on stromal cells. In addition, CAL-101 abrogated protection from spontaneous apoptosis induced by B cell-activating factors CD40L, TNF-α, and fibronectin. In contrast to malignant cells, CAL-101 does not promote apoptosis in normal T cells or natural killer cells, nor does it diminish antibody-dependent cellular cytotoxicity. However, CAL-101 did decrease activated T-cell production of various inflammatory and antiapoptotic cytokines. Collectively, these studies provide rationale for the clinical development of CAL-101 as a first-in-class targeted therapy for CLL and related B-cell lymphoproliferative disorders. © 2010 by The American Society of Hematology.

Hoellenriegel J.,University of Texas M. D. Anderson Cancer Center | Meadows S.A.,Calistoga Pharmaceuticals | Sivina M.,University of Texas M. D. Anderson Cancer Center | Wierda W.G.,University of Texas M. D. Anderson Cancer Center | And 8 more authors.
Blood | Year: 2011

In lymphocytes, the phosphoinositide 3′-kinase (PI3K) isoform p110δ (PI3Kδ) transmits signals from surface receptors, including the B-cell receptor (BCR). CAL-101, a selective inhibitor of PI3Kδ, displays clinical activity in CLL, causing rapid lymph node shrinkage and a transient lymphocytosis. Inhibition of pro-survival pathways, the presumed mechanism of CAL-101, does not explain this characteristic pattern of activity. Therefore, we tested CAL-101 in assays that model CLL-microenvironment interactions in vitro. We found that CAL-101 inhibits CLL cell chemotaxis toward CXCL12 and CXCL13 and migration beneath stromal cells (pseudoemperipolesis). CAL-101 also down-regulates secretion of chemokines in stromal cocultures and after BCR triggering. CAL-101 reduces survival signals derived from the BCR or from nurse-like cells, and inhibits BCR- and chemokinereceptor - induced AKT and MAP kinase (ERK) activation. In stromal cocultures, CAL-101 sensitizes CLL cells toward bendamustine, fludarabine, and dexamethasone. These results are corroborated by clinical data showing marked reductions in circulating CCL3, CCL4, and CXCL13 levels, and a surge in lymphocytosis during CAL-101 treatment. Thus, CAL-101 displays a dual mechanism of action, directly decreasing cell survival while reducing interactions that retain CLL cells in protective tissue microenvironments. These data provide an explanation for the clinical activity of CAL-101, and a roadmap for future therapeutic development. © 2011 by The American Society of Hematology.

News Article | October 29, 2015

Frazier Healthcare Partners, a 24-year-old venture firm that invests only in healthcare and has offices in both Seattle and Menlo Park, Ca., has just closed its eighth fund with $262 million from mostly earlier backers. While a coup, the pool is much smaller than Frazier’s predecessor fund, a $375 million vehicle raised in 2013. Yesterday, to find out why, we talked with general partner Jamie Topper, an M.D. and Ph.D who joined Frazier 13 years ago. TC: You’ve raised a far smaller fund this time around. What happened? JT: In the past, we’ve had multiple strategies within the same fund, including life sciences and health care services. Our newest fund is dedicated exclusively to life sciences. TC: For people who don’t follow healthcare, what distinguishes life sciences investing from health care services? JT: Life sciences investing is drug development, diagnostics, funding pre-clinical drugs and even drugs on the verge of getting commercialized. Health care services are things like pharmaceutical services or companies that package pharmaceuticals or deliver dialysis to patients and may have hundreds of centers. The latter more or less requires growth-stage capital. TC: What happens now to the partners who focused on those bigger, later-stage deals? JT: No one has left Frazier. It’s not splitting up. We’re likely instead to have multiple offerings. TC: What are some of your hits over the last five years? JT: We’ve had 10 M&A [exits] over the last five years and 7 IPOs, including Calistoga Pharmaceuticals’ sale to Gillead Sciences for $600 million; Incline Therapeutics’ sale for $275 million [to The Medicines Company]; and PreCision Dermatology’s sale to Valeant Pharmaceuticals for $575 million. We also had Collegium Pharmaceuticals and ProNai go public over the spring and summer. TC: Good timing. Life sciences IPOs have slowed down dramatically in the last two months, correct? JT: They have, after a four-year bull market in biotech. It’s not a terrible thing. It’s not the crash that happened in 2000. The biggest issue for life sciences investors is that we have to improve healthcare and develop new drugs at lower cost. We don’t need another drug where there are three other examples and we’re just going to jack up the price. Also, reimbursement and access to novel therapies receive more scrutiny in the past. So we look for teams that are innovative; companies that addressing a true, unmet need – not just because we think we can sell it but to ensure that regulators and reimbursers will agree with the companies; and we look for opportunities where we can see certain inflection points met within three to five years. TC: What size checks are you writing? JT: Two thirds of our investments have been seed or Series A deals, so we’re comfortable coming in early, but it has to be the right opportunity. We also create one to two companies per year. We created Calistoga and Incline. In terms of check sizes, we typically syndicate deals, investing around $5 million to $10 million up front, and between $15 million and $25 million across the life of a company. TC: Are you seeing many IT investors coming into deals suddenly? We hear a lot of talk about how big data is making drug development a more accessible, affordable endeavor for everyone. JT: There’s no question that technology is making drug development more effective. I could sequence your genome for $1,000 today and it used to cost $3 million just a few years ago. Computing power is an amazing thing. But you read about these guys from wherever who think, “This drug stuff can’t be hard. I’m going to take my strong computers and figure it out.” I’ve been hearing that a long time. Biology is incredibly complex and leveraging your insights is an enormously difficult enterprise. It takes a lot of experience and teams that are committed to doing it over time. So I don’t care how smart you are or how big your computer is, you won’t solve all the problems. It’s an iterative process.

News Article | July 10, 2008

Calistoga Pharmaceuticals, a Seattle biotech startup backed by Frazier Healthcare Ventures, said today it has started its first test in humans of its lead drug candidate for patients with blood cancers. The treatment, a small-molecule compound called CAL-101, is designed to block the PI3 kinase, which controls cell growth and survival signals. The trial will enroll 60 patients, measuring safety at a range of doses, according to a description at

Gilead Antes Up for Cancer, Genentech Eye Drug Passes Big Trial, Bigger Isn’t Better, & More Bay Area Life Sciences News This was a light news week in SF biotech, but it still flew by, as we get ready to make some small media biz news at our own little startup here on Monday. Stay tuned. —South San Francisco-based Genentech said its hit drug for eye diseases, ranibizumab (Lucentis) passed the second big pivotal trial in patients with diabetic macular edema. This is important not just to patients with a common condition that impairs vision, but it could help Genentech offset some of the sales it may lose if more patients with macular degeneration switch to a cheap, low-dose form of bevacizumab (Avastin) as an alternative. —Gilead Sciences (NASDAQ: GILD) said this week it has agreed to sponsor cancer research at Yale University in a deal that could be worth as much as $100 million over a 10-year period to the university. It’s the latest big bet on cancer by Foster City, CA-based Gilead, which agreed in February to pay as much as $600 million to buy Calistoga Pharmaceuticals, a cancer drug developer on the verge of pivotal studies. —In this week’s installment of the BioBeat column, I argued that Big Pharma has been its own worst enemy through its penchant for mega-mergers that make it next to impossible to foster innovation. —With all the talk about the crisis in venture capital, I’ve been thinking a bit lately about whether angels might somehow find a new niche in biotech financing. Angels, as Morgenthaler Ventures’ Bob Pavey points out in this guest editorial, have always played a role in backing new businesses, and they are particularly visible now in tech startups that can really run lean and mean in the cloud computing era. Biotech drug development has traditionally taken too long and cost too much for angels to play a serious role, but I wonder if readers see ways for angels to get in here now.

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