Biopharmconsortium Blog

Expert commentary from Haberman Associates biotechnology and pharmaceutical consulting.

Posts filed under: Metabolism

The Genentech/NewLink alliance, the IDO/TDO pathway, and targeting metabolism for immuno-oncology

Indoleamine 2,3-dioxygenase 1

Indoleamine 2,3-dioxygenase 1

On October 20, 2014, New Link Genetics Corporation (Ames, IA) announced that it had entered into an exclusive worldwide license agreement with Genentech/Roche for the development of NLG919, an IDO (indoleamine-pyrrole 2,3-dioxygenase) inhibitor under development by NewLink. The two companies also initiated a research collaboration for the discovery of next generation IDO/TDO (tryptophan-2,3-dioxygenase) inhibitors.

Under the terms of the agreement, NewLink will receive an upfront payment of $150 million, and may receive up to over $1 billion in milestone payments, as well as royalties on any sales of drugs developed under the agreement. Genentech will also provide research funding to NewLink in support of the collaboration. Other details of the agreement are outlined in NewLink’s October 20, 2014 press release.

The target of NewLink’s iDO/TDO program, and of its collaboration with Genentech, is cancer immunotherapy. As we discussed in our September 2014 report, Cancer Immunotherapy: Immune Checkpoint Inhibitors, Cancer Vaccines, and Adoptive T-cell Therapies (published by Cambridge Healthtech Institute), Genentech is developing the PD-L1 inhibitor MPDL3280A, which is in Phase 2 trials in renal cell carcinoma and urothelial bladder cancer, and in Phase 1 trials in several other types of cancer. PD-L1 inhibitors such as MPDL3280A constitute an alternative means to PD-1 inhibitors of blocking The PD-1/PD-L1 immune checkpoint pathway.

Two PD-1 inhibitors, pembrolizumab (Merck’s Keytruda) and nivolumab (Medarex/Bristol-Myers Squibb’s Opdivo) are in a more advanced stage of development than MPDL3280A and other PD-L1 inhibitors. The FDA approved pembrolizumab for treatment of advanced melanoma in September 2014, and nivolumab was approved in Japan in July 2014, also for treatment of advanced melanoma.

MPDL3280A, pembrolizumab, and nivolumab are monoclonal antibody (MAb) drugs. Another MAb immune checkpoint inhibitor, ipilimumab (Medarex/BMS’s Yervoy) was approved for treatment of advanced melanoma in 2011. Ipilimumab, which was the first checkpoint inhibitor to gain regulatory approval, targets CTLA-4.

As summarized in the October 20, 2014 New Link press release, IDO pathway inhibitors constitute another class of immune checkpoint inhibitors. However, they are small-molecule drugs. The IDO pathway is active in many types of cancer both within tumor cells and within antigen presenting cells (APCs) in tumor draining lymph nodes. This pathway can suppress T-cell activation within tumors, and also promote peripheral tolerance to tumor associated antigens. Via both of these mechanisms, the IDO pathway may enable the survival, growth, invasion and metastasis of malignant cells by preventing their recognition and destruction by the immune system.

As also summarized in this press release, NewLink has several active IDO inhibitor discovery and development programs, and has also discovered novel tryptophan-2,3-dioxygenase (TDO) inhibitors. As with IDO, TDO is expressed in a significant proportion of human tumors, and also functions in immunosuppression. TDO inhibitors are thus potential anti-cancer compounds that might be used alone or in combination with IDO inhibitors.

The kynurenine pathway and its role in tumor immunity and in neurodegenerative diseases

IDO and TDO are enzymes that catalyze the first and rate-limiting step of tryptophan catabolism through the kynurenine pathway (KP). The resulting depletion of tryptophan, an essential amino acid, inhibits T-cell proliferation. Moreover, the tryptophan metabolite kynurenine can induce development of immunosuppressive regulatory T cells (Tregs), as well as causing apoptosis of effector T cells, especially Th1 cells.

A 2014 review by Joanne Lysaght Ph.D. and her colleagues on the role of metabolic pathways in tumor immunity, and the potential to target these pathways in cancer immunotherapy also highlights the role of IDO and kynurenine in upregulation of Tregs and in the phenomenon of T-cell exhaustion, in which T cells chronically exposed to antigen become inactivated or anergic.

In our cancer immunotherapy report, we discuss the role of Tregs and T-cell exhaustion in immune suppression in tumors, and the role of anti-PD-1 agents in overcoming these immune blockades. Targeting the IDO and TDO-mediated tryptophan degradation pathway may thus complement the use of anti-PD-1 (and/or anti-PD-L1) MAb drugs, and potentially lead to the development of combination therapies.

We have discussed the kynurenine pathway of tryptophan catabolism in another context in our July 11, 2011 article on this blog. This article discusses the potential role of kynurenine pathway metabolites in such neurodegenerative diseases as Alzheimer’s disease (AD) and Huntington’s disease (HD).

As discussed in that article, HD and AD patients have elevated levels of two metabolites in the KP–quinolinic acid (QUIN) and 3-hydroxykynurenine (3-HK)–in their blood and brains. Both of these metabolites have been implicated in pathophysiological processes in the brain. In contrast, kynurenic acid (KYNA), which is formed in a side arm of the KP by conversion of kynurenine by the enzyme kynurenine aminotransferase, appears to be neuroprotective.

Researchers have been targeting kynurenine 3-monooxygenase (KMO) in order to induce a more favorable ratio of KYNA to QUIN. As a result, they have discovered a drug candidate, JM6. They proposed to first conduct clinical trials in HD, since the cause of HD is much better understood than for AD, and disease progression in placebo controls is better characterized than for AD. Moreover, clinical trials in AD are notoriously long and expensive.

A 2014 review of targets for future clinical trials in HD lists JM6 as a “current priority preclinical therapeutic targets in Huntington’s disease”. It also contains an updated discussion of the mechanism of action of JM6.

NewLink’s IDO inhibitor development program

NewLink presented progress posters on its IDO inhibitor development program at the American Society for Clinical Oncology (ASCO) 2014 annual meeting. These described trials in progress, which did not yet have any results. As described in these presentations, NewLink’s most advanced IDO inhibitor, indoximod is in:

  • a Phase 1/2 clinical trial in combination with ipilimumab in advanced melanoma
  • a Phase 1/2 study in combination with the alkylating agent temozolomide (Merck’s Temodar) in primary malignant brain tumors
  • a Phase 2 study in combination with the antimitotic agent docetaxel (Sanofi’s Taxotere) in metastatic breast cancer
  • a Phase 2 study in which indoximod is given subsequent to the anticancer vaccine sipuleucel-T (Dendreon’s Provenge) in metastatic castration-resistant prostate cancer.

The company also presented a progress poster on a first-in-humans Phase 1 study of NLG919, in solid tumors. NLG919, the focus of NewLink’s alliance with Genentech, is the second product candidate from NewLink’s IDO pathway inhibitor technology platform.

The major theme of NewLink’s ASCO meeting presentations is thus the development of the company’s IDO inhibitors as elements of combination immuno-oncology therapies with MAb immune checkpoint inhibitors, cancer vaccines, and cytotoxic chemotherapies.

In this connection, NewLink also hosted a panel discussion on combination therapies entitled “Points to Consider in Future Cancer Treatment: Chemotherapy, Checkpoint Inhibitors and Novel Synergistic Combinations” at the ASCO meeting. The collaboration of NewLink with Genentech will provide the opportunity for the two companies to test combinations of IDO inhibitors with Genentech’s PD-L1 inhibitor MPDL3280A.

Might targeting T-cell metabolism be used to enhance cancer immunotherapy?

In their 2014 review, Dr. Lysaght and her colleagues outline changes in metabolism as T-cells become activated, and differences in metabolism between various T-cell subsets (e.g., effector T cells, Tregs, exhausted or anergic T cells, and memory T cells). These researchers propose devising means to modulate T-cell metabolism in order to enhance anti-tumor immunity. However more research needs to be done in order to make such approaches a reality. In the meantime, development of IDO and TDO inhibitors is already in the clinic, providing the possibility of a metabolic approach to cancer immunotherapy.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or an initial one-to-one consultation on an issue that is key to your company’s success, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Agios Pharmaceuticals continues to progress

Agios Kirykos, Ikaria, Greece. Source: http://commons.wikimedia.org/wiki/File:Agios_Kirikos,_Ikaria.jpg

Agios Kirykos, Ikaria, Greece. Source: http://commons.wikimedia.org/wiki/File:Agios_Kirikos,_Ikaria.jpg

Because of being very busy with other projects, we have not posted an article on this blog since April 10, 2014. However, the Biopharmconsortium Blog is still here. More importantly, Haberman Associates biotech/pharma consulting is still here, and we’re still accepting new clients.

Thanks to the many readers who have continued to follow our website and blog during our blogging hiatus, and who have linked to our blog on Twitter and on other social media.

During the hiatus, several of the companies that we have been following on our blog have been progressing. Over the next several months, we shall be blogging about some of these companies, as well as about other notable industry events that have occurred in recent weeks and that will occur during the remainder of 2014.

The first company that we are writing about is cancer metabolism specialist Agios Pharmaceuticals (Cambridge, MA). Our most recent three articles about Agios on this blog are:

In our September 23, 2013 article, we noted that Agios had initiated its first clinical study—a Phase 1 clinical trial of AG-221 in patients with advanced hematologic malignancies bearing an isocitrate dehydrogenase 2 (IDH2) mutation. AG-221 is a first-in-class, orally available, selective, potent inhibitor of the mutated IDH2 protein. It is thus a targeted (and personalized) therapy for patients with cancers with an IDH2 mutation.

On June 14, 2014, Agios reported on new clinical data in its ongoing Phase 1 trial of AG-221, which was presented at the 19th Congress of the European Hematology Association (EHA) in Milan, Italy by Stéphane de Botton, M.D. (Institut de Cancérologie Gustave Roussy, Villejuif, France).

The presentation reported on the results of AG-221 treatment of 35 patients with IDH2 mutation positive hematologic malignancies. The researchers observed objective responses in 14 out of 25 evaluable patients, and stable disease in an additional 5 patients. Six patients experienced complete remissions which lasted from one to four months, and are still ongoing. AG-221 has shown favorable pharmacokinetics at all doses tested, with large reductions in serum levels of the oncometabolite 2-hydroxyglutarate (2HG). AG-221 was also well tolerated.

The new data confirms and builds upon previously results. The favorable safety and efficacy data supports Agios’ plan to initiate four expansion cohorts in the second half of 2014. Agios also expects to submit additional data from the ongoing Phase 1 trial for presentation at a later scientific meeting in 2014.

Meanwhile, as announced on June 13, 2014, Agios’ partner Celgene exercised its option to an exclusive worldwide license for AG-221. It exercised this option early, based on the Phase 1 data generated so far.

On June 16, 2014, Agios announced that the FDA granted orphan drug designation for AG-221 for treatment of patients with acute myelogenous leukemia (AML). On August 13, 2014, the FDA also granted Fast Track designation to AG-221 for the treatment of patients with AML that carry an IDH2 mutation.

Thus development of Agios’ lead compound, AG-221, continues to progress. Several other Agios R&D programs are also progressing, as detailed in the company’s report for the second quarter of 2014.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Agios Pharmaceuticals becomes a clinical-stage company!

Agios Efstratios, Greece. Source: Christef http://bit.ly/HK636F

Agios Efstratios, Greece. Source: Christef http://bit.ly/HK636F

In a news release on September 23, 2013, Agios Pharmaceuticals (Cambridge, MA) announced that it had initiated its first clinical study. The company further discussed its early clinical and preclinical programs in its press release on its Third Quarter financial report, dated November 7, 2013.

Specifically, the company initiated a Phase 1 muticenter clinical trial of AG-221 in patients with advanced hematologic malignancies bearing an isocitrate dehydrogenase 2 (IDH2) mutation. The study is designed to evaluate the safety, pharmacokinetics, pharmacodynamics and efficacy of orally-administered AG-221 in this patient population. The first stage of the Phase 1 study is a dose-escalation phase, which is designed  to determine the maximum tolerated dose and/or the recommended dose to be used in Phase 2 studies. After the completion of this phase, several cohorts of patients will receive AG-221 to further evaluate the safety, tolerability and clinical activity of the maximum tolerated dose.

We discussed AG-221 in our June 17, 2013 article on this blog. AG-221 is an orally available, selective, potent inhibitor of the mutated IDH2 protein. It is thus a targeted (and personalized) therapy for patients with cancers with an IDH2 mutation.

As we summarized in our June 17, 2013 article, wild-type IDH1 and IDH2 catalyze the NADP+-dependent oxidative decarboxylation of isocitrate to α-ketoglutarate. Mutant forms of IDH1 and IDH2, which are found in certain human cancers, no longer catalyze this reaction, but instead catalyzes the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2-HG). Agios researchers hypothesized that 2HG is an oncometabolite. They further hypothesized that developing mutant-specific small molecule inhibitors of IDH1 and IDH2 might inhibit the growth or reverse the oncogenic phenotype of cancer cells that carry the mutant enzymes.

As we further discussed in our article, Agios researchers published two articles in the journal Science in May 2013 that support these hypotheses. The researchers showed that drugs that inhibit the mutant forms of IDH1 and IDH2 can reverse the oncogenic effects of the mutant enzymes in patient-derived tumor samples. These results constitute preclinical support for the hypothesis that the two mutant enzymes are driving disease, and that drugs that target the mutant forms of the enzymes can reverse their oncogenic effects.

In the results reported in one of these research articles, Agios researchers tested a mutant-IDH2 inhibitor in hematologic malignancies (including one model leukemia and one patient-derived leukemia), and showed that treatment with the inhibitor caused differentiation of the leukemic cells to normal blood cells. This preclinical study thus supports the initiation of Agios’ new Phase 1 study of AG-221 in patients with mutant-IDH2 bearing hematologic malignancies.

Additional pipeline news in Agios’ Third Quarter 2013 Report

In addition to the report of the initiation of Phase 1 studies of AG-221, Agios reported  that it had advanced AG-120, a mutant-IDH1 inhibitor, toward Investigational New Drug (IND) filing. The company plans to initiate Phase 1 clinical trials of AG-120 in early 2014, in  patients with advanced solid and hematological malignancies that carry an IDH1 mutation.

Agios also reported in their Third Quarter 2013 Report that the company had advanced AG-348 into IND-enabling studies. AG-348 is an activator of pyruvate kinase R (PKR). Germline mutation of PKR can result in pyruvate kinase deficiency (PK deficiency), a form of familial hemolytic anemia. Agios’ in vitro studies indicate that PKR activators can enhance the activity of most common PKR mutations, and suggest that these compounds may be potential treatments for PK deficiency.

Agios’ AG-348 program is part of its R&D aimed at development of treatments for inborn errors of metabolism (IEM). We discussed this program in our November 30, 2011 article on this blog.

Agios to present preclinical research at the ASH meeting in December 2013

In a second November 7, 2013 press release, Agios announced that it would present the results of the preclinical studies of its lead programs in cancer metabolism and in IEM at the 2013 American Society of Hematology (ASH) Annual Meeting, December 7-10, 2013 in New Orleans, LA.

Agios researchers will give one presentation on a study of AG-221 treatment in a primary human IDH2 mutant bearing acute myeloid leukemia (AML) xenograft model. They will also present two posters–one on a mutant-IDH1 inhibitor in combination with Ara-C (arabinofuranosyl cytidine) in a primary human IDH1 mutant bearing AML xenograft model, and another on the effects of a small molecule activation of pyruvate kinase on metabolic activity in red cells from patients with pyruvate kinase deficiency-associated hemolytic anemia.

Can Agios Pharmaceuticals become a new Genentech?

On October 13, 2013, XConomy published an article on Agios’ CEO, David Schenkein. The article is entitled “David Schenkein, Cancer Doc Turned CEO, Aims to Build New Genentech”.

As many industry experts point out, the business environment is much different from that in which Genentech (and Amgen, Genzyme and Biogen) were founded, and grew to become major companies. As one illustration of the difference between the two eras, neither Genentech nor Genzyme are independent companies today. Biogen exists as a merged company, Biogen Idec, which between 2007 and 2011 had to fend off attacks by shareholder activist Carl Icahn.

Moreover, this has been the era of the “virtual biotech company”. These are lean companies with only a very few employees that outsource most of their functions, and that are designed to be acquired by a Big Pharma or large biotech company. The virtual company strategy has been designed to deal with the inability of most young biotech companies to go public in the current financial environment. (However, there has been a surge in biotech IPOs in the past year, including Agios’ own IPO on June 11, 2013. So it is possible that the environment for young biotech companies going public is changing.)

Nevertheless, the XConomy article states that when Dr. Schenkein was in discussions with venture capitalist Third Rock on becoming the CEO of one of their portfolio companies, he stated that he wanted “a company with a vision, and investor support, to be a long-term, independent company”. As we have discussed in this blog, and also in an interview for Chemical & Engineering News (C&EN), Agios’ strategy is to build a company that can endure as an independent firm over a long period of time, and that can also demonstrate sustained performance. This strategy has been characterized (especially in the 1990s and early 2000s) as “Built to Last”, a term that I used in the interview.

Later, Agios posted a reprint of the C&EN article on its website, which it retitled “Built to Last”. This illustrates Agios’ commitment to “Built to Last”, as is more importantly shown by the company’s financial and R&D strategy.

Even if Agios cannot become the next Genentech, it–as well as a few other young platform companies mentioned in the CE&N article–might become an important biotech or pharmaceutical company like Vertex. However, all depends on the success of Agios’ products in the clinic and at regulatory agencies like the FDA, as well as the future shape of the corporate, financial and health care environment.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or an initial one-to-one consultation on an issue that is key to your company’s success, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Agios Pharmaceuticals files for an IPO

Agios Nikolaos Orfanos, Thessaloniki, Greece

Agios Nikolaos Orfanos, Thessaloniki, Greece

On June 11, 2013, Agios Pharmaceuticals (Cambridge, MA) filed with the U.S. Securities and Exchange Commission for an Initial Public Offering (IPO). The company plans to raise up to $86 million through this IPO. This news was reported by Fierce Biotech, the Boston Business Journal, and Xconomy, among others.

The Biopharmconsortium Blog has been following Agios since December 31, 2009, and we have posted three additional articles since. Our newest article, posted on December 28, 2012, announced the publication of an article  in the November 19, 2012 issue of Chemical & Engineering News (C&EN) by senior editor Lisa M Jarvis, in which I was quoted. More recently, Agios posted a reprint of that article on its website, which it retitled “Built to Last”. I had used that phrase in my quote in Ms. Jarvis’ article.

Agios specializes in the field of cancer metabolism. The company is working on multiple potential targets, with the goal of dominating that field, using its strong proprietary technology platform. Its financing strategy is aimed at building a company with the potential to endure as an independent firm over a long period of time–hence “built to last”. This contrasts with the recent trend toward “virtual biotech companies”–lean companies with only a very few employees that outsource most of their functions, and that are designed for early acquisition by a Big Pharma or large biotech company. Agios’ ambition to dominate the field of cancer metabolism requires a “built to last” strategy.

As Agios’ CEO David Schenkein said in the C&EN article, “You’re never going to get that with a one-target deal”. In support of that strategy, Agios has raised over a quarter of a billion dollars in funding. This has included two rounds of venture capital funding that raised a total of $111 million, and a partnership with Celgene that brought in a total of $141 million in upfront payments. According to the Fierce Biotech article, Celgene has committed to invest in Agios’ IPO.

As of yet, Agios has no drugs in clinical trials. However, the company has several drug candidates in early development. And according to the Fierce Biotech article, Agios intends to use the proceeds of the IPO to fund its first clinical trials. One of the company’s lead candidates, AG-221, which targets mutant isocitrate dehydrogenase 2 (IDH2), may reach the clinic soon, according to the Fierce Biotech article. Another Agios compound, AG-120, which targets mutant IDH1, is expected to enter the clinic in early 2014.

Recent developments in Agios’ research

The Biopharmconsortium Blog has been reporting on Agios’ research on mutant forms of IDH1 and IDH2, and their roles in human cancer, beginning with our December 31, 2009 article. Briefly, wild-type IDH1 and IDH2 catalyze the NADP+-dependent oxidative decarboxylation of isocitrate to α-ketoglutarate. However, mutant forms of IDH1and IDH2, which are found in certain human cancers, no longer catalyze this reaction, but instead catalyzes the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2-HG). The researchers have hypothesized that 2HG is an oncometabolite, and that developing mutant-specific small molecule inhibitors of IDH1 and IDH2 might inhibit the growth or reverse the oncogenic phenotype of cancer cells that carry the mutant enzymes.

As we reported in our December 28, 2012 article, Agios researchers and their collaborators reported a series of compounds that selectively inhibit the mutant form of IDH1. These compounds were found to lower tumor 2-HG in a xenograft model. More recently, on May 3, 2013, Agios researchers and their collaborators published two research reports in the journal Science, and the company also announced the results of these studies in a April 4, 2013 press release. According to that press release, the two reports are the first publications to show the effects of inhibiting mutant IDH1 and IDH2 in patient-derived tumor samples. These results constitute preclinical support for the hypothesis that the two mutant enzymes are driving disease, and that drugs that target the mutant forms of the enzymes can reverse their oncogenic effects.

In the first of these papers (Wang et al.), the researchers reported the development of the small-molecule compound AGI-6780 (a tool compound, not a clinical candidate), which potently and selectively inhibits the tumor-associated mutant IDH2/R140Q. AGI-6780 is an allosteric inhibitor of this mutant enzyme. Treatment with AGI-6780 induced differentiation of two IDH2-bearing tumors in vitro: a TF-1 erythroleukemia genetically engineered to express IDH2, and primary human acute myelogenous leukemia (AML) carrying the IDH2 mutation. These data provide proof-of-principle that inhibitors targeting mutant IDH2/R140Q could have potential applications as a differentiation therapy for AML and other IDH2-driven cancers.

In the second paper (Rohle et al.), Agios researchers and their collaborators focused on a selective mutant IDH1 (R132H-IDH1) inhibitor, AGI-5198 (also a tool compound), which is one of the mutant IDH1 inhibitors that we referred to in our December 28, 2012 article. The researchers studied the effects of AGI-5198 on human glioma cells with endogenous IDH1 mutations. AGI-5198 inhibited, in a dose-dependent manner, the ability of the mutant IDH1 to produce 2-HG. Under conditions of near-complete inhibition of 2-HG production, AGI-5198 induced demethylation of histone H3K9me3 in chromatin, and also induced expression of genes associated with differentiation to glial cells (specifically astrocytes and oligodendrocytes). Blockade with AGI-5198 also impaired the growth of IDH1-mutant—but not IDH1–wild-type—glioma cells. Oral administration of AGI-5198 to mice with established R132H-IDH1 glioma xenografts resulted in impaired growth of the tumors. Treatment of mice with AGI-5198 was well-tolerated, with no signs of toxicity during 3 weeks of daily treatment.

It is possible that Agios’ IDH1/2 inhibitors do not inhibit tumor growth by inducing differentiation, at least in the case of AGI-5198 in glioma. Rohle et al. noted that although high-dose (450 mg/kg) AGI-5198 induced demethylation of histone H3K9me3 and induced gliogenic differentiation markers, a lower dose of AGI-5198 (150 mg/kg) did not. Nevertheless, the lower dose of AGI-5198 resulted in a similar tumor growth inhibition as did the the higher dose. This suggests that in glioma cells, mutant IDH1 regulates cell proliferation and cell differentiation via distinct pathways. These pathways may have different sensitivities to levels of 2-HG, with the differentiation-related pathway requiring increased inhibition of levels of 2-HG than the proliferation-related program.

Is differentiation therapy with IDH1/2 inhibitors sufficient to provide efficacious treatment of AML and/or glioma?

A companion Perspective, authored by Jiyeon Kim and Ralph J. DeBerardinis (Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX), was published in the same issue of Science as Wang et al and Rohle et al. Kim and DeBerardinis note that the selective mutant IDH1 and IDH2  inhibitors produced cytostatic rather than cytotoxic effects. Specifically, they induced cancer cell differentiation rather than cell death.

It is possible that inducing a permanent state of differentiation may be sufficient for therapeutic efficacy. However, the survival (in a differentiated, nontumor state) of viable cells still containing potentially oncogenic mutations may eventually give rise to cancer. Therefore, it is important to determine whether the therapeutic effects of these compounds will persist over long periods of time.

In discussing AGI-6780 as a differentiation therapy in hematopoietic malignancies, Wang et al. compared their results to the action of all-trans retinoic acid (ATRA) on acute promyelocytic leukemia (APL). ATRA has be used to treat APL, and it apparently works via relieving a block in differentiation present in these leukemic cells. The use of ATRA in APL has thus been taken as a paradigm of differentiation therapy, and it is used as such a paradigm by Wang et al.

We discussed the case of ATRA treatment of APL in our April 15, 2010 article on this blog. APL patients whose leukemia is due to a PML-RARα translocation in their promyelocytes (who constitute the vast majority of APL patients) initially respond to differentiation therapy with ATRA, but eventually develop resistance to the drug. Combination therapy of ATRA and arsenic trioxide (As 2O 3) cures the majority of patients, rendering a cancer that was once uniformly fatal 90% curable. As discussed in our 2010 article, this was first modeled in transgenic mice, and then applied to human patients. APL patients whose leukemia is due to a PLZF-RARα translocation in their promyelocytes are unresponsive to both ATRA and As 2O 3. However, as discussed in our 2010 article, the corresponding mouse model does respond to a combination of ATRA and a histone deacetylase (HDAC) inhibitor such as sodium phenylbutyrate.

When this combination therapy was tested in one patient in 1998 (presumably the first patient in a clinical trial), she achieved a complete remission. Presumably, clinical trials of newer, approved HDAC inhibitors [e.g., suberoylanilide hydroxamic acid (SAHA), Merck’s Vorinostat] in combination with ATRA could be carried out.  (The SAHA/ATRA combination has been tested in a mouse model of PLZF-RARα APL.)

As in the case of Agios’ AGI-5198, ATRA may work in part via a different mechanism than induction of differentiation in APL. This is despite this case being taken as a paradigm of differentiation therapy. We referred to this briefly in our April 19, 2010 blog post. ATRA appears to produce cancer cell growth arrest at least in part via inducing degradation of the PML-RARα fusion protein. Growth arrest and differentiation appear to be uncoupled in the case of the action of ATRA on PLZF-RARα-bearing cells. [The issue of the uncoupling of RARα transcriptional activation (which induces differentiation) and RARα degradation was investigated further in a study published in April 2013.]

Is it possible–as in the case of ATRA in APL–that Agios’ therapies for targeting mutant forms of IDH1/2 will require combination with another agent to achieve long-term therapeutic efficacy? Only clinical trials can answer this question. However, perhaps it might be possible to design animal models to test this issue, and to use these models to identify agents that may be productively used in combination with the IDH1/2 inhibitors.

Conclusions

Agios IPO comes amidst a boom in biotech IPOs–especially Boston biotech IPOs. In addition to Agios, recent Boston-area IPOs include Epizyme (Cambridge, MA), TetraPhase Pharmaceuticals (Watertown, MA) and Enanta Pharmaceuticals (Watertown, MA). According to a June 14 2013 article in the Boston Business Journal, bluebird bio (Cambridge, MA) is also expected to complete its IPO during the week of June 17, 2013. We discussed bluebird bio in our October 11, 2012 Biopharmconsortium Blog article.

As with Agios, neither Epizyme, TetraPhase, Enanta, nor bluebird has any revenues from approved and marketed therapeutics. However, unlike Agios, all of these four companies have drug candidates that have reached the clinic. In addition, TetraPhase and Enanta have compounds that have completed Phase 2 clinical trials, and thus have presumably achieved proof-of-concept in humans. Thus the stock of these two companies appear to be lower risk investments than that of Agios, despite Agios’ very compelling scientific and strategic rationale. At least until its compounds achieve proof-of-concept in human studies, investing in Agios is mainly for sophisticated investors who have a high tolerance for risk. ____________________________________________________

As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company,  please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Co-clinical mouse/human trials for cancer continue to advance

 

RAS/BRAF/PI3K pathways. Source: Source BioScience

Two previous articles on this blog have included discussions of the “co-clinical mouse/human trial” strategy for improving mouse models of human cancer, and simultaneously improving human clinical trials of drugs for these cancers. Now comes an article on the use of a co-clinical trial strategy in personalized treatment of non-small cell lung cancer (NSCLC) in the 29 March 2012 issue of Nature. In the same issue of Nature is a News and Views article by Genentech’s Leisa Johnson Ph.D. that provides a minireview of the research article.

As we discussed in our April 15, 2010 article on this blog, the co-clinical trial strategy has been developed by Pier Paolo Pandolfi, MD, PhD (Director, Cancer and Genetics Program, Beth Israel-Deaconess Medical Center Cancer Center and the Dana-Farber/Harvard Cancer Center) and his colleagues.

As discussed in that article, these researchers constructed genetically engineered transgenic mouse strains that have genetic changes that mimic those found in human cancers. These mouse models spontaneous develop cancers that resemble the corresponding human cancers. In Dr. Pandolfi’s  ongoing co-clinical mouse/human trial project, researchers simultaneously treat a genetically engineered mouse model and patients with tumors that exhibit the same set of genetic changes with the same experimental targeted drugs. The goal of this two-year project is to determine to what extent the mouse models are predictive of patient response to therapeutic agents, and of tumor progression and survival. The studies may thus result in validated mouse models that are more predictive of drug efficacy than the currently standard xenograft models.

The human clinical trials being “shadowed” by simultaneous studies in mice included Phase 3 trials of several targeted therapies for lung and prostate cancer. Xenograft models in which tumor tissue from the patients had been transplanted into immunosuppressed mice were also being tested in parallel with the genetically engineered mouse models. This project represents the most rigorous test to date of how well genetically engineered mouse models of cancer can predict clinical outcomes.

Our October 28, 2011 blog article, which is mainly a review of a 29 September 2011 Nature article by Nature writer Heidi Ledford, Ph.D., focuses on ways to fix the clinical trial system. Our article includes a discussion of a co-clinical trial published in January 2011. This trial utilized two genetically-engineered PDGF (platelet-derived growth factor)-driven mouse models of the brain tumor glioblastoma multiforme (GBM), one of which had an intact PTEN gene and the other of which was PTEN deficient. In this trial, researchers tested the Akt inhibitor perifosine (Keryx Biopharmaceuticals, an alkylphospholipid) and the mTOR inhibitor CCI-779 (temsirolimus; Pfizer’s Torisel), both alone and in combination, in vitro and in vivo. The drugs and drug combinations were tested in cultured primary glioma cell cultures derived from the PTEN-null and PTEN-intact mouse PDGF-driven GBM models, and in the animal models themselves.

The studies showed that both in vitro and in vivo, the most effective inhibition of Akt and mTOR activity in both PTEN-intact and PTEN-null cells in animals was achieved by using both inhibitors in combination.  In vivo, the decreased Akt and mTOR signaling seen in mice treated with the combination therapy correlated with decreased tumor cell proliferation and increased cell death; these changes were independent of PTEN status. The co-clinical animal study also suggested new ways of screening GBM patients for inclusion in clinical trials of treatment with perifosine and/or CCI-779.

The new co-clinical trial reported in the March 2012 issue of Nature

The March 2012 Nature report describes research carried out by a large, multi-institution academic consortium, which included Dr. Pandolfi. It focuses on strategies for treatment of patients with non-small-cell lung cancer (NSCLC) with activating mutations in KRAS (Kirsten rat sarcoma viral oncogene homolog). These mutations occur in 20–30% of NSCLC cases, and patients whose tumors carry KRAS driver mutations have a poor prognosis. Moreover, KRAS is a “hard” or “undruggable” target, and no researchers have thus been able to discover inhibitors of oncogenic KRAS.

Because of the intractability of oncogenic KRAS as a target, researchers have been attempting to develop combination therapies for mutant-KRAS tumors (including, for example, colorectal cancers as well as NSCLCs) that address downstream pathways controlled by KRAS. We discussed examples of these strategies in our book-length report Multitargeted Therapies: Promiscuous Drugs and Combination Therapies, published by Cambridge Healthtech Institute/Insight Pharma Reports in 2011. Strategies discussed in that report are based on the finding that KRAS controls signal transduction via two key pathways: the B-Raf-MEK-ERK pathway and the PI3K-Akt pathway. This is illustrated in the figure at the top of this article. As discussed in our 2011 report, researchers are attempting to develop treatments of mutant-KRAS tumors that involve combination therapies with an inhibitor of the mitogen-activated protein kinase (MEK) together with an inhibitor of phosphatidylinositol 3-kinase (PI3K). Researchers are also attempting to develop combination therapies of MEK inhibitors with standard cytotoxic chemotherapies, which if successful will avoid having to use combinations of two expensive targeted therapies.

In the co-clinical trial that is the focus of the 29 March 2012 Nature research report and News and Views commentary, researchers developed a genetically-engineered mouse model to study treatment of mutant-KRAS NSCLCs with either the antimitotic chemotherapy drug docetaxel alone, or docetaxel in combination with the MEK kinase inhibitor selumetinib (AZD6244, AstraZeneca). In the parallel human clinical trial, researchers are also studying treatment of patients with mutant-KRAS NSCLC with docetaxel alone or docetaxel plus selumetinib. (There is no treatment arm in the human clinical trial in which patients are treated with selumetinib alone, since selumetinib monotherapy of NSCLC patients had shown no efficacy in a previous Phase 2 study; this was confirmed in mouse model studies.)

In humans with mutant-KRAS NSCLC, many tumors with mutations in KRAS have concomitant genetic alterations in other genes that may affect response to therapy. Therefore, the co-clinical trial researchers wished to design mouse models with lung tumors with either Kras mutations alone or with mutations in both Kras and another gene that is often concomitantly mutated in mutant-KRAS NSCLCs in humans. The researchers therefore constructed mouse models with cancers bearing the activating Kras(G12D) mutation, either alone or together with an inactivating mutation in either p53 or Lkb1. The researchers achieved this via a conditional mutation system using nasal instillation of specifically genetically-engineered adenoviruses. As result, a small percentage of lung epithelial cells harbored these mutations. It is from these cells that the NSCLC-like tumors arose, analogous to the clonal origin of sporadic lung tumors in humans.

Of the two tumor suppressor genes that are frequently mutated in human mutant-KRAS NSCLCs and that were modeled by the co-clinical trial researchers, p53, often called the “guardian of the genome”, is familiar to most of you. The other gene, Lkb1 [liver kinase B1, also known as serine/threonine kinase 11 (STK11)], was discussed in an earlier article on the Biopharmconsortium Blog, entitled “The great metformin mystery–genomics, diabetes, and cancer.”

LKB1 (whether in regulation of gluconeogenesis in the liver or in its role as a tumor suppressor) acts by activation of AMPK (AMP-activated kinase, a sensor of intracellular energy status.) In lung cancer (as shown by the same group that performed the 2012 co-clinical trial), LKB1 acts to modulate lung cancer differentiation and metastasis.  Germline mutations in LKB1 are associated with the familial disease Peutz-Jegher syndrome, in which patients develop benign polyps in the gastrointestinal tract. Studying a mouse model of mutant-LKB1 Peutz-Jeger syndrome, Reuben J. Shaw (Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA, who was prominently mentioned in our “great metformin mystery” article) and his colleagues showed that the LKB1-AMPK pathway downregulates the mTOR pathway–specifically the rapamycin-sensitive mTOR complex 1 (mTORC1) and its downstream effector hypoxia-inducible factor-1α (HIF-1α). HIF-1α expression in turn upregulates the expression of its downstream effectors hexokinase II and glucose transporter 1 (GLUT1), which are involved in cellular utilization of glucose. LKB1-deficient polyps in this mouse model thus show increased expression of hexokinase II and GLUT1, resulting in dramatically increased glucose utilization.

In the new co-clinical trial, genetically-engineered mice that showed established lung tumors [as determined via magnetic resonance imaging (MRI)] were randomized to receive either docetaxel, selumetinib, or a combination of the two drugs. For tumors with only a Kras mutation, treatment with docetaxel alone resulted in a modest rate of response, with 30% of mice showing a partial response. Mice that bore mutant-Kras tumors that also had mutations in either p53 or Lkb1 had much lower rates of response to docetaxel monotherapy (5% and 0%, respectively), and more of these mice showed progressive disease on MRI or died of their disease. Of mice treated with the docetaxel/selumetinib combination, those with single-mutant Kras tumors showed a 92% overall response rate, and those with mutant Kras/p53 tumors showed a 61% overall response rate. However, mice with mutant Kras/Lkb1 cancers showed only a modest response to the docetaxel/selumetinib combination; 33% of mice achieved a partial response. The difference in response rate of mice with Kras/Lkb1 tumors to docetaxel/selumetinib compared to the other two genotypes was found to be statistically significant.

Using the genetically-engineered NSCLC mouse model in biomarker development

In human patients in clinical trials or in treatment for their cancers, performing repeated biopsies to monitor treatment is difficult. The co-clinical trial researchers therefore wished to develop less invasive means of monitoring both co-clinical and clinical trials of docetaxel/selumetinib treatment of NSCLC. They therefore tested the use of positron emission tomography (PET) with 18F-fluoro-2-deoxyglucose (FDG-PET) as an indicator of early response to therapy that could be used in the clinic.  Prior to its radioactive decay (109.8 minute half -life), 18F-FDG is a nonmetabolizable glucose analogue that moves into cells that is preferentially taken up by high-glucose utilizing cells. The researchers found that both Kras/p53 and Kras/Lkb1 tumors showed higher FDG uptake in vivo in the mouse model than did single-mutant Kras tumors. As expected from the earlier study, GLUT1 expression was elevated in Kras/Lkb1 mutant tumors. In human patients, pre-treatment, mutant KRAS/LKB1 tumors also showed a higher FDG uptake that did KRAS tumors negative for LKB1.

Treatment of the mice with docetaxel alone gave no significant changes in FDG uptake in Kras, Kras/p53, or Kras/Lkb1 tumors in vivo. However, within 24 hours of the first dosing of docetaxel/selumetinib, FDG uptake was markedly inhibited in Kras and Kras/p53 tumors. In contrast, treatment of mice with Kras/Lkb1 mutant tumors gave no appreciable decrease in FDG uptake in these tumors. These results show that early changes in tumor metabolism, as assessed by FDG-PET, predict antitumor efficacy of docetaxel/selumetinib treatment.

The FDG-PET study in this mouse model supports the use of this imaging method as a biomarker to monitor the course of treatment in humans.

Cellular signaling in mutant Kras, Kras/p53, and Kras/Lkb1 tumors

The researchers assessed activation of relevant intracellular pathways in tumors in treated and untreated mice with mutant Kras, Kras/p53, and Kras/Lkb1 lung cancers. They performed these studies using two different methods–immunostaining of cancer nodules for phosphorylated ERK, and immunoblotting of tumor lysates. In untreated mice, Kras/Lkb1 tumors show less activation of ERK than do Kras and Kras/p53 tumors, with Kras/p53 tumors showing the greatest amount of activation of the MEK-ERK pathway. Docetaxel had no discernible effect on signaling via the MEK-ERK pathway. Selumetinib alone resulted in decreased ERK activation in Kras and Kras/p53 tumors, but there was still residual activity. The docetaxel/selumetinib combination, however, was more effective in eliminating ERK activation. Pharmacokinetic studies indicated that selumetinib levels were higher in both serum and tumors of mice treated with docetaxel/selumetinib that in those treated with selumetinib alone; this might account for the more potent suppression of MEK-ERK signaling by the combination therapy as compared to selumetinib monotherapy. The researchers studied MEK-ERK activation (as determined by phospho-ERK staining) in  a set of 57 human NSCLC tumors with known RAS, p53 and LKB1 mutation status. As with the tumors in the mouse model, of seven patients whose tumors harbored the KRAS activating mutation, the three patients with concurrent p53 mutations showed higher levels of ERK activation.

The decreased activation of ERK in Kras/Lkb1 tumors suggested that these tumors utilize other pathways to drive their proliferation. On the basis of their prior studies of signal transduction in mutant-Lkb1 lung tumors, the researchers focused on AKT and SRC. Immunoblotting studies showed that Kras/Lkb1 mutant tumors had elevated activation of both AKT and SRC. As one can see from the figure at the top of this article, AKT is a downstream effector of PI3K; since the PI3K/AKT pathway regulates expression of GLUT1 and hexokinase, increased activation of the PI3K/AKT pathway is consistent with the increased uptake of FDG of mutant Kras/Lkb1 tumors. In the figure, SRC (which is not shown) represents one of the major “other effectors” controlled by RAS. These results indicate that concomitant mutation of Lkb1 in mutant-Kras NSCLCs may shift the signaling pathways that drive tumor proliferation from MEK-ERK to PI3K/AKT and/or SRC. This shift would result in primarily resistance of Kras/Lkb1 tumors to treatment with docetaxel/selumetinib.

Long-term benefits of treatment of mice with mutant-Kras and Kras/p53 tumors with docetaxel/selumetinib as opposed to docetaxel monotherapy

The researchers studied long-term treatment of mice with mutant-Kras and Kras/p53 tumors with docetaxel monotherapy versus docetaxel/selumetinib. In mice with mutant-Kras tumors, treatment with docetaxel monotherapy gave stable disease for several weeks, while docetaxel/selumetinib treatment resulted in tumor regression and slower regrowth of tumors. The addition of selumetinib to docetaxel significantly prolonged progression-free survival in these mice. In mice with Kras/p53 tumors, treatment with docetaxel alone resulted in progressive disease, but docetaxel/selumetinib treatment resulted in initial disease regression followed by progression, resulting in prolonged progression-free survival. These results indicate that treatment with combination therapy as opposed to docetaxel alone results in improved progression-free survival, but not cure, in mice with Kras– and Kras/p53-mutant tumors.

The researchers also investigated mechanisms of acquired tumor resistance in mice with mutant-Kras and Kras/p53 tumors, which had been treated long-term with docetaxel/selumetinib. In moribund animals that had received this treatment, all tumor nodules examined showed a recurrence of ERK phosphorylation. This suggested that acquired resistance could be at least in part due to reactivation of MEK–ERK signaling despite ongoing treatment with selumetinib. Evaluation of resistant tumor nodules suggested that more than one mechanism for pathway reactivation was occurring; study of these mechanisms is ongoing.

Conclusions of the new co-clinical study

The results of this co-clinical study predict that docetaxel/selumetinib combination therapy will be more effective than docetaxel monotherapy in several sub-classes of mutant-KRAS NSCLC. This prediction is consistent with the early results of a Phase 2 clinical trial of these two drug combinations in second-line treatment of patients with KRAS-mutant NSCLC.

However, the co-clinical trial also predicts that concurrent mutation of LKB1 in mutant-KRAS  tumors will result in primary resistance to docetaxel/selumetinib combination therapy, perhaps via activation of parallel signaling pathways such as AKT and SRC. Since LKB1 status is not being prospectively assessed in the ongoing human clinical trial, the presence of patients with cancers having concurrent LKB1 mutations may diminish the differences between treatment arms based solely on KRAS status. The results of the co-clinical trial suggests that researchers perform retrospective analysis of p53 and LKB1 status in samples from the concurrent human clinical trial. Future clinical trials should then be designed that involve prospective analysis to ensure sufficient enrollment of patients with all three genotypes to enable sufficiently powered sub-group analyses.

Although the results of the co-clinical trial indicate that patients with mutant KRAS/LBK1 tumors be excluded from trials of docetaxel/selumetinib treatment, the research group that has been conducting the co-clinical trial has also been conducting studies that may lead to treatment strategies for KRAS/LBK1 tumors.

The co-clinical trial also allowed researchers to design and validate biomarker strategies, specifically the potential use of the less-invasive FDG-PET to predict efficacy and to monitor treatment. The co-clinical animal-model study also enabled the discovery of mechanisms of both primary and acquired resistance that might benefit future clinical trials and discovery/development of drugs. (The studies on acquired resistance are in a early stage and are ongoing). Any mechanisms of acquired resistance discovered in co-clinical studies should be confirmed in human clinical trials by examining biopsy samples from patients who relapse on therapy. The ability to assess mechanisms of resistance in preclinical or co-clinical animal studies may enable researchers to design rational drug combination strategies that can be implemented in future clinical studies.

The results of the new co-clinical trial strengthens the contention that co-clinical trials in genetically-engineered mice can provide data that can predict the outcome of parallel human clinical trials. Co-clinical trials can also be used to generate new hypotheses for use in analyzing concurrent human trials, and for design of future clinical studies. Moreover, co-clinical trials can result in the validation of improved animal models for human cancers, which can be used in research and preclinical testing of oncology agents, and in validation of biomarkers for clinical studies in oncology. Given the inadequacy of “standard” xenograft models, which is a major factor in the high attrition rate of pipeline oncology drugs, the availability of validated genetically-engineered animal models may be expected to enable improved oncology drug development.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

Forma Therapeutics enters into two Big Pharma alliances in succession for the New Year!

 

RNase/RNase inhibitor protein-protein interaction. Dcrjsr http://bit.ly/zRrlaz

We mentioned Forma Therapeutics in two previous articles on this blog. In one article, we focused on Forma’s R&D efforts in discovering small-molecule inhibitors of protein-protein interactions (PPIs).  The other article included a discussion on Forma’s efforts in cancer metabolism.

This month–January 2012–when the new year had barely started–Forma signed two new Big Pharma alliances, covering both of these areas.

On January 5, Forma announced that it had entered into an R&D collaboration with Boehringer Ingelheim, focusing on discovery and development of small molecule drugs to address oncology-relevant PPIs. Under the terms of the agreement, Forma will receive a total of $65 million in up-front payments and research funding, and could be eligible for up to $750 million in pre-commercial milestone payments for development programs resulting from the collaboration.

As with the Genentech deal in cancer metabolism that we discussed in an earlier article, the new Boehringer Ingelheim agreement provides Forma and its shareholders several opportunities to realize early return through assets developed under the collaboration. However, details of how this might occur were not disclosed. According to a January 6, 2012 article in BioWorld Today, flexibility and liquidity (without the need for a IPO or an acquisition) are importance goal of Forma’s business development activity in general. Nevertheless, Forma CEO Steven Tregay does not rule out a future acquisition, and says that large pharmaceutical companies are interested in such a deal.

On January 10, 2012, Forma announced an exclusive alliance with Janssen Biotech (a Johnson & Johnson company), in which the companies will collaborate on the discovery, development and commercialization of novel small molecule drug candidates that target mechanisms of tumor metabolism.

Under the terms of the agreement, Forma will discover and develop drugs against a panel of tumor metabolism targets. Forma may receive up to $700 million in project and milestone funding. In addition, FORMA may receive royalties on revenues from products commercialized as a result of the collaboration. Moreover, if certain milestones are achieved during the initial phase of the collaboration, FORMA will have the opportunity to co-develop and maintain North American commercial rights to one program selected by Janssen. The two companies may also expand the collaboration to include other targets, including those in areas beyond tumor metabolism.

Once again, Dr. Tregay sees the opportunity to maintain North American rights to a product resulting from the collaboration as in line with the company’s strategy to create long-term shareholder value within Forma.

In December 2011, Forma moved its operations from Cambridge MA to Watertown MA, in the process gaining double the amount of space it had before. This will allow for the company’s growth in new internal and partnered R&D projects, and for the growth in staff that this will entail.

As we discussed in earlier articles on this blog, PPIs have been considered “undruggable” targets. However, given that researchers have been able to discover and in at least one case develop small-molecule agents to address this class of targets, it is best to think of this area as a premature technology. As discussed in our July 27, 2011 article, Forma believes that it has developed a set of enabling technologies to move the PPI field up the technology curve, similar to what happened to the monoclonal antibody field in the 1990s. Apparently, several partner organizations–not only Boehringer Ingelheim, but also Novartis and the Leukemia & Lymphoma Society–agreed with Forma enough to invest in partnerships in this area.

Forma is not the only Boston-area biotech to have a major program in discovery of drugs that modulate PPIs. Ensemble Therapeutics (Cambridge, MA), has internal programs and partnerships in discovery of small-molecule compounds that target PPIs, and Aileron Therapeutics (Cambridge, MA), which we discussed in our November 27th 2009 and our August 24th 2010 blog articles, is developing peptide compounds designed to target PPIs in internal and partnered programs.

As for cancer metabolism, Forma is once again not the only Boston-area biotech to have major programs in drug discovery in this area. We have discussed Agios Pharmaceuticals, which specializes in that area, in our December 31, 2009, April 23, 2010, and November 30, 2011  Biopharmconsortium Blog articles.

In our December 22, 2010 blog article, we discussed the field of intermediary metabolism, asking “Will intermediary metabolism be a hot field of biology again?” In the 1920s through the 1950s, intermediary metabolism was a hot field of biology, but the field was eclipsed by molecular biology starting with the Watson and Crick paper in 1953. However, largely as the result of research that combines intermediary metabolism and molecular biology, metabolism is coming to the forefront of biomedicine again. In the area of cancer metabolism, researchers such as signal-transduction pioneer (and Agios scientific founder) Lewis Cantley have been combining the two fields in order to understand cancer disease pathways, with implications for drug discovery and development.

All of the companies mentioned in this article are research-stage companies, with no drug candidates yet beyond the preclinical stage. The strategies of these companies, and the compounds that have resulted from them, thus must be validated in clinical studies. Nevertheless, we are encouraged by these companies’ success so far, and the interest show in them and their science and technology platforms by large pharmaceutical companies. The success of these companies also provides an object lesson–premature technologies and neglected fields may at least in some cases provide opportunities for drug developers.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

Cancer metabolism specialist Agios Pharmaceuticals continues its spectacular fundraising success

 

Agios Nikolaos, Crete http://bit.ly/uNaFMW

On November 17, 2011, Agios Pharmaceuticals (Cambridge, MA), arguably the leader in cancer metabolism R&D, secured $78 million in an oversubscribed Series C financing.

The company intends to use the proceeds of this financing to advance its preclinical cancer metabolism therapeutics into the clinic, and to expand its R&D efforts into inborn errors of metabolism (IEMs). IEMs comprise a large class of inherited disorders of metabolism, most of which are defects in single genes that code for metabolic enzymes. These conditions have a high level of unmet medical need.

Investors participating in this round included Agios’ existing strategic partner Celgene, existing investors ARCH Venture Partners, Flagship Ventures and Third Rock Ventures, and several new, undisclosed investors, including three leading large public investment funds. In conjunction with the new financing, Perry Karsen, COO of Celgene, joined Agios’ Board of Directors.

Despite being only a preclinical-stage biotech company, and despite the tough early-stage biotech venture capital market, Agios has done very well in fundraising.  In April 2010, as discussed in a Biopharmconsortium Blog article, Agios secured a $130 million upfront payment in a strategic collaboration with Celgene. In October 2011, Celgene extended its collaboration with Agios from three to four years, including making an additional $20 million payment to Agios. According to a November 11, 2011 Fierce Biotech article, Agios has secured a total of over a quarter of a billion dollars in financing, beginning with its $33 million Series A round in July 2008.

Also according to Fierce Biotech, by bringing in public investors in its new financing round, Agios has taken a financing route that has enabled other biotechs to go public. For example, Ironwood Pharmaceuticals took this route. Agios’ CEO, David Schenkein, told Fierce Biotech that his management intends to build an independent company for the long term, including securing an investor base that could support a public offering.

The Biopharmconsortium Blog has been following Agios since December 2009. See our December 31, 2009 and April 23, 2010 articles. Also see our December 22, 2010 article on the reemergence of intermediary metabolism as an important field of biology, which highlighted the role of Agios in developing applications of this field to oncology therapeutics.

Recent research at Agios

More recently, Agios researchers and academic collaborators led by Agios Scientific Advisory Board member David Sabatini M.D., Ph.D (Whitehead Institute and Massachusetts Institute of Technology, Cambridge MA) published a study in the 18 August 2011 issue of Nature. In this study, the researchers demonstrated that 70% of estrogen receptor (ER)-negative human breast cancers exhibit amplification and elevated expression of the gene for phosphoglycerate dehydrogenase (PHGDH). PHGDH catalyses the first step in the serine biosynthesis pathway, and breast cancer cells with high PHGDH expression have increased flux through this pathway. This in turn results in increased levels of α-ketoglutarate, which is a tricarboxylic acid (TCA) cycle intermediate. (The TCA cycle, the central pathway in intermediary metabolism, was illustrated in the figure at the top of our December 22, 2010 blog post).

Suppression of PHGDH [via RNA interference (RNAi)] in breast cancer cell lines with elevated PHGDH expression, but not in those without, causes a strong reduction in cell proliferation, a reduction in serine synthesis, and a reduction in levels of α-ketoglutarate. This result indicates that most ER-negative breast cancers are dependent on deregulation of the serine synthesis pathway, and that targeting this pathway may provide a novel therapeutic strategy for this subset of breast cancers.

In the September 2011 issue of Nature Genetics, Agios founder Lewis C. Cantley, Ph.D., and Agios advisor Matthew Vander Heiden, M.D., Ph.D., (Beth Israel Deaconess Medical Center/Harvard Medical School and MIT, respectively) published a report that provides further evidence that amplification of PHGDH and deregulated activity of the serine pathway are linked to the growth and survival of certain cancers, especially melanoma and subtypes of breast cancer. This study was carried out using a novel research method called metabolic flux analysis, which is an important component of Agios’s technology platform in cancer metabolism.

These studies provide additional validation for the field of cancer metabolism as a source of novel therapeutic strategies.

Pharmaceutical industry interest in cancer metabolism

Agios is not the only company that is active in the field of cancer metabolism. For example, Forma Therapeutics (Cambridge, MA) is also conducting R&D in this field. According to an article in XConomy Boston, Forma entered into a collaboration with Genentech in cancer metabolism on June 27, 2011. Under the agreement, Genentech will receive exclusive rights to acquire one of Forma’s early preclinical-stage cancer metabolism drugs. In return, Forma will receive an upfront payment, research support, R&D milestone payments, and development funding for that drug. If Genentech decides to acquire the drug after it has met its development goals, Forma will forgo any royalty payments. Instead, Genentech will make an asset buyout payment, which will be distributed to Forma’s investors. In addition, Forma will receive milestone payments on sales of the drug.

Thus Forma’s investors will receive a return on their investments, without the need for an acquisition or an initial public offering. Forma will thus remain an independent company, free to develop its other pipeline drugs, including any other of the approximately 8-10 cancer metabolism drugs that it has already discovered.

This deal, which is made possible by the industry’s keen interest in cancer metabolism-based therapeutics, suggests that Forma, like Agios, intends to remain an independent company over the long haul. Forma has raised over $50 million in venture capital so far, and has revenue-producing alliances with Novartis, Cubist, and the Leukemia & Lymphoma Society as well as Genentech.

Conclusions

Agios is leveraging the strong biotech/pharma industry interest in cancer metabolism, and its own leadership in the field, to build and to finance its R&D programs, and also its corporate development. However, as always, all will depend on the performance of the company’s compounds in the clinic. Dr. Schenkein is providing no information on the timeline for entry of Agios’ drugs into clinical trials. However, he says that the funding secured by Agios will provide the means to get its lead drugs through proof-of-concept studies in humans.

Interestingly, Agios Pharmaceuticals’ founders and management have a particular fondness for the Greek language. At the apex of Agios’ values is arete (ἀρετή), an ancient Greek word that connotes virtue, excellence, and courage and strength in the face of adversity. CEO Schenkein also adds another meaning, “living up to ones potential”.

“Agios” itself is a Greek word (Άγιος), which means “holy” or “Saint”. This is why I chose the figure at the top of this article. It is a photo of the town of Agios Nikolaos (Άγιος Νικόλαος), Crete, which is named for Saint Nicholas.
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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

Will intermediary metabolism be a hot field of biology again?

Citric acid cycle

The 3 December issue of Science featured a Special Section on metabolism, headed by an introductory article entitled “Metabolism is Not Boring”.

Way back in the 1920s through the 1950s, intermediary metabolism was a hot field of biology. This culminated in the awarding of the Nobel Prize in Physiology or Medicine in 1953 to Hans Krebs “for his discovery of the citric acid cycle” and Fritz Lipmann “for his discovery of co-enzyme A and its importance for intermediary metabolism”.

As most of you know, that same year, 1953, Watson and Crick published the structure of DNA, which won them the Nobel Prize in Physiology or Medicine in 1962. This began the great era of molecular biology. As the result of the overwhelming success of molecular biology, the study of intermediary metabolism receded into the background. Answering most questions in leading-edge biology required little or no attention to intermediary metabolism. However, as discussed in the review article by Steven L. McKnight included in the Special Section, metabolism is coming to the forefront of biomedicine again. Research problems that require both consideration of molecular biology and of metabolism now appear as interesting and important challenges.

Considerations of intermediary metabolism have always been important in the study of what are known as metabolic diseases, especially type 2 diabetes and obesity and such related conditions as dyslipidemia. However, as detailed both in the McKnight article and in an article by Arnold J. Levine and Anna M. Puzio-Kuter, the study of intermediary metabolism has now also become important in cancer, with the discovery that alterations in metabolic enzymes can result in the production of “oncometabolites” that support the growth of cancer cells.

In an article on this blog dated December 31, 2009, we discussed research in cancer metabolism that is behind the technology platform of Agios Pharmaceuticals (Cambridge, MA). In that article, we highlighted the discovery that mutations in a metabolic enzyme, cytosolic isocitrate dehydrogenase (IDH1) are a causative factor in a major subset of human brain cancers. The wild-type form of IDH1 catalyzes the NADP+-dependent oxidative decarboxylation of isocitrate to α-ketoglutarate. However, the mutant forms of IDH1 catalyzes the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). 2HG appears to be an oncometabolite that is involved in the progression of low-grade gliomas to lethal secondary glioblastomas. Agios researchers and their academic collaborators later implicated mutations in isocitrate dehydrogenase enzymes and the production of the oncometabolite 2HG in the pathogenesis of acute myelogenous leukemia (AML).

Also discussed in our article was the Warburg effect, in which cancer cells carry out aerobic glycolysis (conversion of glucose to lactate, with the production of 2 molecules of ATP even in the presence of oxygen). In contrast, most normal mammalian cells metabolize glucose to CO2 and water via glycolysis coupled to the mitochondrial citric acid cycle, generating 36 molecules of ATP. Agios scientific founder and signal-transduction pioneer Lewis Cantley showed that there is a connection between growth factor-mediated signal transduction and aerobic glycolysis in cancer cells. In particular, Dr. Cantley and his colleagues found that pyruvate kinase M2 (PKM2) is a link between signal transduction and aerobic glycolysis. PKM2 binds to tyrosine-phosphorylated signaling proteins, which results in the diversion of glycolytic metabolites from energy production via mitochondrial oxidative phosphorylation to anabolic processes required for rapid proliferation of cancer cells.

The McKnight and Levine and Puzio-Kuter papers also discuss the Warburg effect in cancer cells, and the role of mutations in several metabolic enzymes that contribute to malignant phenotypes. The McKnight article notes that in addition to dominant mutations in isocitrate dehydrogenates, rare recessive mutations in fumarate hydratase and succinate dehydrogenase are also associated with cancer. Mutations in the genes for these enzymes, coupled with loss of the wild-type allele, result in elevated intracellular levels of fumarate and succinate, respectively. These appear to act as oncometabolites that can induce activation of the hypoxia response pathway, which triggers the induction of aerobic glycolysis (the Warburg effect) and angiogenesis.

The Levine and Puzio-Kuter paper also discusses the role of oncogenes and tumor suppressor genes and their signaling pathways in regulating metabolism and in particular in inducing the Warburg effect. For example, p53 regulation suppresses the Warburg effect and promotes mitochondrial oxidative metabolism. Thus the loss of p53 function seen in most human cancers tends to promote aerobic glycolysis. Other signaling pathways that have been implicated in cancer-associated changes in metabolism include the Akt and mTOR pathways, which are frequently altered by mutations in key genes (e.g., mutations in PTEN and amplifications of such growth factor receptors as Her2 and EGFR) in cancer.  Deregulation of these pathways activates the hypoxia response pathway, thus triggering the Warburg effect.

Levine and Puzio-Kuter suggest that research aimed at a deeper understanding of how cancer-associated signaling pathways regulate biochemical metabolic pathways and trigger the Warburg effect, and the role of the Warburg effect in the pathogenesis of cancer, may lead to novel drug discovery strategies in oncology.

The Special Section on metabolism also includes an article on autophagy, a process by which cells break down cellular components in order to eliminate damaged biomolecules and organelles or to provide substrates for metabolism in case of starvation. Although autophagy promotes the health of cells and can prevent degenerative diseases, it can also enable cancer cells to survive in nutrient poor tumors.

There is also a review by Jay Keasling on metabolic engineering to produce such substances as natural product drugs, chemicals, and biofuels. Metabolic engineering is a branch of synthetic biology that engineers metabolic pathways to produce such substances, hence the inclusion of this review in the Special Section on metabolism. We have several articles on synthetic biology on this blog, most of which focus on metabolic engineering and its role in drug manufacture and drug discovery.

All in all, the 3 December Special Section on metabolism is worth reading by basic researchers, and by drug discovery and development researchers in biotechnology and pharmaceutical companies. It may broaden your perspectives, and lead to new ideas for R&D or partnering, especially in oncology drug discovery.
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