Happy New Year! Source: Roblespepe. http://bit.ly/1cpkyHX

As it does every year, Science published its “Breakthrough of the Year” for 2013 in the 20 December 2013 issue of the journal.

Science chose cancer immunotherapy as its Breakthrough of the Year 2013.

In its 20 December 2013 issue, Science published an editorial by its Editor-in-Chief, Marcia McNutt, Ph.D., entitled “Cancer Immunotherapy”. The same issue has a news article  by staff writer Jennifer Couzin-Frankel, also entitled “Cancer Immunotherapy”.

As usual, the 20 December 2013 issue of Science contains a Breakthrough of the Year 2013 news section, which in addition to the Breakthrough of the Year itself, also contains articles about several interesting runners-up, ranging from genetic microsurgery using CRISPR (clustered regularly interspaced short palindromic repeat) technology to mini-organs to human cloning to vaccine design.

In the Science editorial and news article, the authors focus on the development and initial successes of two types of immunotherapy:

• Monoclonal antibody (MAb) drugs that target T-cell regulatory molecules, including the approved CTLA4-targeting MAb ipilimumab (Bristol-Myers Squibb’s Yervoy), and the clinical-stage anti-PD-1 agents nivolumab (Bristol-Myers Squibb) and lambrolizumab (Merck).
• Therapy with genetically engineered autologous T cells, known as chimeric antigen receptor (CAR) therapy, such as that being developed by a collaboration between the University of Pennsylvania and Novartis.

The rationale for Science’s selection of cancer immunotherapy as the breakthrough of the year is that after a decades-long process of basic biological research on T cells, immunotherapy products have emerged and–as of this year–have achieved impressive results in clinical trials. And–as pointed out by Dr. McNutt–immunotherapy would constitute a new, fourth modality for cancer treatment, together with the traditional surgery, radiation, and chemotherapy.

However, as pointed out by Dr. McNutt and Ms. Couzin-Frankel, these are still early days for cancer immunotherapy. Key needs include the discovery of biomarkers that can help predict who can benefit from a particular immunotherapy, development of combination therapies that are more potent than single-agent therapies, and that might help more patients, and means for mitigating adverse effects.

Moreover, it will take some time to determine how durable any remissions are, especially whether anti-PD1 agents give durable long-term survival. Finally, although several MAb-based immunotherapies are either approved (in the case of  ipilimumab) or well along in clinical trials, CAR T-cell therapies and other adoptive immunotherapies remain experimental.

In addition to the special Science “Breakthrough 2013” section, Nature published a Supplement on cancer immunotherapy in its 19/26 December 2013 issue. This further highlights the growing importance of this field.

Cancer immunotherapy on the Biopharmconsortium Blog

Readers of our Biopharmconsortium Blog are no strangers to recent breakthroughs in cancer immunotherapy. In the case of MAb-based immunotherapies, we have published two summary articles, one in 2012 and the other in 2013. These articles noted that cancer immunotherapy was the “star” of the American Society of Clinical Oncology (ASCO) annual meeting in both years.

Our blog also contains articles about CAR therapy, as being developed by the University of Pennsylvania and Novartis and by bluebird bio and Celgene. Moreover, the Biopharmconsortium Blog contains articles on other types of cancer immunotherapies not covered by the Science articles, such as cancer vaccines.

We look forward to further progress in the field of cancer immunotherapy, and to the improved treatments and even cures of cancer patients that may be made possible by these developments.

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.

Pyramidal neurons. Source: Magnus Manske http://bit.ly/1gUo6GM

In our December 10, 2013 blog article that focused on Novartis’ new neuroscience division, we briefly mentioned two young Cambridge MA neuroscience specialty companies–Rodin Therapeutics and Sage Therapeutics.

Rodin Therapeutics

Rodin was founded by Atlas Venture and the German protein structure-focused biotech Proteros biostructures in June 2013. It is focused on applying epigenetics to discovery and development of novel therapeutics for CNS disorders, especially cognitive disorders such as Alzheimer’s disease. Rodin secured funding from Atlas and Johnson & Johnson Development Corporation (JJDC). The company plans to collaborate with the Johnson & Johnson Innovation Center in Boston and Janssen Research & Development to advance its R&D programs. In addition to several partners at Atlas (led by acting Rodin Chief Executive Officer Bruce Booth, Ph.D.), Rodin’s team includes as its Chief Scientific Officer Martin Jefson Ph.D., former head of Neuroscience Research at Pfizer.

There is little information available on Rodin, because the company is operating in stealth mode.

Sage Therapeutics

Sage was founded by venture capital firm Third Rock Ventures, and officially launched on October 2011. At the time of its launch, Third Rock provided Sage with a $35 million Series A round of financing. Third Rock founded Sage together with scientific founders Steven Paul, M.D. (formerly the Executive Vice President for science and technology and President of Lilly Research Laboratories, and a former scientific director of the National Institute of Mental Health) and Douglas Covey, Ph.D. (professor of biochemistry at the Washington University School of Medicine, St. Louis, MO).

We at Haberman Associates have known Dr. Paul mainly for his work in R&D strategy while at Lilly. We cited Dr. Paul in our 2009 book-length report, Approaches to Reducing Phase II Attrition, published by Cambridge Healthtech Institute.

In October 2013, Sage received $20 million in Series B financing from Third Rock and from ARCH Venture Partners.

Sage’s technology platform is based on targeting certain classes of neurotransmitter receptors. As we discussed in our December 10, 2013 blog article, targeting neurotransmitter receptors was a successful approach to drug discovery and development decades ago, but has proven nearly fruitless ever since.

Nevertheless, Sage is taking a novel and interesting approach to targeting neurotransmitter receptors. The company is focusing on receptors for gamma aminobutyric acid (GABA) and glutamate. GABA and glutamate are, respectively, the primary inhibitory and excitatory neurotransmitters that mediate fast synaptic transmission in the brain. Specifically, Sage is focusing on GABA_A receptors (a major class of GABA receptors) and N-methyl-D-aspartic acid (NMDA) receptors (a major class of glutamate receptors).

Both GABA_A receptors and NMDA receptors are ligand-gated ion channels. These multi-subunit proteins are transmembrane ion channels that open to allow ions such as Na+, K+, Ca2+, or Cl- to pass through the membrane in response to the binding of a ligand, such as a neurotransmitter. [In addition to ligand-gated ion channels, neurotransmitter receptors include members of the G-protein coupled receptor (GPCR) family. One example is the GABA_B receptor.]

The GABA_A receptor is a pentameric (five-subunit) chloride channel whose endogenous ligand is GABA. In addition to its binding site for GABA, this receptor has several allosteric sites that modulate its activity indirectly. Among the drugs that target an allosteric site on GABA_A receptors are the benzodiazepines. Examples of benzodiazepines include the tranquilizer (anxiolytic) diazepam (Valium), and the short-term anti-insomnia drug Triazolam (Halcion).

The NMDA receptor is a heterotetrameric cation channel. It is a type of glutamate receptor. NMDA is a selective agonist that binds to NMDA receptors but not to other glutamate receptors. Calcium flux through NMDA receptors is thought to be critical for synaptic plasticity, a cellular mechanism involved in learning and memory. NMDA receptors require co-activation by two ligands: glutamate and either D-serine or glycine. (NMDA itself is a partial agonist that mimics glutamate, but is not normally found in the brain.) Among the drugs that act as NMDA receptor antagonists are the cough suppressant (antitussive) dextromethorphan and the Alzheimer’s drug memantine.

Imbalance in the levels of GABA and glutamate, or alterations in activity of their receptors can result in dysregulation of neural circuits. Such imbalance has been implicated in neuropsychiatric disorders such as epilepsy, autism, schizophrenia and pain. While GABA_A receptors and NMDA receptors are considered to be validated drug targets, a major challenge has been to modulate these receptors safely and effectively. Current drugs that act at these receptors have major adverse effects (e.g., sedation, seizures, tolerance, dependence, and excitotoxicity) that strongly impair patient quality of life. For example, long-term treatment with benzodiazepines can cause tolerance and physical dependence, and dextromethorphan can act as a dissociative hallucinogen.

Sage’s proprietary technology platform is based on the identification of members of a family of small-molecule endogenous allosteric modulators, which selectively and potently modulate GABA_A or NMDA receptors. Sage is developing proprietary derivatives of these compounds. The goal of Sage’s R&D is to discover and develop  positive and negative allosteric modulators of GABA_A and NMDA receptors that can be used to restore the balance between GABA and glutamate receptor activity that is disrupted in several important CNS disorders. These compounds will be designed to “fine tune” GABA_A and NMDA receptor activity, resulting in a greater degree of both efficacy and safety than current CNS therapeutics.

For example, in October 2013, Sage announced the publication of a research report in the October 30, 2013 issue of the Journal of Neuroscience. The report detailed the results of research at Sage, on the identification of an endogenous brain neurosteroid, the cholesterol metabolite 24(S)-hydroxycholesterol (24(S)-HC).  This compound is a potent (submicromolar), direct, and selective positive allosteric regulator of NMDA receptors. The researchers found that 24(S)-HC binds to a modulatory allosteric site that is unique to oxysterols. Subsequent drug discovery efforts resulted in the identification of several potent synthetic drug-like derivatives of 24(S)-HC that act as the same allosteric site, and serve as positive modulators of NMDA receptors. Treatment with one of these derivatives, Sage’s propriety compound SGE-301, reversed behavioral and cognitive deficits in a variety of preclinical models.

Sage’s pipeline

Sage has four pipeline drug candidates, including two compounds in the clinic. The company says that its initial pipeline focus is on “acute and orphan CNS indications with strong preclinical to clinical translation and accelerated development timelines” that enable the rapid development of important therapeutics to treat these conditions. In addition, Sage is pursuing early-stage programs that utilize the company’s PANAM platform. The goal of the early-stage programs (which target GABA_A and NMDA receptors as we discussed earlier in this article) is to address “prevalent, chronic neuropsychiatric indications.”

Sage’s pipeline drug candidates include compounds in Phase 2 trials to treat status epilepticus and traumatic brain injury, and two preclinical-stage compounds–an anesthetic a treatment for patients with fragile X syndrome.

Status epilepticus (SE) is an acute life-threatening form of epilepsy, which is currently defined as a continuous seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures for over 5 minutes. It occurs in approximately 200,000 U.S. patients each year, and has a mortality rate of nearly 20%. Refractory SE occurs in around a third of SE patients for whom first and second line treatment options are ineffective. These patients are moved to the ICU, and have little or no treatment options.

Sage’s SAGE-547, which is a proprietary positive GABA_A receptor allosteric modulator, is aimed at treatment of the orphan indication of refractory SE. This compound has been selected by Elsevier Business Intelligence as one of the Top 10 Neuroscience Projects to Watch.

In addition to SAGE-547, Sage is developing next-generation treatments for SE and other forms of seizure and epilepsy. These early-stage compounds are novel positive allosteric modulators of GABA_A receptors. Sage presented data on its early-stage therapeutics for SE in a poster session at the American Epilepsy Society (AES) Annual Meeting, Cambridge MA, December 9, 2013.

Sage’s drug candidate for traumatic brain injury is listed on the company’s website as “a proprietary, positive allosteric modulator”.

Sage’s preclinical anesthetic, SGE-202, is moving toward a Phase 1 clinical trial in 2014. It is an intravenous anesthetic for procedural sedation that designed to compete with the standard therapy, propofol. SGE-202 is designed to offer improved efficacy and safety as compared to propofol.

Fragile X syndrome (FSX) is an X chromosome-linked genetic syndrome that is the most widespread monogenic cause of autism and inherited cause of intellectual disability in males. FSX is an orphan condition that affects 60,000 – 80,000 people in the U.S. It causes such impairments as anxiety and social phobia, as well as cognitive deficits. There are no currently approved therapies for FXS, but patients are often prescribed treatments for anxiety, attention deficit hyperactivity disorder (ADHD) and/or epilepsy.

Sage is developing a proprietary positive GABA_A receptor allosteric modulator for treatment of FSX. It is expected to provide symptomatic and potentially disease-modifying therapeutic benefits to patients with FXS, and to ameliorate anxiety and social deficits. The company is moving its FXS program toward a Phase 1 clinical trial in 2014.

EnVivo Pharmaceuticals

Sage is not the only Boston-area biotech that is developing novel classes of compounds to target specific types of neurotransmitter receptors. We discussed EnVivo Pharmaceuticals (Watertown, MA), and its program to develop agents to target subclasses of nicotinic acetylcholine receptors (nAChRs), in a November 2007 report published by Decision Resources.

nAChRs, like GABA_A and NMDA receptors, are ligand-gated ion channels. In normal physiology, nAChRs are opened by the neurotransmitter acetylcholine (ACh). However, nicotine can also open these receptors. Certain subtypes of nAChRs in the brain are involved in cognitive function, and nicotine, by targeting these receptors, has long been known to improve cognitive function. However, the adverse effects of nicotine (especially its well-known addictive properties) make this drug problematic for use as a cognitive enhancer. Therefore, several companies have been working on discovering and developing subtype-specific nAChR agonists for use in such conditions as Alzheimer’s disease, schizophrenia, ADHD, and mild cognitive impairment.

EnVivo’s alpha-7 nAChR program, which targets a subtype of nChRs that have been implicated in cognitive function, has made considerable progress since 2007. Their lead compound, EVP-6124, is now in Phase 3 clinical trials for treatment of schizophrenia, and Phase 3 trials in Alzheimer’s disease are planned. This follows positive Phase 2 results in both conditions.

Outlook

Sage Therapeutics has a sophisticated approach to discovery of compounds that modulate GABA_A and NMDA receptors, and has managed to both attract significant venture financing and to move compounds into the clinic rapidly. However, none of Sage’s compounds has yet achieved clinical proof of concept, so it is too early to determine whether Sage’s approach will bear fruit.

EnVivo’s alpha-7 nAChR program is based on a more straightforward technology strategy than Sage’s. It has made considerable progress since we first covered it in 2007. EnVivo’s lead compound, EVP-6124, has had successful Phase 2 clinical trials in both Alzheimer’s disease and schizophrenia. However, both of these diseases have proven very difficult for drug developers to tackle. This is particularly true for Alzheimer’s disease–we have covered several cases in which drugs failed in Phase 3 on this blog. Therefore, it is best to reserve judgment on the outlook for EnVivo’s alpha-7 nAChR program pending the results of the Phase 3 trials.

Moreover, as we discussed on this blog, many Alzheimer’s experts believe that it would be best to target very early-stage or pre-Alzheimer’s disease rather than even “mild-to-moderate” disease as in the EnVivo Phase 2 trials.

Novartis’ new neuroscience program is a foundational, early-stage biology-driven effort, and clinical compounds are not expected for five years or so. Therefore, if Sage’s and especially EnVivo’s programs bear fruit, we should know about it long before any Novartis CNS programs progress very far at all. However, it is because of the abject failure of neurotransmitter-targeting approaches to CNS drug discovery and development over several decades that Novartis is resorting to a long-term foundational CNS R&D strategy.

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.

Eastern Bluebird

The Biopharmconsortium Blog includes several articles that are–in whole or in part–about adoptive T-cell immunotherapy [or adoptive cell transfer (ACT)] for cancer. In particular, we have produced two blog articles that discuss the Novartis/University of Pennsylvania (Penn) collaboration, which is aimed at finally commercializing adoptive immunotherapy for cancer.

• “Is Novartis Building A Viable Business Model For Adoptive Immunotherapy For Cancer?” (September 28, 2012)
•  “Leukemia–Going For The Cure!” (July 29, 2013 )

The Novartis/Penn collaboration focuses on a particular technology for ACT, known as chimeric antigen receptor (CAR) technology. In this technology, autologous T cells isolated from patient blood are engineered with retroviral vectors carrying a gene for a tumor antigen-specific CAR. The CAR enables the engineered cells to recognize specific surface proteins on tumor cells, and to go on to kill the cells.

Now we find out that at least one more company–one a lot closer to home (at least for us folks in Greater Boston)–is involved in a collaboration to develop and commercialize CAR technology for ACT. This company is bluebird bio (Cambridge, MA). As of June 24, 2012, bluebird successfully completed its initial public offering.

On March 21, 2013, bluebird announced in a press release that it had entered into a multi-year strategic collaboration with Celgene (Summit, NJ) to discover new disease-modifying gene therapies for cancer. The collaboration is to focus on applying bluebird’s gene therapy technology to the design and development of CAR T cells.

According to the news release, the bluebird/Celgene collaboration may lead to the development and commercialization of multiple CAR T-cell products. Celgene has an option to license products that result from the collaboration after the completion of a Phase 1 clinical trial for each product. bluebird bio will be responsible for R&D through Phase 1 clinical trials, and Celgene will be responsible for clinical studies beyond Phase 1 for any product that it licenses, as well as commercialization of any such product.

As also announced in the March 21, 2013 press release, Celgene has entered into a separate strategic collaboration that focuses on CAR T-cell technology with the Center for Cell and Gene Therapy at Baylor College of Medicine, Texas Children’s Hospital and The Methodist Hospital (Houston, TX). The work on CAR T-cell technology in Houston is led by Malcolm Brenner, M.D., Ph.D. (Director, Center for Cell and Gene Therapy Baylor College of Medicine). Dr. Brenner and his colleagues, for example, showed that T cells expressing a CAR specific for the GD2 tumor antigen on neuroblastoma cells produced tumor responses in over half of 19 neuroblastoma patients with refractory or active disease. Three of 11 patients with active disease achieved complete remission.

According to the March 21, 2013 news release, bluebird bio, Celgene and Dr. Brenner’s team will work collaboratively to advance and develop existing and new CAR T-cell products and programs.

Our October 2012 discussion of bluebird bio and adoptive cell transfer in the Biopharmconsortium Blog

On  October 11, 2012, we published an article on this blog entitled “Is Gene Therapy Emerging From Technological Prematurity?” This article included a section on bluebird bio, which represented the very first time we mentioned bluebird on this blog.

In this section–over 5 months before bluebird announced its agreement with Celgene–we discussed the relationship between bluebird’s technology and ACT:

bluebird bio’s platform..represents both a gene therapy technology and an adoptive cellular transfer (ACT) technology. We have discussed ACT technologies (in this case, for immunotherapy for cancer) in a previous article on this blog.  Since some of these technologies involve genetically-engineered autologous T cells, they may also be thought of as representing both ACT and a kind of gene therapy.

We are happy to learn that bluebird also realized (independent from us) the potential utility of their “gene therapy” technology for adoptive immunotherapy/ACT for cancer. We are also happy that bluebird entered into an agreement with Celgene to develop and commercialize such therapies, with the potential to give at least some cancer patients the durable complete responses that they yearn for.

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 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.

Haberman Associates now has a new website, which is available at https://biopharmconsortium.com. Our new site has an attractive, up-to-date look and feel, and also contains updated news and other updated content.

We have also fully integrated our Biopharmconsortium Blog into our new site. Our blog resides at https://biopharmconsortium.com/blog. There has been a hiatus in posting on our blog recently, due to finishing construction of our new site. Thus the last article on our blog before completion of the website was posted on April 5, 2013. However, we posted a new article on May 29, 2013, and intend to publish blog articles on a more regular basis.

The integration of the Biopharmconsortium Blog into our website emphasizes that it is the blog for our consulting group, not an independent entity or a  journalistic blog. Despite the diversity of subjects covered by the blog, the focus is on effective drug discovery and development, and on company strategies designed to facilitate effective new product development.

For more information on our consulting group, Haberman Associates, see our brief December 16, 2012 blog article, entitled What Is Haberman Associates? Better yet, you may explore our website for a more complete picture of our consulting group.

We hope that the diverse community of our readers will benefit from the discussions on our blog. We also hope that those of you in life science companies will get a feeling for how we approach issues in drug discovery and development and company strategies.

However, even the best articles or books on how to solve key industry problems will not solve these problems on their own. Companies need to develop company-specific solutions and to implement them. Haberman Associates consulting may enable your company to formulate and implement the solutions you need to improve your productivity.

If you are in  a life sciences firm, and have questions about Haberman Associates, or wish to send us a consulting inquiry or to commission us to write a report for publication, please telephone or e-mail us.