News

Innovation that Matters

Filter By

2015/07/07

SAGE Therapeutics on Fast Track towards CNS Cures

This month’s Innovation that Matters (ITM) features Albert J. Robichaud, Ph.D., chief scientific officer of Cambridge, Mass.-based SAGE Therapeutics, which is developing next-generation medicines for the treatment of rare and life-threatening central nervous system (CNS) disorders.  CNS disorders represent 35 percent of the worldwide disease burden and one of the largest global health care markets, but many available drugs do not address areas of the most urgent need and are often accompanied by side effects.  SAGE Therapeutics’ initial focus is on acute and orphan CNS indications with strong preclinical to clinical translation and accelerated development timelines. SAGE Therapeutics’ rich chemistry platform fuels a highly differentiated neuroscience pipeline and has attracted considerable attention including a highly successful IPO, fast track designation of the company’s allosteric modulator of GABAA receptors – SAGE-547 – and positive results in a phase 1/2 and exploratory trial of SAGE-547 in super refractory status epilepticus and postpartum depression, respectively. ITM was able to catch up with the fast-paced CSO: SAGE Therapeutics has decided to focus on neuroscience, an area that was abandoned by many in recent years. What is differentiating about SAGE Therapeutics’ platform? Albert: SAGE Therapeutics’ has taken a unique approach to CNS disorders by targeting therapeutic indications which are genetically, molecularly or translationally focused on two key receptor families in the brain – GABA and NMDA. These are well-known systems with potent pharmacological mechanisms, which when imbalanced are implicated in a plethora of CNS disorders. Because these are mechanisms that we understand well, we are able to target new investigational therapeutics to those and bring them rapidly into human clinical testing.   Will the platform address the obstacles faced by prior unsuccessful CNS drug development? Albert: SAGE Therapeutics has set about doing CNS drug discovery and development somewhat differently from others’ past efforts. We have targeted programs that address well-known mechanisms in the brain and are tractable and translatable from a concise collection of preclinical data. Our initial focus is on acute disorders for which there are few to no targeted treatment options, are defined by molecular or genetic patient populations and possess an objective proof-of-concept pathway. This affords us the ability to rapidly obtain data, with hard and unambiguous endpoints, and clear, rapid and efficient regulatory pathways.   How was SAGE-547 discovered and why is it unique?  Albert: SAGE-547 is a novel and proprietary formulation of the natural endogenous neuroactive steroid allopregnanolone. Although allopregnanolone has been known for decades, this potent GABAA modulator suffers from druggability issues. At SAGE Therapeutics, our focus has been on optimizing the drug properties of not just allopregnanolone, but on fit-for-purpose, novel, synthetic neuroactive steroids. To that end, we have designed and advanced a large library of proprietary drug candidates that include SAGE-689 and SAGE-217. These two potent, selective second-generation GABAA modulators are optimized for oral and parenteral administration and expand the functionality of this class of molecules beyond allopregnanolone. What differentiates SAGE-547 and our proprietary family of neuroactive steroids from other potent GABAA modulators, for example benzodiazepines, is the ability to modulate not only the synaptic GABA receptors but also the extrasynaptic GABA receptors.  Defining the utility of this important characteristic of GABA modulation is something that underscores the potential value that the team at SAGE Therapeutics has brought to patients in several highly underserved indications,  such as refractory status epilepticus, a severe condition of chronic seizure, and several orphan genetic epilepsy conditions, such as Dravet and Rett syndrome.   The FDA designated status epilepticus as an orphan indication. The FDA also designated the SAGE-547 program for fast track development. What were the factors leading to that decision and what does it mean for SAGE Therapeutics’ development program? Albert: The receipt of orphan drug designation for status epilepticus and the fast track designation are both significant regulatory milestones for SAGE-547 and the potential patients who may benefit from it.  Orphan drug designation is intended to facilitate drug development for rare diseases, including diseases with small patient populations for which there are no approved therapies.  Status epilepticus is a life-threatening seizure condition that occurs in approximately 150,000 people in the U.S. each year, of which 30,000 will die.  Currently, there are very limited treatment options for these patients and no approved drugs. SAGE-547’s receipt of orphan drug designation in May 2014 has provided important benefits for the drug’s development, including market exclusivity for the product upon regulatory approval. Similarly, SAGE-547 was granted fast track designation by the FDA last July. Fast track designation is granted to expedite the review of drug candidates that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. This advancement has provided SAGE-547 a rapid path to market, fulfilling our mission to deliver treatment options to patients with SE as quickly as possible.   What are the clinical experiences to date with SAGE-547? Albert: We have been focused on advancing SAGE-547 as rapidly as possible to bring this NCE to patients in need.  We have reported positive results from our Phase 1/2 trial of SAGE-547 in refractory status epilepticus and plan to initiate the Phase 3 pivotal trial by-mid 2015.  In the Phase 1/2 trial, we observed an unprecedented 77 percent ORR, and SAGE-547 has been well tolerated with no drug-related SAEs.  Further, a number of patients who responded to SAGE-547 have since been able to go home and return to their daily activities. Based on the positive results, we are planning to initiate the Phase 3 STATUS Trial by mid-2015. In addition, we have been using SAGE-547 to establish proof of principle in exploratory Phase 2a clinical trials for additional CNS disorders, including postpartum depression and essential tremor.  In early June, we announced top-line data from the exploratory clinical trial in postpartum depression that indicated a statistically significant improvement from baseline in depression in four women with the disease within 24 hours after administration of intravenous SAGE-547.  The continued advancement of this important drug candidate serves as the basis of the rapidly evolving library of drug candidates SAGE Therapeutics is developing.   Can you share some insight on SAGE Therapeutics’ other portfolio programs and pipeline?  Albert: As mentioned at the outset, SAGE Therapeutics’ is focused on discovery and development of compounds focused on two receptor families – GABA and NMDA.  In addition to SAGE-547, our robust pipeline of proprietary second-generation product candidates in the GABA platform is led by SAGE-689 and SAGE-217. SAGE-689 is being developed as a potential follow-on IV product for second-line adjunct status epilepticus targeted for the ER, and SAGE-217 has been designed to be dosed orally, intramuscularly and intravenously, making it suitable as a potential oral, chronic therapy for a broad number of indications.  These products have the ability to provide greater efficacy, selectivity and utility, as well as fewer off-target effects.  Phase 1 trial initiations are anticipated for both SAGE-689 and SAGE-217 in late 2015. On the NMDA receptor front, we have an advanced discovery platform that has amassed a collection of selective NMDA allosteric modulators with excellent drug-like properties.  Our goal is to rapidly identify and advance clinical candidates with utility for therapeutic indications defined by glutamate deficiency.  Together with our understanding of the GABA pharmacology, the NMDA platform discoveries affords SAGE Therapeutics a leadership position in the CNS arena with the potential to advance NCEs for several key indications of unmet need.

Read more

2015/07/02

Overcoming Challenges in Developing Antibody Drugs Against Immune Check Point Targets – An Interview with Dr. Jing Li, Vice President, WuXi Biologics

In May, Dr. Jing Li, Vice President of WuXi Biologics, presented to approximately 175 attendees at the Cambridge Healthtech Institute’s (CHI) 11th Annual PEGS Essential Protein Engineering Summit at the Seaport World Trade Center in Boston, MA. This week we sat down with Jing to continue the discussion on the topic of overcoming challenges in developing antibody drugs against immune check point targets. Can you elaborate on the mechanisms and functions of immune check-point elements?? Jing: The immune system is a very complex way to protect our body from foreign attack caused by bacteria or virus, as well as to monitor and clean our internal system (e.g,. cleaning and removing apoptotic tissue or tumor cells).  The delicate balance between activation and inhibition of the immune system is tightly regulated by the communications among various immune cells.  One such crucial communication system is the immune check-point system which utilizes multiple receptors and ligands expressed on various immune cells.  In order to easily understand the roles or functions of the immune check-point elements, let’s imagine the immune system is like a car.  One group of immune check-points elements are the “gas pedals” and the other group of immune check-point elements are the “brakes”.  These elements work together to fine-tune immune responses in order to provide an adequate immune response to a target.  Meanwhile, the elements also work together to avoid autoimmunity and the destructive effects of an excessive inflammatory response.  However, it is also well established that tumors use several mechanisms to avoid elimination by the immune system and one of those involves “hijacking” or controlling these check-point pathways. Given such complexity to the problem, why is there such a large interest in immune check-point targets? Jing: Immune check-point therapy utilizes monoclonal antibodies to release the “brakes” or to activate the “gas pedals” on suppressed T cells, allowing them to be activated and recover their antitumor activity.  This therapeutic approach has revolutionized cancer immunotherapy.  The extraordinary increases in overall survival of human cancer patients have been noted against two immune check-point targets CTLA-4 (cytotoxic T lymphocyte-associated protein 4) and anti-PD-1 (programmed cell death receptor-1) in melanoma and other malignancies.  The approval of anti-CTLA-4 antibody, Ipilimumab (BMS), and the recent approvals of two anti-PD-1 antibodies, Pembrolizumab (Merck)  and Nivolumab (BMS), have greatly attracted more attention to the immune check-point therapy field. This is exciting for the field of oncology, are antibodies to these immune check-point inhibitors the answer and if so, how do we generate such drug candidates? Jing: Antibodies are ideal because they can be engineered to be highly specific, stable, easy to manufacture, well-tolerated in vivo and with high affinity to the target of interest.  There are several approaches to generate antibody therapeutic candidates.  The classic approach is to immunize rodents to generate rodent hybridoma clones expressing functional antibodies. Since the rodent generated antibodies will not be recognized as “self” in the human body and thus may be cleared quickly from the body or cause immune damage due to its immunogenicity, this approach has to be followed by further antibody engineering called humanization to reduce the immunogenicity of the original parental rodent antibodies. This approach has been successfully run for many projects in our group. Alternatively, we can generate hybridoma cell clones expressing fully human antibodies using OMT rats, which are transgenic rats expressing only the human antibody repertoire.  We have formed a strategic partnership with OMT, which de facto gives us the exclusive status of using OMT transgenic rodents in China.  The third approach is to screen for therapeutic candidates from human antibody libraries. The candidates from these libraries are fully human antibodies as well. We have established our own internal proprietary human antibody libraries, and they are ready for use in drug discovery. What would be the special challenge in developing therapeutic antibodies against immune check-point targets? Jing: One critical step in drug discovery and development is to test your therapeutic candidates in certain disease relevant animal models to verify your therapeutic rational and test the efficacy of your therapeutic candidates.  The commonly used preclinical animal models for cancer drug discovery are xenograft mouse models, which are mice implanted with human cancer cells.  However, the cancer immune therapy needs to leverage the inherent mouse immune system to exert its anti-tumor activities.  The immune system and tumor in the animal models have to be in the same immune background.  So the conventional xenograft mouse models may not fit immune therapy drug discovery.  The syngenic mouse tumor models, in which the syngenic mouse tumor cells are implanted in mice, have to be used. This will require your therapeutic antibody candidates to cross-react to mouse targets in such syngenic mouse tumor models. The general protein sequence homology between human and mouse species for those known immune check-point targets is pretty low, posing significant challenge on generating such cross-reactive antibody drug candidates for preclinical in vivo testing. What would be the solution and how easy is that to do? Jing: We need to carefully design our work flow of antibody generation to maximize our chance to achieve the same human and mouse target cross reactivity.  As you can imagine, with such low target protein sequence homology between human and mouse species, to develop a therapeutic monoclonal antibody that has high affinity for both the human and mouse target, is also highly specific, efficacious, soluble, and stable and can be manufactured easily is not trivial.  All of these selection criteria I’ve just mentioned make finding the ideal antibody candidate for clinical trials a real challenge.  Using these various selection criteria, we must screen thousands of antibodies just in the hope of finding 3-5 ideal therapeutic candidates.  In case we cannot find a good candidate which can cross-react with both the human and mouse target with equal activities, we have to initiate a parallel program to generate a surrogate antibody which recognizes the mouse target, for the purpose of verifying the therapeutic rational in preclinical animal models.  Both the human therapeutic antibody and the mouse surrogate antibody must be well-characterized and perform similarly in vitro. This requires though a very experienced team like we have at WuXi  to generate and characterize these complex biological molecules. In your talk you mentioned the using multiple discovery platforms – why would you need to do that? Jing: There are many different antibody discovery platforms and technologies that allow you to screen thousands of antibodies.  However, each of those platforms has its own unique strengths and weaknesses.  We’ve seen time and time again in the industry that relying on one platform may not generate the ideal antibody candidate that you’d like to take into clinical trials.  The strategy of “multiple shots on goal” has been adopted by many big pharma companies when they work on high value targets.  Thus, to overcome the challenge, to maximize your chance of success, and to expedite the drug discovery process, we’ve developed multiple different technology platforms to greatly increase the likelihood of finding the best therapeutic candidate.  You hopefully will not need to use all of them but I showed data in my talk in Boston how utilizing two of our platforms doubled the number of ideal mAb therapeutic candidates.  We were thus able to provide our clients more timely solutions or better candidates to their drug discovery problems. Can all the work you mentioned be performed at WuXi? Jing: Yes, that is what makes WuXi so unique.  Our large highly trained antibody discovery team has significant industry experience.  Many of our senior staff have worked in the biologics discovery field in big pharma for 10-20 years.  We also work closely with our colleagues in discovery biology, oncology, cell line engineering and process development to put together unsurpassed capabilities and capacities for our clients.  This single-source approach provides one-stop-shop drug discovery and development services with significant time savings and efficient trouble shooting for our clients.  Thus all the resources they need for their drug discovery and development efforts are right here in Shanghai.

Read more

2015/03/05

Advances in Targeted Therapies against Lung Cancer

Lung cancer was the leading cause of cancer death worldwide in 2012 according to WHO (World Health Organization, 2012) and the second most commonly diagnosed cancer in both men and women. Smoking is the most convincing risk factor that contributes to the development of lung cancer; other risk factors include exposure to radon, asbestos, radioactive ores, inhaled chemicals and air pollution. There are two main types of lung cancer, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) with NSCLC accounting for 85% of lung cancer cases.  The standard therapy includes surgery, chemotherapy, and radiation therapy alone or in combination. Unfortunately, the prognosis of patients with lung cancer has been poor with these conventional therapeutic approaches. The recent development of targeted therapies has made some advances in achieving a more personalized treatment and resulting in improved life quality for patients.  Below is a list of the current targeted therapies and their intended molecular and/or pathological indications. EGFR (epidermal growth factor receptor) mutations. EGFR mutation is diagnosed mostly by sequencing of the tumor samples with EGFR gene amplification detected by FISH (fluorescence in situ hybridization).  Depending on the nature of the mutations, the available EGFR-TKIs (tyrosine kinase inhibitors) include Tarceva ( Erlotinib ), Iressa ( Gefitinib ), Gilotrifs (Afatinib, previously Tomtovok and Tovok). Third generation irreversible EGFR-TKIs such as Rociletinib (CO-1686, received FDA Breakthrough Therapy Designation in 2014), Avitinib (developed by Hangzhou ACEA Pharmaceutical Research), Dasatinib, WZ-4002, Dacomitinib and AZD-9291 are in early or late clinical trial stage. K-ras mutations. K-ras mutations occur in about 25-35% NSCLC patients and correlates with history of smoking.  Currently, no drug has been approved for inhibition of mutant K-Ras gene product.  However, direct sequencing of K-ras gene in tumor samples should help with the development of an individualized therapy. EML4-ALK rearrangement. Chromosomal translocation resulting the fusion of ALK (anaplastic lymphoma kinase) and EML4 (echinoderm microtubule-associated protein-like 4) gene is observed in about 5% NSCLC cases.  This fusion is commonly detected by FISH on tumor samples.  Available targeted therapies include Xalkori ( Crizotinib ) and Zykadia ( Ceritinib ).  Second generation of ALK-TKIs include alectinib, LDK-378 and AP-26113, which are still in various clinical trial phases. BRAF mutations. Direct sequencing of BRAF gene is the method of detection currently.  Two BRAF-specific inhibitors, Zelboraf ( Vemurafenib ) and Tafinlar (Dabrafenib ) have been approved by the FDA for treatment of metastatic melanoma.  Clinical trials in lung patients with BRAF mutations are needed. MET amplification. MET amplification can lead to acquired resistance to EGFR-TKIs.  MET amplification is detected by FISH and Cometriq (Cabozatinib) is the FDA approved drug targeting this genomic change for some cancers.  But clinical data for treatment of NSCLC is not available at this time. Targeting of angiogenesis. Bevacizumab (Avastin) is a monoclonal antibody against VEGF-A (vascular endothelial factor-A) and is an option for treatment of lung cancer. There is no specific companion diagnosis for prediction of efficacy for Avastin. Blocking immune checkpoints has received a lot attention recently.  Drugs that are in various clinical development stages for treatment of lung cancer include CTLA-4 inhibitors Yervoy (ipilimumab) and tremelimumab (formerly ticilimumab, CP-675,206), PD-1 inhibitors Opdivo (nivolumab, received FDA approval in March 2015) and Keytruda (pembrolizumab, received Breakthrough Therapy Designation in 2014), and PD-L 1 inhibitors MPDL-3280A (received Breakthrough Therapy Designation earlier this year) and MED14736).  Biomarkers for selection of patients are also in development; such as determination of PD-L1 expression by immunohistochemistry (IHC) is being developed as a companion diagnosis for the use of PD-1 inhibitors.  Therapeutic vaccines targeting lung cancer that are currently in clinical trials include L-BLP25, HyperAcute (tergenpumatucel-L) and TG4010 etc. Other antibodies targeting various proteins involved in cancer and in various clinical stages for the treatment of lung cancer include Bavituximab (against phosphatidylserine), Patritumab (anti-HER3), Rilotumumab (anti-hepatocyte growth factor), Cixutumumab (anti-insulin-like growth factor-1 receptor), Erbitus (anti-EGFR receptor, also called Cetuximab), IMMU-132 (an antibody drug conjugate) and Demcizumab (anti-Delta-like ligand 4, also called OMP-21M18). “With the advances of molecular diagnostic technologies and the development of various targeted therapies, lung cancer management is marching towards a more personalized approach to reduce suffering and improve quality of life,” commented Dr. Mao Mao, Senior Vice President of Translational Bioscience and Diagnostics at WuXi AppTec.   Related Links & References: http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-key-statistics http://www.who.int/mediacentre/factsheets/fs297/en/ Haghgoo SM, Allameh A, Mortaz E, Garssen J, Folkerts G, Barnes PJ, Adcock IM. Pharmacogenomics and targeted therapy of Cancer: Focusing on Non-small cell lung Cancer.  Eur J Pharmacol. 2015 Feb 25. pii: S0014-2999(15)00136-3. Anagnostou VK, Brahmer JR. Cancer Immunotherapy: A Future Paradigm Shift in the Treatment of Non-Small Cell Lung Cancer.  Clin Cancer Res. 2015 Mar 1;21(5):976-984.

Read more

2015/03/03

The First True Anti-Aging Drug?

A clinical trial sponsored by Novartis could potentially unlock the secret of the molecular “fountain of youth” and holds the promise of an effective anti-aging drug.  The clinical trial conducted in New Zealand and Australia is a randomized, observer-blind, placebo-controlled trial that enrolled over 200 healthy volunteers age 65 or over.  The objective of the study was to investigate whether RAD001, an analog of rapamycin could improve immune functions in the elderly as assessed by response to influenza vaccination.  The results, which were recently published in  the prestigious Science Translational Medicine , show that indeed RAD001 enhanced the immune response to the influenza vaccine by about 20% in this healthy senior population..  The data from this trial demonstrate that RAD0001 can ameliorate immunosenescence, the decline of immune system functions as people ages, by increasing the antibody titers to influenza and reducing the percentage of certain population of T lymphocytes, whose number increases with age. Rapamycin was first approved by the FDA in 1999 as an immunosuppressant to prevent organ transplant rejection and is also used as a slow releasing coating in conjunction with coronary stents to prevent restenosis following balloon angioplasty.   Currently, many clinical trials are being conducted to investigate its therapeutic effects in several types of cancers and various other diseases.  In regard to anti-aging studies, resveratrol, a compound found in grapes and red wine, is also being studies by GlaxoSmithKline for its anti-aging function in certain populations.  However, rapamycin, having been shown consistently to counteract aging and age-related diseases in several mouse populations and other animals, represents the most promising candidate disrupting aging-related disease progression. With an approval history by the FDA and an excellent safety profile, research communities are hopeful that a fine-tuned dosing regimen will be developed for rapamycin to aid humans to age gracefully with a good quality of life.   Related Links: http://www.bloomberg.com/news/features/2015-02-12/does-a-real-anti-aging-pill-already-exist- http://stm.sciencemag.org/content/6/268/268ra179.short http://www.biospace.com/News/novartis-ag-may-already-have-first-true-anti-aging/364651?type=email&source=GP_021315

Read more

2015/02/26

Genentech’s New Combination Chemotherapy Prolonged Breast Cancer Patient Lives for Extra 16 Months

A phase III clinical trial sponsored by Genentech using a combination of chemotherapy drugs showed unprecedented results in patients with metastatic HER2-positive breast cancer.  The outcome of this study is published in the February issue of the prestigious New England Journal of Medicine.  The trial enrolled over 800 patients with metastatic HER2-positive breast cancer and randomly assigned them to treatment group (pertuzumab + trastuzumab + docetaxel) or control group (placebo + trastuzumab + docetaxel).  The treatment group extended lives by close to 16 months compared to the control group, a result that is so impressive that “doctors have rushed to make it standard therapy”.  In addition, pertuzumab treatment group did not present more side effects in comparison to the control group. Pertuzumab (Perjeta) and trastuzumab (Herceptin) are both humanized monoclonal antibodies developed by Genentech to combat HER2-positive cancer cells.  These two antibodies target different HER2 epitopes, consequently the combination of these two antibodies results in more comprehensive signaling blockade.  Preclinical experiments showed that combining pertuzumab and trstuzumab led to greater activity than that with either antibody alone.  Importantly, combination therapy with these two antibodies and docetaxel resulted in higher efficacy among patients receiving neoadjuvant therapy in another clinical trial, which provided the basis for Perjeta’s first FDA approval in 2013 for use in combination with Herceptin and docetaxel in patients with HER2-positive early breast cancer.  With this exciting and unprecedented result, Perjeta and Herceptin combination is poised to become the most powerful targeted therapy for HER2-positive cancers, a type of cancer notorious for aggressiveness and therapy-resistance. Genentech, based in San Francisco, California is a member of the Roche Group.  HER2 (human epidermal growth factor receptor 2) is an oncogene and it is over-expressed in about 20% breast cancers.  Breast cancer in women is the second most common type of cancer in the US.  According to the American Cancer Society, about 231,840 new cases of invasive breast cancer will be diagnosed in women and about 40,290 women will die from breast cancer in 2015 in the US.  Worldwide, breast is one of the 5 most common sites diagnosed with cancer.   Related Links: http://www.nejm.org/doi/full/10.1056/NEJMoa1413513 https://clinicaltrials.gov/ct2/show/study/NCT00567190?term=NCT00567190&rank=1&sect=Xcba9870156 http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-key-statistics http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm370449.htm

Read more