OSE Immunotherapeutics Developing Tedopi® to Jump-Start Cytotoxic T-cell Response in Lung Cancer Fight

Innovation That Matters

Tumor cells are usually recognized and destroyed through a complex mechanism of immune surveillance involving different immune cells (antigen presenting cells, macrophages, lymphocytes, proteins and mediators such as interleukins). Tumor cells can escape this surveillance mechanism by blocking immune cells’ activation. They can, for example, express specific antigens that are also expressed by normal cells, thus avoiding being recognized, or block immune cell activation checkpoints neutralizing the immune response.

OSE Immunotherapeutics, based in Nantes, France is conducting clinical trials in lung cancer indications using its novel drug Tedopi®, which the company believes can reactivate a cancer patient’s immune system and overcome tumor cells’ “camouflage.”  The drug is a proprietary combination of 10 neo-epitopes aimed at stimulating T-lymphocytes and overcoming tumor cell resistance.

OSE, whose corporate investor deck starts with, “We are armed to fight,” is led by CEO Alexis Peyroles. As part of WuXi AppTec’s Communications program to highlight innovative solutions to develop novel drugs and tests that can make a difference in patients’ lives, WuXi spoke with Peyroles about new treatment paradigms for lung cancer and how his company’s new technology might give doctors and patients new tools in fighting the second most deadly cancer.

Alexis Peyroles has more than 20 years of international management and financial control experience. He joined Sanofi-Aventis in 1996 as Financial Controller in Japan before becoming Head of Financial Control for the Baltic States. He was subsequently named Head of Activities for Business Development in Eastern Europe. In 2005, he joined the Guerbet Group (a leader in the field of contrast products, especially in medical imaging) as Financial Control Manager and in 2009 became Chief Executive Officer for Latin America, based in Brazil.

Since 2013, Peyroles has been involved in OSE Pharma, both as Chief Financial Officer and in charge of Business Development. From May 2016 (the date of the merger of OSE Pharma with Effimune) to April 2018 he served as Chief Operating Officer of OSE Immunotherapeutics, in charge of Finance, Business Development and Operations.

Peyroles graduated from EDHEC Business School and holds an Executive MBA from Imperial College in London.

WuXi: What are the challenges in lung cancer early diagnosis? Are there any specific biomarkers?

Alexis Peyroles: Lung cancer, like many other types of cancer, is significantly easier to treat when caught in its early stages rather than when the disease is advanced. Unfortunately, because symptoms arrive late, most lung cancers are diagnosed when they have already metastasized and are at an advanced stage, making these cancers hard to cure.  Early detection remains a real challenge. Traditional detection methods using CT scans and chest X-rays will soon be combined with circulating biomarker analysis to help improve early detection. Some of these biomarkers can be detected in blood samples, and there are a number of active developmental programs looking at the potential for liquid biopsies with the objective to make possible early diagnosis via blood-based analysis.  

In addition, many top cancer research centers are building large tissue banks with specimens donated by patients containing samples of different tumor types. As these tumor banks grow, researchers will be able to use new bioinformatics techniques to analyze diverse arrays of tumor samples that can help identify new biomarkers that could accurately predict lung and other cancers at an early stage.

These new biomarkers will complement the already identified panels of biomarkers associated with lung cancer and will hopefully be used to develop accurate tests for early detection.

WuXi: What are the hot targets in the field of drug development for lung cancer?

Alexis Peyroles: Lung cancer is an indication that is generating a lot of positive attention and great new innovation in the field. Potential new targets for drug development in lung cancer are identified on a regular basis, but many must be validated beyond the early stages of bench research before they can truly be considered new targets.

As biomarker analysis becomes more prevalent for targeted therapies (therapies which are developed to specifically combat cancer subtypes identified by expression of known biomarkers) the identification of new targeted therapies will also become more prevalent. While targeted therapies have the potential to make a difference for subsets of patients with a particular cancer, they often don’t have the ability to be effective against larger patient populations.

Our efforts to develop novel immuno-oncology treatments are based on our belief that stimulating the immune system to generate active and sustained immune response against cancer cells is the best way to have a lasting anti-cancer effect. We are developing a number of immuno-oncology therapies; some applied to lung cancer that we hope will have a continuing beneficial therapeutic effect.

WuXi: What treatment modalities show the most potential? Are there any with the potential to treat early stage disease?

Alexis Peyroles: There are a number of promising treatment modalities that are being explored in lung cancer. However, almost all therapies in development tend to target late-stage lung cancer (Stage III/IV) since surgery or occasionally one round of chemotherapy ahead of surgery has historically proven to be effective for patients with lung cancer detected at Stage II or earlier.

Modern immunotherapies, particularly checkpoint inhibitors targeting the PD-1/PD-L1 axis, have proven to be effective in select patients with advanced lung cancer. However response rates with modern immunotherapies can range from 20% to 65%, depending on the particular circumstances, which leaves a significant number of patients for which these therapies are ineffective, creating a great unmet need.

While first-generation cancer vaccine strategies initially didn’t have much success in this space, more recently the next-generation of this type of approach is gaining traction in the research community. At OSE we’re advancing a cancer vaccine-like approach to combatting lung cancer in patients who have failed on checkpoint inhibitor therapies, which we discuss in greater detail below.

Additionally, researchers have begun to focus on identifying effective combination therapies to help increase the effectiveness of modern immunotherapies and to help overcome the tumor drug resistance that sometimes develops. By pairing two different cancer therapies there is increased potential to have a longer-lasting and more effective anti-tumor effect. Effective combinations are a major focus of clinical cancer research, and we are sure to hear more about these types of treatments in the future.

Bi-specific antibodies, which are antibodies that have two protein targets rather than one, are a new combination therapy modality that has generated recent attention. By packaging two drug targets into a single molecule, bispecific antibodies have the potential to act like combination therapies. As researchers refine this technology and create clinically test bispecific antibodies we will learn more about their potential to treat different cancers.

WuXi: How is your drug different from existing lung cancer treatments? Is it a new approach? What have been results of your research so far?

Alexis Peyroles: Our lead asset, Tedopi, is a proprietary combination of 10 neo-epitopes selected and optimized from five tumor-associated antigens aimed at stimulating T lymphocytes to recognize and attack cancer cells.

While vaccine-like approaches were used in the past to promote immune response against cancer, Tedopi is differentiated from previous attempts by its innovative design. A rational design approach was used to select neo-epitopes for inclusion in Tedopi based on tumor antigen epidemiology. We used a targeted approach to combat tumor heterogeneity by selecting well-expressed epitopes found in a variety of tumor types.

In early testing Tedopi was shown to generate a specific response of cytotoxic T cells versus cancer cells expressing at least one of these tumor-associated antigens and an associated T-helper cell response.

Phase 2 clinical studies in patients with advanced (Stage IIIB & IV) non-small cell lung cancer (NSCLC) who were treated with Tedopi showed clinical benefit and increased median overall survival compared to the expected survival in this population.

Tedopi is currently being assessed in a Phase 3 trial called Atalante 1. Atalante 1 tests HLA-A2 positive patients with NSCLC at invasive stage IIIB or metastatic stage IV, in 2nd or 3rd line treatment, following failure of a checkpoint inhibitor, compared to docetaxel or pemetrexed chemotherapy treatments in this patient population. Patients who have otherwise failed on checkpoint inhibitor therapies have no other approved treatment options, making this an area of great need.

WuXi: What is the specific mechanism of action?

Alexis Peyroles: As mentioned in the previous answer, Tedopi is intended to work by stimulating a specific cytotoxic T lymphocyte response targeted at cancer cells. The approach is based on our selection of a variety of cancer associated antigen neoepitopes widely expressed by a variety of tumor types.

By packaging 10 neoepitopes together in one vial, we have a strong chance of priming the immune system to recognize cancers that would otherwise avoid immune surveillance.

Tedopi is designed to stimulate an immune response as a single agent, as in the Atalante 1 trial, but is also being explored as a combination therapy in an ongoing Phase 2 trial in patients with advanced pancreatic cancer. In this study, Tedopi is administered both as a single agent and in combination with Nivolumab (Opdivo) to see if there is a potential anti-cancer effect by combining these two immuno-oncology agents.

WuXi: Why did you choose to focus on lung cancer? It has been a very difficult disease to treat.

Alexis Peyroles: We chose to explore the effectiveness of Tedopi in lung cancer for a number of reasons. As you mentioned lung cancer is a devastating disease that has traditionally been very difficult to treat. In the United States, lung cancer is the second most common form of cancer, causing more than 150,000 deaths each year. NSCLC, the target for Tedopi in the Atalante 1 Phase 3 trial, makes up 80-85% of all lung cancer cases. This means we’re targeting one of the largest patient populations with more than 230,000 new cases per year in the U.S. alone.

In addition to the great unmet medical need for this large patient population, lung cancer, and NSCLC in particular, has been a field with a lot of recent innovation and newly approved next generation treatment options. These include PD-1 inhibitors such as blockbuster drugs Nivolumab (Opdivo) and Pembrolizumab (Keytruda) as well as targeted treatments including Erlotinib (Tarceva), Afatinib (Gilotrif) and Gefitinib (Iressa), which are targeted therapies for patients harboring a specific and common mutation to the EGFR gene. These new agents, as well as others not directly referenced here, can be combined with chemotherapy in first line and also radiation in advanced settings to provide lung cancer patients with different options. By testing Tedopi in NSCLC, we have not only chosen a cancer with great need but also one where immuno-oncology approaches have been successful in the recent past.

The third reason why we chose NSCLC for Tedopi is directly related to my previous point. Even with all the recent advances in approved therapies, there are still many patients who do not respond to chemotherapy, radiation, targeted- and immuno-therapies. Our ongoing Phase 3 study is in a patient population that has no other available treatment options as checkpoint inhibitor therapies are not working anymore for these patients. Our goal is to provide a safe and effective new treatment option for this patient population.

WuXi: Have patients been involved in the development of your drug other than participating in clinical trials, of course?

Alexis Peyroles: Patients have been integral in the development of Tedopi. Tedopi was designed using a rational design strategy that identified cancer antigens found on a variety of different tumors. In order to identify these commonly expressed tumor antigens, our research team analyzed samples from numerous tumor biopsy samples. Without the contributions made by patients themselves, agreeing to share their tumor tissue with researchers around the globe, we would not have been able to identify the best antigens with the highest chance of instigating an immune response.

WuXi: What major challenges have you faced in trying to bring a new drug for lung cancer to patients?

Alexis Peyroles: Developing a potential new treatment for patients with lung cancer presents a number of challenges. However, an important challenge that may have overlooked presents itself as both a positive and downside. Lung cancer is a field with a lot of recent innovation and multiple new approved therapies that have come to the market in the past 5-10 years. While these therapies are beneficial for patients, they present an interesting challenge to those developing the next generation of therapeutic options.

In order to properly assess if a new drug is effective, extensive clinical testing must be performed and assessments need to be made between comparable populations of patients, some of whom receive the developmental therapy and some who don’t receive the therapy. With so many new treatments, it is increasingly difficult to find a large consistent group of patients for clinical testing. Many patients entering the clinical testing program have significant treatment histories, all of which create a different backdrop on which to try and assess drug efficacy.

With our ongoing Phase 3 clinical trial, we have had to reassess enrollment criteria to ensure that we are testing Tedopi in a representative population as well as in a consistent enough population to be able to draw significant conclusions about the potential anti-cancer effects of the treatment.

WuXi: What lessons have you learned during the development process?

Alexis Peyroles: As with any research endeavor lessons are learned with every clinical trial. An important lesson learned from our studies in lung cancer patients is that proactivity is crucial when researching new therapies within a rapidly changing treatment landscape. Designs for a clinical trial should not only take into account the current standard of care, but should also be conscious of the fact that throughout a trial the standard of care may continue to change. Adaptive clinical trial designs, particularly ones that are able to account for shifts in patient populations, have a better chance of completion without any logistical issues. Every effort to consider this challenge before finalizing a clinical study protocol will pay off in the end.

WuXi: Have you benefitted from FDA initiatives, such as Breakthrough Therapy and Fast Track designations? If so how?

Alexis Peyroles: To date we have not submitted the Tedopi program to the FDA for consideration for any initiatives such as Fast Track or Breakthrough Therapy designations. We may consider submitting Tedopi to the FDA for one of these initiatives to help streamline the regulatory process in the future.

WuXi: What other drug candidates do you have in the pipeline?

Alexis Peyroles: OSE has a number of additional drug candidates in both immuno-oncology and autoimmune disease spaces in the pipeline to complement our development of Tedopi in both NSCLC and pancreatic cancer. We have already developed several first-in-class products that activate or regulate the immune system and cover a wide range of clinical indications.

In the immuno-oncology space we are advancing BI 765063, formerly OSE-172, a selective SIRPa antagonist targeting the CD47 “don’t eat me” pathway with a differentiated mechanism of action. The CD47 axis has been very active for drug development, but based on preclinical findings we believe that we have a first-in-class product with great potential for success. In June 2019 a Phase 1 first-in-human clinical trial was initiated with our partners in development, Boehringer Ingelheim, evaluating BI 765063 in patients with solid tumors, and we look forward to announcing trial results as soon as they are available.

In addition, in March 2019 we announced a new immuno-oncology platform technology called BiCKI. Based on an engineered anti-PD-1 antibody backbone, these bispecific antibodies have the potential to modify the tumor microenvironment by delivering costimulatory signals that both increase anti-tumor T cell activities while also reinstating macrophage responsiveness to tumor tissue. We look forward to announcing the first clinical development products from this new platform in the coming months.

Our immuno-oncology pipeline is also complemented by preclinical asset OSE-703, a humanized monoclonal antibody directed against the extracellular domain of the alpha-chain of the receptor for interleukin-7 (IL7). IL7 is an immune mediator known for its key role in the hematopoietic growth of T- and B-lymphocytes. IL7 is produced by various types of cells including keratinocytes, dendritic cells, hepatocytes, neurons, and epithelial cells. It has recently been demonstrated that IL7 and the presence of IL7R can have a pro-tumor effect in various cancers by decreasing cancer cell apoptosis or accelerating cell proliferation and lympho-vascular formation.

We are also advancing a number of assets targeting autoimmune diseases. OSE-127, a humanized monoclonal antibody, is an antagonist of the IL7 receptor (IL7R) present on T effector cells, the CD127 receptor, thus down regulating the immune activity. Recent peer-reviewed publications of preclinical data on OSE-127 has demonstrated its unique mechanism of action, suggesting great potential in mediating antigen-specific blockade of memory T cells. OSE and its development partner Servier Laboratories believe this will have applications in a number of autoimmune conditions, including ulcerative colitis and Sjörgren’s syndrome, a rare autoimmune disease that attacks the glands that make tears and saliva.

We also have Phase 2-ready FR-104, a monoclonal antibody fragment and CD28 antagonist that selectively blunts CD28 co-stimulation while sparing the CTLA-4 co-inhibitory signal. The net effect of CD28 antagonism is down regulating effector T-cells while promoting T-Reg activity. Following positive Phase 1 clinical trial results demonstrating that FR104 is generally safe and tolerable, we are looking to advance this asset in the treatment of autoimmune diseases once we have found a suitable partner to work with.

WuXi: What are the top three major impediments in our delivery of “better” medicines “faster” and “better” to patients?

Alexis Peyroles: One important advancement that can greatly expedite the delivery of better medicines to patients is for researchers to think out of the box to identify novel targets that could be efficacious in treating hard-to-treat cancers that currently lack effective treatments. A major part of our research and development efforts at OSE is strong partnerships we have with premier academic institutions around the world. Academic research institutions are where much of the innovation actually occurs and we work with them to help translate academic findings into clinically relevant drug development products. As a source of innovation, we not only partner with premier oncology research centers, but also partner with centers of excellence that specialize in other fields such as transplant science. Since immunology is a major component of transplants we have gained extremely valuable insight into novel targets that may impact oncology and autoimmune disease spaces from our collaborations with transplant scientists. This innovation is a key to identifying the next potentially better new targets for drug development.

WuXi: And finally, for lung cancer what would be the one thing that has the most potential to lead a paradigm shift “from treatment to cure.”

Alexis Peyroles: Using the word ‘cure’ when discussing cancer is always tricky because by nature, cancers are a diverse set of diseases and each person’s cancer different from the next person’s, making a broad cure for cancer a challenging target. Some cancers such as advanced lung cancer are definitely not defined as “curable”. Our focus in immuno-oncology research is based on our strong belief that reactivating the cancer patient’s immune system to rehabilitate the active immune surveillance will prevent the growth, the expansion and the metastasis spreading to increase a patient’s survival and be considered as “functionally cured in some way”.

There is potential for an effective immuno-oncology treatment to have a lasting protective effect that would actively work to prevent the development of new or secondary cancers. Whether or not this ends up being a true ‘cure’ per se rather than a very long-lasting treatment effect is yet to be seen.

One thing I’m sure of is that we’re not alone in working on this endeavor. There is a huge community of researchers, scientists and drug developers actively working together to find new treatments that can potentially be effective cures for devastating cancers. This shared purpose from such a large and engaged community, aided by active patient advocates and the support of everyone that has been affected by cancer directly or indirectly, is the basis for the types of breakthrough discoveries that can turn treatments to cures. We’re excited to be a part of the future work to make this a reality.

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