The pituitary gland sits at the base of the brain and serves as the master hormone regulator, directing the delivery of hormones throughout the body. Tiburio Therapeutics is developing novel therapies for the treatment of rare endocrine diseases that result when problems occur with this master gland.
A Dual Attack
Dopamine–somatostatin chimeric compounds have evolved as a therapeutic drug class with the potential to have broad application across various endocrine diseases.1 With their chimeric structure, these compounds are thought to stabilize heterodimers that form on the surfaces of cells bearing the two different types of receptors, bringing them close together. As a result, they increase the level of activation on downstream signal transduction pathways, amplifying the overall effect.
Data from studies by Tiburio Therapeutics and others have shown that these chimeric compounds may facilitate physical interactions between dopamine and somatostatin receptors that result in enhanced activity, offering new potential for a variety of diseases with unmet need.2
Patients And Physicians Drive Innovation
Most immunotherapies on the market are designed to elicit some form of artificial immune response.The development of meaningful and sustainable products requires a deep understanding of patients’ and physicians’ perspectives on treatment needs. To drive our efforts at Tiburio, we build authentic and long-standing relationships with the patient and clinical communities that we serve.
There is an essential collaboration between the endocrine disease community and emerging biotech and other companies like Tiburio that are developing therapies. Patients and physicians have come together to drive innovation and teach us about the disease and the burden it places on people. With the community so well aligned and supportive of our drug development efforts, we are able to gain a greater understanding of the disease and identify novel pathways and targets for attacking it in different ways.
Two Clinic-Ready Assets
Tiburio Therapeutics, Inc., was launched in January 2019 by Cydan, an orphan drug accelerator dedicated to creating therapies to improve the lives of patients living with orphan diseases, to initially advance two clinical candidates for the treatment of rare neuroendocrine tumors and rare endocrine diseases licensed from Ipsen. Ipsen completed foundational work on the safety profile and mechanism of action of TBR-760 for the treatment of nonfunctioning pituitary adenoma (NFPA) and TBR-065 for additional rare endocrine diseases.
Tiburio has expanded on this initial work on the two dopamine–somatostatin chimeric compounds, giving the proper attention the program and patients suffering from these diseases deserve.
Focus On NFPA
NFPA is a serious condition that is associated with significant morbidity, which results in major impacts on patients’ lives. Non-functioning tumors arise from gonadotroph cells in the pituitary gland and account for 30% of all pituitary adenomas. They are pituitary tumors that disrupt critical structures in the surrounding area of the brain due to mass effect and may cause vision loss, compression of the carotid artery leading to stroke, cranial nerve palsies, intractable headaches, and/or hormone deficiencies.
There are no approved therapies for NFPA. Treatment is limited to trans-sphenoidal surgery (TSS), which is performed through the nose and sinus passage to remove the tumor, and/or radiation to halt tumor growth. These two treatment options come with serious and high-risk consequences and are often ineffective over the longer term. Patients also often require a complex set of medications to manage the endocrine disruption and other symptoms caused by the tumors and side effects of TSS and radiation. Typically, they require ongoing care by a multidisciplinary team of endocrinologists, neurosurgeons, and other specialists.
There has been some off-label work with agents developed for other pituitary tumors, particularly those that are dopamine agonists. We know that NFPA tumor cells express dopamine type 2 and somatostatin type 2 receptors. Unfortunately, existing dopamine agonists cross the blood–brain barrier (BBB), and longer-term use is known to cause adverse effects.
Our new dopamine–somatostatin chimeric compound TBR-760 targets both dopamine and somatostatin receptors, thus providing greater impact in terms of inhibiting NFPA cell proliferation and shrinking and stabilizing NFPAs compared with dopamine agonists alone. In addition, TBR-760 has been shown to not cross the BBB and is thus believed to offer an improved safety profile for chronic treatment, which is crucial for the successful management of NFPA.
Furthermore, in vivo studies in an aggressive mouse model of NFPA show that administering TBR-760 completely arrested tumor growth compared with treatment with somatostatin and dopamine inhibitors alone and in combination. We have also shown that TBR-760 produces a dopaminergic metabolite in vivo that contributes to its greater efficacy against NFPA. Consequently, this novel drug not only provides a synergistic effect due to its chemical structure but also brings additional dopaminergic effects, positioning the compound particularly well to target NFPA.
Tiburio is actively taking TBR-760 to the IND phase and expects to initiate a phase II clinical trial in patients with NFPA in the second half of 2020.
Targeting Rare Endocrine Disorders
Tiburio is also developing a second compound, TBR-065, for the treatment of rare endocrine disorders. TBR-065 is a dopamine– somatostatin agonist from the same family as TBR-760 and has been demonstrated to be safe and well tolerated in clinical studies. This second-generation compound does not generate the dopaminergic metabolite in vivo that is produced by TBR- 760, making it suitable for the treatment of other pituitary diseases caused by more somatostatin-based adenomas, including acromegaly, Cushing’s disease, and carcinoid syndrome. We are presently determining the most ideal indication to target first.
Active Partnering Strategy
Our vision for Tiburio has been to build a broader company focused in the rare endocrine disease space. There is substantial unmet need in this area; endocrine disorders can affect everyone from neonates to older adults, and there is significant opportunity to develop therapies that can improve and extend patient lives.
The strength of Tiburio is our deep scientific and clinical endocrine expertise and our ability to rapidly progress pre-IND compounds to the filing stage and all the way through clinical development to commercial launch. We will continue to use this external innovation model to build out our pipeline. Through our active partnership strategy, we have established Tiburio as a company to which pharma/biotech/ discovery organizations with novel ideas in the rare endocrine space can bring those programs. We currently have active partnering efforts underway and expect to expand our pipeline in a real way over the next 12–18 months.
Passion And Expertise Key To Success
Tiburio was launched with a $31 million Series A financing round, which is funding the advancement of TBR-760 through human proof-of-concept for the treatment of NFPA and further clinical assessment of TBR-065 as a treatment for rare endocrine diseases. We are actively raising the next round of financing, which will allow us to take TBR-760 to a meaningful inflection point in its clinical development and potentially bring in additional compounds to further build out our pipeline.
References
- Culler, M.D. “Somatostatin-Dopamine Chimeras: A Novel Approach to Treatment of Neuroendocrine Tumors.” Horm. Metab. Res.43: 854–857 (2011).
- Halem, H. (2016). A Novel Somatostatin-Dopamine Chimeric Compound Induces Dose-Related Suppression of GHRH-Stimulated Growth Hormone Secretion and Increases Insulin Sensitivity in Normal Rats. Poster. ENDO 2016 meeting, San Francisco, CA. 2016.
