Development of a long-acting growth hormone antagonist to address the unmet need for treatment in acromegaly

Acromegaly is a disease of excess growth hormone secretion and if untreated patients suffer from disfigurement, hypertension, diabetes, arthritis and heart failure. Acromegalic patients have twice the mortality of the general population. First line therapy is surgery but in 50% of patients the tumours are inoperable or cannot be fully removed and these patients need drug therapy. Current drug therapy is not satisfactory as it either only controls the disease in a proportion of patients or involves daily injections with a drug that is not cost effective. We have developed a new technology, Profuse, for making a long-acting drug that blocks growth hormone actions and is expected to be cost effective and control the disease in >95% of patients. The DPFS application is for a 3 year grant to deliver a Profuse drug ready for clinical proof-of-concept. It is the first phase required to bring the Profuse drug to market. The next stages are a clinical trial (Phase 1/2a proof of concept trial) in patients, followed by Phase 2 & 3 trials for market authorisation.

Uncontrolled acromegaly, a disease of excess growth hormone (GH) secretion from a pituitary tumour, has a standardised mortality ratio twice that of the background population. First-line medical treatment with somatostatin analogues controls disease in only 60% of patients leaving 40% with increased mortality (Ref 1). Pegvisomant, a pegylated GH antagonist, controls acromegaly in >95% of patients; however, is rarely used because it is not considered cost-effective. Pegvisomant has low bioactivity, requires high dose, high volume daily injections, and has substantial cost of goods making it expensive and inconvenient. A cost-effectiveness study concluded Pegvisomant would require a reduction in cost by one third to achieve an acceptable incremental cost-effectiveness ratio (ICER) of £30K/QALY (Ref 15). Thus, few patients receive Pegvisomant leaving patients with uncontrolled disease. We developed a fusion technology, Profuse, for making a superior long-acting GH antagonist. The Profuse GH antagonist (GHA) is potent, has low cost of goods, requires only weekly injections and economic evaluation predicts an ICER <£20k/QALY. Profuse links GH antagonist to native GH binding protein delaying clearance and allowing weekly injections. The molecule is potent (reduced dose), has no requirement for post-purification modification (pegylation) reducing cost and potential side-effects and is stable in solution allowing use of a pen device. The DPFS application is for a 3 year grant to deliver a Profuse GH antagonist ready for clinical proof-of-concept. It is the first phase required to bring the Profuse antagonist to market, namely, late pre-clinical candidate selection, manufacture process development, formulation and toxicology. The next stages (funded separately) are a Phase 1/2a proof of concept trial in patients, followed by Phase 2 & 3 trials for market authorisation.

The project outcomes will have impact upon a broad range of non-academic beneficiaries.
i. Patients will be main the beneficiary with the development of this therapy. The proposed therapy could offer alternative treatment where existing treatments are ineffective. We expect that the new treatment can present major advantages in reduced cost of goods, potential for fewer side-effects, reduced dose requirement and greater compliance with weekly injections.
ii. Clinicians and NHS would directly benefit with alternative more cost and clinically effective treatment compare to Pegvisomant and other surgical treatments. On successful integration of the proposed therapy, NHS could offer quality healthcare to acromegaly patients by reducing drug and overall patient care cost.
iii. Researchers (co-investigators, post-doctoral fellow and research technicians): the project will give an opportunity to develop skills and knowledge in developing novel medical therapies by giving insight on translating basic research in to commercially valuable product for healthcare purpose. The project will offer direct opportunity engage with regulatory bodies and working of CROs and CMOs.
iv. Pharmaceutical industry - this research will generate a new therapeutic reagent.
v. Spin-out company Asterion which holds rights of IP can advance in raising funds for Phase 1, 2 & 3 clinical studies. This will directly/indirectly result job creation and boost local investment.
vi. Recognition of funding body where the award will contribute towards developing healthcare technologies and in generating new business ventures.

Training the next generation of scientists
All the researchers on this grant will gain specific training in a wide variety of methods and techniques. These skills will be retained and transferred on to new PhD students and post-docs. We have previously provided training to visiting students and post-docs from other institutes and anticipate this will increase further as we, ourselves develop further unique skills.