Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)
What is acromegaly and who does it affect?
Acromegaly is a chronic, life-threatening disease triggered by a benign tumour of the pituitary gland causing excessive growth hormone release.
Oversupply of growth hormone stimulates liver, fat and kidney cells to produce excess levels of Insulin-Like Growth Factor I (IGFI), which causes abnormal growth of the bones of the hands, face and feet and bodily organs.
Acromegaly most commonly affects adults in middle age. The disease is rare and is found in about 85 people in every million in the US and Europe (i.e. about 85,000).
Why can acromegaly be life threatening?
If left untreated, acromegaly can cause complications that are potentially life threatening. Body organs such as the heart and kidneys may become enlarged causing them to fail.
Other complications include cardiovascular disease, diabetes, and the risk of certain cancers.
How much is known about the causes of acromegaly?
Most cases of acromegaly are caused by benign tumours, known as adenomas, of the pituitary gland.
The pituitary gland produces growth hormone (GH) that is secreted into the blood which leads to the production of IGFI.
The pituitary tumour secretes excessive amounts of growth hormone into the body leading to elevated levels of both GH and IGFI in the blood.
What are the primary treatments for acromegaly?
The normalisation of IGF-I levels in the blood is the therapeutic goal of acromegaly treatment. The first line treatment of acromegaly is surgical removal of the tumour or its debulking.
Radiation therapy may be used if all of the tumour can’t be removed. Surgery is successful in about 60% of cases in normalising IGFI. Patients whose surgery fails receive drug treatment.
The primary medicinal treatment is a class of drugs known as the somatostatin 2 receptor agonists that reduce the production of GH. These drugs are effective in about 60% of cases in normalising IGFI.
These drugs may also shrink the size of the tumour in about a third of patients, however, they fail to normalise IGFI when the tumours express low levels of somatostatin 2 receptors.
For those that fail somatostatin therapy, pegvisomant (Somavert), a GH receptor antagonist, is used to reduce IGF-I production and to normalise IGFI levels.
Why is there an unmet medical need for acromegaly treatments and how do Antisense Therapeutics plan to help meet this?
There is an unmet medical need because there remains are large percentage of patients whose disease is not controlled by existing treatments.
A recent publication on the treatment of acromegalic patients in Germany found that over 50% of patients with elevated IGFI levels remained untreated in that country due to a range of factors including lack of treatment efficacy, patient non-compliance with their medication and the high cost of therapy making certain treatments inaccessible for patients.
Antisense Therapeutics is investigating a new way to treat acromegaly that blocks growth hormone receptor expression to reduce the levels of IGFI in the blood using antisense technology.
Our antisense drug, ATL1103, is being developed initially as a treatment for use in those patients that fail first line medicinal therapy.
The key potential advantages of ATL1103 as a 2nd line therapy include lower cost of manufacture, improved safety profile and a more convenient dosing and administration regimen (prefilled syringe; once or twice weekly dosing) which should aid patient compliance with the use of the treatment.
How does antisense technology work and how does it differ from RNAi?
Our antisense technology works by blocking the production of proteins that cause diseases. Antisense drugs are small (12-21 nucleotides) single stranded pieces of DNA or RNA that are chemically modified to engineer good drug properties.
Conventional medicines typically work by binding to a target protein directly, to interfere with the action of the disease causing protein.
Antisense drugs on the other hand, are rationally designed to bind to a specific messenger RNA sequence where they attract the enzyme RNase H to destroy the messenger RNA throughout the cell,and thereby block or stop the production of the disease causing protein in the first instance.
In acromegaly, our treatment inhibits the production of the growth hormone receptor in the liver, which in turn reduces levels of IGFI in the blood.
There are over 30 antisense drugs of the same type of chemistry as our drugs in clinical development today with one antisense drug approved by the FDA for marketing
RNAi is similar to our antisense drugs in targeting the messenger RNA to block protein production, however it does it via a different mechanism where synthetic or vector delivered double stranded RNA enters the cell’s cytoplasm to be cut by an enzyme called Dicer into double stranded small interfering RNA (siRNA) molecules.
This siRNA binds to an RNA-Induced Silencing Complex (RISC) which separates the two strands, taking one strand to a messenger RNA site to be cleaved to stop the production of the target protein.
By contrast with our antisense drugs, RNAi is at a less advanced stage of clinical development.
What do you think the future holds for acromegaly treatments?
At the moment, the drug treatments available for patients who fail first line therapy are very limited and require relatively frequent injections, mostly daily and sometimes as often as twice daily.
With ATL1103, we’re are expecting to reduce the frequency of injections required by patients and making it available in a more user friendly system that will make it easier for them to self-administer their treatment allowing patients to better manage their disease.
What are Antisense Therapeutics’ plans for the future and what other conditions are you focussing on?
We will continue to focus on advancing our antisense drug pipeline and to move these drugs into late stage clinical trials to hopefully confirm their effectiveness in treating the diseases we are targeting.
As well as a drug for acromegaly we also have an antisense drug in development to treat multiple sclerosis (MS). This drug is designed to block a particular receptor on white blood cells that stops the cells from entering the brain and attacking the protective sheath around nerve fibres that causes MS.
Where can readers find more information?
Our website is at www.antisense.com.au. We are partnered with Isis Pharmaceuticals and its website is at www.isispharm.com.
About Mark Diamond
Mark Diamond has been CEO of Antisense Therapeutics for 13 years. He has over 20 years’ experience in the pharmaceutical and biotechnology industry in senior sales, marketing and international business development roles.