Midatech’s oncology programmes address diseases with no or limited treatment options.
Carcinoid Cancer (and Acromegaly)
Midatech’s lead development product, MTD201 (Q-Octreotide), is based on the company’s polymer microsphere technology Q-Sphera for sustained release delivery. The novel innovation of Q-Sphera technology allows for higher drug loading, more precise control over drug particle size and morphology, and highly linear reproducible drug release kinetics compared to traditional and older microsphere processes.
The market leader for treatment of carcinoid and acromegaly is Sandostatin LAR™ by Novartis, who dominate this $2bn dollar market. MTD201 Q-Octreotide is being developed as a better interchangeable alternative to SLAR. Exploiting Midatech Pharma’s Q-Sphera platform, the improved sustained-release formulation used in Q-Octreotide is expected to improve injectability, avoid needle blockage, enable the use of smaller needles and reduce injection site pain compared to SLAR. Similarly, much quicker and simpler product reconstitution is expected to reduce clogging and the time the nurse/physician needs to administer the injection. Direct medical costs are expected to be reduced through decreased administration time, and significantly less wasted doses (if any). Midatech Pharma are also investigating the potential shown in preclinical studies, that MTD201 can reduce pharmacokinetic variability, leading to predictable and better controlled outcomes for patients, as well as potentially longer dosing intervals up to several months.
MTD201, like SLAR, causes normalization of growth hormone (elevation of which is the cause of these conditions). The product is administered intramuscularly once every four weeks, and will be a mainstay of treatment of both carcinoid tumours and acromegaly, without which patients would suffer severe morbidity and much higher mortality. MTD201 is being developed to be interchangeable with SLAR for the treatment of these diseases thus providing patients, physicians and payers an alternative and better choice. The product is currently in a Phase 1 / Pivotal registration programme.
The graphics below show some of the pre-clinical data, comparing MTD201 with SLAR. The aim is to achieve an MTD201 release profile that is within 80 - 125% of the reference SLAR. As illustrated in the graphs, the data is supportive of this goal, for both pharmacokinetic (octreotide levels) bioequivalence, as well as pharmacodynamic (disease biomarker levels) therapeutic equivalence.
MTD119 is the company’s lead development product re-engineered utilizing MidaCore™ gold nanoparticle technology for targeted delivery to the liver tumour site. MTD119 is an ‘ultra-small’ gold nanoparticle that carries multiple copies of the highly potent tubulin inhibitor and cytotoxic drug, mertansine DM1 (inhibits microtubule assembly and disrupts mitosis in malignant cells), together with glycan moieties that enhance uptake of the nanoparticle complex into liver cancer cells. DM1 is currently utilized in the approved antibody-drug conjugate (ADC) therapy Kadcyla® .
MTD119 research suggests that conjugation of active payloads such as DM1 with Midatech’s gold nanoparticle technology impressively re-focuses the biodistribution of the compound on the tumour site and enhances uptake of DM1 into tumour cells, which in turn substantially improves the on target efficacy and reduces the off target safety effects. MidaCore® drug conjugates such as MTD119 are being developed to repurpose and improve the delivery and efficacy of existing chemotherapeutics for liver cancer.
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, with over 700,000 individuals affected worldwide, and is the third leading cause of cancer death in the world. Survival time for patients with HCC is entirely dependent on how advanced the disease is when first diagnosed. There is no cure for advanced HCC (defined as those patients not suitable for invasive interventions such as surgical resection or liver transplant) with survival typically less than 6 months, thus there exists a significant unmet need for an effective therapy. Midatech has initiated an IND-enabling programme to study drug metabolism, pharmacokinetics, dosing, and toxicity of MTD119 which, if successful, will progress to formal IND submission in 2019.
The graphics below show some of the pre-clinical data. In preclinical safety models, doses achieved with MTD119 (GNP bound DM1) were up to three times higher than those achieved with DM1 alone. The MTD119 construct was tested in preclinical efficacy models implanted with human liver tumor cells. The figure below shows the superiority of MTD119 versus the current standard of care sorafenib, as well as versus DM1 alone. The only group of animals that completed the study was the one treated with high dose MTD119; mice treated with sorafenib or DM1 alone did poorly and did not complete the study. These findings likely reflect the impact the GNP technology has on DM1, including altered biodistribution, targeted efficacy, and reduced off target side effects.
MTX110 is Midatech’s first development programme utilising its MidaSolve nano saccharide inclusion technology that is being developed for the treatment of diffuse intrinsic pontine glioma (DIPG), an aggressive and fatal brainstem tumour in children. The active compound of MTX110 is the drug panobinostat, selected because of it being one of the most potent agents against DIPG tumour cells, as identified in independent as well as Midatech research.
However until recently panobinostat could only be administered orally due to poor solubility, which as a result is not efficacious for brain tumours since it cannot cross the blood-brain-barrier and reach the brain tumour site in therapeutic concentrations. Midatech’s MidaSolve technology however has enabled the aqueous solubility of this class of small molecule cancer therapeutic, which expands delivery options beyond the oral route to provide parenteral delivery in liquid form directly into the tumour under slight pressure via a ground-breaking technique called Convection Enhanced Delivery CED which thus bypasses the blood-brain barrier enabling delivery of therapeutics into the tumour substance via micro-catheters. This is expected to improve both the safety and efficacy of the treatment and reach the tumour site in high therapeutic concentrations. This programme is currently in a first in human combined Phase I/II clinical study.
DIPG is a highly infiltrative brainstem high grade glioma that occurs mostly in children. The tumors are aggressively infiltrative such that cancer tissue typically cannot be differentiated from normal brain tissue. The overall median survival of children with DIPG is approximately 9 months, and remains unchanged despite decades of clinical trial research. The only standard of care is palliative focal radiotherapy, but this has minimal effect on survival and essentially all children die of this disease. Surgical resection is unavailable due to the location of the tumour in the brainstem. New therapeutic strategies are urgently needed. Approximately 1,000 individuals worldwide are diagnosed with DIPG each year. MTX110 has inherent anticancer activity across a number of different brain cancer types in preclinical studies, and therefore has broader potential to be used for the treatment of other cancers including glioblastoma.
MTR103 is another of Midatech’s research programme into the brain cancer Glioblastoma Multiforme GBM. Glioblastoma can occur in children and adults and is one of the most aggressive and difficult cancers to manage. There are limited or no effective treatment options, and available drugs are often associated with significant dose-limiting toxicity. Survival is in the region of 9 to 12 months, and less than 5% or patients survive 5 years.
Midatech’s MidaCore™ and MidaSolve technologies are being evaluated on an ongoing basis in preclinical programmes for their pharmacokinetic and anti-cancer properties when delivered directly by Convection Enhanced Delivery CED. The MTR103 project is currently in the discovery phase with completion of preclinical proof of concept studies (POC) expected in 2019.