Midatech’s oncology programs 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.
Midatech’s immunotherapy franchise aims to create commercial vaccines for cancer and auto-immune diseases, that have no or limited treatment options. Midacore™ , the key underpinning technology of these vaccines, represents an innovative approach whereby gold nanoparticles are designed with antigenic peptides and other immune moieties to either i. activate and enhance the immune response against tumour cells or ii. to suppress the immune response in autoimmune diseases.
Midacore vaccines are easily injectable and rapidly mobile to lymph nodes and antigen presenting cells (APCs) – the gateway cells of the human immune system . Upon reaching the APC’s, the Midacore™vaccine is processed by the intracellular machinery, and then expressed on the surface of the APC’s via MHC class I receptors. This expression is then recognised by CD8+T-lymphocyte attacking immune cells, that then proliferate and seek out and attack cancer cells with the same peptide epitope expressed on their surface. In the case of autoimmune disease such as Type 1 Diabetesthe T lymphocytes that respond to the beta cell antigen peptide on the gold nanoparticle are CD4 T-regulatory cells that instead of stimulating the immune system actually act to dampen down the immune response and thus reduce the body attacking itself. Thus the same gold nanoparticle concept is common to both cancer and autoimmune applications, but the immune system is stimulated in the former and reduced in the latter depending on the gold nanoparticle peptide combination selected. Midacore™ has already been through regulatory assessment and shown to be safe and suitable for human administration.
Childhood Brain Cancer
The MTR111 vaccine complex comprises the gold nanoparticle bound to DIPG specific surface receptor peptide H3.3 K27 mutation. This mutation is found in 80% of DIPG tumour cells and not on normal body cells, hence is expected to result in an immune response very specific to the tumour cells. This enhanced ‘handshake’ between tumour & immune cells, facilitated by Midacore™ technology, stimulates the immune system to increase uptake by immune cells and increase stimulation of killer T-cells that attack the tumour. This program is currently in pre-clinical studies
Adult Brain Cancer
The MTR116 vaccine combines MTP gold nanoparticle technology with GBM specific surface receptor peptide survivin. The Midacore™ ultra-small nanoparticle enters immune processing cells, and induces cell-mediated immune responses and T-cell proliferation to target cancer cells with survivin targets on the cell surface, thus killing the tumour cells. This program is currently in pre-clinical phases, and preliminary data supports the strong scientific rationale for the potential benefits of Midacore™ as a vaccine platform.
Autoimmune Disease (Diabetes)
The Midacore™ technology progresses beyond the current state-of-the-art in diabetes immunotherapy
by generating an antigen specific form of immunotherapy (ASI) without the potential risks of current immunosuppressive approaches. It is a significantly more effective form of ASI than previous or current approaches due to its low toxicity approach by the use of intradermal targeting of inert, renally excreted gold nano particles. It is a low cost form of therapy that does not require clinical grade cell culture facilities or other complex facilities to deliver. The system is based on combining elements – gold nanoparticles and peptide - confirmed to be of low toxicity and already in use in a Phase I clinical trial.