One aspect of finding the right approach for a new treatment is choosing the best technology platform. Molecules used as active substances can be divided into two classes – small and large molecules. They differ not only in terms of size, but also in how they are made, how they behave, their mode of action in the body and their suitability for certain drug forms.
Small molecules: the basis of classic drugs
Classic drug development works with small, chemically manufactured active-substance molecules. One example is acetylsalicylic acid (ASA), aspirin’s active ingredient with a molecular weight of about 180 g/mol or 180 Da. These small molecules can be processed into easily ingestible tablets or capsules. If the tablet dissolves in the gastrointestinal tract, the dissolved active substance is absorbed into the bloodstream via the intestinal wall. From there, the small molecules can reach almost any desired destination in the body because of their tiny size. Their small structure and chemical composition often also helps them to easily penetrate cell membranes.
Small molecules are synthesized in the classic way: by chemical reactions between different organic and/or inorganic compounds. Small amounts of active substance for research are made in the chemistry lab using – among other things – the familiar round-bottom flasks and rotary evaporators. The last ten years have also seen the advent of new automated synthesis methods in research laboratories that enable chemists to conduct whole series of reaction mixtures in parallel (see also Combinatorial chemistry). Click here to learn more.
Akashi Therapeutics represents a unique business model built to overcome the slowness and inefficiencies that plague rare disease drug development. The company was founded by and is owned by Charley’s Fund and the Nash Avery Foundation, putting development of its pipeline squarely in the hands of aggressive Duchenne families. The experienced management team complements the passion and focus of the founders with decades of pharmaceutical experience. The company owns three promising molecules that can be beneficial in combination or as mono-therapies. The company’s lead compound, a powerful anti-fibrotic drug, is in a phase 2 clinical trial for Duchenne patients. Akashi is also developing a selective androgen receptor modulator and a calcium channel regulator.
HT-100: A Powerful Anti-Inflammatory and Anti-Fibrotic
HT-100 is an orally available small molecule drug candidate being developed to reduce fibrosis and inflammation and to promote healthy muscle fiber regeneration in DMD patients. The application of HT-100 to DMD and other fibrotic diseases is based on pioneering work by Dr. Mark Pines at the Volcani Institute in Israel. We have been granted orphan designation for DMD in both the U.S. and EU. A phase 1b/2a clinical program is currently underway at five hospitals across the U.S. For more information on the trial, please visit www.clinicaltrials.gov
DT-200: Muscle Builder
DT-200 is an oral SARM (selective androgen receptor modulator) with positive phase 1 clinical data that has broad potential for multiple neuromuscular diseases. The next step in development is to assess the effects of DT-200 in increasing muscle mass, strength and motor function in healthy volunteers. Successful outcomes in this clinical trial will lead to further development in DMD or other neuromuscular disorders.
AT-300: Calcium Channel Inhibitor
AT-300 is a modified form of a peptide discovered in the venom of the Chilean Rose Tarantula that addresses calcium level imbalance in muscle, an early trigger of critical pathologies in DMD muscle that lead to loss of function. It is the only known specific inhibitor of the stretch-activated class of calcium ion channels. Originally discovered by researchers at the State University of New York at Buffalo, AT-300 (previously known as GsMTx-4) has been shown to positively affect cellular calcium homeostasis in preclinical DMD model studies. It is a patented new molecular entity that has been granted Orphan drug designation by the U.S. Food and Drug Administration. Click here to learn more about this molecule.
Summit is a UK-based company focused on the discovery and development of novel drug candidates to treat areas of high unmet medical need. One of two focus areas is Duchenne Muscular Dystrophy. Summit is developing a drug candidate that is designed to upregulate utrophin, a protein that can compensate for lack of dystrophin. Charley’s Fund, along with a coalition of other foundations, has supported the development of this compound. Summit has completed a phase 2 trial in Duchenne patients and is planning additional trials to further test the safety and efficacy of this compound and therapeutic approach.
Utrophin Modulation: A potential universal treatment for all DMD patients
Their utrophin modulation programme is developing oral, small molecule drugs that increase the production of a protein called utrophin. Utrophin is a naturally occurring protein that is functionally and structurally similar to dystrophin. Utrophin is produced during the early stages of muscle fibre development but is switched-off in maturing muscle fibres, at which point dystrophin is produced to perform the same functional role. When a muscle fibre is damaged, utrophin is also produced during the early stages of the repair mechanism.
Their utrophin modulation approach aims to use small molecule drugs to maintain the production of utrophin to compensate for the absence of dystrophin in DMD patients and so protect healthy muscle function. A significant advantage of utrophin modulation is that it is independent of the underlying genetic fault and therefore has the potential to treat 100% of DMD patients. We also believe it could be complementary to other DMD treatment approaches.
The concept of utilising utrophin as a treatment for DMD was developed by our co-founder and scientific advisor Professor Kay Davies at the University of Oxford.
For more information please visit Summit
PTC Therapeutics NJ-based biotech company is developing oral medications that may delay muscle degeneration in Duchenne. Several classes of compounds have been identified for four protein targets and are being optimized for safety and efficacy.
ACT DMD Clinical Trial Overview
PTC Therapeutics has completed a Phase 3 clinical trial of ataluren (formerly referred to as PTC124®) in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). The trial is referred to as the Ataluren Confirmatory Trial in DMD, or ACT DMD.
The primary objective of this confirmatory, global, randomized, double-blind, placebo-controlled trial was to assess the efficacy and safety of ataluren 10, 10, 20 mg/kg tid (given three times daily – morning, midday, evening) in patients with nmDMD. Efficacy was determined primarily by measuring changes in walking distance based on a 6-minute walk test (6MWT). The study enrolled 228 patients at approximately 50 investigational sites globally. Each participant was randomly assigned to receive either ataluren (10-, 10-, 20-mg/kg tid) or placebo (a substance that looks and tastes like ataluren but does not actually contain the drug), for 48 weeks.
Additional details about this ataluren clinical trial can be found at www.clinicaltrials.gov or by contacting PTC Therapeutics Patient and Professional Advocacy at (866) 282-5873 or (908) 912-9256 or PatientInfo@ptcbio.com. ACT DMD data was announced in October 2015 and can be found in the following press release.