Facio Therapies has selected a second series of potential candidates for FSHD drug development. This series encompasses a family of novel small-molecule compounds that repress DUX4 by engaging a molecular target that differs from the target of Facio’s first series of potential drug development candidates.

The key event in FSHD is the undue production of the DUX4 protein in skeletal muscle. DUX4 sets in motion a cascade of biochemical events that eventually result in the devastating effects of FSHD. In people without FSHD, the production of DUX4 in skeletal muscle is repressed by regulatory mechanisms. Facio’s single goal is to develop therapies that restore this repression as much as possible.

In January 2018, Facio announced the selection of a first series of potential FSHD drug development candidates. Facio pursues additional series because the severity and course of FSHD are highly variable. This makes it likely that more than one therapeutic drug will be needed to treat all people with FSHD. In order to address this issue head-on, Facio is building a portfolio of product candidates. As an additional advantage, the portfolio approach helps improve Facio’s overall chance of success (or, as the saying goes, provides “multiple shots on goal”).

David Dasberg, Facio’s Managing Director, pointed out that the compounds in both Facio’s first and second series repress DUX4 expression in a concentration-dependent, drug-like fashion without impairing the mechanism underlying muscle repair and regeneration in FSHD. “Importantly”, he added, “the compounds in our second series do so by engaging a different target. This shows the power of our strategy to apply a unique drug screening platform to identify compounds that do repress DUX4, rather than compounds that may or may not repress DUX4 by fitting one of the many possible hypotheses about how DUX4 expression is regulated.”

Looking ahead, David said: “We plan to unravel the mode of action of our second compound series over the next months. Meantime, we anticipate announcing progress with our first compound series in the near future.”

Source: Facio Therapies

uniQure has treated the first patient in its Phase IIb dose-confirmation study of AMT-061, an investigational AAV5-based gene therapy incorporating the FIX-Padua variant for the treatment of patients with severe and moderately severe hemophilia B.  AMT-061 has been granted Breakthrough Therapy Designation by the United States Food and Drug Administration and access to Priority Medicines (PRIME) regulatory initiative by the European Medicines Agency.

“The initiation of the AMT-061 dose-confirmation study is an important step toward our goal of advancing a potentially life-changing treatment for patients with hemophilia B,” said Robert Gut, M.D., Ph.D., chief medical officer of uniQure.  “I am extremely proud of the efforts made by the uniQure team to initiate this study, the objective of which is to demonstrate meaningful increases in FIX activity using the Padua variant and confirm dosing for the HOPE-B pivotal trial initiated this past June. We look forward to completing patient enrollment shortly and providing top-line data before the end of the year.”

“As a one-time administered therapy, AMT-061 has the potential to transform the treatment paradigm for hemophilia B patients,” said Annette von Drygalski, M.D., associate clinical professor at the University of California San Diego and director of its hemophilia and thrombosis treatment center. “By incorporating both AAV5 and the FIX-Padua variant, AMT-061 has the potential to deliver clinically relevant increases in FIX activity with low risk of cellular immune responses, which could expand patient eligibility for treatment with gene therapy. I greatly appreciate the opportunity to participate in the AMT-061 clinical program and view the initiation of the Phase IIb and Phase III studies as important milestones in the development of this potentially important therapy for patients with hemophilia B.”

The Phase IIb dose-confirmation study is an open-label, single-arm, single-dose trial being conducted in the United States. Approximately three patients are expected to receive a single intravenous (IV) infusion of 2×1013 vc/kg and be evaluated for a period of approximately six to eight weeks to assess Factor IX (FIX) activity.

Patient enrollment is also underway in the global Phase III HOPE-B clinical trial to evaluate the safety and efficacy of AMT-061.  Approximately 50 adult hemophilia B patients classified as severe and moderately-severe will be enrolled in a six-month observational period during which time they will continue to use their current standard of care to establish a baseline control.  After the six-month lead-in period, patients will go onto receive a single intravenous administration of AMT-061.  Dosing of patients in the HOPE-B pivotal trial is expected to start early in the first quarter of 2019.

Source: uniQure

Goed nieuws: Minister Bruins van het ministerie van VWS heeft besloten om combinatiebehandeling met Darzalex® (daratumumab) van patiënten met multipel myeloom, oftewel de ziekte van Kahler, per 1 september 2018 op te nemen in het basispakket van de zorgverzekering. Een besluit met grote waarde voor patiënten die lijden aan deze ernstige ziekte.

Geneesmiddelenontwikkelaar Janssen en VWS kwamen middels een sluisprocedure tot een akkoord. Michel van Agthoven, directielid Janssen, licht toe: “Wij waarderen het zorgvuldige en constructieve proces waarin de onderhandelingen met het ministerie van VWS hebben plaatsgevonden. We zetten ons in voor een effectieve toepassing in de praktijk om de meeste gezondheidswinst te behalen, op een kosteneffectieve manier. Alleen dan kunnen we de zorg betaalbaar houden.”

Het feit dat Darzalex® Nederlandse roots heeft – het geneesmiddel komt oorspronkelijk uit de pijplijn van Genmab – geeft het mooie nieuws extra glans. Een mooi succes van eigen bodem!

Lees meer:
– Persbericht Janssen
– Persbericht VWS

The Food and Drug Administration approved Alnylam’s patisiran for the treatment of peripheral nerve disease (polyneuropathy), which is caused by hereditary transthyretin-mediated amyloidosis (hATTR). This is the first FDA-approved treatment for patients with polyneuropathy caused by hATTR, a rare, debilitating and often fatal genetic disease characterized by the buildup of abnormal amyloid protein in peripheral nerves, the heart and other organs. It is also the first FDA approval of a new class of drugs called small interfering ribonucleic acid (siRNA) treatment.

“This approval is part of a broader wave of advances that allow us to treat disease by actually targeting the root cause, enabling us to arrest or reverse a condition, rather than only being able to slow its progression or treat its symptoms. In this case, the effects of the disease cause a degeneration of the nerves, which can manifest in pain, weakness and loss of mobility,” said FDA Commissioner Scott Gottlieb, M.D. “New technologies like RNA inhibitors, that alter the genetic drivers of a disease, have the potential to transform medicine, so we can better confront and even cure debilitating illnesses. We’re committed to advancing scientific principles that enable the efficient development and review of safe, effective and groundbreaking treatments that have the potential to change patients’ lives.”

RNA acts as a messenger within the body’s cells, carrying instructions from DNA for controlling the synthesis of proteins. RNA interference is a process that occurs naturally within our cells to block how certain genes are expressed. Since its discovery in 1998, scientists have used RNA interference as a tool to investigate gene function and its involvement in health and disease. Researchers at the National Institutes of Health, for example, have used robotic technologies to introduce siRNAs into human cells to individually turn off nearly 22,000 genes.

This new class of drugs, called siRNAs, work by silencing a portion of RNA involved in causing the disease. More specifically, Onpattro encases the siRNA into a lipid nanoparticle to deliver the drug directly into the liver, in an infusion treatment, to alter or halt the production of disease-causing proteins.

Affecting about 50,000 people worldwide, hATTR is a rare condition. It is characterized by the buildup of abnormal deposits of protein fibers called amyloid in the body’s organs and tissues, interfering with their normal functioning. These protein deposits most frequently occur in the peripheral nervous system, which can result in a loss of sensation, pain, or immobility in the arms, legs, hands and feet. Amyloid deposits can also affect the functioning of the heart, kidneys, eyes and gastrointestinal tract. Treatment options have generally focused on symptom management.

Onpattro is designed to interfere with RNA production of an abnormal form of the protein transthyretin (TTR). By preventing the production of TTR, the drug can help reduce the accumulation of amyloid deposits in peripheral nerves, improving symptoms and helping patients better manage the condition.

“There has been a long-standing need for a treatment for hereditary transthyretin-mediated amyloidosis polyneuropathy. This unique targeted therapy offers these patients an innovative treatment for their symptoms that directly affects the underlying basis of this disease,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research.

The efficacy of Onpattro was shown in a clinical trial involving 225 patients, 148 of whom were randomly assigned to receive an Onpattro infusion once every three weeks for 18 months, and 77 of whom were randomly assigned to receive a placebo infusion at the same frequency. The patients who received Onpattro had better outcomes on measures of polyneuropathy including muscle strength, sensation (pain, temperature, numbness), reflexes and autonomic symptoms (blood pressure, heart rate, digestion) compared to those receiving the placebo infusions. Onpattro-treated patients also scored better on assessments of walking, nutritional status and the ability to perform activities of daily living.

The most common adverse reactions reported by patients treated with Onpattro are infusion-related reactions including flushing, back pain, nausea, abdominal pain, dyspnea (difficulty breathing) and headache. All patients who participated in the clinical trials received premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) to reduce the occurrence of infusion-related reactions. Patients may also experience vision problems including dry eyes, blurred vision and eye floaters (vitreous floaters). Onpattro leads to a decrease in serum vitamin A levels, so patients should take a daily Vitamin A supplement at the recommended daily allowance.

The FDA granted this application Fast Track, Priority Review and Breakthrough Therapy designations. Onpattro also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

Approval of Onpattro was granted to Alnylam Pharmaceuticals, Inc.

Source: FDA