Audentes is developing AT466 for the treatment of myotonic dystrophy type 1.
Myotonic dystrophy type 1 (DM1) is a rare, neuromuscular disease that affects multiple organ systems, and is characterized primarily by myotonia and progressive muscle wasting and weakness. DM1 has several forms, which range in age of presentation and severity, including congenital, infantile, juvenile, and adult (classic). There are more than 100,000 patients living with DM1 across the United States, Europe and Japan. The disease is inherited in an autosomal dominant pattern and is caused by a mutation called a CTG trinucleotide repeat in the dystrophia myotonica-protein kinase (DMPK) gene. Patients with DM1 experience reduced quality of life and shortened life expectancy. There are no disease modifying therapies approved for DM1.
Audentes is evaluating vectorized RNA knockdown and vectorized exon skipping to treat DM1. Both approaches are designed to prevent the accumulation of toxic DMPK RNA in affected cells, thereby restoring normal cellular function. RNA knockdown and exon skipping have both been clinically validated in studies with antisense oligonucleotides (ASOs). Combining these approaches with AAV delivery is expected to overcome the biodistribution limitations of ASO-based therapies. Preclinical studies are underway to determine the optimal construct for AT466.
MORE INFO ON AT466 to TREAT Myotonic Dystrophy Type 1 (DM1)
DM1 is caused by a mutation called a CTG trinucleotide repeat in the DMPK gene, resulting in the accumulation of toxic DMPK RNA in affected cells. AT466 is an AAV-antisense candidate, and Audentes is evaluating vectorized RNA knockdown and vectorized exon skipping to treat DM1. Both approaches are designed to prevent the accumulation of toxic DMPK RNA, thereby restoring normal cellular function.
The treatment strategy, called vectorized exon skipping, uses a modified adeno-associated virus (AAV) to deliver antisense oligonucleotides (ASOs) — small molecules complementary to the RNA sequence — to skip over mutated exons, the bits of DNA that contain the information to generate proteins. Such an approach leads to the production of functional and full-length proteins.
According to Audentes, this strategy may be superior in DMD to microdystrophin gene replacement approaches, which produce shorter-than-normal dystrophin — the protein missing in these patients — with potentially less durable clinical benefits. Also, it may be more beneficial than current ASO therapies, whose efficacy is limited by poor distribution in muscle tissue.
“Today’s announcement represents a significant step forward in expanding our scientific platform and deepening our pipeline of product candidates for neuromuscular diseases with high unmet medical need,” Matthew R. Patterson, Audentes chairman and CEO, said in a press release.
Patterson also said Audentes believes that this strategy, combined with the company’s large-scale current good manufacturing practice (CGMP) manufacturing capability, “can deliver best-in-class therapies for the treatment of [DMD] and [DM1].”
To accelerate these programs, Audentes reached a licensing agreement and will partner with the Nationwide Children’s Hospital, as well as two of its experts on neuromuscular diseases — Kevin M. Flanigan, MD and Nicolas S. Wein, PhD.
“We are excited to be collaborating with Audentes to advance these novel, highly differentiated approaches for DMD and DM1,” said Flanigan, director of Nationwide Children’s Center for Gene Therapy.
Audentes and Nationwide Children’s are collaborating to develop AT702, a treatment candidate designed for skipping of exon 2 of the DMD gene — which codes for dystrophin — in patients with exon 2 duplications and mutations in exons 1-5.
In mouse models, AT702 led to dose-dependent increases in production of full-length or near-full-length dystrophin and improvements in muscle function. The company expects to start a Phase 1/2 trial of AT702 at Nationwide Children’s in the fourth quarter of 2019.
Audentes is also conducting preclinical studies of two other vectorized exon-skipping candidates known as AT751 and AT753. These investigational treatments are intended for DMD patients with genotypes amenable for skipping of exons 51 and 53. Both AT751 and AT753 use the same viral vector backbone as AT702, enabling a potentially quicker clinical development, the company says.
Overall, these three potential therapies target over 25% of patients with DMD, with the company planning to leverage its exon-skipping platform to cover up to 80% of DMD patients.
Besides DMD, Audentes and Nationwide Children’s are assessing vectorized RNA suppression and vectorized exon skipping for DM1. Both strategies have been validated in studies with ASOs and intend to prevent the buildup of toxic RNA of the DMPK protein in cells, a hallmark of DM1.
The company is currently conducting preclinical studies and expects to file an investigational new drug application in the U.S. for its selected DM1 treatment candidate, AT466, in 2020.
Audentes’ current manufacturing capability enables global commercialization of AT132, a potential therapy for X-linked myotubular myopathy and the company’s lead program, as well as continued clinical development of its pipeline programs. The facility is designed for an eightfold expansion of its production capacity.
Audentes recently hosted a conference call and a webcast on the expansion of its AAV technology as well as the DMD and DM1 programs. A replay of the webcast and slides can be found here
There is still lots of interest in finding a cure for myotonic dystrophy through oligonucleotides. These are small molecules different than oral ingestion of a pill. Lots of interest in this type of therapy. Here is a press release from bioworld
Lilly’s ‘Avidity’ for oligos pays off for Calif.-based company
By Michael Fitzhugh News Editor
Eli Lilly and Co. has agreed to pay privately held Avidity Biosciences LLC $20 million up front and up to $405 million per target to support development of an unspecified number of new antibody oligonucleotide conjugates for immunology and other indications. The multiyear deal, which also includes a $15 million equity investment for Avidity, opens a new front in Lilly’s embrace of oligonucleotide-based drugs, the subject of earlier deals it has struck with Dicerna Pharmaceuticals Inc., Ionis Pharmaceuticals Inc. and Noxxon Pharma AG.
Avidity’s platform, which can leverage transferrin and other transporters to deliver oligonucleotides into multiple tissue types, will allow Lilly to reach beyond hepatocytes — the most accessible domain for such medicines so far — to muscle, heart, tumor and immune cells. Andrew Adams, Lilly’s chief scientific officer for RNA therapeutics, called it “a promising avenue of research toward development of new RNA-based medicines.” With Lilly’s own multimillion-dollar R&D center just up the road from Avidity’s La Jolla, Calif., headquarters, the big pharma company’s scientists won’t even have to drive far.
Arthur Levin, Avidity’s head of R&D, told BioWorld the deal “demonstrates that the technology for oligonucleotides has reached the level of maturity where pharma is jumping back in” while validating Avidity’s technology, too. “The field has made great strides recently using targeted approaches to deliver to hepatocytes. Our technology allows us to deliver oligonucleotide payloads to cells outside of simply hepatocytes, and that’s what attracted Lilly,” he said.
The company also brings expertise in what Kent Hawryluk, Avidity’s chief business officer, told BioWorld are some of “the devilish technical details” that would make it difficult for someone to replicate its approach.
“Each one of the components, the antibody, the conjugation to the antibody, the linker, the nature of the payload, the arrangement of the molecules in space… each one of those is important to optimize,” said Levin. “If you just go in and slap an oligonucleotide payload onto an antibody, you’re probably not going to get the results that we get. That’s where the secret sauce lies, in that combination of making the appropriate modifications to each one of those systems,” he said.
Including the new equity investment by Lilly, Avidity has now raised $50 million from investors including Takeda Ventures, Alethea Capital, Alexandria Real Estate Equities, Brace Pharma, Ecor1 Capital, F-Prime Capital, Moore Venture Partners and Boxer Capital of Tavistock Group. Takeda led the company’s series B round.
The global licensing and R&D agreement with Lilly is the company’s first strategic deal and will provide it not only with support for the partnered candidate, but with nondilutive funding to help advance its muscle-focused internal pipeline.
“It turns out that muscle cells are particularly sensitive to molecules transported in on the transferrin receptor and that’s why we’ve concentrated our lead programs on muscle,” said Levin.
Founded as Avidity Nanomedicines in 2013, the company tweaked its name to reflect that its approach could do more than just deliver siRNAs, an early focus of Avidity Nanomedicines. Today, its lead internal program is focused on myotonic dystrophy type 1, a disease caused by the expansion of CTG repeats in the DMPK gene. Following humanization of an anti-human transferrin receptor antibody, Avidity team members on the project are now working to optimize its siRNA payload. “We’re in the process of scaling up the antibody and moving forward with respect to development in the very near future,” said Levin.
Avidity is also applying its antibody oligonucleotide conjugate technology to Duchenne muscular dystrophy (DMD) where the company said its approach has proved 100-fold more potent than existing oligonucleotide therapies for DMD in a mouse model of the disease, a feat it hopes will allow for reduced dose levels and reduced dosing frequency. In October, the company received an undisclosed equity investment from Cureduchenne to help advance preclinical development of its exon-skipping oligonucleotides for DMD.
A consortium of doctors met and came up with some definitive pathways for patients with myotonic dystrophy
A Multi-country conference was held with doctor from most major European Countries and the USA to review respiratory or lung function in patients with Myotonic Dystrophy. Patients with DM have a lot of issues with lung function and respiration. A framework or step by step checklist was reviewed and recommended at this conference. The conclusion of this conference is presented below. This is a very complex subject so print this and bring it with you to your doctor or pulmonologist. When you have myotonic dystrophy its important to have your lung function checked every 6 months or so.
Management of respiratory insufficiency is challenging in DM because of the pathophysiology of the disease, which affects both muscles and central respiratory pathways and patients’ cognitive and behavioral characteristics. Although there are no natural history data on the effects of respiratory care on survival and on morbidity in patients with DM, results of ventilation on survival and on better care in other neuromuscular diseases indicate that adequate ventilatory care may improve survival and QoL of patients with DM1 [41–43]. NIV use varies greatly among the different centers, e.g. varying from 20 to 60% in adults with DM1, 20–40% of patients with the congenital form, and 15–20% of patients with DM2. All participants agreed on the need for standard assessments and recommendations for standard of care. Discussion between the specialists from different countries led to the construction of initial standard protocols which are the necessary preliminary steps for validation processes to follow. Specifically, the workshop led to the creation of: 1) a respiratory symptom check-list to be applied in everyday DM clinic (Table 1); 2) a preliminary version of a screening respiratory protocol to be applied on first assessment during clinic (Figure 1); 3) proposal of criteria for NIV prescription to be used specifically in patients with DM, based on the existing ACI (Consensus Statement from the Agency for Clinical Innovation Respiratory Network on Domiciliary Non-Invasive Ventilation in Adult Patients) guidelines for NIV, including recommendations for timing and tests to be performed on follow-up assessments; 4) proposal of a secretion management protocol (Figure 2). The need for validation of these recommendations and for further research to extend the evidence-base in certain key areas was also highlighted and outline proposals to resolve these deficiencies put forward. All participants agreed on the urge for more natural history data and for specific pathways for emergency care of acute respiratory insufficiency in DM.
