Sarah Boyce, Avidity Biosciences President and CEO

Avidity Biosciences trades its shares under the ticker symbol “RNA,” so it shouldn’t be surprising that, as it prepares to enter the clinic with its first in a new class of oligonucleotide-based treatments this year, the company has committed itself to disrupting delivery of RNA-based therapeutics by opening that modality to treating new cell and tissue types.

Avidity has revealed plans to advance its lead pipeline candidate, AOC 1001, into a Phase I/II trial in adults with myotonic dystrophy type 1 (DM1), in the second half of 2021. AOC 1001 is based on Avidity’s Antibody Oligonucleotide Conjugates (AOCs™) platform, designed to treat diseases of high unmet need by combining the tissue selectivity of monoclonal antibodies (mAbs) with the precision of oligonucleotide therapies.

The platform allows Avidity to deploy various types of oligonucleotides capable of modifying RNA function, including small interfering RNAs (siRNAs) and phosphorodiamidate morpholino oligomers (PMOs). As a result, the company says, its AOC approach can overcome current limitations of oligonucleotide therapies by accessing previously undruggable tissue and cell types, and more effectively target underlying genetic drivers of diseases.

“Our goal is to be able to overcome one of the challenges around delivery of oligos. One of the natural places you go to is muscle because there are a whole range of rare genetic diseases which are ideal for an oligo approach,” Avidity President and CEO Sarah Boyce told GEN.

DM1 is suitable for Avidity’s AOC approach of delivering an oligo to muscle, she said, because it has no approved treatments, and robs about 40,000 Americans of their mobility and independence.

“Great First Place to Start”

“We know very clearly the target we’re trying to hit. We’re trying to knock down the DMPK gene,” Boyce added. “We’ve been able to show success in nonhuman primates. It’s a great first place to start on the basis of level of unmet need and that’s always where we direct our programs.”

Avidity refocused on DM1 last September, when it opted to support development of AOC 1001 by entering into a collaboration in support of END-DM1 (Establishing Biomarkers and Clinical Endpoints in Myotonic Dystrophy Type 1), a natural history study designed to advance the understanding of disease progression in DM1 patients.

END-DM1 is a non-interventional study designed and run by the Myotonic Dystrophy Clinical Research Network (DMCRN), a network of medical centers created to support future clinical trials of potential therapies for DM1.

AOC 1001 consists of a proprietary mAb that binds to a transporter protein, transferrin receptor 1 (TfR1), conjugated with an siRNA designed to address the underlying cause of DM1 by reducing the levels of DMPK RNA. On January 5, Avidity was awarded U.S. Patent No. 10,881,743, covering AOC 1001, “Compositions and methods of treating muscle atrophy and myotonic dystrophy.”

“Success in DM1 could validate RNA’s TfR1 mAb and positively read through to RNA’s other muscle programs in muscle atrophy,” Joseph P. Schwartz, Managing Director, Rare Diseases, and a senior research analyst with SVB Leerink, wrote last November in a research note. SVB Leerink was among underwriters of the company’s IPO last year, setting a 12-month price target of $36 on shares of Avidity.

75% Knockdown

In preclinical studies, Avidity says, AOC 1001 was shown to deliver siRNAs to muscle cells and reduce levels of mRNA for the DMPK gene, the molecular driver of the disease, in a durable, dose-dependent manner.

“We’ve been able to show in nonhuman primates that with a single dose, we can get a 75% knockdown of our target DMPK, and it actually goes out for 12 weeks,” Boyce said. “It’s not just a robust knockdown, it’s also a pretty long duration of action. And that’s because of the siRNA approach. When you load it into the risk pathway, it then becomes very stable.”

AOC 1001 is the first of several AOC candidates Avidity plans to develop. Next in the company’s queue is an AOC program designed to fight facioscapulohumeral muscular dystrophy (FSHD) by targeting the embryonic gene double homeobox 4 (DUX4). The company plans to launch IND-enabling studies later this year, and expects to follow up in 2022 by submission of a regulatory filing to begin a clinical trial.

Also in 2022, Avidity expects to submit a regulatory filing to support a planned clinical trial of the first in a trio of AOCs designed to fight Duchenne muscular dystrophy (DMD) by using a PMO approach to promote the skipping of exon 44 to allow the production of dystrophin gene product. The other two candidates are being developed for mutations amenable to skipping Exon 45 and Exon 51, and are set to enter the clinic sometime after 2022.

Avidity’s two other announced AOC programs are focused on treating Pompe disease by targeting glycogen synthase 1 (GYS1), and on fighting muscle atrophy by targeting the MuRF1 gene. Preclinical studies are ongoing for both.

By targeting GYS1, Avidity reasons, it can inhibit toxic glycogen production in muscle tissue and reduce glycogen accumulation in lysosomes. And by pursuing MuRF1, Avidity’s AOC is designed to use both the catabolic and anabolic pathways associated with the degradation of protein in muscle cells. Avidity cited preclinical success in a mouse model that a single 3 mg/kg dose of its AOC produced a >50% reduction of MuRF1 in the skeletal muscle of mice for more than 20 weeks, with AOC-mediated MuRF1 downregulation mimicking the muscle-sparing activity seen upon genetic ablation of MuRF1.

MuRF1 AOCs are also under study in additional models of muscular atrophy, according to the company. Avidity plans this year to identify an optimal development path for the muscular atrophy AOC after its researchers evaluate AOCs in multiple models of the disease.

Beyond Skeletal Muscle

The company has also signaled its intent to apply its AOC-based therapeutics beyond its initial focus on skeletal muscle, starting with entering its second collaboration with a biopharma giant, albeit indirectly. Avidity agreed to partner with MyoKardia, now a wholly-owned subsidiary of Bristol-Myers Squibb on a research collaboration intended to show the potential utility of AOCs in cardiac tissue by leveraging MyoKardia’s genetic cardiomyopathy platform, which includes a novel target discovery engine and proprietary cardiac disease models.

“We really want to learn more about being able to take our AOC technology to the heart,” Boyce said. “This is where the collaboration with MyoKardia works really well, because they’re experts with regards to targeting the heart… We can learn from each other. And they have a target that looks to be pretty applicable to our technology. That’s where you get the foundation of a great collaboration.”

The companies have not disclosed that cardiac target. MyoKardia has focused until now on developing small molecule therapeutics aimed at the cardiac muscle proteins that modulate cardiac muscle contraction and underlying diseases of systolic and diastolic dysfunction. MyoKardia says it has applied its precision medicine platform to generate a therapeutic pipeline of programs for the chronic treatment of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM).

The MyoKardia partnership (value undisclosed) comes nearly two years after Avidity launched its first collaboration with Eli Lilly, an up-to-$440 million partnership launched in April 2019. The partnership is aimed at discovering, developing, and commercializing new AOC-based treatments in immunology and other indications.

Lilly paid Avidity $20 million in upfront cash, plus a $15-million investment contributed as part of Avidity’s $100 million Series C financing, completed in November 2019. Lilly also agreed to pay Avidity up to approximately $405 million per target for development, regulatory and commercialization milestones, as well as tiered royalties ranging from the mid-single to low-double digits on product sales.

That collaboration could potentially generate more than $2 billion for Avidity since Lilly has agreed to develop up to six mRNA targets, initially in immunology and other select indications besides muscle.

“They have selected all of those targets, and we’re working on those right now with them,” Boyce said, adding that Lilly and Avidity are not disclosing those targets. “I think we’re both really pleased with the progress that we’ve been able to make. We also have our own immunology programs as well.”

Building a Team

Headquartered in La Jolla, CA, Avidity was founded in 2012 as Avidity NanoMedicines and changed its name in 2016. The company will expand its staff of about 70 people, Boyce said, but is not quantifying that growth: “Suffice it to say we’re a growing company and building a team.”

“The areas you’ll see us grow primarily is around clinical operations,” Boyce said. “We’ve been building our clinical team, and you’ll see us expand our clinical team more. We’ve also started to build our Medical Affairs team, looking at things like natural history databases as well. We’ve also been expanding our research team as well, and then the operating team that you need as part of being a publicly traded company.”

Avidity finished the third quarter of 2020 with cash and cash equivalents totaling $341 million as of September 30, up from $94.6 million at the end of 2019. “With its current financial resources, RNA [management] believes they are well-positioned to advance multiple AOCs into the clinic in the next 2 years,” Schwartz observed.

However, Avidity finished the third quarter with a net loss of $11.44 million, nearly double the $6.67 million net loss in Q3 2019. For the first nine months of 2020, Avidity reported a $28.08 million net loss, nearly double the $14.33 net loss of Q1-Q3 2019, as the company’s R&D expenses nearly tripled year-over-year, to $23.98 million from $8.89 million.

Q4 results have yet to be released.

Most of Avidity’s cash consists of the $274.1 million in net proceeds that Avidity raised through its initial public offering (IPO) in June 2020.

The company offered 16.56 million shares at $18 a share, including all 2,160,000 additional shares that the IPO underwriters had the option to purchase at the same price. Cowen, Credit Suisse and Wells Fargo Securities joined SVB Leerink in acting as joint book-running managers for the offering.

“We went public because we have, we believe, a real opportunity to revolutionize the way oligos are delivered and we wanted to make sure that we were appropriately funded to do that,” Boyce said. “We’re now set on a nice cash position right now, and we have what we need to be able to deliver on the program that we’ve been talking about, which is great.”

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