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Astellas Signs $962m Rare Eye Disease Deal With 4D Molecular Therapeutics

Astellas Pharma has said it will be gaining the rights to use one of 4D Molecular Therapeutics' (4DMT) gene therapy vectors for at least one rare eye disease.

Under the terms of the licensing agreement, the US genetic medicines company will receive an upfront payment of $20m in exchange for its proprietary R100 vector technology and will also be eligible for future option fees and milestones of up to $942.5m plus certain royalties.

R100 is an adeno-associated virus vector invented by 4DMT for intravitreal delivery. According to the companies, it "has the ability to penetrate the internal limiting membrane barrier and to efficiently transduce the entire retina, resulting in robust transgene expression within retinal cells".

Astellas will use the vector initially for one genetic target implicated in rare monogenic ophthalmic diseases and will have the option to add up to two more targets after paying additional option exercise fees.

The Japanese drugmaker will be responsible for all research, development, manufacturing, and commercialisation activities for the resulting programmes.

David Kirn, co-founder and chief executive officer of 4DMT, outlined that over 70 patients have been dosed with R100-based product candidates in wet age-related macular degeneration and rare ophthalmic diseases.

"This collaboration with Astellas, a leader in AAV gene therapy, continues to validate R100 for routine intravitreal low dose delivery of genetic payloads for the treatment of retinal diseases," he said.

Adam Pearson, chief strategy officer at Astellas, said: "We believe that this collaboration will bring synergies between the two companies' cutting-edge research, and will ultimately lead to the development of new therapeutics for patients with ophthalmic diseases at high risk of blindness."

The deal comes just less than a month after Astellas and Cullgen entered into a research collaboration and exclusive option agreement aimed at advancing targeted protein degraders.

The partnership, which is worth up to $1.9bn, will utilise Cullgen's uSMITE targeted protein degradation platform, featuring novel E3 ligands, alongside Astellas' drug discovery capabilities.

The two companies will jointly identify clinical development candidates, after which Astellas will have an exclusive option to licence the rights for further development and commercialisation of any discovered compounds.

Genetic Testing Hopes To Speed Up Drug Development In Rare Eye Diseases

When it comes to fighting rare diseases, the biggest barrier to overcome is often the lack of knowledge around the condition. A free genetic test is hoping to combat this and speed up drug development in inherited retinal diseases.

The small patient populations in rare diseases and resulting lack of understanding about the conditions' natural histories has many implications for researchers trying to develop orphan drugs.

"Clinical trials become difficult to set up due to the limited experience in conducting studies for these diseases, including the lack of understanding of what endpoints will be most sensitive," says Daniel de Boer, chief executive officer of ProQR Therapeutics, which is developing RNA therapies to treat inherited retinal diseases (IRD).

"Standard trial designs are not optimised to obtain adequate safety and efficacy data from small numbers of patients, and trials are frequently conducted on an international scale with various regulatory agency oversights."

Like in many rare diseases, there are some dire statistics in IRDs. There are as many as 300 inherited retinal diseases known today, affecting over two million people – but only a fraction of these patients have access to a therapy.

IRDs also require precise and targeted treatments to deliver an accurate genetic diagnosis.

"The programme is taking a crowdsourcing approach to gathering the data researches need when working on orphan drugs"

"From talking to retina specialists, we know that barriers to genetic testing remain a challenge for patients," says de Boer. "For instance, at ProQR we are developing RNA therapies for specific mutations causing Leber's congenital amaurosis 10 (LCA10), Usher syndrome type 2 and autosomal dominant retinitis pigmentosa (adRP). However, there are hundreds of genetic mutations that can cause inherited retinal diseases.

"Without knowing the exact mutations and the prevalence in which they occur, it can be difficult to design therapies and execute clinical trials for these rare and ultra-rare diseases."

In an effort to give researchers the best possible start when developing treatments for eye diseases, The Foundation Fighting Blindness has founded the My Retina Tracker programme, in partnership with Blueprint Genetics and InformedDNA.

The programme is a global, patient-driven registry for inherited retinal diseases (IRD). It offers free, open access genetic testing and genetic counseling for individuals living in the United States with a clinical diagnosis of IRD.

The genetic counseling consists of reviewing a patient's medical and family history, interpretation of genetic variants, correlation with the disease, and medical management recommendations.

The programme also gives individuals the opportunity to contribute to focus groups, patient journey analyses, research studies, and the opportunity to be enrolled in relevant natural history studies and clinical trials.

My Retina Tracker also records subjective information from patients regarding how their disease affects their day to day activities. This recording option is available to doctors, allowing them to enter any additional information during appointments with patients.

In other words, the programme is taking a crowdsourcing approach to gathering the data researches need when working on drugs for IRDs.

Since its establishment in 2017 over 6,000 people with an IRD have participated, with the Foundation FIghting Blindness aiming to test over 20,000 patients within the next few years.

This has created a "powerful genotype/phenotype database", says de Boer.

ProQR has recently become the first industry partner for the programme, giving it access to expert physicians and de-identified data from specific participating IRD patients.

"This data has the potential to expedite the advancement of new treatments by identifying the mutations causing inherited rare diseases," de Boer explains.

The company's RNA therapies aim to edit RNA, the "blueprint" for proteins. Targeting RNA does not affect a person's DNA, the source of the genetic code, but instead reduces the risk of permanent side effects.

"For inherited retinal diseases, RNA therapies can be administered through intravitreal injections, which is a far less invasive procedure than the retinal surgery required for gene therapies," de Boer says. "RNA therapies do not need a vector to enter cells – rather, intravitreal injection allows the drug to be distributed to the entire retina, which is where the therapy is needed."

The data can have additional benefits in clinical trial recruitment by identifying patients with these rare diseases.

"Data like this is instrumental when recruiting participants for a trial. Treatments for inherited retinal diseases, like our RNA therapies, are specifically designed for a certain genetic mutation. Identifying the exact mutation that causes the disease encourages patients to participate in trials that target their mutation."

There are also benefits in diagnosis – a confirmed genetic diagnosis may help patients and doctors better understand prognosis and help guide medical management.

"With this information, physicians can determine the correct diagnosis and potential treatment for a patient," says de Boer. "The data may match the patient's mutation to an existing therapy or an ongoing clinical trial.

"In terms of research and the development of therapeutics, it is crucial to increase our knowledge on the prevalence of the specific gene variants that cause an IRD."

Astellas Inks Rare Eye Disease Deals With 4D Molecular

Yesterday after market close, US genetic medicines company 4D Molecular Therapeutics (Nasdaq: FDMT;4DMT) announced a license agreement with Japanese drug major Astellas Pharma (TYO: 4503) that sent its shares up 4.5% to $18.76 pre-market today.

Under the accord, Astellas gains rights to utilize the intravitreal retinotropic R100 vector invented by 4DMT for one genetic target implicated in rare monogenic ophthalmic disease(s), with options to add up to two additional targets implicated in rare monogenic ophthalmic diseases after paying additional option exercise fees.

R100 is an adeno-associated virus (AAV) vector invented by 4DMT for intravitreal delivery. It has the ability to penetrate the internal limiting membrane barrier and to efficiently transduce the entire retina, resulting in robust transgene expression within retinal cells. All three 4DMT clinical-stage ophthalmic product candidates utilize the R100 vector, including 4D-150 for wet age-related macular degeneration and diabetic macular edema.

4DMT will provide its proprietary R100 vector technology to Astellas to deliver on the Japanese firm's unique genetic payloads for the treatment of rare monogenic diseases. Astellas will conduct all subsequent research, development, manufacturing, and commercialization activities.

4DMT will receive $20 million upfront, and potential future option fees and milestones of up to $942.5 million including potential near-term development milestones of $15 million for the initial target. In addition, 4DMT is entitled to receive mid-single digit to double-digit, sub-teen royalties on net sales of all licensed products.

"This collaboration with Astellas, a leader in AAV gene therapy, continues to validate R100 for routine intravitreal low dose delivery of genetic payloads for the treatment of retinal diseases," said Dr David Kirn, co-founder and chief executive of 4DMT. "With over 70 patients dosed to-date with R100-based product candidates in wet age-related macular degeneration and rare ophthalmic diseases, this collaboration also demonstrates the modularity of the Therapeutic Vector Evolution platform resulting in efficient design and development of new intravitreal products. 4DMT retains rights to large market non-hereditary ophthalmic diseases," he noted.

Adam Pearson, chief strategy officer at Astellas, added: "At Astellas, we have a strong commitment to developing novel treatments for ophthalmic diseases, and have positioned Blindness & Regeneration as one of the Primary Focuses of our R&D strategy. Staying at the forefront of gene therapy technology is a key part of our strategy. We believe that this collaboration will bring synergies between the two companies' cutting-edge research, and will ultimately lead to the development of new therapeutics for patients with ophthalmic diseases at high risk of blindness."

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