4D Molecular Therapeutics Surges 85% on Positive Phase II Data for 4D-150 Gene Therapy After Earlier Roche Setback

Recently, gene therapy company 4D Molecular Therapeutics (4DMT) announced that its randomized Phase II PRISM clinical trial of the intravitreal AAV gene therapy 4D-150 has yielded positive interim data,The results indicate that 4D-150 can significantly reduce the treatment burden for patients with wet age-related macular degeneration (AMD).。

As a result, by the close of U.S. stock trading on February 5,4DMT Stock Surges 84.62%, Reaching a Total Market Capitalization of $1.381 Billion。

It is worth noting that in June 2021, Roche announced the termination of its collaboration with 4D Molecular Therapeutics to co-develop ophthalmic therapies, ending its development support for the gene therapy drug 4D-110 for eye diseases and returning the rights to 4D-110 to 4D Molecular Therapeutics.

4DMT is a clinical-stage gene therapy company focused on developing innovative genetic medicines for the treatment of ophthalmic, pulmonary, and cardiovascular diseases. Leveraging its proprietary Therapeutic Vector Evolution platform, the company employs directed evolution to engineer highly targeted adeno-associated virus (AAV) vectors capable of delivering genetic material to specific tissues. Currently, 4DMT is advancing five clinical-stage candidates across three major therapeutic areas: ophthalmology, cardiology, and pulmonology.

  4DMT’s Pipeline in Development

Image source: 4DMT

Among these, 4D-150 is the candidate drug that 4DMT is currently prioritizing for development in the field of ophthalmic diseases. The company stated that 4D-150 is the first retinal gene therapy designed to inhibit all four VEGF-related molecules that drive angiogenesis.

4D-150 is a dual-transgene intravitreal gene therapy consisting of an RNAi payload expressing aflibercept and anti-VEGF-C, along with the proprietary vector R100 capable of intravitreal delivery. It is designed to inhibit four angiogenic factors—VEGFA, VEGFB, VEGFC, and PlGF—which are central to the pathogenesis of wet age-related macular degeneration (AMD) and diabetic macular edema (DME).

Notably,The R100 vector used in 4D-150 was developed by the company using Nobel Prize-winning technology, enabling efficient transduction and transgene expression through single, low-dose intravitreal delivery. It penetrates the internal limiting membrane barrier and achieves widespread distribution throughout retinal cells, thereby avoiding significant inflammation.。

The PRISM trial is a Phase I/II, dose-escalating, randomized, controlled trial in which 51 patients with wet age-related macular degeneration (AMD) characterized by severe disease activity and high treatment burden were randomized to receive either high-dose 4D-150 (3E10 vg/eye), low-dose 4D-150 (1E10 vg/eye), or aflibercept (Eylea) as the control. Aflibercept is currently the leading therapeutic agent for the treatment of wet AMD, retinal vein occlusion-associated macular edema, and diabetic macular edema (DME).

The Phase II PRISM clinical trial data for 4D-150 released this time show that,After 24 weeks of follow-up assessment, 84% of patients in the high-dose group did not require supplemental aflibercept injections; in the low-dose group, only one patient required a supplemental aflibercept injection.。

Furthermore, 63% and 50% of patients in the high-dose and low-dose groups, respectively, did not require rescue therapy with aflibercept within 24 weeks after treatment. Overall, high-dose 4D-150 reduced the annualized aflibercept injection rate by 89%, while the low dose reduced it by 85%. Compared with aflibercept treatment, visual acuity and central subfield thickness (CST) remained stable in patients receiving 4D-150.

In terms of safety, no significant cases of inflammation were observed in the trial, and no patients in the high-dose group experienced inflammation of grade ≥1+. Furthermore, 97% of patients completed the planned 20-week tapering regimen of prophylactic topical corticosteroids, and all patients had successfully discontinued topical corticosteroid use by the time of data collection.

This trial also updated the positive long-term follow-up results from the Phase I study. The data showed that during a follow-up period of up to 104 weeks, all 15 patients treated with 4D-150 maintained a favorable safety profile, with no new inflammatory events observed and no changes in steroid use. Previously reported results indicated that three patients receiving high-dose 4D-150 did not require supplemental anti-VEGF injections at the 52-week follow-up, and all three patients remained free of supplemental anti-VEGF injections through 80–104 weeks of follow-up.

4DMT stated that, based on ongoing negotiations with the FDA and the European Medicines Agency,The company plans to initiate the Phase III study of 4D-150 in the first quarter of 2025., this study is a non-inferiority trial designed to compare high-dose 4D-150 with aflibercept. In the second half of 2024, the company expects to conduct an interim data analysis at 24 weeks for the expanded cohort of the PRISM trial.

Since its establishment in 2013 through June 2021, 4D Molecular Therapeutics (4DMT) has attracted significant attention. Over seven years, the company completed four rounds of financing and successfully went public in 2021, raising a total of $295 million. Its investor roster included nearly 20 prominent institutional investors and corporations, such as Viking Global Investors and Pfizer. Furthermore, 4DMT entered into agreements with AstraZeneca’s MedImmune and Roche to develop multiple AAV-based gene therapy products.

In April 2015, Roche and 4D Molecular Therapeutics (4DMT) announced a collaboration and license agreement to discover and develop optimized next-generation AAV vectors for indications with high unmet medical needs. In April 2016, 4DMT announced an expansion of its research collaboration with Roche, establishing a broad, long-term partnership to develop and commercialize multiple ophthalmic products. 4D-110 is the first program under this collaboration, with additional candidates targeting retinal diseases then in development.

In September 2018, 4D Molecular Therapeutics (4DMT) announced a collaboration with MedImmune on chronic lung diseases, including chronic obstructive pulmonary disease (COPD). 4DMT will lead early-stage development, including vector discovery, engineering, and optimization, while MedImmune will leverage AstraZeneca’s expertise in respiratory diseases to oversee clinical development.

Collaborations with Roche and AstraZeneca have significantly boosted 4D Molecular Therapeutics’ valuation, attracting $90 million in Series B financing, $75 million in Series C financing, and $120 million from its initial public offering in 2021.

But the good times were short-lived; just months after its IPO, 4D Molecular Therapeutics encountered development challenges.

First, the sector was impacted by clinical failures involving other companies in the AAV ophthalmic therapy industry. In April 2021, ocular gene therapy company Adverum Biotechnologies announced that during its Phase II INFINITY clinical trial, one patient experienced serious adverse events—including elevated intraocular pressure, panuveitis, and vision loss—30 weeks after receiving a high dose of ADVM-022.

At this time, 4D Molecular Therapeutics (4DMT) also disclosed a series of adverse events in the development of its candidate drug. Although not as concerning as the blindness cases observed in the Adverum trial, half of the patients treated with 4D-110 reported ocular inflammation. Additionally, Biogen had earlier announced that the clinical trial of its gene therapy candidate for X-linked retinitis pigmentosa (XLRP), cotoretigene toliparvovec, failed to meet its primary endpoint, which was demonstrating improvement based on tests assessing the retina.

The successive failures of two companies have cast a shadow over AAV-based ophthalmic drug development. At this critical juncture, Roche, which had previously funded the early-stage clinical trials of 4DMT’s candidate drug 4D-110, also announced the termination of its prior collaboration, with all rights to the drug reverting to 4DMT.

Industry black swan events and Roche’s exit dealt a severe blow to 4D Molecular Therapeutics, with the company’s stock price plunging from over $40 per share to $21.61 per share, a decline of 13%.

Nevertheless, 4DMT stated that it would continue to develop the therapy despite Roche’s announcement of the termination of their collaboration and the adverse events associated with 4D-110. At the time, David Kirn, M.D., Chief Executive Officer of 4DMT, said in a statement: “We are pleased to regain full rights to our 4D-110 choroidemia candidate product and to further develop it within our wholly owned ophthalmology portfolio.”

More than a year later, 4DMT Delivers Good News Again。

In November 2022, 4D Molecular Therapeutics (4DMT) announced interim clinical data from the first cohort of its Phase I/II clinical trial evaluating 4D-150 for the treatment of wet age-related macular degeneration (AMD). The data demonstrated that patients in Cohort 1 (n=5) who received a single intravitreal injection of 4D-150 (3E10 vg/eye) experienced a 96.7% reduction in the annualized anti-VEGF injection rate. Furthermore, 80% of patients in Cohort 1 did not require any supplemental aflibercept injections within approximately 10 months following administration of 4D-150. The safety and tolerability profile of 4D-150 in Cohort 1 was confirmed, with no reports of clinically significant intraocular inflammation or ptosis.

July 2023,Astellas Announces Collaboration Agreement with 4DMT with Total Potential Value of $962.5 Million, Astellas will utilize 4D Molecular Therapeutics’ AAV vector R100 to develop gene therapies for monogenic inherited eye diseases, with an option to add up to two additional targets related to rare monogenic ophthalmic diseases upon payment of additional option exercise fees.

Under the terms of the agreement, 4DMT will receive a $20 million upfront payment, as well as potential future option fees and milestone payments totaling up to $942.5 million, which includes $15 million in potential near-term development milestones for the initial targets. Additionally, 4DMT is entitled to tiered royalties ranging from single-digit to double-digit percentages on net sales of all licensed products.

In addition, in January this year, 4DMT announced a collaboration with gene therapy company Arbor Biotechnologies to jointly develop and commercialize up to six AAV-delivered CRISPR/Cas-based therapeutic candidates, with costs and profits shared equally according to a mutually agreed-upon plan.

After terminating its collaboration with 4D Molecular Therapeutics, Roche announced in January 2022 that the U.S. Food and Drug Administration (FDA) had approved the Biologics License Application (BLA) for its bispecific antibody faricimab (brand name: Vabysmo) for the treatment of diabetic macular edema (DME) and wet age-related macular degeneration (AMD). Vabysmo thus became the first bispecific antibody approved for ophthalmic diseases, generating sales of CHF 2.357 billion (approximately USD 2.708 billion) for Roche in mid-2023.

In addition to Vabysmo (faricimab), commonly used ophthalmic anti-VEGF drugs include Lucentis (ranibizumab), aflibercept, and conbercept.

Comparison of Different Therapeutic Agents

Data source: Compiled from public information; chart by VCBeat

In comparison, 44D Molecular Therapeutics’ 4D-150 May Enable Dosing Once Every 24 Weeks (Approximately 6 Months), these clinical results demonstrate its favorable safety and tolerability profile, leading to a surge in the company’s stock price. Going forward, can 4D-150 break through the competition and secure a foothold in the ophthalmic drug market? Only time will tell!