Evicenter
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4D-150

Neovascular age-related macular degeneration

Regulatory submission
Not announced
Launch
Not announced
Last updated
180 sources

Product information and disease descriptionProduct descriptionProduct information

Contraindications/Warnings/Precautions/Adverse effects

11 evidence topics · 5 sources

Warnings and precautions
FDA-approved prescribing information, contraindications, boxed warnings, and REMS

Not applicable.

Intraocular inflammation observed in the PRISM clinical trial

“As previously reported, within approximately the first 6 months (28 weeks) post-4D-150 dosing, 2.8% (2 of 71) of patients had 4D-150-related 1+ (mild) intraocular inflammation (IOI) (SUN/NEI scales), which were transient 1+ vitreous cells noted at a single timepoint” (opens the source at this quote in a new tab)

“Following the first 28 weeks post-4D-150 dosing, no new cases of inflammation with 2 to more than 4 years of follow-up on all patients as of the data cutoff” (opens the source at this quote in a new tab)

Events not observed in the clinical program to date

“No 4D-150-related hypotony, endophthalmitis, vasculitis, occlusive/non-occlusive retinal vasculitis or choroidal effusions observed to date” (opens the source at this quote in a new tab)

“Supplemental aflibercept injection-related case of endophthalmitis (presumed bacterial infection), resolved over following 2 visits” (opens the source at this quote in a new tab)

Dose-related ocular inflammation in nonhuman primates

“A dose response was observed for white blood cells in the aqueous and vitreous humor.” (opens the source at this quote in a new tab)

“At 1 × 1011 vg/eye, no inflammation was observed in any eyes (0/14) in either the aqueous or vitreous humor.” (opens the source at this quote in a new tab)

“Hypotony was not observed in any 4D-150–treated eyes” (opens the source at this quote in a new tab)

Class risks described for AAV gene therapy in neovascular AMD

“Potential risks of gene therapy include a potential immune response that may be elicited by the vector, accidental activation of oncogenes or inactivation of tumor suppresor genes leading to malignant transformation via insertational mutagenesis and integration of the viral DNA inserts into the host's DNA.” (opens the source at this quote in a new tab)

“Although AAV vectors typically support long-term and well-tolerated protein production, excessive or ectopic expression can disrupt retinal homeostasis or trigger immune-mediated inflammation” (opens the source at this quote in a new tab)

“One of the most significant limitations is the presence of preexisting NAbs against AAV capsids in the human population” (opens the source at this quote in a new tab)

Dependence of intraocular inflammation on vector dose and route of delivery

“Inflammation is dependent on the dose and delivery routes of the vector.” (opens the source at this quote in a new tab)

“The AAV capsid leads to a dose-related humoral immunity response and antigen-specific T cell activation.” (opens the source at this quote in a new tab)

“In terms of injection sites, the subretinal space is the least immunogenic followed by the suprachoroidal and ending with the vitreous cavity.” (opens the source at this quote in a new tab)

“Moreover, because IVT administration inherently relies on passive diffusion of AAV particles within the vitreous, achieving therapeutically relevant transduction generally necessitates the use of high vector doses. This requirement, in turn, increases the likelihood of dose-dependent ocular inflammation and systemic immune activation, which remain key safety considerations in the clinical application of this route” (opens the source at this quote in a new tab)

Dilution of the vector in the vitreous and the dose required for intravitreal delivery

“First, once the vector and its cargo are injected into the vitreous, dilution of the vector occurs. Therefore a higher dose has to be injected to compensate for this dilution effect. A higher dose may elicit a stronger immune response.” (opens the source at this quote in a new tab)

Episomal persistence of the AAV genome and the risk of insertional mutagenesis

“In addition, AAV genomes rarely integrate into the host genome, thereby minimizing the risk of insertional mutagenesis, and instead persist as stable episomal forms that enable long-term transgene expression” (opens the source at this quote in a new tab)

Transgene overexpression as a dose-related risk and the limits on expression control

“Another important consideration is the risk of toxicity from transgene overexpression, especially when high vector doses are needed to reach therapeutic levels” (opens the source at this quote in a new tab)

“This risk is heightened by the limited packaging capacity of AAV vectors, which constrains the use of complex regulatory elements that could otherwise fine-tune expression” (opens the source at this quote in a new tab)

Preexisting capsid antibodies, treatment eligibility, and re-dosing

“These antibodies, which may arise from natural exposure to wild-type AAVs, can neutralize the vector before it reaches target tissues, reducing transduction efficiency and potentially rendering patients ineligible for treatment” (opens the source at this quote in a new tab)

“Furthermore, a single exposure to an AAV vector can prime the immune system, complicating future re-dosing efforts and raising safety concerns” (opens the source at this quote in a new tab)

Ocular compartmentalization and the age of the treated population as modifiers of immune risk

“Fortunately in ocular gene therapy, the therapeutic gene is compartmentalized to the eye. Smaller doses of genetic material need to be delivered minimizing systemic side effects.” (opens the source at this quote in a new tab)

“In addition, the patient population affected by NV-AMD is typically an older population. This may represent an advantage since aging individuals may not mount an exuberant immune response” (opens the source at this quote in a new tab)

Dose-related inflammation after intravitreal AAV aflibercept delivery in nonhuman primates

“Intravitreal injection of ixo-vec caused a dose related ocular inflammatory response consisting of anterior chamber cells, keratic precipitates, lens deposits and vitreous cells.” (opens the source at this quote in a new tab)