Anti-VEGF Gene Therapy for Acoustic Neuroma

Recruiting at 2 trial locations

Overseen By Akouos Clinical Trials

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Akouos, Inc.

Disqualifiers: NF2, Bilateral vestibular schwannoma, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 1 day

27 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial will evaluate the safety and tolerability of a single unilateral administration of one of three dose levels of AAVAnc80-antiVEGF and will evaluate the Akouos delivery device to safely achieve the intended product performance.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment AAVAnc80-antiVEGF for acoustic neuroma?

Research on similar treatments, like bevacizumab, shows that blocking the VEGF pathway can slow tumor growth and improve hearing in patients with neurofibromatosis type 2, which involves similar types of tumors. This suggests that AAVAnc80-antiVEGF, which also targets VEGF, might have similar benefits for acoustic neuroma. ^{1 2 3 4 5}

How is the treatment AAVAnc80-antiVEGF different from other treatments for acoustic neuroma?

AAVAnc80-antiVEGF is a gene therapy that targets VEGF (a protein that promotes blood vessel growth), which is different from traditional treatments like surgery or radiation. This therapy uses a viral vector to deliver anti-VEGF genes directly to the tumor, potentially reducing its growth by cutting off its blood supply, which is a novel approach compared to existing treatments. ^{3 5 6 7 8}

Research Team

Kathy Reape, MD

Principal Investigator

Akouos, Inc.

Eligibility Criteria

This trial is for individuals with vestibular schwannoma, also known as acoustic neuroma. Participants must meet certain health criteria to be eligible, but specific inclusion and exclusion details are not provided.

Inclusion Criteria

Able and willing to comply with all trial requirements, including willingness to participate in a separate long term follow-up study after completion of this trial

I have a growing tumor on my balance nerve in one ear.

Profound hearing loss, defined by pure-tone audiometry thresholds or word recognition score, in the affected ear

Exclusion Criteria

I have been diagnosed with NF2 or have tumors on both hearing nerves.

Prior participation in a clinical trial with an investigational drug within six months prior to administration (Day 0), or any prior participation in a gene therapy clinical trial

I have had surgery or radiation for a brain tumor on my hearing nerve.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single unilateral intracochlear administration of AAVAnc80-antiVEGF using a sterile, one-time use investigational medical device

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including changes in tumor size and frequency of adverse events

approximately one year

Treatment Details

Interventions

• AAVAnc80-antiVEGF

Trial Overview The study tests the safety of a gene therapy called AAVAnc80-antiVEGF delivered through the Akouos device. It will assess three different dose levels administered once unilaterally (to one ear).

Participant Groups

Group I: Cohort 3 Experimental Treatment 1 Intervention

Adult participants to receive a single unilateral intracochlear administration of AAVAnc80-antiVEGF (dose level 3) in the study ear using a sterile, one-time use investigational medical device

Group II: Cohort 2 Experimental Treatment 1 Intervention

Adult participants to receive a single unilateral intracochlear administration of AAVAnc80-antiVEGF (dose level 2) in the study ear using a sterile, one-time use investigational medical device.

Group III: Cohort 1 Experimental Treatment 1 Intervention

Adult participants to receive a single unilateral intracochlear administration of AAVAnc80-antiVEGF (dose level 1) in the study ear using a sterile, one-time use investigational medical device.

Who Is Running the Clinical Trial?

Akouos, Inc.

Lead Sponsor

Trials

4

Recruited

220+

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Findings from Research

In a study of 17 patients with sporadic vestibular schwannomas, both vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were found to be expressed at the mRNA and protein levels in all tumor samples, indicating their potential role in tumor biology.

The expression levels of bFGF and VEGF were positively correlated with tumor volume, growth index, and microvessel density, suggesting that these factors may influence the growth characteristics of vestibular schwannomas through angiogenic and neurotrophic mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression of vascular endothelial growth factor and basic fibroblast growth factor in sporadic vestibular schwannomas correlates to growth characteristics. Koutsimpelas, D., Stripf, T., Heinrich, UR., et al.[2017]

In a study of 7 pediatric patients with neurofibromatosis type 2 (NF2) receiving bevacizumab for progressive vestibular schwannomas, the treatment resulted in a significant reduction in tumor growth rate, from 138% annually before treatment to 36% after one year.

Bevacizumab was well tolerated and led to one instance of hearing improvement, suggesting it could be a promising option for managing vestibular schwannomas in children, especially if initiated early in the treatment process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab decreases vestibular schwannomas growth rate in children and teenagers with neurofibromatosis type 2. Hochart, A., Gaillard, V., Baroncini, M., et al.[2022]

Bevacizumab shows potential in controlling vestibular schwannoma (VS) growth in patients with neurofibromatosis type 2 (NF2), with 41% of patients experiencing partial tumor regression and 20% showing hearing improvement after treatment.

However, serious side effects were noted in 17% of patients, indicating that while bevacizumab can be effective, its use should be carefully considered due to the risk of adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of bevacizumab for vestibular schwannoma in neurofibromatosis type 2: a systematic review and meta-analysis of treatment outcomes. Lu, VM., Ravindran, K., Graffeo, CS., et al.[2020]

In a study of 12 patients with rapidly growing vestibular schwannomas treated with bevacizumab, certain MRI-derived parameters were found to predict tumor response, with larger tumors showing better responses to treatment.

Key predictive biomarkers included lower relaxation rate (R1(N)) and higher contrast transfer coefficient (K(trans)), indicating that these MRI metrics can help assess the effectiveness of antiangiogenic therapy in managing vestibular schwannomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vascular biomarkers derived from dynamic contrast-enhanced MRI predict response of vestibular schwannoma to antiangiogenic therapy in type 2 neurofibromatosis. Li, KL., Djoukhadar, I., Zhu, X., et al.[2018]

Bevacizumab, an anti-VEGF therapy, significantly reduced tumor growth and improved survival rates in animal models of schwannomas, with a 50% decrease in tumor growth rate and at least a 50% extension in survival for mice with intracranial schwannomas.

The treatment normalized the blood vessel structure and function in the tumors, leading to increased tumor necrosis and apoptosis, suggesting that it works by restoring a balance between VEGF and semaphorin 3 signaling.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-vascular endothelial growth factor therapies as a novel therapeutic approach to treating neurofibromatosis-related tumors. Wong, HK., Lahdenranta, J., Kamoun, WS., et al.[2022]

Bevacizumab treatment in a 40-year-old woman with Neurofibromatosis type 2 (NF2) led to significant improvements in hearing and a reduction in tumor volume after 6 months, demonstrating its efficacy in managing this condition.

The patient experienced no adverse events during treatment, indicating that bevacizumab is a safe option for NF2 patients who are not suitable for surgery or radiation therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab treatment for vestibular schwannoma in a patient with neurofibromatosis type 2: hearing improvement and tumor shrinkage. Sponghini, AP., Platini, F., Rondonotti, D., et al.[2017]

The anti-VEGF agent bevacizumab has shown therapeutic efficacy in treating vestibular schwannomas, leading to tumor size reduction and improved hearing in patients with neurofibromatosis type 2, indicating its potential as a treatment option.

VEGF plays a significant role in various hearing loss conditions, including otitis media with effusion and sensorineural hearing loss, with studies showing that VEGF receptor inhibitors can improve hearing in animal models and that recombinant VEGF can reproduce clinical findings in otitis media.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of vascular endothelial growth factor and vascular stability in diseases of the ear. London, NR., Gurgel, RK.[2014]

In a study of 22 patients with neurofibromatosis type 2 (NF2), high-dose bevacizumab (10 mg/kg every 2 weeks) resulted in a hearing response in 41% of participants after 6 months, which is similar to the 35%-40% response seen with standard doses.

Despite the high-dose treatment, there was no significant improvement in tumor shrinkage for pediatric patients, and the treatment did not lead to a decrease in free vascular endothelial growth factor, suggesting that alternative strategies may be needed for children with NF2.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter, Prospective, Phase II and Biomarker Study of High-Dose Bevacizumab as Induction Therapy in Patients With Neurofibromatosis Type 2 and Progressive Vestibular Schwannoma. Plotkin, SR., Duda, DG., Muzikansky, A., et al.[2020]

References

1. United States pubmed.ncbi.nlm.nih.gov

Expression of vascular endothelial growth factor and basic fibroblast growth factor in sporadic vestibular schwannomas correlates to growth characteristics. [2017]

2. United States pubmed.ncbi.nlm.nih.gov

Bevacizumab decreases vestibular schwannomas growth rate in children and teenagers with neurofibromatosis type 2. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of bevacizumab for vestibular schwannoma in neurofibromatosis type 2: a systematic review and meta-analysis of treatment outcomes. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Vascular biomarkers derived from dynamic contrast-enhanced MRI predict response of vestibular schwannoma to antiangiogenic therapy in type 2 neurofibromatosis. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Anti-vascular endothelial growth factor therapies as a novel therapeutic approach to treating neurofibromatosis-related tumors. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Bevacizumab treatment for vestibular schwannoma in a patient with neurofibromatosis type 2: hearing improvement and tumor shrinkage. [2017]

7. United States pubmed.ncbi.nlm.nih.gov

The role of vascular endothelial growth factor and vascular stability in diseases of the ear. [2014]

8. United States pubmed.ncbi.nlm.nih.gov

Multicenter, Prospective, Phase II and Biomarker Study of High-Dose Bevacizumab as Induction Therapy in Patients With Neurofibromatosis Type 2 and Progressive Vestibular Schwannoma. [2020]