Clinical And Commercial Development Activities

ZoSaLa anticipates that support for achieving the above milestones will be provided by a combination of private seed stage financing and NIH small business grants.

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Having achieved the initial set of milestones described above, the company will begin IND enabling studies, CMC, and cGMP manufacture of its therapeutics.

 

Design of Efficacy Clinical Trials

Once the Company has sufficient safety data on its final therapeutic formulation, we will undertake efficacy trials. A strength of this opportunity is that the clinical trial design is well understood, including endpoints. ZoSaLa SAB Member John Curci, MD has been involved in a plurality of clinical trials for candidate therapies for AAA. One was a Phase 2 trial that evaluated whether doxycycline can impede expansion of small AA (B. Timothy Baxter, MD et. al. Effect of Doxycycline on Aneurysm Growth Among Patients With Small Infrarenal Abdominal Aortic Aneurysms JAMA. 2020;323(20):2029-2038.  doi:10.1001/jama.2020.5230). The trial was sponsored by NIH/NIA and was conducted across 22 Centers. By its conclusion,129 patients were treated with twice daily 100 mg doxycycline for two years and 125 were assigned to placebo. Unfortunately, the primary outcome, scores reflecting change in aortic diameter, did not differ significantly between treated and untreated. Dr Curci’s experience as a key member of this trial, aka N-TA^3CT, is extremely valuable for ZoSaLa. The small molecule metformin is currently being evaluated for its potential to impact primary outcomes experienced by AAA patients including rupture and the need for aneurysmal repair. One such trial is designed to run for 3.5 years and involve about 2000 participants about half of whom will receive 1500 mg of metformin per day. This is expected to be powered to reveal whether a reduction in the primary outcome repair or rupture.(Protocol for the Metformin Aneurysm Trial (MAT) Clinical Trial Golledge et al. Trials doi.org 10.1186/s 13063-021-059159-

Evaluating the efficacy of ZoSaLa’s therapies in TAA patients would involve far fewer patients but would also require 3-4 years.

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ZoSaLa’s Therapies Address Orphan Indications

Eligibility to be designated as an Orphan Drug or medicine in the US and in Europe carries significant advantages. In the US these include:

 

• A 25% tax credit on clinical testing expenses associated with qualifying clinical trials.

• Waiver of the Prescription Drug User Fee Act (PDUFA) application fee (~$3.1 million in 2022) that is required to be paid with NDA/BLA application submission.

• 7-year market exclusivity from date of approval

 

Benefits accruing to an Orphan Medicine designation in Europe include:

 

• Protocol assistance: A type of scientific advice specific for designated orphan medicines. This allows sponsors to get answers to their questions on the types of studies needed to demonstrate the medicine's quality, benefits and risks, and information on the significant benefit of the medicine.

• 10 years of market exclusivity. This period of protection is extended by two years for medicines that also have complied with an agreed pediatric investigation plan granted at the time of review of the orphan medicine designation.

• Fee reductions are also available depending on the status of the sponsor and the type of service required.

 

The criteria for Orphan Designation in the US and EU are similar and would clearly be met by an innovative therapy for TAA. The main criterion is that a product be intended for the diagnosis, prevention, or treatment of a rare disease or condition. The actual incidence and prevalence of TAA is uncertain and epidemiologic data is understudied. But available information underscore that TAA is indeed a rare condition. In the US, rarity for Orphan Drug purposes is quantified as fewer than 200,000 persons with the target condition or indication. In EU rarity is defined as an incidence of fewer than 1 in 5000. A recent, systematic review and meta-analysis based on searching searched MEDLINE, EMBASE and CENTRAL from inception to October 2020 concluded that the pooled incidence and prevalence of TAAs was 5.3 per 100,000 individuals/year (95% confidence). Based on the population of the US (331MM), one would anticipate that there are about 20,000 persons with TAA at risk for developing TAAD. In Europe the number would be expected to be approximately 44,000 persons.

Entezar Mehrabi Nasab and Seyyed Shamsadin Athari, “The Prevalence of Thoracic Aorta Aneurysm as an Important Cardiovascular Disease in the General Population,” Journal of Cardiothoracic Surgery 17, no. 1 (March 23, 2022): 51, https://doi.org/10.1186/s13019-022-01767-0.

 

ZoSaLa has confirmed with regulatory experts that it is likely that there is an Orphan path available for the company’s therapy for AAA. This would depend on the label the company sought. Patients most in need of a therapy to restore aortic wall integrity are those with the largest AAAs. As illustrated in the below table the same population is also statistically more likely to experience a repair or rupture in the ensuing 24 months due to a combination of the starting size and the relatively rapid growth rate of their AAA. The number of patients in the US with so called large AAA is far fewer than 200,000.

 

Population of Patients with Diagnosed AAA Segregated by AA Size (US Data 2019)