scarlet1967 wrote:
It seems unlike fast track designation the BTD can’t be requested at IND stage, the drug needs to show safety and good efficacy among others to be considered for BTD. It could be as early as during phase1 but ideally not later than end of phase2. It is somehow hard to look at historical examples.
The PDC technology is quite new compared to specifically traditional chemotherapy and ADC. We all know the advantages of targeted drug delivery versus traditional chemo but compared to ADC there are some clinical and other benefits such as in case of PDC the use smaller molecules which can bypass the MDR easier(penetration of tumour cells), better solubility, less immune reaction also cheaper to manufacture.
Generally speaking the clinical advantages of PDCs and targeted drug delivery in theory could end up with surprising good safety and efficacy early in the process so it all depends on the results if really promising they can apply for the BTD at the end of part1 phase1. They had really good results on late stage cancers with sortilin over expression up to 80% in animal models if they can duplicate those results in humans especially as their PDC only needs 1/4 of dosage compared to docetaxel alone they could be at a therapeutic dose by now absent toxicity, by end of 6th cycle they will be well above those therapeutic windows so primary significant tumour regression early on during the trial is quite possible, that would be definitely a good case to apply for break through therapy designation.
I was hoping that they would share more data but it turn out to be wishful thinking maybe they want to share after end of part1 when more patients have been dosed so the PoC is more reliable, their optimistic language during the webinar to me is a very good sign that thus far results are good which is great. Later on if the results are promising they can apply for priority review and accelerated approval as well so I guess the explanation of wide estimated duration of the program varying from 2 to 5 years depends on the rolling results.
“ADCs can also generate dangerous immune reactions, yielding toxicity and halting further therapy.28 Furthermore, the complicated structure of ADCs results in high production costs, in some cases restricting access to these drugs as their cost-effectiveness may be called into question by health insurers. Owing to their high molecular weight and protein-like physicochemical properties, ADCs also suffer from restricted distribution which can prevent these therapies from penetrating some types of solid tumours and limiting their efficacy.
To overcome these issues, many research groups have explored alternative approaches such as peptide-based drugs, protein–protein interaction inhibitors (PPIs) and drug delivery transporters.”
https://pubs.rsc.org/en/content/articlelanding/2021/cs/d0cs00556h#!divAbstract
“There are multiple approaches that a sponsor may utilize to show substantial improvement. For example, a head-to-head comparison of the new drug to the current standard of care in an early stage trial may offer enough evidence of a meaningful basis for the breakthrough designation. Early patient data without a direct comparison in a clinical trial study that provides better understanding of disease progression may also suffice. For instance, if a certain cancer type has an 80 percent progression rate in a one-year period, yet a drug in early trials shows a 10 percent progression during the same timeframe, a head-to-head trial to prove substantial improvement may not be needed.[25]”
https://pharmdevgroup.com/fda-expedited-programs-explained/
“An effect on an established surrogate endpoint
An effect on a surrogate endpoint or intermediate clinical endpoint considered reasonably likely to predict a clinical benefit (i.e., the accelerated approval standard)
An effect on a pharmacodynamic biomarker(s) that does not meet criteria for an acceptable surrogate endpoint, but strongly suggests the potential for a clinically meaningful effect on the underlying disease
A significantly improved safety profile compared to available therapy (e.g., less dose-limiting toxicity for an oncology agent), with evidence of similar efficacy
A drug that receives Breakthrough Therapy designation is eligible for the following:
All Fast Track designation features
Intensive guidance on an efficient drug development program, beginning as early as Phase 1
Organizational commitment involving senior managers
Ideally, a Breakthrough Therapy designation request should be received by FDA no later than the end-of-phase-2 meetings if any of the features of the designation are to be obtained. Because the primary intent of Breakthrough Therapy designation is to develop evidence needed to support approval as efficiently as possible, FDA does not anticipate that Breakthrough Therapy designation requests will be made after the submission of an original BLA or NDA or a supplement.”
https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/breakthrough-therapy