CYP Technical Analysis, page-36

Happy New Year! Wishing us all a prosperous 2023! Maybe this year will finally be a good one, breaking the downtrend of the previous 5 years...

@bedger I think the broader stem cell factor may not be much of an indicator here, since the issues CYP (and MSB for that matter) are facing are not so much related to stem cells in general, rather MSC-specific. There are plenty of general stem cell related therapies around the world that have received regulatory approvel, yet MSCs, first decribed in 1970 (Friedenstein), currently the most researched type of stem cells with over 1,000 registered clinical trials so far have only seen 10 therapies approved (2021):


https://www.researchgate.net/publication/343147875_Shattering_barriers_toward_clinically_meaningful_MSC_therapies#pf4

It is important to note, that only Alofisel, Prochymal and Temcell are allogeneic therapies, the rest are autologous therapies.
Prochymal, despite being receiving regulatory approval in Canada and New Zealand back in 2012, it never hit the shelfs.
There is still no FDA approved MSC therapy.

There's an excellent paper dated February 2021, which summarises past and present issues very well in my opinion:

"Introduction

Multipotent mesenchymal stromal cells (MSCs) are a heterogeneous population that when expanded in vitro includes stem, progenitor, and differentiated cells. MSCs have been implicated as a therapeutic modality in tissue injuries, chronic degenerative disorders, and inflammatory diseases on account of their regenerative potential and anti-inflammatory properties (Friedenstein et al., 1968, 1970; Galipeau and Senséb, 2018). Although therapeutic use in humans is the end goal, preclinical research relies on animal models for proof of concept and technique development, and thus animal applications cannot be overlooked. The first isolation and culture of MSCs were performed using bone marrow from guinea pigs (the 1970s) and then extended to rats in the 1980s (Friedenstein et al., 1987; Owen and Friedenstein, 1988). Isolation and culture of human MSCs did not begin until the early 1990s (Haynesworth et al., 1992; Lazarus et al., 1995; Pittenger et al., 1999). Since then, MSCs have become a widely studied experimental therapeutic product tested in over 1300 registered clinical trials (clinicaltrials.gov “mesenchymal” 6/5/20) (Galipeau and Senséb, 2018). In human clinical trials, allogeneic MSCs have been consistently shown to be safe but have not been able to replicate the large effect sizes predicted from preclinical research. For this reason, small and large trials have failed to meet efficacy endpoints (Li et al., 2016; Galipeau and Senséb, 2018).

A vast preclinical dataset, from both in vitro and in vivo animal studies, supports the notion that MSCs are a potent cellular therapeutic agent. Here, we will review the in vitro preclinical data, but reviews of the in vivo preclinical data can be found here (Vu et al., 2014; Squillaro et al., 2016; Lukomska et al., 2019; Dave et al., 2020). Why is there such a gap between the expectations set by preclinical data and human MSC trials? The inconsistent results could be due to product irregularities, transferability across species, or poor estimation of effect size from preclinical data leading to insignificant findings. Our thesis here is that to move forward strategically, the MSC field needs to recognize and address shortcomings that have been given little consideration in the rush toward clinical development. Preclinical data needs to be strengthened in regards to its ability to be translated. Instead of continuing to produce inconsistent preclinical in vitro and in vivo data that poorly translates, effort should be placed on determining the root of the transferability issues so that consistent, reliable data can be generated allowing for replication across research laboratories. In addition, although the potential of MSCs remains undisputed, questions remain concerning the mechanisms-of-action (MOAs), how in vitro testing correlates to in vivo activity, the number of cells in a dose, the route of administration, and how all of this relates to the therapeutic effects for the various indications (Mendicino et al., 2014).

To do this, we believe that first, characterization guidelines need to be updated to accommodate different MSC populations. This includes addressing variations in the literature that may obscure rather than explain MSC's physiological effects that impact therapeutic response. These inconsistencies include, but are not limited to, MSC tissue source and species-to-species differences. Second, along with updated characterization guidelines, improved standardization in the field would help to eliminate product and lot-to-lot variation as well as address the concern of purity vs. potency. Lastly, to properly address these concerns, more research funding is required. With federal funding on research and development (R&D) declining, and businesses spending over three times the amount of the federal government on R&D, it is clear that industry-sponsored research is critical. Businesses are more prone to fund research that has commercial applicability rather than research that simply addresses a question (Sargent, 2020). By focusing research efforts on areas with commercial potential, not only could this increase research funding but also could decrease time to market."
https://www.frontiersin.org/articles/10.3389/fcell.2021.632717/full

Definitely worth a read, as it also looks a bit deeper in the potency assay issue:

"Regulatory Gaps in MSC Therapy

[...]

In the US, culture-expanded MSC-like cells are considered to be a more-than-minimally-manipulated cellular and gene therapy (CGT) product regulated by section 351 of the Public Health Service (PHS) Act 42 U.S.C.262 (Galipeau et al., 2016). Due to this designation, MSC-like cells require an Investigational New Drug (IND) application and approval from the FDA to be used in a clinical trial (Galipeau et al., 2016). Under this regulation, a test to measure potency as part of the release criteria is required although standardization among the field and ISCT minimal criteria are not required (Food and Drug Administration, 2011b; Galipeau et al., 2016). The FDA has released guidelines for CGT products, regulated under the Code of Federal Regulations (CFR) 210, 211 that outline release testing. The guidance released by the FDA includes: demonstration of biological activity (potency); quantitative data; pre-defined acceptance and/or rejection criteria; employment of appropriate standards, controls, and reference materials; documentation of accuracy, sensitivity, specificity, and reproducibility of test methods; ingredient strength and identity; dating periods; and labeling requirements (Food and Drug Administration, 2011a; Galipeau et al., 2016).

Similarly, in Europe, clinical MSCs are considered an advanced therapy medicinal product (ATMP) in accordance with the European Medicines Agency (EMA) regulation 1394/2007 of the European commission (EC) (European Commission, 2007; Ancans, 2012; Rojewski et al., 2019). Under the ATMP, the identity and impurities of the MSCs must be described using the ISCT minimal criteria or a modification to the criteria (Horwitz et al., 2005; Dominici et al., 2006; European Commission, 2007; Wuchter et al., 2015; Rojewski et al., 2019). In addition, release criteria, which vary by type of clinical trial and requirements from other national competent authorities, are also governed under the ATMP and include contamination screening (microbial, endotoxin, and mycoplasma), viability, clonogenicity, identity, purity, and functional tests (European Commission, 2007; Ancans, 2012; Rojewski et al., 2019). Europe's regulatory approval process for cell therapy products is reviewed more thoroughly here (Ancans, 2012; Blasimme and Rial-Sebbag, 2013). Although, the ISCT made a point to clarify that their 2006 proposed guidelines should not be confused with final product release criteria, the ATMP regulations, along with the literature and FDA regulation submissions point to the fact that they may be seen as synonymous by some (Mendicino et al., 2014).

Although the FDA has released recommendations for developing tests to measure potency of the MSC product, the FDA does not provide recommendations regarding which specific assay should be used. Currently, each IND application is reviewed based on individual product attributes and is not compared to other MSC products (Galipeau et al., 2016; Galipeau and Senséb, 2018). Due to the biological nature and limited amount of the MSC product, hurdles exist that make development of assays and standardization difficult. Galipeau and Senséb (2018) review these challenges thoroughly and they list a number of problems such as variability of raw materials, limited product for testing, absence of appropriate standards, and in vivo fate of the product. For “biologics” (i.e., biologically-derived therapeutics) such as MSC-based therapeutics to be successfully manufactured at large scale, they must meet four criteria: (1) a stable and well-defined cell line; (2) a good manufacturing practice (GMP)-grade supply chain with a process control plan that has set variability values that produce a product with the desired therapeutic effect; (3) a standardized procedure that allows for process changes while maintaining product consistency; and (4) integrated redundancy and flexibility to allow for adaptation without sacrificing product consistency (Melsheimer et al., 2018). Even with these criteria met, biologics are still produced from living organisms and this variability causes product changes (e.g., quality, behavior, safety) that in turn affect the clinical use (Melsheimer et al., 2018).

An analysis of FDA IND applications by Mendicino et al. (2014) revealed variability in MSC tissue sources, manufacturing methods, and MSC characterization. Interestingly, it was noted that only 7 of the 9 ISCT-recommended MSC markers were ranked in the top 20 markers used by applicants to characterize human MSCs (Mendicino et al., 2014). In addition, they discovered that applications were submitted with MSC-characterization markers reported well below the 95% proposed by the ISCT, e.g., submissions with CD105 reported at only ~80%, although it is unclear whether this impacts MSC function or not (Mendicino et al., 2014). This data brings the ISCT guidelines into question. If the end goal is clinical use as an FDA-approved therapeutic, yet the FDA does not require the proposed criteria, and they are not consistently demonstrated by applicants, what purpose are they serving related to that goal? If applicants are struggling to meet these guidelines, how well are the guidelines serving the human MSC product? Further, how can it be expected that nonhuman MSCs will adhere to these standards? To combat MSC product inconsistencies and ensure successful clinical translation, variability in the process and product must be realized, described, and managed.

Additionally, as noted in a review from the FDA, MSC manufacturing reflects a broadening of MSC characterization release criteria that are associated with phased clinical testing (Mendicino et al., 2014). This is the opposite of what the FDA expects and is a double-edged sword—allowing cells which fail to meet MSC criteria in the released MSC product may have secondary consequences of reduced potency and increased lot-to-lot variation. It should be noted that although MSC characterization is not required by the FDA, generating a consensus MSC definition would benefit all MSC shareholders as it would enable comparison across studies and enable therapeutic use by producing more consistent effect sizes (Mendicino et al., 2014)."

All these "issues" may have contributed to the lack of interest in "MSC-stocks". This general view on MSC therapies will (hopefully) change once the first MSC therapy will gain approval in the US, showing that MSC therapies work afterall.

Combine these general issues with the many CYP-specific missteps (loan fiasco, director blocktrade, FujiFilm delay after bad/no communication then handing back license, MEND, communication in general) and you understand why the SP is at 30c now.

However, I do see quite a few catalysts here @Wasabibarako, short and medium term:

• US P2 aGvHD trial to commence (60 patients) - although there won't be a Cohort A & B this time, given that the P2 trial is not targeting SR-aGvHD patients, the pool of eligible patients is larger than our P1 trial
• AU P1 DFU trial completion (recruitment) including results
• AU P3 OA trial completion (recruitment) and given the increase in numbers over the past few months (so we've been told, also judging by the clinicaltrials history), I don't believe it will take until December to get there
• NL P1b Renal trial to commence (10 patients)

I am also expecting at least one more externally funded trial to be announced in the coming months (CLI or IPF), based on the pre-clinical data and recent comments made during presentations/AGM.

Of course we will also get updates on pre-clinical research and patent announcements, however the real catalysts (as we have seen) are patient-derived data.

Additionally, I am counting on some process-improvement updates now that FCDI has taken over the manufacturing process (not including US P2 aGvHD however).

Will we see a new (first) licensee in 2023?
To be honest, I wouldn't count on it - unless we see compelling data from our ongoing trials, addressing at least some of the MSC-specific concerns.

Good luck to us all!