Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressants, other immunosuppressants, ATC code: L04AX08.
Mechanism of action
Darvadstrocel contains expanded adipose stem cells (eASC), which exhibit immunomodulatory and anti-inflammatory effects at inflammation sites.
Anal fistulas typically present as fissures penetrating the intestinal lumen and perianal skin surface, and are characterised by local inflammation that is exacerbated by bacterial infections and faecal contamination. In the inflamed area, there is infiltration of activated lymphocytes and local release of inflammatory cytokines.
Inflammatory cytokines, in particular IFN-γ released by activated immune cells (i.e., lymphocytes), activate eASC. Once activated, eASC impair proliferation of activated lymphocytes and reduce the release of pro-inflammatory cytokines. This immunoregulatory activity reduces inflammation, which may allow the tissues around the fistula tract to heal.

Pharmacodynamic effect
In the ADMIRE-CD study, 63/103 of the eASC-treated patient population were analysed for the presence of donor-specific antibodies (DSA) at baseline and week 12. At week 12, 23/63 (36%) showed anti-donor antibody production. Of patients with DSA at week 12, 7/23 (30%) had cleared DSA by week 52. Lack of de novo DSA generation was observed between week 12 and week 52. No association between DSA results and safety or efficacy up to week 52 was seen in the subset tested.

Clinical efficacy

The efficacy of Alofisel was assessed in the ADMIRE-CD study. This was a randomised, double blind, parallel group, placebo-controlled, multicentre clinical trial to assess efficacy and safety of Alofisel for the treatment of complex perianal fistulas in Crohn’s disease patients.

A total of 212 patients were randomised, and 205 patients received a local injection of either darvadstrocel 120 × 106 cells or placebo in a 1:1 design. Patients had draining complex perianal fistulas with an inadequate response to at least one of the following treatments: antibiotics, immunosuppressants or anti-TNFs. Concomitant use of stable doses of immunosuppressants (18% of patients) or anti-TNFs (33%) or both (28%) was allowed during the study.

The primary endpoint was the combined remission at week 24 after study treatment, defined as clinical closure of all treated fistulas (absence of draining despite gentle finger compression) and absence of collection (>2 cm) confirmed by blinded central MRI. The key secondary endpoints were defined as clinical remission (clinical closure of all treated fistula) and response (clinical closure of at least 50% of all treated fistulas) at week 24. In addition, a long term follow-up was conducted up to week 52.

Alofisel group                        Control group                P value (Alofisel+standard of                (Placebo+standard of care*)                               care*)
N= 103                              N= 102
Combined remission at week
52                                  35                        0.019
24 (% patients)
Combined remission at week
56                                  38                        0.009
52 (% patients)
* Including abscess drainage, seton placement/removal, curettage, suture of internal openings and medical treatments 
Results of the key secondary endpoints show that the proportion of patients with clinical remission at week 24 was 55 % in the Alofisel group and 42 % in the control group (p = 0.052) and the corresponding figures for response were 69% and 55% (p = 0.039).

The proportion of patients with clinical remission at week 52 was 59 % in the Alofisel group and 41 % in the control group (p = 0.012) and corresponding figures for response were 66% and. 55% (p = 0.114). In a limited number of patients followed up to week 104, clinical remission at week 104 was 56% in the Alofisel group and 40% in the control group.

In Alofisel group, the number of patients who had combined remission at week 24 and subsequently developed anal abscess/anal fistula by week 52 was 2.9% (3/103), whereas the number of patients without combined remission at week 24 who subsequently developed anal abscess/anal fistula by week 52 was 9.7% (10/103).

In control group, the number of patients who had combined remission at week 24 who developed anal abscess/anal fistula by week 52 was 4.9% (5/102), whereas the number of patients without combined remission at week 24 who developed anal abscess/anal fistula by week 52 was 2.9% (3/102).

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

The nature and intended clinical use of darvadstrocel are such that conventional studies of pharmacokinetics (absorption, distribution, metabolism and elimination) are not applicable.
Biodistribution studies in preclinical models were conducted with the objective of evaluating the persistence of eASC at the site of injection and their potential migration into other tissues or organ systems. After perianal and intrarectal injection of human eASC in athymic rats, cells were present in the rectum and jejunum at the site of injection for at least 14 days and were undetectable after 3 months. eASC were not present in any of the tissues analysed after 3 months or 6 months.