At the 2019 American Society of Hematology (ASH) annual meeting, Aprea Therapeutics presented results from two ongoing Phase II clinical trials of APR-246, a novel p53-activating drug, in combination with azacitidine (AZA), in patients with TP53 mutant myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML).

At the 9 December event, it was reported that in both Phase Ib/II trials, one conducted in the US by the Moffitt Cancer Center (NCT03072043) and the other in France by the Groupe Francophone des Myelodysplasies (NCT03588078), efficacy results amongst evaluable patients were very encouraging, with complete remission (CR) rates of about 60% and overall response rates (ORRs) over 70%. 

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Based on these data and strongly favourable opinions from key opinion leaders (KOLs), GlobalData posits that APR-246 could be a future game-changer for patients with TP53 mutant MDS, a subgroup of patients with exceptionally poor prognoses. 

At ASH 2019, investigators from the US Phase II trial of APR-246 (NCT03072043) reported that the ORR in 33 evaluable MDS patients (out of 55 total patients enrolled) was 88%, with a 61% CR rate, by International Working Group (IWG) criteria. 

Data reported from the French trial (NCT03588078) were similar, with the ORR and CR rate in 24 evaluable MDS patients (out of 53 total patients enrolled) being 74% and 59%, respectively. The median duration of follow-up in the US trial was 10.8 months, with a median duration of response at 8.4 months and a median duration of CR at 7.3 months. 

In the French trial, the median duration of follow-up was only 6.4 months and thus the median overall survival (OS) for all enrolled patients had not yet been reached. In the US trial, among all enrolled patients, median OS was 13.7 and 3.9 months for responders and non-responders, respectively, and 10.8 months overall. 

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In the US trial, investigators reported that safety was acceptable and that there were no major differences from the typical safety profile seen with AZA alone. Interestingly, data from the French trial suggested that compared to baseline, mutant TP53 variant allele frequency (VAF) was significantly decreased in patients responding to APR-246 and undetectable in those who had achieved a CR. 

Data from these two trials suggest that APR-246 is very efficacious in patients with TP53 mutant MDS. If APR-246 in combination with AZA is shown to be more efficacious than AZA alone in Aprea’s ongoing Phase III trial (NCT0374571), this product could completely change the treatment paradigm for patients with this subset of disease.

Across the board, KOLs interviewed by GlobalData were enthusiastic about the future prospects of APR-246. TP53 mutant MDS accounts for 5–10% of de novo MDS and 25–30% of therapy-related MDS and represents a distinct cohort with a poor prognosis. KOLs cited a serious unmet need for treatment options within this subpopulation of patients. 

Furthermore, KOLs believed that the future of MDS treatment as a whole centred on the type of molecular targeting used by APR-246. These experts supported the increased usage of next-generation sequencing (NGS) to assess the mutational profiles of both higher- and lower-risk MDS patients and believed the field was quickly moving toward the routine use of mutational status to make better treatment decisions.

Based on the preliminary Phase II data presented at ASH 2019 and insight from KOLs, GlobalData anticipates APR-246 to be an important future addition to the MDS armamentarium. However, the efficacy and safety of APR-246 in combination with AZA, compared to AZA alone, still remains to be seen. The primary completion for Aprea’s ongoing Phase III trial is expected in June 2020.

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