Mendus — Improving survival beyond standard of care

The clinical data for DCP-001 as an AML maintenance therapy continue to impress, after Mendus reported updated survival and immunomonitoring data from the Phase II ADVANCE II trial (NCT03697707) at the 64th ASH Annual Meeting. As a reminder, ADVANCE-II is an ongoing, open-label Phase II trial investigating DCP-001 as a potential relapse vaccination in AML patients who are in their complete remission but still have MRD. The results reported at ASH 2022 follow interim data from May, which, at the time of analysis, showed an MRD response in seven out of 20 patients (aged 34–79, median 60) treated with DCP-001 over the 32-week study period, with five patients converting from MRD-positive to MRD-negative and two demonstrating an at least 10-fold reduction in MRD. A further seven patients had stable MRD and six patients relapsed during this time. At this point the study had not yet reached median RFS or OS.

Results presented at ASH 2022 showed that, at a median follow-up period of 19.4 months, median RFS for the entire patient population was not yet reached (but 12-month RFS was estimated at 64%, range 41–80%, Exhibit 1), and median OS stood at 30.9 months (Exhibit 2) and those patients who were still in complete remission (12 out of 20 patients) had been so for 16 to 47 months after start of treatment (Exhibit 1). Patients who had converted to MRD-negative displayed a significantly prolonged RFS and OS, with neither mRFS nor mOS being reached in this sub-group. DCP-001 continued to display a good safety profile, with no serious or severe adverse events reported (the main adverse events continued to be injection site reactions occurring within 48 hours after treatment). This very important in AML, where the main standard of care is cytotoxic chemotherapy, which is unsuitable for many. Following completion of the initial 70-week follow-up period, patients enrolled in ADVANCE II have now entered a long-term follow up, which we expect will provide median-RFS data, once reached.

Immunomonitoring data, also presented at ASH, showed the number of patients with an MRD response, and the nature of those responses, was unchanged from the preliminary results reported in May (seven of 20 patients, five MRD conversions from positive to negative, two 10x MRD reductions), however 17 out of 20 patients displayed immune responses to DCP-001 specific tumour-associated antigens. High immune responses were observed to correlate with patient MRD responses and the five patients who displayed MRD conversion following DCP-001 treatment had significantly better overall survival, with all being alive at the time of analysis. We believe this represents convincing evidence that DCP-001 can affect a meaningful immune response that may improve patient survival and relapse in AML patients in remission with persistent MRD.

The data presented by Mendus demonstrate DCP-001 has the potential to affect a meaningful improvement in patient relapse and survival, in our view. When viewed in comparison with the only approved AML maintenance therapy currently, oral azacitidine (Onureg, Bristol Myers Squibb), this becomes more evident. Onureg was approved by the FDA as an AML maintenance therapy in 2020, based on data from the randomised, placebo-controlled, double-blind Phase III QUAZAR AML-001 (NCT01757535) study, in which the drug demonstrated an mOS of 14.6 months (vs 10.4 months in placebo group) and mRFS of 7.1 months (vs 2.7 months in placebo group) in baseline MRD+ patients. Recent mOS data from the ADVANCE trial (30.9 months) compares very favourably, in our view, with the QUAZAR AML-001 data for Onureg (14.6 months). That the trial has not reach relapse-free survival at a median-follow up period of 19.4 months also suggests significantly improved relapse rates with DCP-001 treatment, in our view, in comparison with the results shown in QUAZAR AML-001. We caveat, however, that comparisons made between clinical trials must be undertaken with care and the design of the QUAZAR AML-001 trial (randomised, placebo controlled, double blind) means direct comparison with the Phase II ADVANCE II study (open-label without a placebo or control comparator arm) survival data is not necessarily applicable.

We note that Venetoclax (AbbVie), a selective B-cell lymphoma 2 (BCL-2) inhibitor, which forms the backbone of many first-line treatment regimens in AML, is also in development as a potential maintenance therapy for AML, in combination with azacitidine. The randomised, double-blind, multi-arm Phase III VIALE-M (NCT04102020) is currently enrolling patients to investigate this combination’s effect as a maintenance therapy in AML patients experiencing first remission after chemotherapy. The trial will assess OS and RFS up to three years and is expected to complete in late-2027. While the potential approval of venetoclax as an AML maintenance therapy could affect DCP-001’s commercial prospects, given the toxicity concerns associated with its use (in contrast to DCP-001’s good safety profile to date, in our view) we do not see venetoclax as a meaningful threat to DCP-001.

In a recent event, hosted by the company, the need for effective AML maintenance therapies was highlighted by two KOLs in the field. MRD status (defined as the presence of leukaemia cells at levels as low as 1:104 to 1:106 white blood cells) is an emerging prognostic biomarker that is recognised as an important risk factor in AML. In current practice, once AML patients have reached complete remission (CR) through treatment with intensive chemotherapy (eg the 3+7 regimen of three days of anthracyclines followed by seven days of cytarabine), they will either receive a stem-cell transplant (if eligible) or maintenance therapy (currently Onureg) to reduce the risk of relapse. It is estimated that the 3+7 regimen has a 54% CR rate, and while a stem cell transplant is generally recognised as the only curative treatment option but is not always appropriate. It is estimated that the chemotherapy-stem cell transplant standard of care is unsuccessful in 60–80% of patients due to the persistence of MRD, hence the need for effective maintenance therapies. In addition, the event highlighted the shortcomings of immune checkpoint inhibitors and the opening in the treatment landscape this has left, relative to other oncology indications.

Considering the recently presented survival and immunomonitoring data and the emerging importance of MRD as a prognostic biomarker for patient survival, we continue to believe that DCP-001 could form an important part of maintenance therapy regimens for AML patients in CR who still harbour MRD. The significant length of patient survival demonstrated in the ADVANCE II trial is especially positive news for Mendus, as the company continues to build DCP-001’s competitive profile as an AML maintenance therapy. In addition, we expect this positive data will aid in hastening any licensing/acquisition talks and drawing further industry attention to Mendus’s DCOne development platform.

We view the positive data presented at ASH not only as proof-of-concept for DCP-001’s use in AML maintenance but for the use of immunotherapy in AML in general (other immunotherapies have historically been ineffective). With this data in hand, we expect the company will assess the full potential impact of DCP-001 in other haematological malignancies. There may now be opportunities for the company to expand the treatment’s reach in AML by targeting post-haematopoietic stem cell transplant (HSCT) patients (who are still at risk of relapse), and in combination with azacitidine in both pre- and post-HSCT patients. Management has also communicated that it may consider investigating the use of DCP-001 in other blood-borne malignancies such as myelodysplastic syndromes (MDS) and/or chronic myeloid leukaemia (CML).

Our forecasts and valuation, described in our prior note, are unchanged.