Iadademstat – specific LSD1 inhibitor for cancer
Iadademstat is a highly selective LSD1 inhibitor that can be orally administered. Oryzon’s initial focus in developing iadademstat was on acute leukaemias. The drug candidate entered a Phase I/IIa trial in January 2014 and in April 2014 it was licensed to Roche, which has paid $21m in upfront and milestones to Oryzon during the engagement period. Under the terms of the agreement, Oryzon was responsible for finalising the leukaemia Phase I/IIa study (which was already ongoing and sponsored by Oryzon at that time). In December 2016, Oryzon reported supportive preliminary efficacy results from this trial at the ASH conference, which was a major milestone. In parallel, Roche, which was responsible for the global development of iadademstat, initiated a clinical trial in SCLC. In July 2017, Roche decided to discontinue the development of iadademstat and return the rights to Oryzon; according to Oryzon, the decision was due to Roche reprioritising its portfolio and not driven by data.
Oryzon regained the rights from Roche for iadademstat in January 2018 and resumed development in both AML and SCLC. The Phase IIa ALICE study is recruiting elderly AML patients who are treated with iadademstat in combination with azacitidine. Part 1 explored the recommended dose, while Part 2 is evaluating initial clinical activity. The Phase IIa CLEPSIDRA trial is recruiting relapsed, extensive-stage disease SCLC patients who receive iadademstat in combination with platinum-etoposide chemotherapy. Oryzon is also using biomarkers to select a more precise patient population. Similarly, Part 1 established a recommended dose, while Part 2 is evaluating clinical activity. Interim results from both studies were presented in 2019 and more data are expected in 2020.
Interim Phase IIa ALICE results
Oryzon presented the most advanced data from the Phase IIa ALICE trial at the 61st ASH annual meeting in Orlando, Florida on 9 December 2019. The single-arm, open-label study is enrolling newly diagnosed, elderly acute myeloid leukaemia (AML) patients and investigates iadademstat in combination with standard-of-care chemotherapy drug azacitidine. Oryzon intends to enrol 18 patients in the ongoing Part 2 of the ALICE trial (expansion cohort; Part 1 dose finding has been completed). At the time of writing the ASH poster, 13 patients have been enrolled in ALICE. Besides dose finding data and PK/PD evaluation (including a set of blood biomarkers), initial efficacy was evaluated as overall response (OR) measured by bone marrow aspirate.
The latest data from the ALICE trial showed that of the 13 enrolled patients, 8 had at least one bone marrow aspirate, and therefore were evaluable (3 patients died before their first BM evaluation and 2 were just starting the treatment). OR results were:
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Six of the 8 evaluable patients (75%) achieved ORs: two complete responses (CRs), three complete responses with incomplete haematologic recovery (CRi) and one partial response (PR).
Exhibit 6: Patients enrolled in the Phase IIa ALICE trial
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Source: C Buesa et al. Iadademstat Shows Efficacy in Elderly AML Patients in Combination with Azacitidine. ALICE Trial. Poster presentation at ASH 2019.
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Overall, the authors of the ASH poster concluded that the combination of iadademstat and azacitidine shows a good safety profile in elderly AML patients. In Part 1 (dose finding), the recommended dose of 90µg/m2 was established. Later, the dose was lowered to 60µg/m2 by the safety monitoring committee (SMC). This decision was made after one patient withdrew consent after experiencing severe fatigue and another patient died due to an intracranial haemorrhage. Oryzon did not see any clinically relevant non-haematological adverse events.
LSD1 inhibitor class drugs are known to have haematological side effects at higher doses. However, these are usually predictable and manageable. We note that proving a clear drug-side effect relationship is not always straightforward. For example, intracranial haemorrhage (haemorrhagic stroke) can have many causes, especially in such elderly, highly ill patients. So, the decision to lower the dose could serve as a precaution. The tolerability of the drug will improve at the lower dose and Oryzon believes this will not come at the expense of efficacy, as existing PK/PD data show that a 60μg/m2/d level is also able to saturate LSD1 target engagement with a clear biomarker effect.
Putting iadademstat efficacy results in perspective
OR rates in AML patients treated with azacitidine monotherapy are 32% depending on age (Maurillo et al, 2012). A recently published article (DiNardo et al, 2019) described a clinical trial (n=145) where AML patients received venetoclax plus azacitidine or decitabine (both chemical analogs of cytidine) and the OR rate was 67%. Venetoclax (Venclexta, AbbVie/Genentech) is a novel anticancer drug approved (accelerated approval) by the FDA for frontline treatment of AML in combination with azacitidine or decitabine or low-dose cytarabine.
In the first set of data from the ALICE trial published in June 2019, the OR rate was 80% in 5 evaluable patients (3 CRi and 1 PR). The most recent data from 8 evaluable patients (OR rate of 75%) are in line with this result. Given the small sample size, an outcome in just one patient can significantly influence the results. In addition, the trial is not complete yet. However, the OR rates have been consistent so far within the 75–80% range. This is much higher than the historical response rates with classic chemotherapy and compares well with venetoclax’s OR of 67%. Consensus expects venetoclax to reach $971m in sales in AML alone by 2024 (EvaluatePharma).
Iadademstat, as a selective LSD1 inhibitor, has been shown to be effective in preclinical AML models, including combinations with azacitidine. In addition, Oryzon has already completed a Phase I first-in-man trial, where iadademstat was given as a monotherapy, and demonstrated preliminary antileukaemic activity (reviewed in detail in our initiation report).
The second part of the ALICE study will enrol a total of 18 patients, so these results will be expanded in the coming months with additional patients and longer follow-up times. Oryzon also indicated that even though the results are not final yet, existing evidence ‘may warrant further trials with this combination therapy in a confirmatory study setting’.
Interim Phase IIa CLEPSIDRA results
The most advanced dataset from the ongoing Phase IIa CLEPSIDRA trial with iadademstat in extensive disease SCLC was presented on 28 September 2019 at the ESMO congress in Barcelona. A poster presentation detailed the efficacy results from eight SCLC patients. In CLEPSIDRA patients receive 4–6 cycles of iadademstat plus carboplatin-etoposide chemotherapy (subsequently, the patients may be given iadademstat monotherapy). Patients in the trial are stratified by proprietary biomarkers, which allow identifying SCLC sensitive to LSD1 inhibitors and can position iadademstat as a personalised therapy. The rationale to test iadademstat for SCLC comes from the fact that the inhibition of LSD1 activates the NOTCH pathway, resulting in the suppression of ASCL1 (a known SCLC tumour driver). Complete and durable tumour regression was seen with iadademstat in in vivo PDX models (discussed in our previous report).
Results include:
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An OR was seen in 6 out of 8 patients (75%). Of these, 4 patients demonstrated a partial response and 2 had long-term stable disease.
The OR rate of 75% compares well with the historical average of SCLC second-line chemotherapy drug topotecan (15–24%). SCLC is generally considered a non-immunogenic cancer, so OR rates to immune checkpoint inhibitors are also relatively low (22% nivolumab plus ipilimumab; 19% pembrolizumab as monotherapy; Saleh, 2019). The high OR rate in CLEPSIDRA may be due to the use of biomarkers. One of the patients with partial response showed 79% tumour reduction following six cycles of iadademstat plus carboplatin-etoposide and then received iadademstat as monotherapy. This patient is still in remission nine months after the treatment and demonstrated continuous improvement (86% tumour reduction) with iadademstat monotherapy.
The most common side effects were haematological changes seen in patients who received a triple combination and included decreased platelets, neutrophils and anaemia. No other organ-specific side effects, such as neurological, hepatic or renal toxicity, were observed. In addition, iadademstat alone did not cause haematological or other toxicity. Such results are not unexpected as platinum-etoposide chemotherapy is known to have haematological toxicity. The fact that side effects were observed in patients receiving the combination treatment, but not iadademstat alone, would imply better tolerance of the latter. Oryzon will continue to explore different dosing regimens during the reminder of the CLEPSIDRA trial.