Keros Therapeutics’ KER-050 to treat anaemia in myelodysplastic syndrome (MDS) patients needs 30% of Phase II part 2 trial participants to become transfusion independent, a secondary endpoint, to be worth investigating further in Phase III, experts said. Encouragingly, KER-050 has the potential to reach a higher benchmark of 50% based on available data and its mechanism, although there are caveats, they noted.

Keros has focused on the secondary efficacy endpoint erythroid response when establishing success benchmarks for the Phase II trial’s 30-patient part 2 portion. However, experts differed, noting erythroid response may not guarantee transfusion independence due to patient heterogeneity in Phase II MDS patients with very low, low, or intermediate risk of anaemia.

Instead, experts pointed to the composite endpoint of red blood cell (RBC) transfusion independence for eight weeks or more and reduced frequency of RBC transfusions as being more clinically worthy. Haemoglobin levels need to higher than 7g/dL for a patient to be transfusion independent, they noted. However, patients may still need transfusions even if this threshold is reached, they added. If a patient’s haemoglobin levels increase by 2g/dL from baseline, this would be enough to significantly reduce the frequency of transfusions and would be clinically valuable, they said.

Experts are optimistic KER-050 could offer transfusion independence in half of the 30 participants due to positive Phase I data and KER-050’s mechanism as an inhibitor of the cytokine TGF-beta. However, one expert noted Phase I data is from healthy volunteers and may not be relevant in MDS patients, as they have compromised bone marrow and impaired RBC production.

The first part of the trial is investigating four KER-050 doses in 24 patients, with data due midyear. The highest of the four doses is likely to move on to part 2 due to KER-050 having no concerning safety signals so far. Phase II has a primary endpoint looking into adverse events. Sales of KER-050 are expected to hit $283m in 2027, according to GlobalData’s consensus forecast. Keros, which has a market cap of $1.28bn, did not respond to a request for comment.

Transfusion independence a key metric over erythroid response

Erythroid response, while valuable, is not an ideal Phase II success metric because improvements in this measure do not guarantee transfusion independence, which is what delivers a significant quality of life (QoL) boost, experts said. Keros said the Phase II part 2’s success bar is for 40% of the 30 patients to show erythroid response, which equates to a 1.5g/dL increase of haemoglobin from baseline in low transfusion burden (LTB) patients. In high transfusion burden (HTB) patients, this means a reduction to four transfusions from a baseline of eight transfusions over a period of eight weeks.

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Blood transfusion independence has a direct link to QoL improvement, added Dr Philip McCarthy, professor, oncology and internal medicine, Roswell Park Cancer Centre, Buffalo, New York. Chronic transfusions can lead to complications such as iron overload, which can damage patients’ pancreas and heart, he noted. If transfusion independence is not reached, KER-050 should show it can reduce the number of complicated transfusion visits, experts said. The Phase II is recruiting LTB patients who have received less than four units of RBCs within eight weeks, and HTB patients who needed four or more RBC units in the same timeframe. One transfusion session leads to an increase of roughly 1g/dL of haemoglobin and takes around two hours to complete, McCarthy said. Subcutaneously administered KER-050 is investigated for use once every four weeks for up to four cycles.

Transfusion independence typically occurs once a patient’s haemoglobin increases to 7g/dL, said Dr Margaret Kasner, professor, medical oncology, Jefferson University Hospital, Philadelphia. However, not all patients will become transfusion independent even if they reach this haemoglobin threshold, because of heterogeneous responses to treatment, noted Dr Joachim Deeg, professor, Clinical Research Division, Fred Hutch Cancer Centre, Seattle. MDS predominantly effects older people, with a median age of approximately 70 years, Kasner noted. Additionally, patients ages 70 years or older might need to reach a threshold higher than 7g/dL to be transfusion independent, she said. Phase II LTB patients need to have less than 10g/dL haemoglobin at baseline, and HTB patients need to have 9g/dL haemoglobin at baseline, to be recruited.

Bristol Myers Squibb’s Reblozyl (luspatercept), which shares the same transforming growth factor (TGF)-beta inhibitor mechanism as KER-050 may be a Phase II KER-050 success bar, said Dr Nick Short, professor, department of leukaemia, MD Anderson Cancer Centre, University of Texas. In a Phase III trial, 38% of 153 Reblozyl patients reached transfusion independence after eight weeks in a 24-week timeframe (P<0.001) (Fenaux, P., et al., N Engl J Med, 2020, 382, 140–151).

Experts noted KER-050 has the potential to improve upon Reblozyl. While Reblozyl targets the later stages of erythropoiesis, KER-050 can also target the early stages to accelerate progression of precursor cells, potentially resulting in greater RBC production, Kasner noted. In a preclinical analysis, there was an increase in platelets after a single dose of KER-050, which is a differentiator from other agents only affecting RBCs, such as Reblozyl, a 6 May company presentation shows.

Even if KER-050 delivers a lower infusion independence result of 30%, as seen with erythropoiesis stimulating agents (ESAs) such as Amgen’s Aranesp (darbepoetin), the Phase II KER-050 trial would still be considered a success, said Short. In the Phase III Aranesp trial, it significantly reduced transfusions (36.1%) versus placebo (59.2%) from weeks 5–24 (P=0.008) (Platzbecker, U., et al., Leukaemia, 2017 Sep, 31(9), 1944–1950). Based on real-world experience, ESAs lead to 30% of patients becoming transfusion independent, Short added.

However, Short added ESAs have a time limit on how long they work, typically around 17 months (Park, S., et al., Journal of Clin Oncol, 2017 Oct, 35, no. 14). In the Phase II KER-050 trial, part 2 patients are followed for 25 weeks. This duration at a Phase II should be long enough to collect a signal on efficacy durability, Short added.

Phase I data suggest KER-050 could best low efficacy benchmark

Nevertheless, experts said KER-050 has the capability of reaching at least 50% of patients being transfusion independent. In the Phase I trial in healthy postmenopausal women, 38 patients were administered with different doses of KER-050, with the highest dose (4.5mg/kg) eliciting a 2.1g/dL mean increase from baseline in 66.7% patients, according to a June 2020 media release. Part 1 of the Phase II trial is dosing six patients in four separate arms, with patients already enrolled in the 0.75 and 1.5mg/kg cohorts, and the two higher doses yet to be revealed.

The 2.1g/dL magnitude of increase in the 4.5mg/kg KER-050 dose, if replicated in Phase II MDS patients, would significantly reduce the transfusion burden in all patients and would lead to independence in the majority of patients, said Short and McCarthy. The Phase III Reblozyl trial only counted how many participants experienced at least 1g/dL haemoglobin increase from baseline.

Postmenopausal women were selected for the Phase I KER-050 trial because they have no blood loss, McCarthy said. However, Kasner noted replicating these results in sick MDS patients was far from certain. MDS patients have damaged bone marrow, meaning they have ineffective erythropoiesis producing RBCs, she explained.

The company will likely push the dosing higher than the 4.5mg/kg used in the Phase I for the Phase II because of the positive safety showed in the Phase I, which showed mild, reversible hypertension events in subjects who increased haemoglobin by 3g/dL from baseline, McCarthy and Deeg said.

Sean Rai-Roche is a Healthcare Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.