Portfolio spotlight: Imara

17th June 2020

Developing effective, accessible treatments for patients with rare genetic disorders of haemoglobin

See also: Imara - Advancing Sickle Cell Therapies

Executive Summary

Imara Inc. (Imara, NASDAQ: IMRA) is a clinical-stage biotechnology company dedicated to developing and commercialising novel therapeutics to treat patients suffering from rare inherited genetic disorders of haemoglobin, which include Sickle Cell Disease (SCD) and β-Thalassemia.
Arix has a 9% equity stake in Imara. Arix co-led the $63m Series B financing of Imara in March 2019, having been impressed by the preclinical and clinical evidence generated with Imara’s product candidate, IMR-687, and the high quality team driving the programme forward. Since this investment, Imara has reached a number of important milestones:
  1. Positive Interim Phase 2a data – An additional interim analysis of the ongoing randomised, blinded, placebo-controlled study of IMR-687 in adult SCD patients has been conducted and was recently presented at the virtual European Haematology Association (EHA) Annual Congress (Abstract S290). This analysis provided further evidence that once-daily, orally delivered IMR-687 is safe and well tolerated alone or in combination with hydroxyurea (HU), and that patients on the highest dose of IMR-687 saw more induction of HbF and more cells containing HbF (F-cells) than on lower dose or placebo. Topline data from this study is expected in Q4 2020.
  2. Successful Initial Public Offering – Imara completed a successful IPO in March 2020 despite the challenging market backdrop of COVID-19 and unprecedented volatility in public markets. Gross proceeds from the IPO were $75.2m and underwriters exercised the full option to purchase additional shares, yielding a further $11.3m. The company is in excellent financial health and has sufficient cash to fund Phase 2b studies for both SCD and β-Thalassemia.
  3. Clarity on regulatory pathway – Feedback from FDA in a Type B meeting in January 2020 indicates that it is open to the use of foetal haemoglobin (HbF) as an approvable surrogate endpoint for IMR-687 in Sickle Cell Disease (SCD). This is a critical step towards a potential Accelerated Approval pathway, allowing them to conduct confirmatory studies of clinical benefit in parallel with commercial launch of IMR-687.
  4. On track for Phase 2b study initiation – Despite the unprecedented impact posed by COVID-19, guidance from Imara is that they are aiming to dose the first patients in their Phase 2b studies for SCD and β-Thalassemia by the end of June 2020. The clean safety profile of IMR-687 and findings from preclinical toxicology and Phase 1 studies allow Imara to push the dose of IMR-687 higher in these Phase 2b studies with the hope that even greater HbF induction is possible.
  5. Launched “Real Impact” community support grants – Imara recently launched a programme to fund up to 20 projects organised by non-profit community-based organisations that support patients with SCD or β-Thalassemia. Imara is dedicated to having a positive impact on patients’ lives, especially during the current COVID-19 pandemic that has placed additional burdens on these patients.


Imara (Nasdaq: IMRA) is a clinical stage biopharma company developing IMR-687 for the treatment of haemoglobinopathies: Sickle Cell Disease (SCD) and β-Thalassemia. Imara’s goal is to leverage the differentiated mechanism of action, ease of administration and stable drug properties of IMR-687 to potentially serve a broad range of patients suffering from hemoglobinopathies around the world, including those in underserved regions.

SCD is a rare inherited recessive disease most commonly found in patients with African or Caribbean heritage, and affects approximately 100,000 people in the US and 134,000 in Europe, with an estimated 4.4 million patients worldwide. Historically, engagement with healthcare has been low among this patient group, in part due to poor treatment options but also due to broader complex socio-economic reasons. Patients with haemoglobinopathies express mutant versions of β-globin (a key subunit of haemoglobin), which results in unhealthy red blood cells and life changing symptoms in patients. In SCD this includes painful vaso-occlusive crises (VOCs), organ damage (e.g., kidney function loss), stroke, acute chest syndrome and ultimately lower life expectancy.

IMR-687 is an orally delivered, small molecule inhibitor of PDE9, which has been shown in preclinical and clinical studies to induce expression of foetal haemoglobin (HbF). The induction of HbF expression results in the replacement of mutant β-globin with healthy HbF (a version of haemoglobin usually only expressed during foetal development), therefore rescuing the health of the red blood cells.

For years the standard of care in SCD has been hydroxyurea (HU), a chemotherapeutic which induces HbF expression and is considered effective for managing SCD; however, the safety profile, poor tolerability and need for frequent monitoring results in sub-optimal compliance among SCD patients.

Despite the considerable unmet need for novel therapies there has been little innovation in this space until relatively recently, with two drugs approved for SCD in 2019 (Global Blood Therapeutics’ Oxbryta and Novartis’ Adakveo). While these novel therapies are warmly welcomed and will no doubt be helpful for some patients, there remains a critical need for a simple, convenient and tolerable maintenance therapy for SCD. Other highly innovative approaches such as genetically engineered haematopoietic stem cells provide potentially curative options but are unlikely to be available to most patients due to cost and requirement to be healthy enough to tolerate the harsh conditioning regimens but sick enough for this intervention to be appropriate.

25th EHA Annual Congress 2020 – Interim Phase 2a data (Abstract S290)

A second interim analysis of the ongoing randomised, blinded, placebo-controlled study of IMR-687 in adult SCD patients has been conducted and was recently presented at the virtual European Haematology Association (EHA) conference. As prespecified in the protocol, this analysis was performed once 18 patients in Population A (those not receiving HU) had completed 6 months of treatment with IMR-687 (N=5 on 100/200mg; N=7 on 50/100mg) or placebo (N=6). Patients receiving IMR-687 spent 3 months on the lower dose before escalation to the higher dose.

The analysis provides evidence that IMR-687 is safe, tolerable and is able to induce HbF expression in SCD patients. The key takeaways from this analysis are:

  1. Safety – unblended safety measures were available for 57 patients with or without concomitant HU and revealed no clinically significant changes in white blood cell counts (including neutrophil counts) or vital signs. There were no treatment related serious adverse events or any adverse events leading to discontinuation of therapy. This supports the proposition that IMR-687 will be a safe and tolerable alternative to HU, which is poorly tolerated by patients and requires active monitoring and titration by physicians.
  2. HbF induction – although the sample size is small, this emerging data continues to look promising and to support the potential of IMR-687 in SCD. First, there is a dose-dependent effect on magnitude of HbF induction, with patients receiving the highest dose (100/200mg) having the greatest increase and patients on placebo having no change. A similar effect was observed on F-cells, the proportion of red blood cells containing HbF, which may be a more physiologically relevant measure since it reflects the proportion of red blood cells that may be healthier. This clinical data is highly supportive of IMR-687’s proposed mechanism of HbF induction, which the FDA has indicated is potentially an approvable endpoint. The potential to dose higher than 200mg for longer, as being tested in the upcoming Phase 2b, is encouraging as it is hoped that IMR-687 can produce even greater induction of HbF and therefore clinical benefit to patients.

19 June 2020 is officially designated World Sickle Cell Day. On 22nd December 2008, the United Nations General Assembly adopted a resolution that recognises sickle cell disease as a public health problem and “one of the world’s foremost genetic diseases.” The international awareness day is observed annually with the goal to increase public knowledge and an understanding of sickle cell disease, and the challenges experienced by patients and their families and caregivers.