Helion Biotech ApS

Mannan Binding Lectin

Phase II ready project available for partnering

Restoration of inherited immune defect by replacement therapy with recombinant human mannan-binding lectin in MBL deficient preterm neonates for prevention of neonatal infections and sepsis.

Deficiency in mannan-binding lectin, a key component of the innate immune defence, is a very strong risk factor for neonatal infection and sepsis. Restoration of this immune defect in deficient neonates by replacement therapy with recombinant human MBL is hence an attractive option for the prevention of neonatal sepsis. Previous clinical experience with rhMBL, an established manufacturing process and a complete US regulatory dossier allows for bridging directly into a Phase II clinical trial.

Background

Mannan-binding lectin is a constitutively expressed component of the innate immune defence. It is responsible for activation of the complement system upon binding to carbohydrate structures widely present on bacteria, viruses and fungi. MBL therefore plays a key role in the first line immune defence against invading pathogens.

Large inter individual variations in plasma levels of MBL exist in the population due to genetic mutations and other non-genetic factors, but within any one given individual the plasma level stays relatively constant over time. Normal functional levels of MBL range from 1-10 μg/ml (average 1.5 μg/ml), but approximately 1/3 of individuals have MBL levels below 0.7 μg/ml, which results in a non-functional MBL pathway of complement. Due to a large degree of redundancy in the immune system, this MBL deficiency does not normally manifest itself in an increased risk of infections. However, under circumstances where other parts of the immune system are also impaired, either due to immaturity or immune suppression, MBL deficiency results in an increased risk of infections. Replacement therapy with recombinant human MBL (rhMBL) is therefore warranted in specific at-risk populations of MBL deficient individuals in order to normalize their immune system and prevent infections.

MBL deficiency is a strong risk-factor for neonatal sepsis

Since 2006, more than 10 independent studies have been published identifying MBL deficiency as a very strong risk factor for neonatal infection and sepsis. A strong case for the use of rhMBL replacement therapy in premature low-birth weight neonates for prevention of neonatal infection and sepsis has therefore emerged. The studies have shown that premature low-birth weight neonates, who do not develop sepsis, have normal average MBL plasma levels of around 1.5 μg/ml, whereas those who develop culture-proven sepsis have plasma levels of around 0.2-0.4 μg/ml. In fact, very premature neonates or neonates <1000g birth weight, with plasma levels <0.7 μg/ml, had a 70% risk of developing sepsis, and the odds ratio for development of neonatal sepsis or pneumonia was 15 and 12 respectively at MBL levels below 0.4 μg/ml. Finally, the plasma levels of neonates receiving antibiotics for >10 days had MBL levels of 0.4 μg/ml and those receiving antibiotics for <10 days had MBL levels of 1.6 μg/ml.

In support hereof, MBL has been found to recognize most pathogens relevant for neonatal infection and sepsis, including E. coli, Pseudomonas, Klebsiella, H. influenza B, N. meningitides, Coagulase-negative staphylococcus, S. aureus, and C. albicans. Further more, animal models of rhMBL replacement therapy in MBL k/o mice and phagocytosis assays have documented a protective effect by rhMBL against S.aureus, Pseudomonas and E.coli.

Clinical development

Several Phase I clinical trials with rhMBL replacement therapy has been performed: a regular phase I trial in healthy adult volunteers by NatImmune A/S, as well as trials in adult immune compromised liver transplant and multiple myeloma patients by Enzon Pharmaceuticals Inc. The regular Phase I and the trial in multiple myeloma were successfully completed with positive PK results. The liver transplant trial was discontinued due to slow enrolment rates. In addition, a protocol in paediatric haematological cancers were approved by the FDA, but never initiated. The program was subsequently abandoned due to changes in strategy at Enzon. In addition to the trials with rMBL, clinical experience also exists with plasma-derived MBL both in adults and children.

As a consequence, an extensive safety record and complete regulatory dossier for supporting initiation of a Phase II trial exists. This includes a a cGMP manufacturing cell line and a cGMP manufacturing process already implemented at a CMO for production of a new clinical batch of rhMBL. Extensive toxicology and safety studies both in animals and man, and PK data exists for both adults and children.

Helion Biotech proposes to bridge from this previous clinical experience in adults and children to replacement therapy with rhMBL in MBL-deficient very preterm neonates for the prevention of neonatal infections and sepsis. Following the manufacture of a new clinical batch of rhMBL, a Phase II clinical trial can be initiated in very preterm or <1000g birth weight MBL deficient neonates, with the aim of demonstrating a reduction in incidence of neonatal sepsis (currently 70% in that population), reduced antibiotic use, reduced duration of fever and shorter hospital stay.

Commercial potential in neonates

In the general population, approximately 1/3 is MBL deficient due to sub-functional plasma levels (<0.7 μg/ml). However, during the first weeks of life in very preterm neonates the percentage is even higher (approx. 50%) presumably due to delayed onset of production of MBL by a yet immature liver. This means that approximately 35.000 very preterm or <1000g birth weight MBL deficient neonates would be in need of MBL replacement therapy annually in the EU and US, and if extended to <1500g BW, the figure would approximately double, but still keeping it well within the definitions of an orphan drug indication.

Prevention of infections and not least sepsis in these very preterm neonates would address a large unmet medical need and significantly reduce morbidity, mortality and associated healthcare cost. In addition hereto, it would address the problems faced by the ever-growing incidence of antibiotic resistant pathogens. Further more, prevention through reconstitution of the MBL pathway of complement would not be considered antibiotic prophylaxis, as it is merely restoration of a defect in the immune system not present in more than 50% of neonates experiencing much lower risk of infection and sepsis.

Options for subsequent market expansion

In addition to MBL replacement in very preterm neonates, options exist for subsequent expansion into immunocompromised individuals. Trials in immune compromised neutropenic patients not receiving aggressive antibiotic prophylaxis would likely pave the way in this indication.

Intellectual Property Rights

All rights to materials, documents and IPR relating to the manufacture, development and use of rhMBL now resides in Helion Biotech Aps, a Danish biotech company. In addition to previously filed IPR, new IPR has been developed in relation to a novel expression method for rhMBL which looks set to improve process economics even further. Finally, MBL replacement therapy in deficient neonates qualifies for orphan drug designation.