After Halozyme Therapeutics abruptly bungled a clinical trial of an experimental PEGPH20 in a first-line therapy for metastatic pancreatic cancer in November 2019, the decision was made to halt all oncology efforts, instead of focusing on ENHANZE subcutaneous drug delivery technology. This technology is expected to generate $1 billion in revenue by 2027. And it’s achievable, because ENHANZE turns existing intravenous drugs into subcutaneous drugs, which means patients don’t need to go to a hospital — they can administer the next dose on their own. Or, if additional monitoring is required, without a long stay under an IV in a hospital facility. In addition to the obvious convenience of administering the drug, the potential risk of COVID-19 infection is reduced due to the lack of contact with medical staff.

That’s what happened. While in 2019 Halozyme earned $196 million, in 2020 its revenues rose to $268 million. Moreover, it managed to go from a net loss of $72 million to a net profit of $129 million. Thanks to the flow of money from ENHANZE’s collaborative agreements.

The ENHANZE drug delivery platform is based on recombinant human hyaluronidase (rHuPH20) which removes the traditional limitations of the volume of biological drugs injected subcutaneously. Hyaluronic acid (hyaluronan), being a large linear polysaccharide and being a common component of normal tissues, vigorously binds water and forms a gel pillow in the subcutaneous layer, thus creating a significant obstacle to the free flow of fluids, limiting the volume of subcutaneous drug injections. ENHANZE technology, due to temporal and local depolymerization of hyaluronan in the extracellular matrix, enhances dispersion and absorption of drugs. Tissue half-life of rHuPH20 does not exceed 15 minutes and the normal density and architecture of the subcutaneous space are restored in a few days.

The reasonableness of the ENHANZE technology is confirmed by the appropriate transformation of a number of medications.

Rituxan/MabThera (rituximab) and Herceptin (trastuzumab), two blockbuster anticancer drugs by Roche, have in June 2017 and February 2019, respectively, evolved into Rituxan Hycela/MabThera SC (rituximab + hyaluronidase) and Herceptin SC/Herceptin Hylecta (trastuzumab + hyaluronidase), eliminating tedious and complicated infusion procedures. Thus, while the original infusion Herceptin during therapy of metastatic HER2-overexpressing breast cancer is first administered at a dose of 4 mg/kg for 90 minutes and then on a weekly basis at a dose of 2 mg/kg for 30 minutes, the subcutaneous ENHANZE-formulated trastuzumab is administered every three weeks at a dose of 600 mg given in 2–5 minutes.

The appearance in June 2020 of the combined Phesgo (pertuzumab + trastuzumab + hyaluronidase) of the same Roche, actually combining Perjeta (pertuzumab) and Herceptin, has made it very comfortable to treat HER2-overexpressing early breast cancer.

Notable is the release of HyQvia (HyQvia, human immunoglobulin + hyaluronidase), developed by Baxalta, now owned by Takeda Pharmaceutical, for the treatment of primary immunodeficiency. HyQvia, which saw the light of day in September 2014, was the first commercial drug to appeal to ENHANZE drug delivery technology. Instead of traditional infusions on a weekly or bi-weekly basis, patients were able to receive another maintenance dose of the drug once a month.

The May 2020 rebirth of Johnson & Johnson’s Janssen’s anti-myeloma Darzalex (daratumumumab) into Darzalex Faspro (daratumumumab + hyaluronidase) has incredibly simplified the treatment of multiple myeloma, which, being essentially a chronic disease, involves “endless” treatment, thus requiring frequent visits to the medical facility for another dose of medicine.

ENHANZE versions of many existing drugs are in clinical trials, such as Opdivo (nivolumab), a PD-1 blocker by Bristol-Myers Squibb; Tecentriq (atezolizumab), a PD-L1 blocker by Roche; Ultomiris (ravulizumab), a complement component 5 (C5) inhibitor by Alexion Pharmaceuticals, a subsidiary of AstraZeneca; Tepezza (teprotumumab), an IGF1R inhibitor by Horizon Therapeutics, the first and so far only drug to treat thyroid eye disease.

Tepezza: First Drug for Thyroid Eye Disease

Teprotumumab can really help with exophthalmus and diplopia in Graves’ disease and beyond.

In late 2019, South Korea’s Alteogen signed an agreement with an undisclosed Big Pharma player granting it non-exclusive rights to a proprietary subcutaneous drug delivery technology that, similar to ENHANZE, temporarily hydrolyzes hyaluronic acid in the extracellular matrix. Up to $13 million has been received in advance, plus up to $1.373 billion has been promised as certain development, regulatory approval and commercialization milestones are passed.

Alteogen has modified recombinant human hyaluronidase (PH20) via Hybrozyme technology, which, by exchanging the domains of two structurally similar enzymes while maintaining the existing catalytic mechanism, improves the conformational flexibility and thermal stability of the target enzyme. As a result, ALT-B4, the Hybrozyme variant of PH20, having obtained the above, is characterized by optimized enzymatic activity so that, first, it allows the administration of a smaller amount of the drug compound and, second, prolongs the shelf life of the drug — in comparison with conventional hyaluronidase.

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ENHANZE®. Delivering a volume of benefits. Halozyme Therapeutics. [PDF]

Halozyme Therapeutics. Fourth quarter and full year 2020 financial results presentation. February 23, 2021. [PDF]

Halozyme Therapeutics. J.P. Morgan 39th Annual Healthcare Conference. January 13, 2021. [PDF]

ENHANZE® drug delivery technology: a novel approach to subcutaneous administration using recombinant human hyaluronidase PH20. Drug Deliv. 2019; 26(1): 98–106. [source]

Subcutaneous Delivery of High-Dose/Volume Biologics: Current Status and Prospect for Future Advancements. Drug Des Devel Ther. 2021; 15: 159–170. [source]

Immunogenicity Challenges Associated with Subcutaneous Delivery of Therapeutic Proteins. BioDrugs. 2021 Feb 1 : 1–22. [source]

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Timur Burkhanayev

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