Karyo Biologics Business Model
We select a product based on its FTO, difficulties in manufacturing, hurdles in regulatory approval using a proprietary selection algorithm. We develop the product in our global facilities leading to the stage of IND approval by FDA, at which point we license out the product to sponsors who pay all expenses directly while Karyo supervises approval; Karyo benefits after the product is approved as a royalty-fee.
With current cost of $150-$250 Million and 7-8 years to develop a biosimilar product cannot make biosimilars accessible. With decades of experience, we are able to burst this bubble by reducing the CAPEX and OPEX, working closely with FDA, and outsourcing whatever that can be outsourced. The development cost is substantially reduced because of our proprietary patented technologies. We can demonstrate 50-70% reduction in cost of taking a product to US market. Dr. Niazi is the world's largest solo inventor of bioprocessing technology that helps reduce time of development and provides lowest COGS.
We begin with making a selection of product that will have least legal risk, manufacturing difficulties, structural complications and then the market valuation. The selection is qualified based on a robust FTO. We have identified 25 products, out of about 120 candidates screened and now developing 25 products including bevacizumab, trastuzumab, darbepoietin alfa, erythropoietin alfa, insulin aspart, insulin glargine, and liraglutide.
In the next step, KBL identifies and licenses developed technology yielding highly similar product; generally, the technology transferred includes?: validated MCB, reproducible upstream and downstream steps, suitable and appropriate analytical testing methods, evidence of analytical similarity with the reference product, DP and DS stability, final packaging and device and on-clinical testing in at least one species. This selection save about 24-36 months of time.
CMO: GMP Clinical Scale Process
The technology licensed in is now transferred to a qualified CMO to produce at-scale GMP batches for clinical testing; the testing is also outsourced to GMP-compliant CROs. Using KBL patented technology of batch-pooling allows infinitely scalable process and substantially reduced cost.
KBL now tests appropriate number of batches of its product against the reference product in a FDA-approved protocol to meet the first and the foremost requirement of biosimilarity (see below).
Formulation and Device
The first stage of FTO (freedom-to-operate) also defines the choice of formulation and any devices used; generally, the formulation will be identical to the reference product, unless there is an IP protecting it. The devices such as auto-injectors are developed early since the stability studies are conducted in the final packaging. KBL has partnered and licensed in with industry-standard suppliers of devices including Ypsomed for its insulin products.
To establish the shelf-life, the biosimilar candidate product is subjected to temperature stress studies side-by-side with a reference product to demonstrate not only the extent of degradation over time but also the nature of chemical degradants. This study is conducted at early stage to assure that the product meets the IND requirements of stability, product remaining stable during the course of the study.
Animal toxicology studies involve comparative studies at a dose level suitable to demonstrate recorded toxicity to compare with the reference product; these testing protocols are not readily available in the public domain and require detailed discussions with FDA early in the development. The choice of species becomes important where toxicity is related to mode of action, such as in the case of antibodies where rodents are not a good choice and studies are conducted in primates.
Development Master Plan (DMp)
The decades of experience of developing biosimilars is distilled into this critical step by KBL, where all study protocols, non-clinical, clinical, clinical pharmacology, analytical similarity, manufacturing consistency, and many more are identified and written by KBL, in consultation with CDMOs who may be executing these protocols. Creating protocols that will be acceptable to the FDA requires in-depth review of of all public information including the minutes of advisory committee meetings held by the FDA and the EPARs posted by EMA, scientific and promotional literature, experience of KBL teams and affiliated. The goal of the DMP is to identify minimal number and smaller scope of studies that will be acceptable to the FDA.
First FDA Meeting
FDA allows developers to meet with FDA to discuss their development plans. KBL has long experience in requesting and conducting these meetings. The meetings of the first meeting request form the basis for establishing a cost and timeline for development that KBL makes available to potential commercial sponsors.
Once the FDA meetings are concluded, KBL refines its development master plan and engages experienced CROs to provide cost estimates of all protocols agreed with FDA including CMC development, analytical similarity testing, non-clinical testing, human PK/PD studies and any in-patients studies if required by FDA (e.g., in the case where clinical pharmacology is disease dependent).
KBL secures approval of IND from FDA to demonstrate that its biosimilar candidate is safe and suitable for administration to humans, healthy or patients. The IND approval is a significant step to provide potential commercial sponsors to manage their financial risk.
Partnering with commercial sponsors is the unique model element created by KBL. Since KBL provides commercial supply or the approved product through a qualified CMO, one of the highest cost component of maintaining a manufacturing facility translates into lower cost of good, timely supply and no regulatory involvement in GMP audits. KBL assures that the CMO provides a GMP product, opening opportunities for specialty pharmacies and other GPOs to enter the bisimilar market.
These studies are mandated in the BPCIA statute, to demonstrate safety and efficacy of a biosimilar comparable to the reference product. These are not "phase 1" studies as many developer label them erroneously; none of the conditions of a phase 1 study apply at this stage; instead these studies are intended to demonstrate that there is no "clinically meaningful difference" between a biosimilar and a reference product. FDA may be able to allow licensing of a biosimilar based on these studies alone; unfortunately, many developers waste time and resources in conducting additional trials that may not be required.
Type 2 Meeting
Upon completion of PK/PD and immunogenicity studies, KBL meets with FDA to discuss if there is any “residual uncertainty” remains that might require additional clinical studies (healthy subjects of patients); there are no "phase 3" studies in biosimilars development as erroneously labeled by most developers.
Residual Clinical Studies
Should the Type 2 meeting result in FDA requiring additional studies in patients, these study protocols are agreed upon in the Type 2 meeting.
Type 3/4 Meeting
These meetings are intended for a detailed review of all data and study results by FDA, prior to the filing of BLA. Type 4 meeting is more related to the format and organization of the proposal filing.
351K/505 (b)(2) Filing
Biosimilars are filed for BLA under 351k and as drugs like insulins under 505 (b)(2) until March 2020.
Once the BLA or drug application is approved, KBL begins supplying commercial quantities to its Commercial Sponsor through its designated CMOs.
We seek commercial sponsors (CS) to pay third party cost: CMC, non-clinical, clinical, formulation and analytical similarity testing. The CS also pays milestones and a royalty upon commercialization.
Karyo staff coordinates and conducts the task of meeting all deadlines committed to the CS, including conduct of non-clinical studies, PK/PD studies, immunogenicity testing, PPQ lots, initial stability testing, device development and label claim to arrange a Type 2 meeting with FDA to reach agreement on any patient studies, if any, required.
Post-approval Compliance fees
Karyo maintains licensing in good standing to meet with all regulatory requirements, while supplying commercial quantities to CS.
alternate development model
A CS may request technology transfer to their own facility at any time; or take over responsibility of development coordination as well. In such instance, the CS agrees to a timeline of development.
Karyo can take over any development in process or start a new product at the request of a client; terms are negotiated based on the scope of work required.