Biocon and Mylan: The Race to Approve Insulin Glargine Follow-on

Biocon received a second complete response letter relating to manufacturing plant problems in Malaysia. This may seem like a straight forward issue that could hamper its efforts to produce an insulin glargine follow-on agent, but it can become a major problem barring a very quick resolution.

In the filing Biocon made to the India Stock Exchange, the company said, “The CRL did not identify any outstanding scientific issues with the application. We remain confident of the quality of our application and do not anticipate any impact of this CRL on the commercial launch timing of our insulin glargine in the US.” However, that may be a fairly optimistic opinion.

Insulin copies are part of the class of biologics designated “transitional products” that will be approved only through the 351(k) biosimilar approval pathway after March 2020. The latest rules issued by the Food and Drug Administration (FDA) specify that if a product in this drug class (and others like growth hormones) does not receive approval by this date, the manufacturer must submit an entirely new biologic licensing application (for approval as a full-fledged biosimilar). That would require completing all of the necessary developmental steps—proving the physiochemical and pharmacodynamic equivalence to what would now be termed the reference product—Lantus®.

The FDA rules for transition products do not exempt agents that have already received complete response letters and may still be in the FDA’s queue. This is relevant because neither of Biocon’s rejection letters (the first issued in June 2018) pointed to problems with the scientific evaluation of its insulin glargine. Rather, both involved failed inspections at the plants at which Biocon was going to manufacture the agent. The drug was approved by the European Medicines Agency and is currently available by prescription in the EU.

As indicated in a previous post, pharmaceutical company interest in insulin biosimilars is fairly low. That may be because of the approaching transition date.

The question remains, can Biocon correct its Malaysian manufacturing plant deficiencies, can FDA reinspect, and can FDA issue final approval for this 505(b)2 agent before February 29, 2020? If not, even if Biocon’s plant passes inspection in December 2019, that will likely result in years’ long delay before the new BLA can be submitted.

Follow-on Biologics Versus Line Extensions, and What Are the Implications for Biosimilars?

Is a citrate-free formulation of Humira®, which is supposed to result in less injection-site pain, just another part of the patent thicket, or is it a real-improvement in the brand? Payers aren’t impressed, based on discussions we had at the Academy of Managed Care Pharmacy (AMCP) annual meeting last week.

In her presentation, Jennifer Day, PharmD, Coordinator Emerging Therapeutics Strategy Program, Kaiser Permanente Drug Information Services offered that these products, and potential follow-on biologic products like ravulizumab (Ultomiris®), may create new barriers for biosimilar development and uptake.

According to several pharmacy directors and medical directors I spoke to in private conversations, they are approaching citrate-free Humira in the same way as they view Herceptin Hylecta® and Rituxan Hycela®, subcutaneous formulations of Roche’s two maintstay biologics for the treatment of cancer. They are more line extensions than follow-on biologics, and as such do not necessarily provide any additional value.

This is not to say that Roche’s products cannot produce some type of savings (either based on site of care or lower administration costs). The cancer chemotherapies would likely still be administered in a doctor’s office or clinic, they agreed, but faster administration time could result in lower fees. This doesn’t necessarily tip the scales in favor of the newer products, particularly if a biosimilar is available in the original formulations at lower costs. Yet, the subcutaneous formulations may make a stronger case for these oncology medications to be managed under the payer’s pharmacy benefit, with distribution via specialty pharmacy.

The payers are not placing significant value on the citrate-free version of adalimumab, partly because injection site pain is a lesser concern for them. Although it may be attractive to patients, payers are wary of ascribing any added value to this agent. If adalimumab biosimilars were available today as alternatives in the United States, based on what we are hearing, the citrate-free formulation would not prevent a run to lower-cost biosimilars.

The greater issue may be follow-on biologics like Ultomiris, which is being sold by the manufacturer of eculizumab (Soliris®). Eculizumab may be among the next generation of biologics targeted by biosimilar manufacturers. It was approved in 2007 by the Food and Drug Administration (FDA), and its utilization can be preempted by Alexion’s push to use the newer agent. At least one prospective manufacturer (Amgen) is working on a biosimilar agent for eculizumab.

It would be logical to expect that the threat of biosimilar activity could accelerate the development of follow-on agents, particularly in view of the success that biosimilar manufacturers have had in obtaining FDA approval. If the extraordinary patent defenses erected by some manufacturers, like AbbVie, are under continuing attack, accelerated development and marketing of a follow-on agent may be the next best action.

In related biosimilar news…Several disparate organizations are joining the front against AbbVie’s patent thicket strategy for Humira. Fierce Pharma is reporting that since the initial lawsuit by a union of New York grocery store workers last month, others like another union in New York of heavy machine operators, the police department of Miami, the mayor’s office in Baltimore, and Minnesota pipe fitters and electrical workers groups have filed class action lawsuits. The AbbVie lawsuit by police organization also implicated Amgen, in signing a pay-for-delay deal allowed it an effective 180 days of exclusivity where none was statutorily allowed.

New CMS Proposal Lowers Cost Sharing for Part D Biosimilars and Follow-on Biologics

The Centers for Medicare and Medicaid Services (CMS) has released another proposal through the Federal Register, which attempts to correct an anomaly in how biosimilars, follow-on biologics, and brands are treated under Medicare part D.

This can be confusing, because CMS treats biosimilars as generics for the purposes of the part D coverage gap. It now wants to ensure that biosimilars are treated as generics in terms of the coverage gap for only those receiving low-income subsidies. Currently, biosimilars are more expensive for patients in the coverage gap compared with originator brands; the new policy could seriously lower overall cost sharing for patients.

CMS logoUnder the policy in place, patients receiving biosimilar therapy who enter the coverage gap are required to pay the same amount as they would for a branded biologic, rather than a generic. This discouraged the use of biosimilars in the coverage gap. The new proposal by CMS rectifies the situation for those receiving the low-income subsidy.

The Affordable Care Act seeks to reduce and eventually eliminate the coverage gap. The 2017 coverage gap begins once a patient has drug expenditures of $3,700 and ends after $4,950. After exiting the coverage gap, beneficiaries pay 5% of total costs. This seems straightforward, but complicating the matter is a provision to help close the coverage gap by 2020. That refers to the Coverage Gap Discount Program, in which drug makers must provide a 50% discount on brand-name products dispensed to Medicare beneficiaries who are presently in the coverage gap. In 2017, the health plan pays 10% of the costs in the gap (this increases through 2020 to 25%), and the beneficiary pays 40% (which decreases by 2020 to 25%). For generics and biosimilars, patients pay 51% of the cost, as CMS assumed that the prices of these would be far lower than that of brands. This is not the case with biosimilars, however; patients in the coverage gap would actually pay more for a part D biosimilar than for a brand until the coverage gap disappears.

Under the new proposal, CMS would “revise the definition of generic drug at § 423.4 to include follow-on biological products approved under section 351(k) of the PHS Act (42 U.S.C. 262(k)) solely for purposes of cost-sharing under sections 1860D-2(b)(4) and 1860D-14(a)(1)(D)(ii-iii) of the Act. Lower cost sharing for lower cost alternatives will improve enrollee incentives to choose follow-on biological products over more expensive reference biological products, and will reduce costs to both Part D enrollees and the Part D program.” This proposal is specific only to non-low-income subsidy beneficiaries’ catastrophic care (i.e., beyond the coverage gap threshold) and all low-income subsidy beneficiary cost sharing.

The real impact of this new policy on biosimilars will not be known for some time. After a comment period ends in January, implementation can take some time (perhaps around the time the coverage gap is closed). More pragmatically, no part D biosimilar is currently marketed (infliximab and filgrastim are reimbursed under part B). Follow-on biologics, such as insulins or growth hormones, are generally covered under part D, and the policy applies to these agents as well.

What Will Be Considered a Biosimilar in 2020?

Payers, providers, and patients in the US are narrowly focused on a limited set of biosimilar products; we all know them well—the anti-TNFs, the colony-stimulating growth factors, and most recently some antitumor drugs (e.g., trastuzumab, rituximab, and bevacizumab). In 2020, before the first biosimilar to Humira® hits the market, some medications may be reclassified as biosimilar status.

Tucked away in the Biologics Price Competition and Innovation Act of 2009 (BPCIA) is a set of obscure provisions that has the potential to create a good deal of confusion at that time.

“Transition drugs.” If you’re familiar with the term, you’re one of the few. Some medications are “transitioning” in the next couple of years. Specifically, drugs that will be transitioned include the insulins, but also other naturally occurring proteins, such as hyaluronidase, human growth hormones, and menotropins.

The mechanism is actually quite simple. Today, these products are all approvable under the original Food, Drug, and Cosmetics (FD&C) Act of 1962. By 2020, these agents will be approvable as biologics under the BPCIA. That means that they will not only be categorized as a biologic, but they will be subject to biosimilar—not generic—competition. No more new drug applications or abbreviated new drug applications, only biologic license applications of the 351(a) and 351(k) varieties.

In March 2016, the Food and Drug Administration (FDA) issued draft guidance on these transitional producinsulin-pensts. As the Regulatory Affairs Professional Society described it earlier this year, “Put simply: FDA will not approve any pending or tentatively approved application for a biological product under the Federal [FD&C] Act after 23 March 2020.”

This may have the effect of slowing approval of today’s so-called follow-on biologics, which will have to go through the 351(k) application process. For example, Lilly received approval for its insulin glargine product under a 505(b)2 application. This application process allowed Lilly to use clinical data from Sanofi’s originator product Lantus®. Under the letter of the new law, because no insulin glargine product has been approved via the biologic license application route, there are no “reference” or originator insulin products.

This can result in labeling and exclusivity period issues as well, possibly discouraging manufacturers of these products from applying for FDA approval. “Nothing in the [BPCIA] suggests that Congress intended to grant biological products approved under section 505 of the FD&C Act—some of which were approved decades ago—a period of exclusivity upon being deemed to have a license under the PHS Act that would impede biosimilar or interchangeable product competition in several product classes until the year 2032,” FDA said.

A legislative proposal was introduced in 2015 by Representative Michael Burgess (R-TX), which would have asked the Government Accountability Office to review the provisions and their potential impact before the 2020 transition took place. The proposal did not advance in the House.

A search revealed no updates on the legislative or regulatory sides of the fence, so we assume the transition will occur as intended. Currently stated policy by the FDA is that all biologics will receive a new four-character suffix to their nonproprietary names. Will this apply to the older insulins and growth hormones as well? Will coding, descriptors, or nomenclature for Lantus® have to change to reflect a new status as a reference biologic product? Or will this only apply to medications approved after March 2020 (in which case, there could be a confusing dichotomy here).

It could get a bit messy, folks.

Insulin Glargine Biosimilars: Don’t Forget to Consider the Insulin Delivery Device

Competition among insulin makers is intense. In most cases, manufacturers realize that various forms of insulin are well matched in clinical efficacy and safety by competing insulin makers. The only real differentiator among the products may be how the insulin is delivered. In fact, these manufacturers spend a tremendous amount of design research, engineering, testing, and market research resources in producing a delivery device that patients will find relatively comfortable, easy to use, and portable (see example). It brings to mind an executive for a major insulin producer who I had repeatedly seen stabbing himself with a pen-type injection device (without insulin) to demonstrate to others that the delivery system and the narrow-gauge needle was about as pain-free as possible to engineer.

This raises the question of whether a patient with diabetes mellitus whose glycemic levels are under control are actually loyal to the insulin brand or its delivery system. In reality, however, health plans and insurers pay far more attention to the insulin formulation than to the insulin delivery device in making coverage decisinsulin-pensions. In some cases, they may cover only certain types of delivery systems, yet this seems to contradict the precepts of value-based benefits (providing best access to interventions that are proven to improve diabetes control and/or adherence). Health plans and insurers may instead focus on other aspects of the insulin itself, such as whether it has a relatively lower risk of hypoglycemic events.

A few years ago, the question about which basal insulin to cover was straightforward, usually amounting to pricing, rebates, and existing marketshare (e.g., how difficult it might be to switch the majority of patients who were taking Lantus® to Levemir®). This was no different than other competitive drug categories. The introduction of the first follow-on (or let’s face it, biosimilar) insulin glargine (Basaglar®) has added new impetus to this discussion. Lilly, the company licensing Basaglar, won a couple of big coverage victories for 2017 over Sanofi’s Lantus, including CVS Health and UnitedHealthcare. The partnership of Merck and Samsung Bioepis hope to receive a positive FDA decision on their insulin glargine biosimilar in the third quarter of this year. Lilly, a veteran of the insulin wars, promotes the use of its existing KwikPen® system for Basaglar. Should Merck get a positive decision, it will market another pen-delivery system. (For the record, Merck is not a complete stranger to the insulin market. It does have an insulin product marketed to the veterinary sector, with its own pen-delivery system [VetPen®]). This raises the question of whether the biosimilar must be paired with its own, perhaps prefilled pen-delivery device and whether it results in the same or similar patient satisfaction ratings. This could have implications for adherence and thus glycemic control.

The US continues to lag behind Europe in terms of pen-injector use (more than two-thirds of patients in Europe use pen-based systems, whereas only 15% use pens in the US), where needles and syringes still dominate. The reasons for this are likely related to reimbursement or patient cost sharing. For those using needles and syringes, the payer’s preference for insulin glargine is more straightforward.

However, as the patents of this and other insulin analog molecules expire, it is reasonable to expect the availability of biosimilar or follow-on copies to increase, making the drug-delivery system pairing even more important.

Taking the “Biobetter” or “Follow-on” Biologic Route

For conventional drug manufacturers, standard lifecycle management considerations include extending patent life through development of new dosage forms, formulations of extended- or sustained-release versions, or even the “next-generation” molecule (e.g., Prilosec® vs. Nexium®).

For manufacturers of biologics, the tools at their disposal for extending patent life are a bit more limited. A change in dosage forms is likely, as are extended-release versions. They can still attempt to develop next-generation versions that are more effective or safer than the parent molecule, which would offer at least some protection against biosimilar competition. These offspring are considered “biobetters.” Unlike the term, this concept is not really new. In the past, agents like colony-stimulating factors have been “pegylated” to produce enhanced effects.

Let’s consider one example. Roche’s (Genentech’s) product obinutuzumab (Gazya®) was approved by the FDA. This agent is a CD20-receptor antibody that is similar to the original CD20 product rituximab (Rituxan®). There are differences, however. The molecular structures differ slightly. Roche believes that Gazya has more antibody-dependent cell-mediated cytoxicity than Rituxan. This may translate into improved progression-free survival. Gazya has only one of Rituxan’s 7 indications (chronic lymphocytic leukemia), so it will not be a strict replacement for Rituxan. Rituxan may be facing biosimilar competition by 2018, and it will indeed be interesting to see how payers will utilize another version of rituximab. This may also be dependent on the extrapolation of indications for the original product.

Roche made the decision to seek approval for Gazya through the  supplemental biologics license application (BLA) pathway, and it will be able to take advantage of full exclusivity periods, and possibly premium pricing (at least until biosimilars arrive). That may well justify the cost of conducting the full clinical trial program required for BLA approval.

Others took the “follow-on biologic” route—in this case, the molecule is not considered substantially different. Teva filed for approval of Granix® (tbo-filgrastim) as a BLA, because at that time, the 351(k) pathway did not yet exist. As a result of its approval, Teva received the full market exclusivity benefits of an originator biologic even though it is truly a biosimilar version of filgrastim. Entering a competitive marketplace, Granix has eroded Neupogen®’s marketshare, but it is subject to biosimilar competition to Zarxio®, in addition to whatever future filgrastim agents are approved. That might make a follow-on biologic little more than a “me-too,” with limited lifecycle prospects.