CommentaryPublication Exclusive

Imatinib in 2016: What will the era of generic targeted therapy for cancer look like?

The therapeutic landscape for patients with Philadelphia chromosome-positive leukemias, most notably those with chronic phase chronic myeloid leukemia, has undergone unprecedented change — including paradigm-shifting response, record-time initial FDA approval and treatment-free remission (functional cure) on the horizon — thanks to imatinib mesylate.

Imatinib mesylate (Gleevec, Novartis) — which received FDA approval in 2001 — was under development at a time when “targeted therapy” was a limited-use term in cancer therapy.

Tamoxifen, an antiestrogen, was the earliest “targeted” anticancer therapy, and trastuzumab (Herceptin, Genentech) — an anti–HER-2/neu receptor inhibitor — perhaps represented the first rationally designed targeted agent.

Michael J. Mauro, MD
Michael J. Mauro

Now, Ph+ leukemias are treatable with five different oncogene-targeted, specific and evolved agents: nilotinib (Tasigna, Novartis), dasatinib (Sprycel; Bristol-Myers Squibb, Otsuka America Pharmaceutical Inc.), bosutinib (Bosulif, Pfizer), ponatinib (Iclusig, Ariad) and the prototype imatinib.

A new chapter

On Feb. 1, Sun Pharmaceutical Industries Ltd. — based in Mumbai, India — launched generic imatinib, heralding a new chapter in the so-far, so-good story of targeted therapy for CML and related conditions.

Sun Pharmaceutical received final FDA approval to produce generic imatinib for the U.S. market in December 2015. Being a first-to-file product, Sun received 180 days of marketing exclusivity, or protection against competition from other generic manufacturers.

As is common, first-to-file rights affect the pricing of the first available generic form of a drug. The expected initial savings for imatinib has been estimated at 30%. A 1-year supply of imatinib 400 mg — the standard dose for chronic phase CML — costs roughly $120,000.

Imatinib currently is in the running with nilotinib and dasatinib for first-line therapy for CML, and the cost to purchase a year’s supply of these is roughly the same or slightly higher.

In an op-ed piece in The New York Times early last year, Peter B. Bach, MD, MAPP, a colleague of mine at Memorial Sloan Kettering Cancer Center, highlighted how the price of imatinib nearly doubled between 2001 — its initial approval year — and 2014. Since then, the price of imatinib has risen to match the cost of its competitors.

To its credit, Novartis in 2002 launched a comprehensive international patient assistance/access program. The GIPAP program — administered by the MAX Foundation, based in Seattle — has helped more than 70,000 patients.

It is clear the business side of therapy for Ph+ leukemias follows the agenda of the pharmaceutical industry, which needs to answer to shareholders, remain profitable and survive to invest heavily into further drug development to both advance medicine and give rise to a new cycle of marketable brand-name drugs.

With inherent differences in how the “other” sides — patients and providers — view the situation, there has been considerable discussion in the United States about the cost of the ever-growing number of oral, generally targeted cancer therapies and how they are priced.

A unique example

CML and tyrosine kinase inhibitors have been singled out as a unique example. Despite this, the advent of generic options for CML came online with surprisingly little fanfare, at least to this observer.

Being on the front lines — clinically managing CML and the increasing number of successfully treated, potentially (functionally) curable patients — I anticipate a tempestuous period ahead, despite initial calm. I also understand the fears and concerns of patients, as well as the dilemma treating physicians may face.

Unfortunately, there are what many have called a spoil of riches when choosing initial therapy for a patient with CML. A prescriber is expected to understand the breadth of relative risks and benefits of three agents — imatinib, nilotinib and dasatinib — and navigate, with a patient, the right decision for each.

Although statistically significant advantages are known regarding relevant response — both cytogenetic and deep molecular — and protection from progression comes with use of nilotinib and dasatinib, such benefits seemingly are offset by a more complex and potentially perilous risk profile compared with imatinib. As well, the most convincing benefit of a new “standard” therapy — improvement in OS — has been noticeably absent as landmark FDA approval-generating trials come to final data collection after many years.

Lastly, the most optimistic element of the success of these drugs in the treatment of CML, the potential for treatment-free remission — or the ability to carefully observe patients who, after a defined period of stable and deep molecular remission, might retain remission off therapy and be functionally cured — appears feasible and may be more likely with use of newer agents, but it is not sanctioned as a standard approach.

Logically, if therapy duration were defined rather than infinite, cost–benefit arguments would take on a whole new look. In fact, CML represents a new and unique paradigm in which the therapy that induced remission is maintained thereafter without stop; many other new drugs of great promise may follow a similar pattern and pose similar potentially unmanageable cost expectations.

Thus, prior to Feb. 1 — a period when differential cost of therapy was not on the radar of prescribers or, more importantly, hitting the spreadsheets of payers — the playing field was blurry.

Colorful history

The history of generic imatinib already was colorful.

Once recognized as highly effective for Ph+ leukemias, a long battle ensued that culminated in the Supreme Court of India rejecting Novartis’ rights to patent imatinib in India in 2013. Although Novartis did gain exclusive marketing rights and were able to halt some generic manufacturing, non-Novartis–produced imatinib has been in use for a long time in India. Other court battles have featured imatinib and its patent.

In 2010, Brazil’s highest appeals court, the Superior Court of Justice, denied a 1-year patent extension. Thus, generic imatinib became available in South America in early 2013.

At the same time, Health Canada approved generic versions of imatinib from Apotex and Teva, in this case based on expiry of patent on the alpha crystal formulation.

The beta crystal formulation expires in 2018 in Canada. Thus, without a degree in patent law, it might have been hard to predict how the transition from Novartis’ branded Gleevec — or Glivec, as it is known outside the United States — may have proceeded and how to prepare.

To put what has happened with generic imatinib into context, it may be best to understand what standards a generic must uphold to “replace” a branded drug.

The FDA defines a generic as “a drug product that is comparable to a brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use.”

Generics are judged and, thus, approved based on being a therapeutic or pharmaceutical equivalent, which means they contain the same active ingredient(s), dosage form, route of administration and strength as the original drug.

The FDA assigns therapeutic equivalence evaluation codes to generics. Sun Pharmaceutical’s imatinib generic received an AB designation, which means “actual or potential bioequivalence problems have been resolved with adequate in vivo and/or in vitro evidence supporting bioequivalence.” The ideal designation is AA, which means “there are no known or suspected bioequivalence problems.”

As one might expect, although harmonization efforts to standardize how bioequivalence is defined worldwide, this is a work in progress. In the United States, real attention into generics and their regulation is followed only after the Drug Price Competition and Patent Term Restoration Act — known as the Hatch-Waxman Act — was signed into law in 1984 by President Ronald Reagan.

Although the Hatch-Waxman Act brought clarity and more breadth to the abbreviated new drug application, it prohibits the FDA from asking for more than bioequivalence studies, making it one of the few articles of legislation that restricts the powers and reach of a federal agency.

Lessons learned

What have we learned from the earlier transitions to generic imatinib outside the United States? Has there been concern of response loss or lack of initial response? A look at the literature may reassure and raise concern simultaneously.

Review of case reports does yield instance of response loss with the switch and lack of response gained in the literature using “copy” or generic imatinib, as well as the potential for an increase in side effects. However, more confidence should be instilled from data from increasingly larger case series of patients reported from Serbia, Turkey, Canada and India that show equivalence, for the most part.

Most of the experience outside of India to date has been with a switch to generic rather than initiation of generic, keeping this question — and others — open.

Due to a number of factors — legislation and regulation, such as the Hatch-Waxman Act; expected financial pressure from burdened health care systems; and willing and eager competition between brand and generic manufacturers — we should not expect to see randomized trials of brand and generic drugs to settle our fears.

We move ahead, then, into this era with a degree of anxiety and fear, and a long forgotten sense of anticipation that this day would come in our clinics where CML and other conditions can be treated so well and so precisely — not only with a sturdy list of five oral TKIs at our disposal, but now a sixth that really should not be viewed as new or different.

Until the dust settles, more data can be produced and confidence is restored — and as we monitor and treat an ever-growing number of patients thanks to these drugs — here is some advice about what to do in this new era of generic imatinib.

First, if a newly diagnosed patient is started on generic imatinib, monitor them as you should. If there is any question of inadequate response or missed milestones, evaluate as you should, including raising the question of generic equivalence and a switch to branded imatinib, along with a switch to subsequent-generation kinase inhibitors.

Second, if you switch a patient to generic imatinib, pay close attention as you should — or perhaps closer, including early confirmation of stable response soon after change (ie, 6 weeks) — and ensure that response trajectory or stability continues as expected. Otherwise, raise the question of generic equivalence and a return to branded imatinib.

One final note: DAW (“dispense as written”) may not be an easily exercisable option with payers — although it remains an option — and it may be interpreted as “denial and withstanding” in this new era of generic imatinib.

References:

Bach PB. Why drugs cost so much. The New York Times. Available at: www.nytimes.com/2015/01/15/opinion/why-drugs-cost-so-much.html?smid=tw-share&_r=1. Accessed Feb. 9, 2016.

Berndt ER, et al. Health Aff (Millwood). 2007;26:790-799.

Congressional Research Service. Patent law and its application to the pharmaceutical industry: An examination of the Drug Price Competition and Patent Term Restoration Act of 1984 (The Hatch-Waxman Act). Available at: www.ipmall.info/hosted_resources/crs/RL30756_050110.pdf. Accessed on Feb. 9, 2016.

de Lomas ML and Kyritsis V. J Oncol Pharm Pract. 2015;doi:10.1177/1078155214522143.

Eskazan AE, et al. Leuk Lymphoma. 2014;doi:10.3109/10428194.2014.905774.

FDA. Drugs@FDA Glossary of Terms. Available at: www.fda.gov/drugs/informationondrugs/ucm079436.htm. Accessed on Feb. 9, 2016.

In the Supreme Court of India. Civil appellate jurisdiction. Novartis AG vs. Union of India & Others. Available at: http://judis.nic.in/supremecourt/imgs1.aspx?filename=40212. Accessed Feb. 9, 2016.

Kang M, et al. Blood. 2014;124:5527.

Kantarjian H. N Engl J Med. 2010;doi:10.1056/NEJMoa1002315.

Parikh P. Indian J Med Paediatr Oncol. 2013;doi:10.4103/0971-5851.123716.

Saglio G. N Engl J Med. 2010;doi:10.1056/NEJMoa0912614.

Sun Pharmaceutical Industries Ltd. Sun Pharma launches imatinib mesylate in USA. Available at: www.sunpharma.com/media/press-releases/press%20release%20-%20sun%20pharma%20launches%20imatinib%20mesylate%20in%20USA.pdf. Accessed Feb. 9, 2016.

The Pharma Letter. Brazil Superior Court denies extension of Novartis Glivec/Gleevec patent. Available at: www.thepharmaletter.com/article/brazil-superior-court-denies-extension-of-novartis-glivec-gleevec-patent. Accessed Feb. 9, 2016.

The Max Foundation. Glivec international patient assistance program. Available at: www.themaxfoundation.org/gipap/default.aspx.

Urosevic IM, et al. Blood. 2014;124:5533.

Uyanik MS, et al. Eur J Cancer Care (Engl). 2015;doi:10.1111/ecc.12423.

For more information:

Michael J. Mauro, MD, is leader of the myeloproliferative neoplasms program and attending physician on the leukemia service at Memorial Sloan Kettering Cancer Center, as well as professor of medicine at Weill Cornell Medicine. He also serves as a HemOnc Today’s leukemia section editor. He can be reached at Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email: maurom@mskcc.org.

Disclosure: Mauro reports research funding to his institution from Novartis. He also has served as a consultant to Bristol-Myers Squibb and Novartis.

The therapeutic landscape for patients with Philadelphia chromosome-positive leukemias, most notably those with chronic phase chronic myeloid leukemia, has undergone unprecedented change — including paradigm-shifting response, record-time initial FDA approval and treatment-free remission (functional cure) on the horizon — thanks to imatinib mesylate.

Imatinib mesylate (Gleevec, Novartis) — which received FDA approval in 2001 — was under development at a time when “targeted therapy” was a limited-use term in cancer therapy.

Tamoxifen, an antiestrogen, was the earliest “targeted” anticancer therapy, and trastuzumab (Herceptin, Genentech) — an anti–HER-2/neu receptor inhibitor — perhaps represented the first rationally designed targeted agent.

Michael J. Mauro, MD
Michael J. Mauro

Now, Ph+ leukemias are treatable with five different oncogene-targeted, specific and evolved agents: nilotinib (Tasigna, Novartis), dasatinib (Sprycel; Bristol-Myers Squibb, Otsuka America Pharmaceutical Inc.), bosutinib (Bosulif, Pfizer), ponatinib (Iclusig, Ariad) and the prototype imatinib.

A new chapter

On Feb. 1, Sun Pharmaceutical Industries Ltd. — based in Mumbai, India — launched generic imatinib, heralding a new chapter in the so-far, so-good story of targeted therapy for CML and related conditions.

Sun Pharmaceutical received final FDA approval to produce generic imatinib for the U.S. market in December 2015. Being a first-to-file product, Sun received 180 days of marketing exclusivity, or protection against competition from other generic manufacturers.

As is common, first-to-file rights affect the pricing of the first available generic form of a drug. The expected initial savings for imatinib has been estimated at 30%. A 1-year supply of imatinib 400 mg — the standard dose for chronic phase CML — costs roughly $120,000.

Imatinib currently is in the running with nilotinib and dasatinib for first-line therapy for CML, and the cost to purchase a year’s supply of these is roughly the same or slightly higher.

In an op-ed piece in The New York Times early last year, Peter B. Bach, MD, MAPP, a colleague of mine at Memorial Sloan Kettering Cancer Center, highlighted how the price of imatinib nearly doubled between 2001 — its initial approval year — and 2014. Since then, the price of imatinib has risen to match the cost of its competitors.

To its credit, Novartis in 2002 launched a comprehensive international patient assistance/access program. The GIPAP program — administered by the MAX Foundation, based in Seattle — has helped more than 70,000 patients.

It is clear the business side of therapy for Ph+ leukemias follows the agenda of the pharmaceutical industry, which needs to answer to shareholders, remain profitable and survive to invest heavily into further drug development to both advance medicine and give rise to a new cycle of marketable brand-name drugs.

With inherent differences in how the “other” sides — patients and providers — view the situation, there has been considerable discussion in the United States about the cost of the ever-growing number of oral, generally targeted cancer therapies and how they are priced.

A unique example

CML and tyrosine kinase inhibitors have been singled out as a unique example. Despite this, the advent of generic options for CML came online with surprisingly little fanfare, at least to this observer.

Being on the front lines — clinically managing CML and the increasing number of successfully treated, potentially (functionally) curable patients — I anticipate a tempestuous period ahead, despite initial calm. I also understand the fears and concerns of patients, as well as the dilemma treating physicians may face.

Unfortunately, there are what many have called a spoil of riches when choosing initial therapy for a patient with CML. A prescriber is expected to understand the breadth of relative risks and benefits of three agents — imatinib, nilotinib and dasatinib — and navigate, with a patient, the right decision for each.

Although statistically significant advantages are known regarding relevant response — both cytogenetic and deep molecular — and protection from progression comes with use of nilotinib and dasatinib, such benefits seemingly are offset by a more complex and potentially perilous risk profile compared with imatinib. As well, the most convincing benefit of a new “standard” therapy — improvement in OS — has been noticeably absent as landmark FDA approval-generating trials come to final data collection after many years.

PAGE BREAK

Lastly, the most optimistic element of the success of these drugs in the treatment of CML, the potential for treatment-free remission — or the ability to carefully observe patients who, after a defined period of stable and deep molecular remission, might retain remission off therapy and be functionally cured — appears feasible and may be more likely with use of newer agents, but it is not sanctioned as a standard approach.

Logically, if therapy duration were defined rather than infinite, cost–benefit arguments would take on a whole new look. In fact, CML represents a new and unique paradigm in which the therapy that induced remission is maintained thereafter without stop; many other new drugs of great promise may follow a similar pattern and pose similar potentially unmanageable cost expectations.

Thus, prior to Feb. 1 — a period when differential cost of therapy was not on the radar of prescribers or, more importantly, hitting the spreadsheets of payers — the playing field was blurry.

Colorful history

The history of generic imatinib already was colorful.

Once recognized as highly effective for Ph+ leukemias, a long battle ensued that culminated in the Supreme Court of India rejecting Novartis’ rights to patent imatinib in India in 2013. Although Novartis did gain exclusive marketing rights and were able to halt some generic manufacturing, non-Novartis–produced imatinib has been in use for a long time in India. Other court battles have featured imatinib and its patent.

In 2010, Brazil’s highest appeals court, the Superior Court of Justice, denied a 1-year patent extension. Thus, generic imatinib became available in South America in early 2013.

At the same time, Health Canada approved generic versions of imatinib from Apotex and Teva, in this case based on expiry of patent on the alpha crystal formulation.

The beta crystal formulation expires in 2018 in Canada. Thus, without a degree in patent law, it might have been hard to predict how the transition from Novartis’ branded Gleevec — or Glivec, as it is known outside the United States — may have proceeded and how to prepare.

To put what has happened with generic imatinib into context, it may be best to understand what standards a generic must uphold to “replace” a branded drug.

The FDA defines a generic as “a drug product that is comparable to a brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use.”

Generics are judged and, thus, approved based on being a therapeutic or pharmaceutical equivalent, which means they contain the same active ingredient(s), dosage form, route of administration and strength as the original drug.

The FDA assigns therapeutic equivalence evaluation codes to generics. Sun Pharmaceutical’s imatinib generic received an AB designation, which means “actual or potential bioequivalence problems have been resolved with adequate in vivo and/or in vitro evidence supporting bioequivalence.” The ideal designation is AA, which means “there are no known or suspected bioequivalence problems.”

As one might expect, although harmonization efforts to standardize how bioequivalence is defined worldwide, this is a work in progress. In the United States, real attention into generics and their regulation is followed only after the Drug Price Competition and Patent Term Restoration Act — known as the Hatch-Waxman Act — was signed into law in 1984 by President Ronald Reagan.

Although the Hatch-Waxman Act brought clarity and more breadth to the abbreviated new drug application, it prohibits the FDA from asking for more than bioequivalence studies, making it one of the few articles of legislation that restricts the powers and reach of a federal agency.

Lessons learned

What have we learned from the earlier transitions to generic imatinib outside the United States? Has there been concern of response loss or lack of initial response? A look at the literature may reassure and raise concern simultaneously.

PAGE BREAK

Review of case reports does yield instance of response loss with the switch and lack of response gained in the literature using “copy” or generic imatinib, as well as the potential for an increase in side effects. However, more confidence should be instilled from data from increasingly larger case series of patients reported from Serbia, Turkey, Canada and India that show equivalence, for the most part.

Most of the experience outside of India to date has been with a switch to generic rather than initiation of generic, keeping this question — and others — open.

Due to a number of factors — legislation and regulation, such as the Hatch-Waxman Act; expected financial pressure from burdened health care systems; and willing and eager competition between brand and generic manufacturers — we should not expect to see randomized trials of brand and generic drugs to settle our fears.

We move ahead, then, into this era with a degree of anxiety and fear, and a long forgotten sense of anticipation that this day would come in our clinics where CML and other conditions can be treated so well and so precisely — not only with a sturdy list of five oral TKIs at our disposal, but now a sixth that really should not be viewed as new or different.

Until the dust settles, more data can be produced and confidence is restored — and as we monitor and treat an ever-growing number of patients thanks to these drugs — here is some advice about what to do in this new era of generic imatinib.

First, if a newly diagnosed patient is started on generic imatinib, monitor them as you should. If there is any question of inadequate response or missed milestones, evaluate as you should, including raising the question of generic equivalence and a switch to branded imatinib, along with a switch to subsequent-generation kinase inhibitors.

Second, if you switch a patient to generic imatinib, pay close attention as you should — or perhaps closer, including early confirmation of stable response soon after change (ie, 6 weeks) — and ensure that response trajectory or stability continues as expected. Otherwise, raise the question of generic equivalence and a return to branded imatinib.

One final note: DAW (“dispense as written”) may not be an easily exercisable option with payers — although it remains an option — and it may be interpreted as “denial and withstanding” in this new era of generic imatinib.

References:

Bach PB. Why drugs cost so much. The New York Times. Available at: www.nytimes.com/2015/01/15/opinion/why-drugs-cost-so-much.html?smid=tw-share&_r=1. Accessed Feb. 9, 2016.

Berndt ER, et al. Health Aff (Millwood). 2007;26:790-799.

Congressional Research Service. Patent law and its application to the pharmaceutical industry: An examination of the Drug Price Competition and Patent Term Restoration Act of 1984 (The Hatch-Waxman Act). Available at: www.ipmall.info/hosted_resources/crs/RL30756_050110.pdf. Accessed on Feb. 9, 2016.

de Lomas ML and Kyritsis V. J Oncol Pharm Pract. 2015;doi:10.1177/1078155214522143.

Eskazan AE, et al. Leuk Lymphoma. 2014;doi:10.3109/10428194.2014.905774.

FDA. Drugs@FDA Glossary of Terms. Available at: www.fda.gov/drugs/informationondrugs/ucm079436.htm. Accessed on Feb. 9, 2016.

In the Supreme Court of India. Civil appellate jurisdiction. Novartis AG vs. Union of India & Others. Available at: http://judis.nic.in/supremecourt/imgs1.aspx?filename=40212. Accessed Feb. 9, 2016.

Kang M, et al. Blood. 2014;124:5527.

Kantarjian H. N Engl J Med. 2010;doi:10.1056/NEJMoa1002315.

Parikh P. Indian J Med Paediatr Oncol. 2013;doi:10.4103/0971-5851.123716.

Saglio G. N Engl J Med. 2010;doi:10.1056/NEJMoa0912614.

Sun Pharmaceutical Industries Ltd. Sun Pharma launches imatinib mesylate in USA. Available at: www.sunpharma.com/media/press-releases/press%20release%20-%20sun%20pharma%20launches%20imatinib%20mesylate%20in%20USA.pdf. Accessed Feb. 9, 2016.

The Pharma Letter. Brazil Superior Court denies extension of Novartis Glivec/Gleevec patent. Available at: www.thepharmaletter.com/article/brazil-superior-court-denies-extension-of-novartis-glivec-gleevec-patent. Accessed Feb. 9, 2016.

The Max Foundation. Glivec international patient assistance program. Available at: www.themaxfoundation.org/gipap/default.aspx.

Urosevic IM, et al. Blood. 2014;124:5533.

Uyanik MS, et al. Eur J Cancer Care (Engl). 2015;doi:10.1111/ecc.12423.

For more information:

Michael J. Mauro, MD, is leader of the myeloproliferative neoplasms program and attending physician on the leukemia service at Memorial Sloan Kettering Cancer Center, as well as professor of medicine at Weill Cornell Medicine. He also serves as a HemOnc Today’s leukemia section editor. He can be reached at Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email: maurom@mskcc.org.

Disclosure: Mauro reports research funding to his institution from Novartis. He also has served as a consultant to Bristol-Myers Squibb and Novartis.