renewed interest in long-acting injectable and implantable...

DDE WhitepaperSeptember 2019

Renewed Interest in Long-Acting Injectable and Implantable Drug ProductsThe pharmaceutical industry is witnessing a renewed interest in the last 10 years (2010 to 2019) in phar-maceutical products that are designed as long-acting injectables or as implantable systems.

Approved Long-Acting Products

Historically, many of the long-acting products were based on biodegradable polymer systems with the majority using PLGA polymer (see Table 1). With one exception (Neutropin Depot, human growth hormone, Jannsen / Alkermes), all of these products are small molecule or peptide therapeutics. The other systems being evaluated extensively are implantable products (See Table 2) with durations of action typ-ically lasting from a minimum of 3 months to more

than 2 years. All of these products are either small molecule or peptide therapeutics. Currently, there are 36 long-acting therapies approved in the US that are based on release-controlling polymer formulations and systems.

There are another 37 products approved that are not based on polymer matrices. Most of these are older injectable suspension products based on drug dis-persed in oil that in most cases did not have that long a duration of action, but are included here for com-pleteness (see Table 3a and 3b). However, 5 of these products are the modern schizophrenia drugs ap-proved since 2000 which are aqueous nano- or micro- particle suspensions and are based on low solubility drugs and prodrugs (See Table 4).

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About Drug Delivery Experts: Drug Delivery Experts (DDE) is a drug product research and development company that specializes in drug delivery systems from preclinical to clinical development and commercialization. DDE has specific expertise with peptides, proteins, and oligonucleotides along with formulation, process, and combination drug product development. With over 200 years of pharmaceutical development experience at a broad range of companies, the leadership team at DDE has worked on products across many routes of administration and dosage forms including various non-invasive and sustained release injection products. DDE is located at 11494 Sorrento Valley Road, Suite J, San Diego, California.

Figure 1. Images of Long-Acting Injectable and Implantable Products.1a. Eligard (leuprolide acetate for injectable suspension)2a. Bydureon BCise (exenatide extended-release injectable suspension)3a. Probuphine (buprenorphine) Implant4a. Aristada (aripiprazole lauroxil extended-release injectable suspension)

A significant area of unmet need is for technologies that are suitable for formulation and processing of biologics. There are 72 long-acting products that have been approved in the US. Of these 72 products, only 15 are based on peptide therapeutics and only one has been developed from a protein (Nutropin Depot, hu-man growth hormone, Jannsen / Alkermes, discontin-ued). With pharma pipelines expanding significantly into biologics, there is a need for process and formula-tion technologies that are suitable for use for biologics long-acting products.

Clinical Need Drives the Interest in Long-Acting Technologies

There is a great deal of interest for long-acting thera-pies in areas where patient compliance is important to control (psychiatric conditions such as schizophrenia), where administration into a local and sensitive cavity requires a minor procedure in the physician’s office (intravitreal injection for retinal disease, or intraar-ticular injection in the knee), or for chronic diseases where continuous exposure of the drug is required for maximal efficacy (diabetes and obesity).

Figure 2. Implantable products with varying in-use time frames.2a. Nuvaring (etonogestrel/ethinyl vaginal ring) monthly administration (duration 3 weeks)2b. Zoladex (goserelin acetate implant) subcutaneous administration every 3 months2c. Iluvien (fluocinolone acetonide intravitreal implant) up to 3 years2d. Jadelle (levonorgestrel implants) for subdermal administration up to 5 years

Injectable long-acting drug products have ranged in duration from frequent administration times for chronic disease requiring regular self-administra-tion (daily, weekly, and monthly injection). These products must strive to be created in simplistic dosage forms that patients can readily be trained to self-administer. There is room for improvement in the devices used for many of the approved products. Given the recent product successes in schizophrenia with long-acting injectable suspension products with 3 months administration frequency, there is work ongoing to extend injectable technologies beyond 3 months to 6 months without the use of polymer sys-tems, but simply based on insoluble drug suspensions.

Administration Frequency

Implantable systems range from shorter adminis-tration frequencies for self-administered products such as intravaginal implants (typically monthly), to longer-acting systems which require physician admin-istration with minor procedures (typically every 3 or 6 months, or once in 1, 2, 3, or 5 years).


It appears that the consumer market and pharma companies are ready to consider subdermal implants as a viable path forward for commercial products, par-ticularly in chronic diseases where drugs are potent, and in emerging economies where frequent visits to a doctor are prohibitively expensive or simply impossi-ble to achieve. In emerging economies, the therapeu-tic areas under investigation are infectious diseases and reproductive health.

Diabetes continues to be a test case with a 6-month implant product from Intarcia (ITCA 650 exenati-de implant) pending FDA approval and a longer 12-month implant in development, along with other competitors working on implanted products. This product, if approved, will test the market acceptance for a physician administered implant in diabetes with 6 months administration frequency, as opposed to very patient-friendly weekly injectables and oral ge-nerics. There is likely to be a market for some patients and physicians. The question is simply the size of

the commercial market and we will have to wait for a product to be approved to understand acceptance.

Drug development requirements

Long-acting injectable and implantable products are considered complex combination drug products. These products are composed of an active ingredient, a functional excipient (if needed), the formulation, and the administration device, which may control the rate of release of the drug from the product. As a result, the approval process requires a typical full clinical program, although the magnitude of clinical safety data is typically reduced compared to the orig-inal application for the solution injectable product. For example, Bydureon (exenatide microspheres for injectable suspension, FDA approved 2010) was ap-proved with a total of about 1200 patients in clinical studies while the original exenatide product for twice daily injection (Byetta, FDA approved 2005) required about 6000 patients in total.


Figure 3. Byetta (exenatide injection) and Bydureon (exenatide microsphere for injectable suspension), Bydureon Pen, and Bydureon BCise development programs outlined.

The regulatory program for a long-acting injectable or implantable system follows the 505(b)2 NDA approv-al process because they reference clinical and safety data from the original NDA for the immediate release product, whether oral or injection. The development programs are risk-reduced due to the knowledge of the pharmacokinetics and pharmacodynamics (PKPD) and safety of the original molecule. They require a typical NDA approval process which can be achieved with a lower number of patients due to the reference drug information.

The primary risk in conversion of solution injectable to a long-acting injectable and the primary focus of the development program is on the potential for changes in the following: 1) local tolerability related to the long-acting system, 2) changes in PKPD or safety, 3) changes in immune response to the new dosage form combination with the drug.

The development programs for the long-acting sys-tems have to date required phase 1 and 2 safety and dose-finding studies, as well as phase 3 programs in 1 or 2 pivotal studies (depending on the indication and severity of disease). The primary reason for this is the need to demonstrate long-term efficacy for the continuous exposure product, the proof that continu-ous exposure can be maintained for a given duration, and the safety of the product at the administration site, as well as the proof that there is no dose dump-ing throughout the period where drug release is being controlled. If a product was improperly controlled, a dose dump in the first few days after administration (or at any time during the release controlling period) could cause a very large patient exposure to drug, potentially higher than had ever been tested in toxicity studies.

The other challenge for long-acting products is that they require careful administration from a patient or physician, often requiring a complicated reconstitu-

tion prior to administration, which has the poten-tial to cause product failures if done incorrectly (for example, too low a dose due to needle clogging or incomplete dosing, or dosing into the wrong tissue of the body). Safety is the primary concern of the agen-cy, as it should be, and this is the reason that there is no simple pathway to approval of these products and probably should not be.

Currently No Generic Regulatory Pathway Available

There is currently no clear pathway in the US for a generic of a long-acting injectable or implantable and currently no product approved in this space that is generic. LHRH in its many forms (injectable in-si-tu forming gel and microsphere for 1,3,4,6 months injection frequency) were produced by two different pharmaceutical companies and were both full new drug application programs. There has not yet been an approval of a long-acting system that followed a generic approval pathway. This is largely because of the complexity of the release-controlling systems, the fact that the clinical exposure is quite long compared to an immediate release injection, and the fact that the excipients are functional and most often control the rate of release of the active drug.

Despite the fact that many of these drug products are life cycle management programs for existing commer-cial drugs, it is not likely in the near future that there will be a generic pathway established. The programs are all new drug applications and benefit from clini-cal development market exclusivity as well as patent exclusivity (if available). They also have a high barrier to entry due to the clinical burden of proof as well as the more challenging chemical, manufacturing, and controls work required to build one of these products from research, to clinical trials, to commercial manu-facturing, and supply chain.



Still Interested in Long-Acting Therapies?

The upfront investment to develop a long-acting injectable or implantable is quite significant and the work is complicated with many challenges along the way, some of which will be unpredictable. The program is usually risk-reduced compared to a new

chemical entity because we know a lot about the active ingredient as it is generally available in an ap-proved drug product. The decision to proceed into this space should not be taken lightly and should be done with the consultation of experts in the field with drug development experience for one or more of these technologies.

Product Drug Company Technology Indication RouteAtridox doxycycline

hyclateDen-Mat Atrigel Periodontitis Oral -peri-

odontal pocket

Bydureon exenatide AstraZeneca Microsphere Diabetes, type II SCEligard leuprolide ace-

tateTolmar Atrigel Prostate cancer SC

Lupron Depot leuprolide ace-tate

Abbvie Microsphere Prostate cancer

Central precocious puberty

IM

Ozurdex dexamethasone Allergan Implant (rod) Retinal vein occlusion

Non-infectious uveitis

Diabetic macular edema

Intravitreal

PROPEL and SINUVA

mometasone furoate

Intersect ENT Implant maintain patency of the sinus cavity or sinus ostium

Sinus cavity Implant

Perseris risperidone Indivior Atrigel Schizophrenia SC (abdom-inal)

Risperdol Consta

risperidone Janssen Microsphere Schizophrenia, Bipolar disorder

IM

Sandostatin LAR Depot

octreotide acetate

Novartis Microsphere Acromegaly IM

Signifor LAR pasireotide pamoate

Novartis Microsphere Acromegaly IM

Sublocade buprenorphine Indivior Atrigel Opioid use disorder SCTrelstar triptorelin pa-

moate Allergan Microgranules Advanced prostate

cancerIM

Triptodur triptorelin pa-moate

Arbor Microgranules Central precocious puberty

IM

Vivitrol naltrexone Alkermes Microsphere Alcohol or opiod de-pendence

IM

Zilretta triamcinolone acetonide

Flexion Microsphere Osteoarthritis pain of the knee

Intra-artic-ular

Zoladex goserelin ace-tate

AstraZeneca Implant (rod) Prostate cancer, breast cancer, others

SC Implant

Table 1. Long-acting Products based on PLGA Polymer (Most are Injectables)


Product Drug Company Technology Indication Route

GLIADEL1 carmustine Arbor Pharma polyanhydride implant (disk)

glioma Intracranial

SUSTOL1 granisetron Heron Thera-peutics

triethylene glycol poly (orthoester) gel

antiemetic for can-cer therapies

SC

TESTOPEL1,2 testosterone Endo

(also Slate)

API pellets androgen replace-ment therapy

SC

VIADUR leuprolide acetate

Bayer DUROS titanium implant

prostate cancer SC (upper arm)

RETISERT fluocinolone acetonide

Bausch & Lomb

implant, (silicon cup reservoir)

chronic noninfec-tious uveitis

Intravitreal

YUTIQ fluocinolone acetonide

Eyepoint Pharma

polyimide implant chronic noninfec-tious uveitis

Intravitreal

ILUVIEN fluocinolone acetonide

Alimera Sci-ences

polyimide implant chronic noninfec-tious uveitis

Intravitreal

Various estradiol Multiple com-panies

silicone ring menopause symp-toms

Intravaginal

Various levonorgestrel Multiple com-panies

silicone device contraception Intrauterine

JADELLE3 levonorgestrel Bayer silicone implant contraception Intradermal

TODAY4 nonoxynol-9 Mayer Labo-ratories

polyurethane sponge

contraceptive Intravaginal

CERVIDIL dinoprostone Ferring Phar-ma

polyethylene oxide/urethane polymer

cervical ripening/induction of labor

Intravaginal

SUPRELIN LA histrelin acetate Endo Pharma methacry-late-based implant

central precocious puberty

SC

VANTAS histrelin acetate Endo Pharma methacry-late-based implant

prostate cancer SC

NEXPLANON etonogestrel Organon USA EVA implant (with Barium Sulfate)

contraceptive Subdermal (upper arm)

IMPLANON etonogestrel Organon USA EVA implant contraceptive Subdermal (upper arm)

PROBUPHINE buprenorphine Titan Pharma EVA implant opioid use disorder Subdermal (upper arm)

VITRASERT ganciclovir Discontinued tablet coated with EVA

CMV retinitis in AIDS patients

Intravitreal

Table 2. Long-acting Products based on Polymers other than PLGA (Most are Implants)


Table 3a. Oil-based Suspension Products with Extended-Release Profiles


Table 3b. Oil-based Suspension Products with Extended-Release Profiles


Table 4. Modern Long-Acting Injectables in the Schizophrenia Therapeutic Area

Product Drug Company Technology Indication Route

Zyprexa Relprevv

Olanzapine Eli Lilly Suspension of salt particles

Schizophrenia IM

Invega Sus-tenna

Paliperidone prodrug

Janssen Palmitate ester pro-drug particles

Schizophrenia IM

Invega Trinza

Paliperidone prodrug

Janssen Palmitate ester pro-drug particles

Schizophrenia IM

Abilify Maintena

Aripiprazole Otsuka / Lundbeck

Particle suspension injection

Schizophrenia IM

Aristada Aripiprazole prodrug

Alkermes Lauroxil ester prod-rug particles

Schizophrenia IM

renewed interest in long-acting injectable and implantable...

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