something new under the skin

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NATURE BIOTECHNOLOGY VOLUME 29 NUMBER 2 FEBRUARY 2011 107 Something new under the skin One-size-fits-all intravenous delivery of biologics may be giving way to alternate delivery routes that enable safer and more efficient drug administration. Michael Eisenstein reports. Roche’s monoclonal antibody (mAb) therapeu- tic Herceptin (trastuzumab) may already be a blockbuster, netting nearly $5 billion in 2009, nonetheless, the Basel-based company sees room for improvement for this all-star molecule. This past December, Roche announced that it had completed enrollment for a phase 3 clinical trial that will test a subcutaneous formulation of this drug, implementing technology devel- oped by Halozyme Therapeutics of San Diego. A positive outcome from this trial could sim- plify treatment for thousands of cancer patients worldwide, but may also provide momentum for pharmaceutical companies looking for smarter and safer ways to get mAbs and their analogs into patients. If successful, Herceptin will join the anti- inflammatory drug Humira (adalimumab), which, when it went on the market in 2003, was the first mAb to be subcutaneously injected from a patient-friendly prefilled syringe. This prod- uct, owned by Abbott Laboratories in Abbott Park, Illinois, represented a significant improve- ment for rheumatoid arthritis patients: instead of visiting the doctor every four weeks for several hours of intravenous (IV) infusion, they could take treatment into their own hands. Although most therapeutic mAbs today are still initially developed for IV delivery, inter- est has grown in finding more efficient deliv- ery routes, and pharmaceutical companies are working aggressively to repurpose their biologic drugs for subcutaneous or other means of deliv- ery to improve patient compliance and response. “The vast majority of oncology products that are mAbs are given by IV administration, because the patient will be in the oncologist’s office any- way,” says Ian Tomlinson, senior vice president of biopharmaceutical R&D at GlaxoSmithKline in London. “But if you’re talking about rheu- matoid arthritis, it’s quite nice for those to be self-administered at home with a device that is capable of being used by a patient.” Getting under their skin Nevertheless, even leading cancer therapeu- tics, such as Herceptin and Rituxan (ritux- imab), distributed by Roche/Biogen Idec of Basel/Cambridge, Massachusetts, are under- going similar reformulation, due in part to the potential for mitigating severe adverse effects that can accompany rapid infusion. For exam- ple, studies have indicated that subcutaneous injection of the anti-CD52 humanized rat mAb drug Campath (alemtuzumab) at lower doses may match the effectiveness of IV delivery for the treatment of chronic lymphocytic leuke- mia while diminishing costs and minimizing infusion-associated toxicity 1,2 , and several clinical trials are assessing this mode of therapy (Table 1, see Supplementary Table for more information). “I hear many biopharmaceuti- cal and pharmaceutical companies saying that their basic target product profile for antibodies in the future is to be subcutaneously deliver- able,” says Gregory Frost, CSO and cofounder of Halozyme Therapeutics. Diverse methods exist for subcutaneous delivery of therapeutics, from basic pre-filled syringes to simple-to-use ‘pen’-style autoinjec- tors. However, reformulation can often pose a challenge, and there are no guarantees that an antibody that works well at infusion-scale volumes will maintain its efficacy when con- centrated 100-fold. “The solution has to be stable, and you have to retain the biological and biophysical properties of your drug,” explains Laurent Audoly, CSO at Pieris in Freising- Weihenstephan, Germany. “You may get aggre- gation, and that can ultimately result in the potential for immunogenicity, which is on the forefront of everybody’s mind with biologics.” His is among a growing number of companies that are trying to bypass this and other delivery- associated issues by working with alternative proteins that mimic the strong specificity and affinity of antibodies but offer reduced size and improved stability, making them more suitable for concentration, dehydration and other manip- ulations. Some are based on natural immu- noglobulin frameworks, such as the variable chain–derived domain antibodies developed at Domantis (now part of GlaxoSmithKline, Brentford, UK) or the tiny and robust single- domain camel- and llama-derived antibod- ies being marketed as ‘nanobodies’ by Ghent, Belgium–based Ablynx. However, a wide range of engineered protein scaffolds are also making their way into the clinical pipeline, including Pieris’s anticalins or the DARPins produced by Molecular Partners in Zurich. “All of these smaller, more stable proteins show some promise,” says Arne Skerra, a professor of biological chemistry at Germany’s Technische Universität München. “I think that in particular for those special routes of delivery…alternative scaffolds provide a clear advantage over con- ventional antibody fragments.” Many of these technologies are relatively unproven as thera- peutics—roughly a dozen ‘scaffold’ drugs are now in the clinical pipeline, but only Cambridge, Massachusetts–based Dyax’s Kalbitor (ecallant- ide), a 60-amino-acid peptide based on the first Kunitz domain of human lipoprotein-associated coagulation inhibitor D1, has been approved by the US Food & Drug Administration (FDA) to date. Nevertheless, such scaffolds demonstrate clear potential for delivering treatments to loca- tions where antibodies fear to tread; accordingly, many of these companies are engaged in high- profile partnerships with large pharmaceutical companies. “Scaffolds were identified as a pri- ority by the European Commission, and they have released a call for grants,” says Alain Beck, head of the department of physicochemistry at the Centre d’Immunologie Pierre Fabre in Saint-Julien-en-Genevois, France. “This is a good indication that it’s an important goal in Europe as well.” On the other hand, Halozyme has developed a strategy that enables larger volumes of solu- tion to be safely and efficiently injected below the skin, making subcutaneous delivery a real- istic option for many mAbs. In this approach, mAbs are co-injected with a recombinant human hyaluronidase enzyme, rHuPH20, which transiently punches holes in the poly- saccharide matrix that surrounds skin cells and thereby allows rapid entry of even large pro- tein molecules. “Essentially, as fast as somebody can expel the contents of an antibody solution through the needle, the enzyme is working,” says Frost. “For many drugs, we’ve found that An array of 36 dissolving microneedles, barely discernable to the touch, may soon be the way vaccinations are given. (Credit: Gary Meek, Georgia Tech) NEWS FEATURE © 2011 Nature America, Inc. All rights reserved.

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Page 1: Something new under the skin

nature biotechnology volume 29 number 2 FebruArY 2011 107

Something new under the skinOne-size-fits-all intravenous delivery of biologics may be giving way to alternate delivery routes that enable safer and more efficient drug administration. Michael Eisenstein reports.

Roche’s monoclonal antibody (mAb) therapeu-tic Herceptin (trastuzumab) may already be a blockbuster, netting nearly $5 billion in 2009, nonetheless, the Basel-based company sees room for improvement for this all-star molecule. This past December, Roche announced that it had completed enrollment for a phase 3 clinical trial that will test a subcutaneous formulation of this drug, implementing technology devel-oped by Halozyme Therapeutics of San Diego. A positive outcome from this trial could sim-plify treatment for thousands of cancer patients worldwide, but may also provide momentum for pharmaceutical companies looking for smarter and safer ways to get mAbs and their analogs into patients.

If successful, Herceptin will join the anti-inflammatory drug Humira (adalimumab), which, when it went on the market in 2003, was the first mAb to be subcutaneously injected from a patient-friendly prefilled syringe. This prod-uct, owned by Abbott Laboratories in Abbott Park, Illinois, represented a significant improve-ment for rheumatoid arthritis patients: instead of visiting the doctor every four weeks for several hours of intravenous (IV) infusion, they could take treatment into their own hands.

Although most therapeutic mAbs today are still initially developed for IV delivery, inter-est has grown in finding more efficient deliv-ery routes, and pharmaceutical companies are working aggressively to repurpose their biologic drugs for subcutaneous or other means of deliv-ery to improve patient compliance and response. “The vast majority of oncology products that are mAbs are given by IV administration, because the patient will be in the oncologist’s office any-way,” says Ian Tomlinson, senior vice president of biopharmaceutical R&D at GlaxoSmithKline in London. “But if you’re talking about rheu-matoid arthritis, it’s quite nice for those to be self-administered at home with a device that is capable of being used by a patient.”

Getting under their skinNevertheless, even leading cancer therapeu-tics, such as Herceptin and Rituxan (ritux-imab), distributed by Roche/Biogen Idec of Basel/Cambridge, Massachusetts, are under-going similar reformulation, due in part to the potential for mitigating severe adverse effects that can accompany rapid infusion. For exam-

ple, studies have indicated that subcutaneous injection of the anti-CD52 humanized rat mAb drug Campath (alemtuzumab) at lower doses may match the effectiveness of IV delivery for the treatment of chronic lymphocytic leuke-mia while diminishing costs and minimizing infusion-associated toxicity1,2, and several clinical trials are assessing this mode of therapy (Table 1, see Supplementary Table for more information). “I hear many biopharmaceuti-cal and pharmaceutical companies saying that their basic target product profile for antibodies in the future is to be subcutaneously deliver-able,” says Gregory Frost, CSO and cofounder of Halozyme Therapeutics.

Diverse methods exist for subcutaneous delivery of therapeutics, from basic pre-filled syringes to simple-to-use ‘pen’-style autoinjec-tors. However, reformulation can often pose a challenge, and there are no guarantees that an antibody that works well at infusion-scale volumes will maintain its efficacy when con-centrated 100-fold. “The solution has to be stable, and you have to retain the biological and biophysical properties of your drug,” explains Laurent Audoly, CSO at Pieris in Freising-Weihenstephan, Germany. “You may get aggre-gation, and that can ultimately result in the potential for immunogenicity, which is on the forefront of everybody’s mind with biologics.”

His is among a growing number of companies that are trying to bypass this and other delivery-associated issues by working with alternative proteins that mimic the strong specificity and affinity of antibodies but offer reduced size and improved stability, making them more suitable for concentration, dehydration and other manip-ulations. Some are based on natural immu-noglobulin frameworks, such as the variable chain–derived domain antibodies developed at Domantis (now part of GlaxoSmithKline, Brentford, UK) or the tiny and robust single-domain camel- and llama-derived antibod-ies being marketed as ‘nanobodies’ by Ghent, Belgium–based Ablynx. However, a wide range of engineered protein scaffolds are also making their way into the clinical pipeline, including Pieris’s anticalins or the DARPins produced by Molecular Partners in Zurich.

“All of these smaller, more stable proteins show some promise,” says Arne Skerra, a professor of biological chemistry at Germany’s Technische Universität München. “I think that in particular for those special routes of delivery…alternative scaffolds provide a clear advantage over con-ventional antibody fragments.” Many of these technologies are relatively unproven as thera-peutics—roughly a dozen ‘scaffold’ drugs are now in the clinical pipeline, but only Cambridge, Massachusetts–based Dyax’s Kalbitor (ecallant-ide), a 60-amino-acid peptide based on the first Kunitz domain of human lipoprotein-associated coagulation inhibitor D1, has been approved by the US Food & Drug Administration (FDA) to date. Nevertheless, such scaffolds demonstrate clear potential for delivering treatments to loca-tions where antibodies fear to tread; accordingly, many of these companies are engaged in high-profile partnerships with large pharmaceutical companies. “Scaffolds were identified as a pri-ority by the European Commission, and they have released a call for grants,” says Alain Beck, head of the department of physicochemistry at the Centre d’Immunologie Pierre Fabre in Saint-Julien-en-Genevois, France. “This is a good indication that it’s an important goal in Europe as well.”

On the other hand, Halozyme has developed a strategy that enables larger volumes of solu-tion to be safely and efficiently injected below the skin, making subcutaneous delivery a real-istic option for many mAbs. In this approach, mAbs are co-injected with a recombinant human hyaluronidase enzyme, rHuPH20, which transiently punches holes in the poly-saccharide matrix that surrounds skin cells and thereby allows rapid entry of even large pro-tein mol ecules. “Essentially, as fast as somebody can expel the contents of an antibody solution through the needle, the enzyme is working,” says Frost. “For many drugs, we’ve found that

An array of 36 dissolving microneedles, barely discernable to the touch, may soon be the way vaccinations are given. (Credit: Gary Meek, Georgia Tech)

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108 volume 29 number 2 FebruArY 2011 nature biotechnology

thermal ablation, which uses highly focused pulses of heat to selectively disrupt the skin, and iontophoresis, which uses electrical current to force drugs into the skin. However, some of the most promising work to date relies on micronee-dles that can pierce the skin with minimal dis-comfort. For example, ongoing clinical trials by Zosano Pharma in Fremont, California, have demonstrated the efficacy of patches featuring arrays of drug-coated microneedles for deliv-ering parathyroid hormone to patients with osteoporosis, and the company is currently testing the same approach in preclinical work with an undisclosed therapeutic mAb. “As far as the patient is concerned, it looks like a patch—if you have really good eyes or a magnifying glass, you might be able to see some microscopically small needles on there,” says Prausnitz. “When you press the patch against the skin, the coat-ing dissolves off, and then the needles can be removed and can be discarded.”

Even so, Prausnitz and colleagues have also made use of alternative materials that could make that last step unnecessary, construct-ing strong, sharp microneedles that dissolve shortly after penetrating the epidermis. In one recent study, Ajay Banga, chair of the depart-ment of pharmaceutical sciences at Mercer University in Atlanta, partnered with scientists at Pfizer to demonstrate that arrays of dissolv-ing maltose-based microneedles could be used to generate microchannels in rat epidermis that enable the subsequent entry of mAbs or other biologics3. “You can potentially add your drug to these dissolving microneedles,” says Banga. “The main limitation is that the amount you can put into the needle is very small; in a very big array of needles, you could probably only incorporate one milligram or so, which is okay for vaccines and some very potent molecules, but not for others.” In such cases, this limitation could potentially be overcome either through a two-stage treatment process, in which a drug is applied as a lotion or patch after the needles

feeling is that for the entire spectrum of anti-inflammatory antibodies, there’s not one of them that couldn’t be used topically or locally,” says Thomas Kindt, CSO at InNexus Biotechnology in Chandler, Arizona.

His company has developed a strategy called TransMab, in which single-chain mAb variable fragments (scFvs) are conjugated to a mem-brane transport sequence peptide that enables them to cross cell plasma membranes, but also facilitates scFv passage across the epider-mis. InNexus scientists recently generated one such molecule, IXSCD11a, which targets cell-adhesion molecule CD11a; according to Kindt, this target was chosen in an effort to develop a safer alternative to Raptiva (efalizumab), a mAb that effectively treats plaque psoriasis but was withdrawn by Genentech, of S. San Francisco, California, because it raised the risk of severe brain infection. “We’re just starting small animal experiments, but these small fragments clear very rapidly—with maybe a half-life of several hours—unlike an antibody that can have a half-life of twenty days,” says Kindt, “so you’re not going to see systemic immune suppression from topical use.” He suggests such a molecule could be ideal for a patch or lotion formulation.

On the other hand, this strategy also requires additional optimization to produce scFvs that are both therapeutically effective and sufficiently stable when fused to an membrane transport sequence, and other groups are looking for more universal strategies to facilitate the passage of large molecules through the skin’s outermost protective layer. “If you can make that barrier sufficiently permeable, you can apply a topi-cal formulation or patch on the surface of the skin so that the drug can diffuse into the body through the holes or defects that you’ve made,” explains Mark Prausnitz, professor of chemi-cal and biomedical engineering at the Georgia Institute of Technology in Atlanta.

Several technologically sophisticated methods have been demonstrated in this regard, including

the residence time in the skin is significantly decreased with rHuPH20, and that very large volumes can be administered without signifi-cant resistance from the tissue.” Initial phase 3 trial results with Herceptin have been prom-ising and Halozyme is looking to embark on similar phase 3 trials with Rituxan. “The tol-erability and the linearity of pharmacokinet-ics of Herceptin [with rHuPH20] is similar to Herceptin IV,” says Frost.

Missing the pointEven so, most subcutaneous strategies fail to avoid one issue: needles. “Needle phobia is actually not a trivial problem,” says Eva-Lotta Allan, chief business officer at Ablynx. “There are people who have to inject themselves or go to a general practitioner to get injected on a reg-ular basis, and a large number of these patients either have or develop a needle phobia.” Ablynx has found some success in preliminary animal studies using a needle-free solid dose injector device developed by Abingdon, UK–based Glide Pharma to deliver tiny pellets containing a variant of ALX-0681, a nanobody targeting von Willebrand factor in patients suffering from the blood clotting disorder thrombotic thrombocy-topenic purpura. “We’ve demonstrated that it’s perfectly possible to get the same pharmacoki-netic/pharmacodynamic profile through this needle-free delivery,” says Allan, although she adds that these were only feasibility studies and that this does not represent an active preclinical program.

Transdermal patches are already in wide-spread use for the straightforward, painless delivery of hormones and small-molecule drugs, and several researchers believe that similar tech-nologies could also provide a practical means for delivering biologics. Such methods might not only bolster patients’ willingness to take their medication, but could also enable targeted treatment of affected tissues without pumping excessive amounts of drugs into the body. “My

Table 1 Selected drugs in development using alternative deliverya

Company (location) Drug Condition Drug type Delivery Phase

Abbott ABT-874 (briakinumab) Psoriasis Human mAb (anti-IL12/23) subQ Awaiting fDA approval

novartis AIn457 (secukinumab) uveitis/psoriasis arthritis/Ms/rheumatoid arthritis

Human mAb (anti-IL17a) subQ Phase 3/2/2/2

Biogen Idec/Genentech/roche MabThera/rituxan Hodgkin’s lymphoma Chimeric mouse-human mAb (anti-CD20)

subQ Phase 3b

GlaxosmithKline/Genmab (Copenhagen)

Arzerra (ofatumumab) rheumatoid arthritis Human mAb (anti-CD20) subQ Phase 3b

roche Herceptin Breast cancer Humanized mouse mAb (anti-Her2)

subQ Phase 3b

roche Actemra/roActemra (tocilizumab)

rheumatoid arthritis Humanized mouse mAb (anti-IL6r)

subQ Phase 3b

subQ, subcutaneousaComplete table available online. bfDA approved for other delivery modes and/or indications.

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nature biotechnology volume 29 number 2 FebruArY 2011 109

the drug in the lung at the site of the infection, although we administer a lower dose than is required for a benchmark monoclonal antibody drug.” Anti-RSV prophylaxis is available but is generally only given to infants at high risk for exposure, and Ablynx suggests ALX-0171 could offer protection for the estimated 1.2 million children worldwide who need—but presently lack access to—safe and efficacious treatment for existing infection.

Hard targetsEarly progress aside, it is important to note that with the exception of subcutaneous delivery, none of these alternative modes of biologic drug delivery has formally entered the marketplace, and many kinks still remain to be sorted out. For example, even though these alternative drug delivery routes may bypass many adverse effects seen in conventional systemic administration, it is hard to predict the amount of immunogenic-ity associated with these less-well-established methods. “This is still one of the most chal-lenging questions because there are no models that reliably predict the potential, and unfortu-nately, we only figure it out once the molecule is in the human body in the safety studies,” says ESBATech’s Urech.

Several targets also remain difficult to reach, and the brain presents a particular challenge. Some mAb therapeutics appear to success-fully cross the blood-brain barrier (BBB) after infusion, such as bapineuzumab, the human-ized anti-β-amyloid mouse mAb being jointly developed by S. San Francisco, California–based JANSSEN Alzheimer Immunotherapy and Pfizer; however, the mechanism underlying this BBB penetration is poorly understood and appears to be a matter of happy accident rather than design. “In the mouse, there are a lot of interesting studies reported in the litera-ture about crossing the [BBB],” says the Centre d’Immunologie Pierre Fabre’s Beck, “But to my knowledge, the proof of concept has not been shown in man.”

From Skerra’s perspective, these early efforts are just the beginning of what promises to be a long and ongoing struggle to untangle the chal-lenges of safe and effective drug delivery. “There are now a number of biotech conferences that have whole sessions on this topic, but I would still describe this as a ‘high-hanging fruit’,” he says. “For each route of delivery and each pro-tein, one has to optimize and develop the sys-tem—it’s not a ‘plug-and-play’ technology.”

Michael Eisenstein, Brooklyn, New York

1. Cortelezzi, A. et al. Leukemia 23, 2027–2033 (2009).2. stilgenbauer, s. et al. J. Clin. Oncol. 27, 3994–4001

(2009).3. Li, G. et al. Int. J. Pharm. 368, 109–115 (2009).4. Ottiger, M. et al. Invest. Ophthalmol. Vis. Sci. 50, 779–

786 (2009).

transition effectively to topical delivery in the future. “Your typical wet AMD patient is in their seventies or eighties, and they’re actually happy to go to a doctor to get treatment,” he says. “But as you move into treating a more active popu-lation in their forties, fifties or sixties, then the eye drops will probably be a more successful product in the long run.” Even Avastin may have potential as a topical treatment for some conditions, and researchers at the Walter Reed Army Medical Center in Washington, DC are now testing such applications.

Second wind for inhaled therapeuticsPfizer’s 2007 withdrawal of their inhalable insulin formulation Exubera due to poor sales—resulting in an estimated loss of $2.8 bil-lion—left the industry shaken, and several other companies subsequently abandoned their own efforts at developing inhaled protein therapeu-tics. Nevertheless, many still see this as another promising delivery route, especially for disor-ders such as asthma and chronic obstructive pulmonary disease. “I would say that for larger molecules, inhalation is one of the most promis-ing routes,” says Banga. “I think the technology is good—it’s just that maybe they didn’t pick the right product for the first launch.”

“Pulmonary is easy to achieve as you can directly address the lung just by aerosol for-mation,” adds Technische Universität’s Skerra. “There’s not much of a barrier in the lung epi-thelium, and if you look for transmission of a protein through this cell layer, it probably just depends on the size of the protein—the smaller it is, the easier it can penetrate.” In this regard, scaffold proteins have a clear advantage over traditional mAbs and mAb derivatives, and Pieris and Domantis/GSK both have thera-peutic scaffold proteins in development for the treatment of respiratory conditions, although both drugs are in the preclinical phase and these companies are only disclosing limited details about their compounds at this time. “We’ve already got data showing that anticalins are compatible with inhaled formulations—and we have preclinical in vivo data support-ing moving forward with this approach,” says Pieris’s Audoly. “At this point, we’re looking at being able to get into the clinic in the next 18 to 24 months.”

Ablynx is going after a more unconventional target with ALX-0171, a trivalent nanobody drug that can be delivered by nebulizer to neutralize the respiratory syncytial virus (RSV), a pathogen that is among the leading causes of respiratory illness in both young children and the elderly. “Our RSV program is currently on track to file an IND [investigational new drug application] and start phase 1 in 2011,” says Allan. “We have shown that we can get a higher concentration of

have punctured the skin, or by employing hol-low microneedles that enable active delivery of larger drug volumes. “I think the skin is a par-ticularly powerful portal for entry into the body,” says Prausnitz. “It is our outer surface, which is incredibly easy to access—you can put some-thing onto the skin, leave it there and, when you’re ready, take it off.”

Keeping your target on the eyeIn other cases, even more selective therapeutic delivery is desirable. “For most antibodies, it doesn’t matter that the drug is coursing around your entire body,” says GSK’s Tomlinson. “But what’s the point of having a mAb coursing around your entire body if in fact you only need it to be in the eye?” Localized treatment for ocu-lar diseases such as age-related macular degen-eration (AMD) with existing drugs, such as the humanized mouse mAb Avastin (bevacizumab) or its smaller derivative Lucentis (ranibizumab), entails a relatively unpleasant procedure—direct injection into the vitreous fluid of the eye once a month.

Accordingly, alternative therapeutics are now emerging that enable topical delivery to the sur-face of the eye. For example, ESBATech, recently acquired by Hünenberg, Switzerland–based Alcon, has published some promising results demonstrating that its scFv drug ESBA105, which targets tumor necrosis factor-α (TNFα), can achieve efficient ocular penetration when applied in eye-drop form4, and the company is currently recruiting patients with uveitis for a phase 2 clinical trial. Based on the present data, ESBATech’s head of research and preclini-cal development David Urech suggests that ESBA105 will compete in this arena against existing TNF inhibitors, which are better suited for systemic administration against autoimmune disorders. “For uveitis…it’s believed that locally elevated TNFα concentrations are driving dis-ease, and in such a setting the safety profile of marketed TNF inhibitors would in many cases not justify their use,” he says. “You would prefer a fragment that could be locally applied but gen-erates only very low systemic exposure.”

Several other drug candidates are gunning for the same target as Lucentis and Avastin, the cell signaling molecule vascular endothelial growth factor (VEGF). One of these, IXS312, was designed by InNexus using the same TransMab technology as their anti-CD11a scFv, although this compound is still in the early in vivo testing stage. On the other hand, Molecular Partners is nearing completion of phase 1 clinical trials for both wet AMD and diabetic macular edema with its VEGF-targeting DARPin, MP0112. These studies are assessing delivery by intra-vitreal injection, but Molecular Partners’ CSO Michael Stumpp anticipates that DARPins will

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