Pharm Exec's 2017 Pipeline Report

December 7, 2016

Pharmaceutical Executive

Volume 36, Issue 11

The industry is readying for a leap into a new age of complex therapies, as new heights are reached in fields such as regenerative cell-based therapies, CAR-T and immuno-oncology combinations. Elaborate manufacturing and soaring drug costs, however, loom as deep chasms to cross in bridging the potential with reality.

The industry is readying for a leap into a new age of complex therapies, as major advances seem mere steps away from market approval. Regenerative cell-based therapies, CAR-T and immuno-oncology combinations are just some of the fields where researchers are reaching for new heights that could alter the treatment paradigm. Elaborate manufacturing and rising drug costs, however, loom as deep chasms to cross.

 

As researchers blaze the meandering and thorny path toward curative treatments, a clearing is visible on the horizon. But to get there, the industry must confront a daunting chasm-making the previous generation’s small molecule-to-antibody transition look like an easy stride across a tame stream.

Much focus is on the industry’s neck-and-neck race to market the first chimeric antigen receptor T-cell (CAR-T) therapy. The race is full of drama, pitting western biotech regional hubs with big science, big personalities and big dollars, not to mention the theatre that goes with medical experimentation swinging from the triumph of high  rates to trial missteps and deaths.

The first company across will get a certain placard, but as there will be additional finish lines in other indications, sustained growth will be closely monitored as the opposing technologies come into direct competition in subsequent approvals. And as the companies progress their therapies into more and more cancer types, the challenges of consistently scaling up these complex therapies, which engineer individual patients’ cells, will be a noteworthy test.

When questioned on CAR-T, many a seasoned industry veteran will utter the cautionary word, Provenge. Dendreon, now owned by Valeant, gained approval for the autologous cell therapy treating castrate-resistant (hormone-refractory) prostate cancer in 2010 but by mid-2011, was well off the pace expected by analysts and their sales projections. Manufacturing woes were the primary culprit, as most experts recall the challenges faced to turn a profit for the complex, personalized therapy. The $93,000 price tag resulted in reimbursement headwinds, but as Susan Schaeffer wrote for BioCentury in August 2011, resolving “manufacturing constraints” to some degree masked a slow uptake that was largely due to “cost density” and its impact on cash flow at oncology practices that might consider prescribing the novel treatment. Physicians were reluctant to foot the large dollar amount that impacted the bottom lines of their clinics, which were built upon reimbursing chemotherapy agents infused over months, rather than a 4-6 week time frame.

Doubts around efficacy and value, considering the price point, continue to hold Provenge out of any blockbuster lists, though Valeant has tried to bolster sales. Assuming beneficial clinical impact can be sustained through the next series of pivotal trials, CAR-T manufacturers, along with their patient support, payment structures and distribution networks, must take heed to the cautionary tale and the lessons learned regarding both manufacturing complexity and market access as their pipeline products approach real-world practice.

CAR-T cutting it close

In the industry’s great race-that’s not really a race-Kite Pharma, which lists four pivotal studies for KTE-C19, believes it will have sufficient data from its interim look at the ZUMA-1 trial in an aggressive form of Non-Hodgkin lymphoma (NHL) called diffuse large B-cell lymphoma (DLBCL). If FDA agrees that the impressive early results, 76% objective response rate and 47% complete remissions, both highly statistically significant, are adequate, then a filing late this year could bring the first CAR-T therapy to market in 2017.

Santa Monica-based Kite is talking “launch readiness,” but FDA could want to see the durability of the results beyond the three-month measures published in September. Interim results represented 51 patients, and the trial is still enrolling, targeting 124 patients in total with a primary final completion date next March. Investors, along with Kite, hope that the aggressive nature of the disease and the unmet need that KTE-C19 might impact will encourage FDA to look past the preliminary nature of the figures.

The ZUMA suite of trials includes an alphabet soup of B-cell malignancies. ZUMA-1 will also add data from patients struck by follicular lymphoma (TFL) and primary mediastinal B-cell lymphoma (PMBCL). ZUMA-2, also in Phase II, is enrolling 70 patients with relapsed/refractory mantle cell lymphoma (MCL) while ZUMA 3 and 4 are enrolling acute lymphoblastic leukemia (ALL) patients, adults and pediatrics, respectively.

One reason for the distinct leg-up that Kite now enjoys was this summer’s brief but serious clinical hold for deadly cerebral edemas in Juno Therapeutics’ 90-patient trial testing its JCAR015 in advanced ALL. With confidence that the fatalities were due to a heightened dose of chemotherapy agent fludarabine, used to precondition patients prior to CAR-T dosing, Juno’s trials are now back on track, and some believe that with the greater risk, could come greater reward. Juno’s 82% Phase I clinical response impressed many. Seattle-headquartered Juno had a similar timeline to Kite, though a September presentation identifies  the first half of 2018 for JCAR015’s market entry. The company includes follow-up configurations of its CD19 targeting approach, including JCAR017, as essential to its strategy, which it believes will become best in class and could also reach market in 2018. Some analysts see JCAR017 as the greater prospect, with peak sales that could reach $2 billion annually. Sales projections for the entire class of CAR-T therapies vary greatly and are typically guarded with large disclaimers of 50% and lower likelihood of success for each asset to make it to the market.

Both Kite and Juno possess deep pipelines trying seemingly, every hematologic malignancy under the sun. Further out, CAR-T and adjacent innovations may enter the solid tumor treatment arena. Kite’s T-cell receptor treatment option, MAGE A3/A6, is listed in Phase II in solid tumors, while Juno’s JCTR016, targeting WT1-expressing non-small cell lung cancer and mesothelioma is being tested in a Phase I/II study, now recruiting.

After the Juno trial’s fatalities occurred, an additional blow to the field’s bulls came this summer when Novartis announced it was dissolving its 400-member cell and gene therapy unit. The phrase “re-integrate” had many doubting, and the big Swiss biopharma reassuring its commitment to CAR-T and its lead candidate in relapsed/refractory ALL, CTL019, which is in Phase II. Novartis intends to submit its CAR-T therapy for regulatory approval in 2017 in the US and Europe. The restructuring meant letting 120

of the unit’s 400 employees go, but Novartis will continue to use the 173,000-square-foot New Jersey plant that it bought from Dendron in 2012 in hopes of scaling up its cell therapy. Many will continue to question Novartis’ commitment to the field and where CAR-T fits into its overall strategy without a set-aside unit. Novartis’s prestigious collaboration with UPenn remains intact, however, lending some credence.

Questions of Novartis’s commitment not withstanding, biotech and pharma partners have lent their bona fides to the field through partnerships with Juno and Kite. Juno counts on its key backing with Celgene, and Kite lists Amgen, bluebird bio and Genentech. Pfizer and Servier also have footprints in the field through their work on Cellectis’ UCART19. Cellectis joined the CAR-T initial public offering circus in 2015 with $228 million. Servier is sponsoring the current Phase I trial in pediatric B-cell ALL, which launched in June. If successful, UCART19 could differentiate from other CAR-T therapies as allogeneic, rather than autologous. A frozen, “off-the-shelf” cell product could have significant upside for Servier, and Pfizer who would capture US market rights.

Finally, Houston-based Bellicum, which also joined in on the Wall Street CAR-T craze with a $140 million initial public offering in December 2014, has its eyes set on solid cancer. Its GoCAR-T product, BPX-601, characterized by the ability to turn on or off by a co-stimulatory activation switch, will be tried in pancreatic cancer, with a Phase I trial planned to launch by year-end.

As we yearn for simple solutions for cancer, the rise of highly complex treatments like these CAR-T prospects informs clearly that there are no silver bullets. The more we’ve learned about cancer, the more complex the molecular profiles have proven to be. And as large classifications are parsed until we’re left with only rare and orphan subpopulations, the phantasm of a sole shadowy entity representing the whole of “cancer” is something even government moonshots should concede as comically simplistic.

 

 

Combos, to name a few

Developments in the arena of CAR-T therapy indicate the trajectory for treatment will be highly complex, technically challenging, and largely personalized. The other undeniable trend, which is largely complementary, is a greater emphasis on combinatorial cocktail regimens. The immune-oncology (IO) model of removing a checkpoint inhibitor to unleash the body’s own immune system, which is seeing much success in monotherapy settings, leaves far too many patients inadequately treated. The next step will be to further recognize and diagnose the great complexity at play, and to logically, and in a

coordinated fashion, release multiple brakes holding the immune system back. These approaches will combine two or more IO therapies in an additive, or even multiplicative manner. In addition, others will combine IO therapies with more traditional targeted therapies, or with chemotherapy regimens, or even with CAR-T treatments.

How to pay for these combinatorial therapies, should they prove efficacious, will be left to another article a year or two from now, but proving their clinical merit is a step companies are working out now. The therapies represent expensive materials going into trials, and willing patients are the most valuable resource, so determining the most logical pairing of therapies will be a crucial, as not to stab wastefully at every conceivable permutation. Drug developers now face the challenge of deciphering in which cancer types and in which patients does a combination make the most sense from our understanding of the mechanisms of action.

Fortunately for Bristol-Myers Squibb, its two approved IO therapies have complementary mechanisms. Opdivo plus Yervoy earned FDA’s acceptance as the first IO combination in patients with BRAF V600 wild-type unresectable or metastatic melanoma in 2015, then added patients to its label with the clause, regardless of BRAF mutational status, in 2016.

Giving the IO field context, the most dramatic industry disruption in 2016 may have been the defeat felt by BMS and its PD-1 inhibitor (notably this magazine’s 2016 Brand of the Year) in first-line NSCLC. The field is now recalibrating Opdivo’s position in relation to the climb of Keytruda from Merck & Co., and the role of the diagnostics that take into account the levels of tumor PD-L1 biomarker. Both companies, joined by Roche/Genentech with its approved PD-L1 inhibitor Tecentriq, will continue to jockey for position in the monotherapy setting, but are also aggressively looking to expand on the PD-1/PD-L1 inhibitor literature with combination trials. And, rest assured, there will be reams of articles with at least 20 experimental PD-1 or PD-L1 targeting candidates in over 800 clinical trials.

A PD-1 backbone?

Some industry critics lament the lack of creativity or adventurousness in the industry given that so many feel the need to walk down the same PD-1 or PD-L1 path as others. But regardless of whether there are three or 23 therapies with the same or similar targets, the accepted belief, with analysts’ sales forecasts in agreement, is that the pathway will be one of the foundations of IO combinations. For others positioning themselves in the field, competing on the monotherapy market may be in the cards, but they also may be trying to position themselves in the combination space, where they would rather not have to pay rent to one of the firms with an approved entity.

BMS’s message to placate its investors at the European Society of Medical Oncology conference last month, in light of its recent rout, was clear. Combinations are BMS’s future and Opdivo is the “backbone.” The presentation listed ongoing Phase III trials testing Opdivo and Yervoy in SCLC, NSCLC, renal cell carcinoma and head and neck cancer, all for first-line treatment. The company promises over a dozen data readouts for the combo in various clinical settings from now through 2018. In addition, BMS is testing Opdivo combined with Empliciti, being co-developed with AbbVie, in a Phase III trial in multiple myeloma.

The Opdivo-as-the-backbone approach also highlights combination attempts with platinum-based doublet chemotherapy (PT-DC), existing targeted therapies like Avastin and novel mechanisms of action. Merck also has clear combination strategies building on its recent successes, pairing Keytruda with carboplatin and pemetrexed chemotherapy in non-squamous NSCLC and VEGF receptor 2 antagonist, ramucirumab, through a partnership with Lilly.

Also in lung cancer, BMS will see Opdivo paired with CV301, a cancer vaccines made by Danish company Bavarian Nordic, which it announced in August. The two companies have an encompassing clinical partnership that could reach $ 1 billion in value, adding Bavarian Nordic’s cancer vaccines to BMS’s IO agents. The two earlier announced a trial pairing BMS’s Yervoy with Prostvac in early prostate cancer.

The partnership is one of several IO/cancer vaccine agreements. AstraZeneca has a deal to try its PD-L1 inhibitor durvalumab with TapImmune’s vaccine technology, TPIV 200, a multi-epitope anti-folate receptor vaccine, in patients with platinum-resistant ovarian cancer. And announced last month, Pfizer and Merck KGaA, who have an agreement to co-develop and co-commercialize anti-PD-L1 avelumab, will study the drug in combination with a cancer vaccine made by Transgene, TG4001, in patients with HPV-positive head and neck cancers in a Phase I/II study.

The CAR-T companies will also play in the combination IO space. Kite lists as one of its 2016 milestones, to launch a Phase Ib/II trial pairing KTE-C19 and Genentech’s Tecentriq in aggressive NHL. A Phase I/II study for the pair in refractory DLBCL is listed as actively recruiting patients. Juno has plans to combo its JCAR014 CD19 CAR-T cells and signed a deal with AstraZeneca/MedImmune to pair its PD-L1 inhibitor, durvalumab, in 2015, also in NHL.

 

 

An intriguing path could be one offering a bridge over some of the complexity brought about by combining potent IO agents. Lexington, Mass.-based Curis hopes to add another agent to the crowded PD-1/PD-L1 space, but with the key differentiating profile of an oral small molecule. In collaboration with Aurigene, Curis is testing CA-170, a first-in-class oral, small molecule antagonist that targets PD-L1 and VISTA and could prove to be a potent T-cell suppressor. The agent is in an early Phase I study, but the simpler manufacturing, and more malleable dosing thanks to its shorter systemic half-life, could prove it to be a beneficial ingredient in a cocktail approach. The company expects early data to be available in 2017.

The role of data cannot be understated when looking at the oncology pipeline in all its complexity-from deciphering which combinations are suitable, diagnosing and parsing patient populations, to sequencing thousands more patients to elucidate additional targets. The entry of genomics players like 23andMe, Sema4, Human Longevity, NantHealth and Google’s Verily will certainly reshape the field.

Targeted therapy: Is that still a thing?

Meanwhile, there are several oncology targets that seem to resemble drug development in relatively “traditional” biopharma. Pfizer’s CDK4/6 inhibitor Ibrance, which sits alone in HR+, HER2- breast cancer, will be joined by Novartis’ ribociclib and Lilly’s abemaciclib. Lilly had a lead, but some believe Novartis is closing the gap. In recent developments, ribociclib had a trial halt thanks to strong interim data. This matched a positive data clinical halt that Ibrance saw in Phase III, but abemaciclib’s monitoring committee did not make the same decision after looking at the Lilly trial’s interim data. The result for Pfizer means the market is all Ibrance until probable launches in 2018. Analysts position the two up and comers to earn close to $900 million in 2020, with Ibrance well ahead at $5.6 billion by then.

Another set of assets inspiring major stock market swings are the PARP inhibitors, a class presumed lifeless a few years ago. AstraZeneca’s Lynparza gained approval in 2014 for BRCA+ ovarian cancer patients and has Phase III trials in multiple breast and prostate cancers. The expanded indications would be key should the drug reach its $2 billion projections. Tesaro’s niraparib blew analysts away earlier this year and followed up with results in October showing excellent data for both BRCA+ and BRCA- patients, leading many to envision a broader label for the Waltham, Mass.-based firm. J&J owns the prostate cancer rights to niraparib with a $500 million deal.

Pfizer purchased Medivation in September for $14 billion in part to gain its PARP inhibitor, talazoparib, which has similar levels of excitement as Tesaro’s. And AbbVie’s veliparib could take a substantial piece of the PARP pie if it makes its entry in triple-negative breast cancer. AbbVie said clinical trial data is likely in 2017.

The PARP class, however, has been a difficult one, exhibited by Clovis Oncology’s swings. The company’s stock is down substantially in 2016, mostly due to the failure of its EGFR inhibitor rociletinib, and it hopes to stay afloat with a new focus on PARP inhibitor rucaparib. Clovis announced that FDA had accepted its submission with accelerated approval and a potential approval date in BRCA+ ovarian cancer in February 2017.

PARP inhibitors are seen as maintenance drugs, which inhibit tumor repair and growth after chemotherapy has done its best to kill malignant cells. Some analysts forecast a market for PARP inhibitors as large as $30 billion.

NASH players

Several other disease areas that have gone untreated or undertreated will likely see new monotherapies hitting the market, but because of their complexity, cocktail approaches will not be far behind. Perhaps the next hottest area in biopharma drug development is nonalcoholic steatohepatitis (NASH), a diseased believed by many to be underdiagnosed and that could affect 2-5% of Americans. Most patients do not feel sick, though they can progress to cirrhosis and liver failure, even though they drink little to no alcohol.

With notable failures in  industry efforts to reach the obesity market with deliverable pills or injections, many see NASH as an inroad to overweight patients who currently are relegated to the standard prescription of better diet and exercise. A growing market as long as adipose trends continue, equates to a market size that is highly debated and perhaps in the $20 billion range should

drugs become available. A Gilead Sciences press release notes that the leading cause for liver transplantation by 2020 is expected to be NASH-related cirrhosis, hinting at the systemic benefit of advancing therapies.

In September, Allergan made the headlines in the space with the purchase of Tobira Therapetuics for $1.7 billion and Akarna Therapeutics for $50 million upfront and milestones. Tobira brings Allergan its Phase III-ready cenicriviroc (CVC), a dual inhibitor of the CCR2 and CCR5 pathways, which are involved in fibrosis and inflammation. With the Akarna purchase, Allergan gets farnesoid X receptor (FXR) agonist AKN-083, which could see first attempts in humans in 2017.

The other big player in NASH is Gilead, building off its general position as a leader in liver diseases. Gilead’s pipeline in NASH is substantial, with five assets. Its lead therapy, monoclonal antibody simtuzumab, is aimed at lysyl oxidase-like-2 (LOXL2), an extracellular matrix enzyme. Simtuzumab is in Phase II for NASH and primary sclerosing cholangitis, with top-line safety data expected by year-end.

 Also in Gilead’s Phase II NASH pipeline is a small molecule inhibitor of apoptosis signal-regulating kinase 1 (ASK1), GS-4997, for which it announced top-line results last month. Phase II results have the company ready for Phase III, pending regulatory discussion. A look at simtuzumab and GS-4997 alone, and in combination, could be the way forward as Gilead readies for its Phase III campaign.

Intercept Pharmaceuticals may be the most advanced company in the space, with Phase III obeticholic acid, which was already approved in 2016 as Ocaliva for primary biliary cirrhosis. Thompson Reuters pins the drug as a potential top performer, with sales estimates to reach $2.6 billion in 2020.

Genfit’s elafibranor is also in Phase III; the RESOLVE-IT trial launched in March. And until recently, a NASH forecast could have ranked Galectin Therapeutics toward the top with its candidate, GR-MD-02. But recent Phase IIa data have investors highly doubtful for its prospects moving forward.


UPDATE: Reports from early November have Gilead rethinking it’s NASH pipeline. With mixed Phase II results, the company is said to be quietly dropping its two leading NASH assets, selonsertib (GS-4997) and GS-6624 (simtuzumab). Time will tell how this will alter its leading position in the space, but clearly, the unknowns of developing drugs in a relatively untouched disease arena are many.
 

 

State of Alzheimer’s

The most anticipated upcoming data dump across the entire industry could be for Eli Lilly’s solanezumab in Alzheimer’s disease (AD). An announcement in March had many backers shaking at the knees, bringing the stock down 8%. The Indianapolis-based pharma stated that it would be shifting from a co-primary endpoint, looking at both a cognitive assessment, the ADAS-Cog14 (Alzheimer’s Disease Assessment Scale-Cognitive subscale) and a functional test, ADCS-iADL (Alzheimer’s Disease Cooperative Study-Instrumental Activities of Daily Living) to a single primary endpoint, i.e., cognition only.

The initial drop and investor read on the situation was that Lilly lacked confidence, practically admitting to failure. The company assured its supporters that it has not seen the data, and more importantly, as nothing with the conduct of the trial itself would change, the new protocol simply reflects a common agreement among those in the field, that cognitive decline precedes functional losses-thus the more appropriate endpoint.

From a betting standpoint, attaining one endpoint gives better odds than a dual endpoint parlay. And perhaps the Lilly team is banking on the sense of panic in the industry, not to mention a similar sense of urgency from regulators and society at large-the baby boomer crunch on the system looms. A positive event, a drug approval that could offer even a semblance of disease modification, might merit a ticker tape parade.

So why a higher hurdle of two endpoints when one might do? A headline saying “Primary Endpoint Acheived” reads much better than “Trial Results Split Co-Primary Endpoints.” Look for an announcement from Lilly in December. Forbesreported in August that Lilly’s teams are already adjusting their holiday travel schedules. Certainly employees have the option to carry days over into 2017, but an approval would have them awfully busy for years to come.

Results from the 2,000-patient EXPEDITION3 trial are expected around year-end. A positive readout, and approval, could make solanezumab the first amyloid beta-targeting monoclonal antibody to market, a sizable bazaar indeed with 5.4 million and growing desperate patients. Analysts project $5 billion in sales estimates with ease, and depending on how the market shapes up, $20 billion and upwards could be split between Lilly and its potential competitor, Biogen, with aducanumab.

Biogen did its part to excite the public with new data and headlines this summer reading “High hopes: new drug could be a ‘game changer’ against long-incurable Alzheimer’s.” But the industry, and the biopharma investment community, has been down this road many times with AD “breakthroughs.” Biogen did earn fast-track designation from FDA in September, and it is in the midst of two global Phase III studies, ENGAGE and EMERGE, which are slated for primary endpoint completion in 2020. Expect more headlines from aducanumab before then, but its biggest near-term catalyst will likely be the fallout from solanezumab data.

Roche also maintains a Phase III program for it’s amyloid beta-seeking antibody, gantenerumab. The drug was rescued from certain demise, and with an upped dose, the company is running a Phase II/III study and two Phase III trials with gantenerumab.

The AD pipeline’s next class of hopefuls are the BACE inhibitors, which take their action upstream of amyloid beta, though would still be considered as acting upon the amyloid hypothesis of AD disease causation. Lilly is also active in the BACE space, with its AstraZeneca-partnered AZD3293 (which Lilly had been referring to as LY3314814). The companies trumpeted an FDA fast-track designation in August. The duo will continue its Phase II/III trial, AMARANTH, and initiated enrollment of the Phase III DAYBREAK-ALZ study. Also in Phase III is Merck BACE inhibitor MK-8931, and CNP520, the Amgen/Novartis-partnered Phase II/III product. The pair announced the neuroscience collaboration in the fall of 2015, with sights set on AD as well as a migraine portfolio.

Several small players continue to perform at the margins of the AD drug development zeitgeist. Anavex Life Sciences took a boost in September when Biogen expressed a modicum of interest for its Phase II ANAVEX 2-73, the oral candidate targeting sigma-1 and muscarinic receptors. Biogen agreed to have a look under the hood of the molecule in a cell-based assay, which could lead to a remyelination study and further collaboration or partnership.

Axovant, lead by its 30-something-year-old CEO, is rocketing its candidate through development. The company plans to produce data for intepirdine, which it took off a dusty shelf at GlaxoSmithKline for $5 million, from the Phase III MINDSET study, with a new drug application filing soon after, in 2017. The company also has Phase II efforts for intepirdine, testing it for gains in gait and balance impairments in dementia, and visual hallucinations in Lewy body dementia.

Axovant’s intepirdine and other AD, and AD-associated efforts, like AC-1204 from Accera, a dietary approach aiming for FDA’s acknowledgement with Phase III efforts ongoing, hint at a future with multiple approved products on the market, some disease modifying and others targeting symptom alleviation. AD and other complex neurological disorders that strike at different ages, with  varied symptoms and rates of progression are, like oncology, another arena for therapies and treatment regiments to grow with exponential complexity.

Moving fast in Zika

Battling infectious diseases is another confounding and dynamic field. Not long ago, the media was asking medical experts about tragic cases of microcephaly, but there were few answers. The Zika virus was suspected as a culprit, but the long known, little researched flavivirus has rocketed into prominence as one of the industry’s top priorities. The Olympics held in Rio de Janeiro seemed to go off with minimal impact, but a steady march north, with Puerto Rico and Miami experiencing outbreaks, means the US and other major nations must now do more than issue travel warnings.

 

 

The NIH hit the clinic with its DNA vaccine, VRC-ZKADNA085-00-VP, and Phase I safety and immunogenicity data are expected by January. NIH was second to the clinic, following Inovio’s DNA vaccine GLS-5700. In June, Inovio started its first 40-patient trial at three sites in the US and  shortly after launched the second trial, which will recruit 80 patients in Puerto Rico.

Hyderabad, India-based Bharat Biotech claimed the first vaccine candidate for Zika, its inactivated vaccine, Zikavac in February. The company is ready and

waiting for Indian authorities to give it the nod to initiate trials; it plans a Phase I study in 100 volunteers, according to recent reports.

Other players expected to enter the fray with Zika virus candidates include large, traditional vaccine players like Sanofi and GSK, as well as some new to the vaccine game, like Takeda who announced its Zika plan, which includes up to $312 million from BARDA, the US government’s Biomedical Advanced Research and Development Authority. France’s Sanofi is also working with the US government, in a deal with the Walter Reed Army Institute of Research, to develop its Zika purified inactivated virus (ZPIV), which could have its first trials in humans this fall.

Inovio’s CEO told Reuters that Zika could represent a $1 billion market, largely because of its impact on American travelers and the effect on desirable geographic destinations. The nature of the market could lend itself to up-and-coming vaccine developer, PaxVax, with its socially responsible mandate to market traveler-oriented vaccines, bringing capital and resources to underserved, and overlooked markets in the developing world. In October, PaxVax announced the availability of its vaccine, Vaxchora, which offers cholera protection to US citizens who might travel to impacted regions like Haiti. PaxVax told Pharm Exec in March that the company was in the early stages applying its proprietary technology from dengue fever research to early stage Zika research.

An eye on complexity

Ophthalmology is another field that may add a level of complexity to the treatment regimen. The established VEGF-inhibitors, Lucentis, Eylea and off-label Avastin have been stalwarts for their manufacturers, Regeneron/Bayer and Genentech/Novartis. Back-of-the-eye specialists swear by these drugs and their ability to stave of blindness caused by wet age-related macular degeneration (AMD). But recurring with the theme, many patients are underserved and progress toward blindness in spite of the largely effective monotherapy treatments. Adding tools, with new mechanisms of action, and attacking the disease with cocktails of molecular actors is the clear path forward. In addition to impeding the visual degradation, eye drug developers aim to develop longer-acting treatments, hoping for a superior product that removes some of the burden felt by their aging population, by permitting equal

efficacy with less frequent doctor visits and fewer intravitreal injections.

Ophthotech has blazed the path with its wet AMD candidate, Fovista, a PDGF inhibitor. Phase III results for its trial combining Fovista with Lucentis are expected before the end of the year. Results for its Phase III trials pairing Fovista with Eylea and Avastin will follow. Phase IIb trials adding Fovista to Lucentis were impressive, with patients gaining 10.6 letters of visual acuity compared to 6.5 of Lucentis alone. Solid results toward the end of 2016 could lead to approval in 2017, with a label for the pairing with Lucentis, and additional Phase III data could allow expansion with Eylea and Avastin added to the label. Given the large sales numbers produced by the VEGF inhibitors on the market, another product of an aging population, some analysts project that Fovista could peak at $2 billion to 3.5 billion in sales.

The bulls backing Ophthotech experienced some dread this year, however, when Regeneron dropped its VEGF/PDGF combination therapy data. The biotech saw a Phase II failure for its version, rinucumab paired with Eylea, and will shift to combination efforts to anti-angiopoietin-2 nesvacumab, for which it expects Phase II results in 2017. The company noted that preclinical data for nesvacumab were more supportive of a Phase III combination effort anyways.

The verdict: A pipeline of puzzles

Viewing a smattering of assets in the industry’s pipeline, across oncology and in into several disease areas, some common elements emerge, and it’s not a simple picture. As researchers look to conquer difficult diseases, they are bumping into multivariate impacts like aging and lifestyle on the macro level, and intricate cellular systems and molecular pathways on the micro level. Scientists are pursuing complex answers for these convoluted systems. Time-and big data-will tell which solutions will help patients. It will require another Herculean effort to bring these treatments to patients, giving their complex manufacturing requirements, as well as the other challenges of our tangled healthcare systems.

 

Casey McDonald is Pharm Exec’s Senior Editor. He can be reached at casey.mcdonald@ubm.com

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