The annual meeting of the American Society of Hematology (ASH) in early December serves as the traditional curtain closer for the year's clinical development efforts. In 2015, it's fair to say, the FDA upstaged the ASH bash by approving a bevy of important drugs targeting blood disorders – many of them just weeks before the meeting.

The multiple myeloma (MM) space, alone, saw a half dozen FDA nods, including several drugs viewed as potential game-changers. At the fulcrum of those approvals was Revlimid (lenalidomide), the star performer for Summit, N.J.-based Celgene Corp., which accounted for $5 billion in 2014 sales and in February earned approval in newly diagnosed MM patients. (See BioWorld Today, Jan. 13, 2015.)

The same month, Novartis AG gained conditional FDA approval for Farydak (panobinostat), the first histone deacetylase, or HDAC, inhibitor approved to treat MM, despite a dicey advisory committee meeting. The Basel, Switzerland-based pharma originally sought to market Farydak in combination with Velcade (bortezomib, Takeda Oncology Co.) and the corticosteroid dexamethasone after MM patients had received at least one prior therapy, but the FDA's Oncologic Drugs Advisory Committee withheld support for that indication.

Instead, a pre-specified subgroup analysis reported after the committee's meeting helped Novartis to convince the agency to approve Farydak for MM patients who previously received at least two standard therapies, including Velcade and an immunomodulatory drug, such as Pomalyst (pomalidomide, Celgene Corp.) and Revlimid. Not surprisingly, Farydak didn't arrive with huge market expectations; 2020 global sales are projected to be just $240 million, according to Cortellis Competitive Intelligence. (See BioWorld Today, Feb. 25, 2015.)

Most of the other MM drugs green-lighted this year gained approval in combination with Revlimid and dexamethasone. Kyprolis (carfilzomib, Amgen Inc.), for example, which in 2012 won accelerated approval for then-developer Onyx Pharmaceuticals Inc. as a third-line MM treatment, was expanded in July to treat patients with relapsed MM who received at least one prior therapy. Full approval seemed all but assured after Amgen, of Thousand Oaks, Calif., reported stellar interim phase III data roughly a year after its $10.4 billion pick-up of Onyx. (See BioWorld Today, Aug. 27, 2013, and Aug. 5, 2014.)

'We now eagerly await feedback from clinicians'

But MM watchers are especially pumped about a trio of drugs green-lighted in November. The FDA gave a swift nod to Ninlaro (ixazomib), also for use with Revlimid and dexamethasone. Developed by Takeda, of Osaka, Japan, the oral proteasome inhibitor (PI) is expected eventually to replace blockbuster Velcade, which is set to lose patent protection later this decade. (See BioWorld Today, Nov. 23, 2015.)

Ninlaro wasn't the first PI on the block, since it will compete with the older-generation Velcade as well as Kyprolis, but its once-weekly, oral administration is expected to be an advantage. The drug could quickly usurp Velcade – which achieved about $1.6 billion in 2014 sales, according to Cortellis – with projected 2020 global sales of approximately $1.3 billion.

Empliciti (elotuzumab), from New York-based Bristol-Myers Squibb Co. (BMS), also gained approval in combination with Revlimid and dex. The anti-CS1 humanized monoclonal antibody was developed by PDL Biopharma Inc., of Redwood City, Calif., which in 2008 inked a potential $1.16 billion deal with BMS that included the compound. (See BioWorld Today, Aug. 21, 2008.)

Empliciti is expected to generate some $1.36 billion in global sales by 2020, according to Cortellis.

The lone exception in November to the combo approvals in MM was Darzalex (daratumumab), which gained accelerated approval almost four months ahead of its PDUFA date of March 9, 2016, and just two months after the FDA accepted the biologics license application for priority review. Developed by Genmab A/S, of Copenhagen, Denmark, the anti-CD38 antibody is administered as a single agent to treat MM patients who received at least three prior lines of therapy, including a PI and an immunomodulatory (IMiD) agent, or who are double-refractory to a PI and IMiD agent. (See BioWorld Today, Nov. 17, 2015.)

In 2012, Genmab granted Janssen Biotech Inc., a subsidiary of New Brunswick, N.J.-based Johnson & Johnson (J&J), an exclusive global license to develop, manufacture and commercialize the antibody in a deal potentially valued at more than $1.1 billion, including $135 million up front. The drug is expected to achieve $1.75 billion in sales by 2020, according to Cortellis. (See BioWorld Today, Sept. 5, 2012.)

Analysts have high hopes for Darzalex, and presentations at ASH could heighten those expectations. In his ASH preview, Credit Suisse analyst Vamil Divan cited the drug at the top of his list for "significant data flow at the ASH meeting providing for progressive clinical de-risking and likely revenue estimate increases."

In his note following approval of Darzalex, Jefferies International analyst Peter Welford predicted the drug "could change the treatment paradigm for MM as a backbone therapy," adding, "We now eagerly await feedback from clinicians" at ASH.

Excitement about the approvals of Darzalex, Empliciti and Ninlaro was underscored by an ASH special interest session, scheduled for Monday afternoon, in which FDA product reviewers will discuss safety and efficacy issues from drug trials and toxicity studies. The FDA-sponsored session also will feature a panel of clinicians who will offer perspective on using the products in real-world settings.

And in a preview of high-impact ASH studies, the society called out a Monday morning presentation on updated findings from the phase I/II GEN503 study of Darzalex in combination with Revlimid and dex in patients with relapsed or relapsed and refractory MM as well as a Monday afternoon briefing on data from the phase III Tourmaline-MM1 study (NCT01564537) of Ninlaro in combo with Revlimid and dex.

In all, the three MM drugs approved last month are the focus of more than five dozen oral and abstract presentations at ASH.

Also piquing analyst interest at ASH were results from two trials of Keytruda (pembrolizumab, Merck & Co. Inc.) in relapsed/refractory MM. The ongoing phase I KEYNOTE-023 trial combines the PD-1 inhibitor with Revlimid and low-dose dexamethasone, while a phase II trial is combining Keytruda with Pomalyst and dex.

More data on Imbruvica after one of year's biggest M&As

One of the year's top M&As also was driven by a hematological agent. In January, shares of Pharmacyclics Inc. lit up the boards when CEO Bob Duggan predicted during the J.P. Morgan Healthcare Conference in San Francisco that the company's blood cancer drug, Imbruvica (ibrutinib), would hit blockbuster status in 2015. Days later, the FDA expanded Imbruvica's approved use, more than two months ahead of its PDUFA date, as the first therapy to treat patients with Waldenström's macroglobulinemia, a rare form of B-cell lymphoma. The approval represented the fourth indication for the drug, developed jointly by Pharmacyclics and J&J's Janssen. (See BioWorld Today, Jan. 14, 2015, and Jan. 30, 2015.)

Pharmacyclics made no secret of its intention to gain label extensions to treat all comers in chronic lymphocytic leukemia and to extend treatment as far upstream as possible in other indications. Its success in pursuing that strategy caught the eye of Abbvie Inc., which snagged Sunnyvale, Calif.-based Pharmacyclics in March with a surprise $21 billion deal. (See BioWorld Today, March 6, 2015.)

Imbruvica, a Bruton's tyrosine kinase inhibitor, was considered a complementary fit with the hematological oncology roster at North Chicago-based Abbvie, including ABT-199, a B-cell lymphoma 2 inhibitor partnered with Roche AG, of Basel, Switzerland, and duvelisib, a phosphoinositide-3-kinase (PI3K)-delta and PI3K-gamma inhibitor partnered with Cambridge, Mass.-based Infinity Pharmaceuticals Inc. (See BioWorld Today, Sept. 4, 2014.)

A final analysis of data from the randomized phase III RESONATE-2 study of Imbruvica vs. chlorambucil in treatment-naïve chronic lymphocytic leukemia or small lymphocytic lymphoma patients 65 and older was on the ASH dais Monday morning.

Approvals in hemophilia A lead a full pipeline in bleeding disorders

Outside cancer, drugs to treat bleeding disorders and agents to reverse the effect of blood thinners grabbed the spotlight.

Treatment of hemophilia A gained two options with approval of Nuwiq (simoctocog alfa) from Octapharma AG, of Lachen, Switzerland, in September, and Baxalta Inc.'s long-acting Adynovate (antihemophilic factor [recombinant], pegylated) last month. Nuwiq – a recombinant factor VIII (rFVIII) produced using a human cell line – is expected to be launched early next year, while Adynovate (formerly BAX-855) goes to market this month. Baxalta, of Bannockburn, Ill., built the therapy around its existing treatment, Advate (octocog alfa, or antihemophilic factor [recombinant]), using pegylation technology from Nektar Therapeutics Inc. to extend treatment times to twice-weekly dosing. Global sales are expected to exceed $1.1 billion by 2020, according to Cortellis. (See BioWorld Today, Nov. 17, 2015.)

"At a very high level, we at Baxalta fundamentally believe in the concept of direct factor replacement therapy," Brian Goff, executive vice president of Baxalta and president of Baxalta Hematology, told BioWorld Insight. "Hemophilia has a well-known pathophysiology. For hemophilia A, direct replacement of factor VIII – as has been known now for decades – is the way to go. Our whole portfolio development is focused on that."

Baxalta investigators are presenting more than a dozen scientific updates on the company's approved hemophilia treatments and candidates at ASH, including data on the characteristics of patients without bleeds from the pivotal trial of Adynovate and on the perioperative efficacy of the therapy in individual procedures.

A plenary scientific session, scheduled for Sunday, also was expected to draw crowds to hear detailed findings from the Sippet study, which examined the source of FVIII replacement – plasma-derived (pd) or recombinant – and the related incidence of inhibitory alloantibodies in previously untreated patients with severe hemophilia A. The session abstract reported that the rFVIII product class was associated with a 1.87-fold higher incidence of inhibitors than the pdFVIII class – a difference that remained even when second-generation, full-length rFVIII concentrate was excluded from the analyses.

Another noteworthy accelerated approval in the hematology space was the nod, in October, for Boehringer Ingelheim GmbH's Praxbind (idarucizumab), the fast-acting antidote and first approved agent to reverse the company's widely used anticoagulant, Pradaxa (dabigatran). (See BioWorld Today, Oct. 19, 2015.)

The treatment is designed to give doctors a tool to reverse the action of Pradaxa in patients requiring urgent procedures or with serious bleeding complications. Although not expected to reach blockbuster status, Praxbind's approval could actually boost sales of Pradaxa, according to Credit Suisse's Divan.

"Now that physicians can better manage the bleeding risk with Pradaxa, we expect some shift in share from warfarin to Pradaxa," he wrote following approval of Praxbind. "There may also be some pressure on the factor Xa inhibitors (Xarelto, Eliquis and Savyasa), at least until [Portola Pharmaceuticals Inc.'s] antidote andexanet alfa potentially enters the market in late 2016/early 2017."

Praxbind is being featured in seven sessions at ASH.

Editor's note: Next week's BioWorld Insight will examine emerging hematology treatments featured at ASH, including sickle cell disease research and experimental gene therapy.